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  1. Calcium channel blockers and Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Yi Tan; Yulin Deng; Hong Qing

    2012-01-01

    Alzheimer's disease is characterized by two pathological hallmarks: amyloid plaques and neurofi-brillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer's disease. Calcium channel blockers are effective therapeutics for treating Alzheimer's disease. This review provides an overview of the current research of calcium channel blockers in-volved in Alzheimer's disease therapy.

  2. Calcium channel blockers in cardiovascular pharmacotherapy.

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    Godfraind, Theophile

    2014-11-01

    This paper summarizes the pharmacological properties of calcium channel blockers (CCBs), their established therapeutic uses for cardiovascular disorders and the current improvement of their clinical effects through drug combinations. Their identification resulted from study of small molecules including coronary dilators, which were named calcium antagonists. Further experiments showed that they reduced contraction of arteries by inhibiting calcium entry and by interacting with binding sites identified on voltage-dependent calcium channels. This led to the denomination calcium channel blockers. In short-term studies, by decreasing total peripheral resistance, CCBs lower arterial pressure. By unloading the heart and increasing coronary blood flow, CCBs improve myocardial oxygenation. In long-term treatment, the decrease in blood pressure is more pronounced in hypertensive than in normotensive patients. A controversy on the safety of CCBs ended after a large antihypertensive trial (ALLHAT) sponsored by the National Heart, Lung, and Blood Institute. There are two main types of CCBs: dihydopyridine and non-dihydropyridine; the first type is vascular selective. Dihydropyrines are indicated for hypertension, chronic, stable and vasospastic angina. Non-dihydropyridines have the same indications plus antiarrythmic effects in atrial fibrillation or flutter and paroxysmal supraventricular tachycardia. In addition, CCBs reduced newly formed coronary lesions in atherosclerosis. In order to reach recommended blood pressure goals, there is a recent therapeutic move by combination of CCBs with other antihypertensive agents particularly with inhibitors acting at the level of the renin-angiotensin system. They are also combined with statins. Prevention of dementia has been reported in hypertensive patients treated with nitrendipine, opening a way for further studies on CCBs' beneficial effect in cognitive deterioration associated with aging.

  3. Renal vascular effects of calcium channel blockers in hypertension.

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    Benstein, J A; Dworkin, L D

    1990-12-01

    Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro, their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high, glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension, calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease, calcium channel blockers slow the progression of renal damage; however, variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage, including compensatory renal hypertrophy, platelet aggregation, and calcium deposition, may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.

  4. End organ protection by calcium-channel blockers.

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    Tzivoni, D

    2001-02-01

    In recent years, much attention has been given to end organ protection by antihypertensive, anti-heart failure, and anti-ischemic medications. This review describes the available information on end organ protection by calcium-channel blockers (CCBs). In normotensive patients and patients with hypertension treated with long-acting dihydropyridines, medial thickness was thinner than in patients treated with atenolol or in untreated hypertensive patients. Long-term treatment was associated with significant reduction in left ventricular mass. Calcium-channel blockers also improved endothelial-dependent relaxation and reversed the vasoconstrictive response to nitric oxide inhibitors. In diabetic patients, CCBs were effective in preserving kidney function and microalbuminurea. The combination of angiotensin-converting enzyme (ACE) inhibitors and CCBs was more effective than ACE inhibitors alone in preserving kidney function. In animal experiments, CCBs prevented development of coronary atheroschlerosis; however, in humans only limited data are available on their antiatherogenic effect. Some studies suggest that CCBs exert antiplatelets properties and may therefore be beneficial in patients with coronary artery disease.

  5. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning.

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    Engebretsen, Kristin M; Kaczmarek, Kathleen M; Morgan, Jenifer; Holger, Joel S

    2011-04-01

    INTRODUCTION. High-dose insulin therapy, along with glucose supplementation, has emerged as an effective treatment for severe beta-blocker and calcium channel-blocker poisoning. We review the experimental data and clinical experience that suggests high-dose insulin is superior to conventional therapies for these poisonings. PRESENTATION AND GENERAL MANAGEMENT. Hypotension, bradycardia, decreased systemic vascular resistance (SVR), and cardiogenic shock are characteristic features of beta-blocker and calcium-channel blocker poisoning. Initial treatment is primarily supportive and includes saline fluid resuscitation which is essential to correct vasodilation and low cardiac filling pressures. Conventional therapies such as atropine, glucagon and calcium often fail to improve hemodynamic status in severely poisoned patients. Catecholamines can increase blood pressure and heart rate, but they also increase SVR which may result in decreases in cardiac output and perfusion of vascular beds. The increased myocardial oxygen demand that results from catecholamines and vasopressors may be deleterious in the setting of hypotension and decreased coronary perfusion. METHODS. The Medline, Embase, Toxnet, and Google Scholar databases were searched for the years 1975-2010 using the terms: high-dose insulin, hyperinsulinemia-euglycemia, beta-blocker, calcium-channel blocker, toxicology, poisoning, antidote, toxin-induced cardiovascular shock, and overdose. In addition, a manual search of the Abstracts of the North American Congress of Clinical Toxicology and the Congress of the European Association of Poisons Centres and Clinical Toxicologists published in Clinical Toxicology for the years 1996-2010 was undertaken. These searches identified 485 articles of which 72 were considered relevant. MECHANISMS OF HIGH-DOSE INSULIN BENEFIT. There are three main mechanisms of benefit: increased inotropy, increased intracellular glucose transport, and vascular dilatation. EFFICACY OF HIGH

  6. LERCANIDIPINE, CALCIUM CHANNEL BLOCKER OF THE THIRD GENERATION: NEW POSSIBILITIES IN THE TREATMENT OF ARTERIAL HYPERTENSION

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    O. D. Ostroumova

    2013-01-01

    Full Text Available Classification, modes of action and clinical effects of calcium channel blockers are presented. Advantages of the third generation of dihydropyridine calcium channel blockers are considered. Clinical pharmacology, studies on the efficacy, safety and prevention of hypertensive complications with lercanidipine are detailed.

  7. A combined role of calcium channel blockers and angiotensin receptor blockers in stroke prevention

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    Ji-Guang Wang

    2009-07-01

    Full Text Available Ji-Guang WangCentre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaAbstract: Stroke is a leading cause of death and disability worldwide. The importance of lowering blood pressure for reducing the risk of stroke is well established. However, not all the benefits of antihypertensive treatments in stroke can be accounted for by reductions in BP and there may be differences between antihypertensive classes as to which provides optimal protection. Dihydropyridine calcium channel blockers, such as amlodipine, and angiotensin receptor blockers, such as valsartan, represent the two antihypertensive drug classes with the strongest supportive data for the prevention of stroke. Therefore, when combination therapy is required, a combination of these two antihypertensive classes represents a logical approach.Keywords: stroke, angiotensin, calcium channel, cerebrovascular, hypertension, blood pressure

  8. Dihydropyridine type calcium channel blocker-induced turbid dialysate in patients undergoing peritoneal dialysis.

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    Yoshimoto, K; Saima, S; Nakamura, Y; Nakayama, M; Kubo, H; Kawaguchi, Y; Nishitani, H; Nakamura, Y; Yasui, A; Yokoyama, K; Kuriyama, S; Shirai, D; Kugiyama, A; Hayano, K; Fukui, H; Horigome, I; Amagasaki, Y; Tsubakihara, Y; Kamekawa, T; Ando, R; Tomura, S; Okamoto, R; Miwa, S; Koyama, T; Echizen, H

    1998-08-01

    We previously reported that manidipine, a new dihydropyridine type calcium channel blocker, produced chylous peritoneal dialysate being visually indistinguishable from infective peritonitis in 5 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [Yoshimoto et al. 1993]. To study whether such an adverse drug reaction would also be elicited by other commonly prescribed calcium channel blockers in CAPD patients, we have conducted postal inquiry to 15 collaborating hospitals and an institutional survey in International Medical Center of Japan as to the possible occurrence of calcium channel blocker-associated non-infective, turbid peritoneal dialysate in CAPD patients. Our diagnostic criteria for drug-induced turbidity of dialysate as a) it developed within 48 h after the administration of a newly introduced calcium channel blocker to the therapeutic regimen, b) absence of clinical symptoms of peritoneal inflammation (i.e., pyrexia, abdominal pain, nausea or vomiting), c) the fluid containing normal leukocyte counts and being negative for bacterial and fungal culture of the fluid, and d) it disappeared shortly after the withdrawal of the assumed causative agent. Results showed that 19 out of 251 CAPD patients given one of the calcium channel blockers developed non-infective turbid peritoneal dialysis that fulfilled all the above criteria. Four calcium channel blockers were suspected to be associated with the events: benidipine [2 out of 2 (100%) patients given the drug], manidipine [15 out of 36 (42%) patients], nisoldipine [1 out of 11 (9%) patients] and nifedipine [1 out of 159 (0.6%)] in descending order of frequency. None of the patients who received nicardipine, nilvadipine, nitrendipine, barnidipine and diltiazem (25, 7, 2, 1 and 8 patients, respectively) exhibited turbid dialysate. In conclusion, we consider that certain dihydropyridine type calcium channel blockers would cause turbid peritoneal dialysate being similar to that observed in

  9. A different dihydropyridine calcium channel blocker in hypertensive patients who developed pedal edema on dihydropyridine calcium channel blocker therapy

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    Ayşe Yüksel

    2014-03-01

    Full Text Available Abstract Aim. Dihydropyridine calcium channel blockers (CCB are widely preferred for the treatment of hypertension for their efficacy, metabolic neutrality and low side effect profile. However pedal edema formation limits their usage. The aim of the present study is to evaluate the incidence of pedal edema formation with a different dihydropyridine CCB in hypertensive patients who developed pedal edema during a dihydropyridine CCB therapy. Method. Fifty-eight hypertensive patients (34 female, 24 male, mean age: 65.3±10.5 in whom pedal edema developed during treatment with a dihydropyridine CCB (amlodipine 10mg/day in 40 patients, amlodipine 5mg/day in 14 patients, nifedipine GITS 30mg/day in 4 patients were enrolled. CCB which caused pedal edema was withdrawn and a different CCB (felodipine or lacidipine were initiated after the resolution of the pedal edema. CCB therapy was continued as long as the patient tolerated pedal edema. Results. At the end of one year, 44 out of 58 patients (36 [81.8%] free of pedal edema, 8 [19.2%] with pedal edema continued CCB therapy. Eleven (37.9% patients in the felodipine group and 9 (31.0% patients in the lacidipine group developed pedal edema. In 7 patients in felodipine group and in 5 patients in the lacidipine group the study drug was withdrawn due to pedal edema. In two patients, study drug was withdrawn due to intractable headache (felodipine group or due to flushing (lacidipine group. Conclusion. A different group of dihydropyridine CCB be used as an alternative therapy for hypertension whenever pedal edema develops during treatment with a dihydropyridine CCB.

  10. Reduced myocardial {sup 18}F-FDG uptake after calcium channel blocker administration. Initial observation for a potential new method to improve plaque detection

    Energy Technology Data Exchange (ETDEWEB)

    Gaeta, Chiara; Flotats, Albert; Artigas, Carles; Deportos, Jordi; Geraldo, Llanos; Carrio, Ignasi [Sant Pau Hospital, PET Unit, Department of Nuclear Medicine, Barcelona (Spain); Fernandez, Yolanda [Center for Experimental Molecular Imaging (CIME), CETIR-ERESA, Barcelona (Spain); Pavia, Javier [Center for Experimental Molecular Imaging (CIME), CETIR-ERESA, Barcelona (Spain); Networking Research Centre on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona (Spain)

    2011-11-15

    Physiological glucose uptake by the myocardium may hamper visualization of coronary atherosclerotic plaques in {sup 18}F-FDG PET studies. Intracellular myocardial calcium relates to glucose influx. We assessed whether administration of a calcium channel blocker such as verapamil could decrease myocardial {sup 18}F-FDG uptake in mice. Experiments were conducted on ten male C57BL/6JOlaHsd mice. The mice were studied by {sup 18}F-FDG PET/CT under basal conditions and after a single administration of verapamil injected 1 h prior to {sup 18}F-FDG administration at doses of 1 mg/kg (group A, n = 5) and 20 mg/kg (group B, n = 5). PET scanning was started 60 min after injection of {sup 18}F-FDG employing a dedicated small-animal PET/CT system (ARGUS-CT). In each mouse, post-verapamil PET images were coregistered with the basal PET images. Volumetric regions of interest (VOI) were drawn on the basal study containing the myocardium of the whole left ventricle and quantitatively compared with the same VOI applied to the post-verapamil scan. The SUV{sub mean} was used to express the mean myocardial {sup 18}F-FDG uptake. The relative coefficient of variation (RV) between the basal and post-verapamil conditions was calculated. Verapamil administration decreased myocardial {sup 18}F-FDG uptake in all animals. The median (range) SUV{sub mean} values in group A were 2.6 (1.6-4.1) under basal conditions and 1.7 (1.1-2.9) after verapamil administration (p = 0.043), and in group B were 1.6 (1.3-2.0) under basal conditions and 1.0 (0.9-1.4) after verapamil administration (p = 0.043). The median (range) RV values were -31% (-5%, -50%) in group A, and -37% (-10%, -51%) in group B (p = 0.6). In this animal model there was a significant reduction in {sup 18}F-FDG uptake in the myocardium following verapamil administration. This type of intervention could facilitate the definition of coronary atherosclerotic plaque inflammation on {sup 18}F-FDG PET scans. (orig.)

  11. Aging Reduces L-type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium Channel Blockers

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    Sulayma A Albarwani

    2016-05-01

    Full Text Available Calcium channel blockers are widely used to treat cardiovascular disease (CVD including hypertension. As aging is an independent risk factor for CVD, the use of calcium channel blockers increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5 - 3 months (young and 22 - 26 months (old were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1nM - 10 µM, verapamil (0.1nM-10 µM or diltiazem (0.1nM - 10µM. Relaxation-concentration response curves produced by cumulative concentrations of three different calcium channel blockers (CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pEC50 ± s.e.m: (8.37 ± 0.06 vs 8.04 ± 0.05 , 7.40 ± 0.07 vs 6.81 ± 0.04 and 6.58 ± 0.07 vs 6.34 ± 0.06 in young vs old. It was observed that the maximal contractions induced by 100 mM KCl, phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 increased resting tension by 23±4.8% in young arteries and 4.7±1.6% in old arteries. LTCC current density were also significantly lower in old arteries (-2.77 ± 0.45 pA/pF compared to young arteries (-4.5 ± 0.40 pA/pF; with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may

  12. Calcium channel blockers and cancer : A risk analysis using the UK Clinical Practice Research Datalink (CPRD)

    NARCIS (Netherlands)

    Grimaldi-Bensouda, Lamiae; Klungel, Olaf; Kurz, Xavier; De Groot, Mark C H; Afonso, Ana S Maciel; De Bruin, Marie L.; Reynolds, Robert; Rossignol, Michel

    2016-01-01

    OBJECTIVE: The evidence of an association between calcium channel blockers (CCBs) and cancer is conflicting. The objective of the present study was to evaluate the risk of cancer (all, breast, prostate and colon cancers) in association with exposure to CCB. METHODS: This is a population-based cohort

  13. [Influence of rifampicin on antihypertensive effects of dihydropiridine calcium-channel blockers in four elderly patients].

    Science.gov (United States)

    Yoshimoto, H; Takahashi, M; Saima, S

    1996-09-01

    Rifamicin, an antituberculosis agent, is one of the most potent inducers of hepatic drug-oxidation enzymes. Rifampicin can reduce the efficacy of several therapeutically important drugs (including verapamil and diltiazem) by accelerating systemic elimination or by increasing hepatic first-pass metabolism. Because dihydropyridine calcium-channel blockers are mainly metabolized by the liver, rifampicin may also increase the extraction of these drugs and thereby reduce their antihypertensive effects. Here we report four possible cases of interaction between rifampicin and dihydropiridine calcium-channel blockers. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropiridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine), shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicate that rifampicin may lessen the antihypertensive effects of dihydropiridine calcium-channel blockers.

  14. Antioxidant effect of T-type calcium channel blockers in gastric injury.

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    Bilici, Dilek; Banoğlu, Z Nur; Kiziltunç, Ahmet; Avci, Bahattin; Ciftçioğlu, Akif; Bilici, Sefa

    2002-04-01

    It is known that calcium ion has an important role in the cellular function. For this reason, calcium channel blockers may have a protective action against gastric injury which is induced by various stimuli. In this study, the influence of mibefradil on ethanol-induced gastric injury was investigated in rats. Mibefradil was given at a dose 50 mg/kg intraperitoneally 30 min before administration of 1 ml absolute ethanol given by gavage. We compared this effect of mibefradil with that of omeprazol. Ethanol-induced mucosal damage was evaluated using three different approaches: analysis of biochemical parameters and pathologic and macroscopic investigation. It was found that pretreatment with mibefradil significantly reduced ethanol-induced macroscopic, pathologic, and biochemical changes in the gastric mucosa. In conclusion, it is speculated that this findings may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans.

  15. Aging Reduces L-Type Calcium Channel Current and the Vasodilatory Response of Small Mesenteric Arteries to Calcium Channel Blockers

    Science.gov (United States)

    Albarwani, Sulayma A.; Mansour, Fathi; Khan, Abdul Aleem; Al-Lawati, Intisar; Al-Kaabi, Abdulla; Al-Busaidi, Al-Manar; Al-Hadhrami, Safa; Al-Husseini, Isehaq; Al-Siyabi, Sultan; Tanira, Musbah O.

    2016-01-01

    Calcium channel blockers (CCBs) are widely used to treat cardiovascular disease (CVD) including hypertension. As aging is an independent risk factor for CVD, the use of CCBs increases with increasing age. Hence, this study was designed to evaluate the effect of aging on the sensitivity of small mesenteric arteries to L-type voltage-gated calcium channel (LTCC) blockers and also to investigate whether there was a concomitant change in calcium current density. Third order mesenteric arteries from male F344 rats, aged 2.5–3 months (young) and 22–26 months (old) were mounted on wire myograph to measure the tension during isometric contraction. Arteries were contracted with 100 mM KCl and were then relaxed in a cumulative concentration-response dependent manner with nifedipine (0.1 nM–1 μM), verapamil (0.1 nM–10 μM), or diltiazem (0.1 nM–10 μM). Relaxation-concentration response curves produced by cumulative concentrations of three different CCBs in arteries of old rats were shifted to the right with statistically significant IC50s. pIC50 ± s.e.m: (8.37 ± 0.06 vs. 8.04 ± 0.05, 7.40 ± 0.07 vs. 6.81 ± 0.04, and 6.58 ± 0.07 vs. 6.34 ± 0.06) in young vs. old. It was observed that the maximal contractions induced by phenylephrine and reversed by sodium nitroprusside were not different between young and old groups. However, Bay K 8644 (1 μM) increased resting tension by 23 ± 4.8% in young arteries and 4.7 ± 1.6% in old arteries. LTCC current density were also significantly lower in old arteries (−2.77 ± 0.45 pA/pF) compared to young arteries (−4.5 ± 0.40 pA/pF); with similar steady-state activation and inactivation curves. Parallel to this reduction, the expression of Cav1.2 protein was reduced by 57 ± 5% in arteries from old rats compared to those from young rats. In conclusion, our results suggest that aging reduces the response of small mesenteric arteries to the vasodilatory effect of the CCBs and this may be due to, at least in part, reduced

  16. Calcium-channel blockers for the prevention of stroke: from scientific evidences to the clinical practice

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    S. Taddei

    2013-05-01

    Full Text Available AIM OF THE REVIEW The present review aims to analyze the role of calcium-channel blockers, and particularly newer molecules, as first-line therapy for cerebrovascular disease. BACKGROUND Stroke is the leading cause of disability in the general population. Among traditional cardiovascular risk factors, hypertension has a key role in the genesis of both hemorrhagic and ischemic stroke and a direct correlation exists between blood pressure values and the risk of stroke. Moreover, blood pressure reduction has been demonstrated to be the most important route to reduce stroke incidence and recurrence. However, the mere reduction of blood pressure values does not normalize the cardiovascular risk of the hypertensive patient. It is therefore necessary to use drug classes that beyond their blood pressure-lowering effect have also an additional effect in terms of organ protection. Among these, calcium-channel blockers have a crucial profile. Firstly, they are effective in inducing left ventricular hypertrophy regression, with a strength at least equal to that of ACE-inhibitors. Secondly, they have an antithrombotic and an endothelium-protecting effect, mediated by their antioxidant activity. Finally, calcium-channel blockers are the most powerful drugs in preventing vascular remodeling. For these reasons this drug class has probably the strongest antiatherosclerotic effect, and it is the first-choice treatment mainly for cerebrovascular disease. Among different available calcium-channel blockers, the newer ones seem to possess pharmacokinetic characteristics allowing a more homogeneous 24 hours coverage as compared to older molecules, and preliminary data seem to suggest a greater beneficial effect also on left ventricular hypertrophy and lower incidence of side effects. CONCLUSIONS Although blood pressure reduction is the main tool to reduce cerebrovascular risk in hypertensive patients, some drug classes, such as calciumchannel blockers, seem to provide

  17. N-type calcium channel blockers: novel therapeutics for the treatment of pain.

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    Schroeder, C I; Doering, C J; Zamponi, G W; Lewis, R J

    2006-09-01

    Highly selective Ca(v)2.2 voltage-gated calcium channel (VGCC) inhibitors have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Cone snail venoms provided the first drug in class with FDA approval granted in 2005 to Prialt (omega-conotoxin MVIIA, Elan) for the treatment of neuropathic pain. Since this pioneering work, major efforts underway to develop alternative small molecule inhibitors of Ca(v)2.2 calcium channel have met with varied success. This review focuses on the properties of the Ca(v)2.2 calcium channel in different pain states, the action of omega-conotoxins GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved Ca(v)2.2 calcium channel therapeutics, and finally the development of small molecules for the treatment of chronic pain.

  18. Applying Theoretical Approach for Predicting the Selective Calcium Channel Blockers Pharmacological Parameter by Biopartitioning Micellar Chromatography

    Institute of Scientific and Technical Information of China (English)

    WANG Su-Min; YANG Geng-Liang; LI Zhi-Wei; LIU Hai-Yan; GUO Hui-Juan

    2006-01-01

    The usefulness of biopartitioning micellar chromatography (BMC) for predicting oral drug acute toxicity and apparent bioavailability was demonstrated. A logarithmic model (an LD50 model) and the second order polynomial models (apparent bioavailability model) have been obtained using the retention data of the selective calcium channel blockers to predict pharmacological properties of compounds. The use of BMC is simple, reproducible and can provide key information about the acute toxicity and transport properties of new compounds during the drug discovery process.

  19. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

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    Bisognano, John D; McLaughlin, Trent; Roberts, Craig S; Tang, Simon SK

    2007-01-01

    This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP) ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus) and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort) were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were −17.5/−8.8, −15.7/−6.3, and −13.0/−8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs. PMID:18078009

  20. Efficacy and safety of calcium channel blockers in hypertensive patients with concomitant left ventricular dysfunction.

    Science.gov (United States)

    Parmley, W W

    1992-04-01

    The use of calcium channel blockers (CCBs) in the treatment of hypertension and concomitant left ventricular dysfunction is reviewed. Some CCBs, particularly second-generation dihydropyridine agents such as felodipine, isradipine, nicardipine, nimodipine, and nitrendipine, have properties that enhance their usefulness in these patients. All CCBs have a similar mechanism of action. Differences in their selective action at various tissue sites determine which are most appropriate for patients with concomitant hypertension and left ventricular dysfunction. Most CCBs do not produce reflex stimulation of the heart or induce intravascular expansion. While all CCBs produce arteriolar dilation, all local beds and regional circulations in target organs are not affected equally. Most CCBs can decrease cardiac mass, and second-generation CCBs tend to have little or no negative inotropic effects at therapeutic dosages. In addition, they increase blood flow and reduce myocardial oxygen requirements. Because of differences in functional and electrophysiologic effects, specific CCBs may not be appropriate for all patients. Since second-generation dihydropyridine CCBs lack clinically relevant negative inotropic effects, and have been shown to improve exercise tolerance and coronary artery perfusion, they are appropriate for hypertensive patients with left ventricular dysfunction, angina, and coronary heart disease. Second-generation CCBs tend to lack cardiodepressant side effects and are less likely to react with digoxin than are first-generation CCBs.

  1. Effects of Calcium Channel Blockers on Antidepressant Action of Alprazolam and Imipramine

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    Gorash ZM

    2007-01-01

    Full Text Available Alprazolam is effective as an anxiolytic and in the adjunct treatment of depression. In this study, the effects of calcium channel antagonists on the antidepressant action of alprazolam and imipramine were investigated. A forced swimming maze was used to study behavioral despair in albino mice. Mice were divided into nine groups (n = 7 per group. One group received a single dose of 1% Tween 80; two groups each received a single dose of the antidepressant alone (alprazolam or imipramine; two groups each received a single dose of the calcium channel blocker (nifedipine or verapamil; four groups each received a single dose of the calcium channel blocker followed by a single dose of the antidepressant (with same doses used for either in the previous four groups. Drug administration was performed concurrently on the nine groups. Our data confirmed the antidepressant action of alprazolam and imipramine. Both nifedipine and verapamil produced a significant antidepressant effect (delay the onset of immobility when administered separately. Verapamil augmented the antidepressant effects of alprazolam and imipramine (additive antidepressant effect. This may be due to the possibility that verapamil might have antidepressant-like effect through different mechanism. Nifedipine and imipramine combined led to a delay in the onset of immobility greater than their single use but less than the sum of their independent administration. This may be due to the fact that nifedipine on its own might act as an antidepressant but blocks one imipramine mechanism that depends on L-type calcium channel activation. Combining nifedipine with alprazolam produced additional antidepressant effects, which indicates that they exert antidepressant effects through different mechanisms.

  2. COMPUTER AIDED DESIGN OF SELECTIVE CALCIUM CHANNEL BLOCKERS: USING PHARMACOPHORE - BASED AND DOCKING SIMULATIONS

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    Reetu

    2012-03-01

    Full Text Available In the present study, 3-D QSAR analysis was performed on the previously synthesized and evaluated derivatives of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers. Calcium Channel blockers is the molecular target responsible for the treatment of neuropathic and inflammatory pain. The 3D-QSAR study based on the principle of the alignment of pharmacophoric features by PHASE module of Schrodinger suite has been carried out on the same set of calcium channel blockers. Statistically significant 3-D QSAR model (R2=0.9288 were generated using 21 molecules in the training set. The predictive ability of model was determined using a randomly chosen test set of 6 molecules which gave predictive correlation coefficients (R2pred of 0.946 for 3-D models, indicating good predictive power. PHASE pharmacophore hypothesis AAHR.13 may correspond very closely to the interactions recorded in the active site of the ligand bound complex. These studies produced models with high correlation coefficient and good predictive abilities. Docking studies were also carried out wherein these analogues were docked into the active sites of COX-2 to analyze the receptor-ligand interactions that confer selectivity for COX-2. Compound 2 have the highest dock score (-7.28. In the active site, there are some strong hydrogen-bonding interactions observed between residues GLU67, ALA103, ASP96, SER184 and ASP22. Additionally a correlation of the quantitative structure –activity relationship data and the docking results is found to validate each other and suggest the importance of the binding step in overall drug action.

  3. Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults

    Science.gov (United States)

    Anseeuw, Kurt; Cantrell, Frank Lee; Gilchrist, Ian C.; Hantson, Philippe; Bailey, Benoit; Lavergne, Valéry; Gosselin, Sophie; Kerns, William; Laliberté, Martin; Lavonas, Eric J.; Juurlink, David N.; Muscedere, John; Yang, Chen-Chang; Sinuff, Tasnim; Rieder, Michael; Mégarbane, Bruno

    2017-01-01

    Objective: To provide a management approach for adults with calcium channel blocker poisoning. Data Sources, Study Selection, and Data Extraction: Following the Appraisal of Guidelines for Research & Evaluation II instrument, initial voting statements were constructed based on summaries outlining the evidence, risks, and benefits. Data Synthesis: We recommend 1) for asymptomatic patients, observation and consideration of decontamination following a potentially toxic calcium channel blocker ingestion (1D); 2) as first-line therapies (prioritized based on desired effect), IV calcium (1D), high-dose insulin therapy (1D–2D), and norepinephrine and/or epinephrine (1D). We also suggest dobutamine or epinephrine in the presence of cardiogenic shock (2D) and atropine in the presence of symptomatic bradycardia or conduction disturbance (2D); 3) in patients refractory to the first-line treatments, we suggest incremental doses of high-dose insulin therapy if myocardial dysfunction is present (2D), IV lipid-emulsion therapy (2D), and using a pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block without significant alteration in cardiac inotropism (2D); 4) in patients with refractory shock or who are periarrest, we recommend incremental doses of high-dose insulin (1D) and IV lipid-emulsion therapy (1D) if not already tried. We suggest venoarterial extracorporeal membrane oxygenation, if available, when refractory shock has a significant cardiogenic component (2D), and using pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block in the absence of myocardial dysfunction (2D) if not already tried; 5) in patients with cardiac arrest, we recommend IV calcium in addition to the standard advanced cardiac life-support (1D), lipid-emulsion therapy (1D), and we suggest venoarterial extracorporeal membrane oxygenation if available (2D). Conclusion: We offer recommendations for the stepwise management of calcium channel blocker

  4. POSITIONS OF CALCIUM CHANNEL BLOCKER LERCANIDIPINE ACCORDING TO EVIDENCE BASED CARDIOLOGY

    Directory of Open Access Journals (Sweden)

    Yu. V. Lukina

    2010-01-01

    Full Text Available Data of evidence based cardiology including results of international clinical trials on efficacy and safety of the modern calcium channel blocker (CCB, lercanidipine, are presented. Results of these trials show the firm position of lercanidipine in the modern cardiology and confirm that treatment with lercanidipine leads to significant reduction of systolic and diastolic blood pressure (BP with no effect on heart rate (HR. Peripheral edema (the common side effect of CCBs occurs rarer with lercanidipine treatment than this with any other CCB treatment. Lercanidipine can be recommended to patients with concomitant diseases due to its additional features.

  5. Calcium channel blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors: Effectiveness in combination with diuretics or β-blockers for treating hypertension

    Directory of Open Access Journals (Sweden)

    John D Bisognano

    2007-11-01

    Full Text Available John D Bisognano1, Trent McLaughlin2, Craig S Roberts3, Simon SK Tang31Internal Medicine Department, Cardiology Division, the University of Rochester Medical Center, Rochester, NY, USA; 2NDC Health, Phoenix, Arizona, USA; 3Pfizer Inc, New York, NY, USAAbstract: This retrospective database analysis compared the effectiveness of dihydropyridine calcium channel blockers (DHPs, angiotensin-converting enzyme (ACE inhibitors, and angiotensin receptor blockers (ARBs added to diuretics or β-blockers. Adults with hypertension treated with diuretic or β-blocker monotherapy between 1998 and 2001 were identified from a large US electronic medical records database of primary care practices. Patients were required to have a baseline blood pressure (BP ≥140/90 mmHg (≥130/80 mmHg for diabetes mellitus and recorded BP measurements within 6 months before and 1–12 months following index date. Patients were matched 1:1:1 by propensity score to correct for differences in baseline characteristics. 1875 patients met study criteria and 660 (220 in each cohort were matched based on propensity scores. Matched cohorts had no significant differences in baseline characteristics. Mean changes in systolic/diastolic BP were –17.5/–8.8, –15.7/–6.3, and –13.0/–8.0 mmHg with DHPs, ACE inhibitors, and ARBs, respectively. Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High BP 6/7 goal attainment for each regimen was 47.3%, 40.0%, and 32.2%, respectively. DHPs, ACE inhibitors, and ARBs improved BP when added to patients’ β-blocker or diuretic therapy. The greatest benefits were observed with DHPs, followed by ACE inhibitors, then ARBs.Keywords: hypertension, amlodipine besylate, lisinopril, valsartan, Joint National Committee (JNC 6 and 7

  6. [Effect of calcium channel blockers on developing nervous syndrome of high pressure and nitrogen narcosis in mice].

    Science.gov (United States)

    Sledkov, A I

    1997-01-01

    In the experiments conducted on mice which prior to compression in a heliox environment have been injected the blockers of various types of calcium channels (flunarezine, verapramil and nifedipine) as well as bemethyl (actoprotector) and oxymethacye (antioxidant) there escaped detection of noticeable effect of these drugs on developing the high pressure nervous syndrome (HPNS). On exposure to the hyperbaric nitrogen-oxygen environment verapromil (phenylalkulamine blocker of L-type calcium channels) had a protection effect with respect to a convulsive component of the nitrogen narcosis.

  7. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

    Science.gov (United States)

    Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

    2016-01-01

    Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).

  8. Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

    Directory of Open Access Journals (Sweden)

    Shuyuan Liu

    Full Text Available Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers, amlodipine (AML, nifedipine (NIF, benidipine (BEN and flunarizine (FNZ with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1 expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2. The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin and YVC1 (encoding calcium channel protein in vacuole membrane.

  9. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

    Science.gov (United States)

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

    2015-10-27

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

  10. Use of clopidogrel and calcium channel blockers and risk of major adverse cardiovascular events

    DEFF Research Database (Denmark)

    Schmidt, Morten; Johansen, Martin B; Robertson, Douglas J

    2012-01-01

    Eur J Clin Invest 2011 ABSTRACT: Background  The CYP3A4 inhibition by calcium channel blockers (CCBs) may attenuate the effectiveness of clopidogrel. Using time-varying drug exposure ascertainment, we examined whether CCB use modified the association between clopidogrel use and major adverse......-month follow-up, we tracked the use of clopidogrel and CCBs and the rate of MACE (composite of myocardial infarction, ischaemic stroke, stent thrombosis, target lesion revascularization, or cardiac death). We used Cox regression to compute hazard ratios, controlling for potential confounders. Results......  Overall, the 12-month risk for MACE was 14·5%. The rate was 130 per 1000 person years for concomitant clopidogrel and CCB use, 106 for clopidogrel without CCB use, 213 for CCB without clopidogrel use, and 248 for no use of either drug. The adjusted hazard ratio for MACE comparing clopidogrel use...

  11. Effect of fixed-dose ACE-inhibitor/calcium channel blocker combination therapy vs. ACE-inhibitor monotherapy on arterial compliance in hypertensive patients with type 2 diabetes.

    Science.gov (United States)

    Winer, Nathaniel; Folker, Amy; Murphy, Julie A; Hung, Elena; Bard, Mara; Perkelvald, Alexander; Sowers, James R; Bakris, George L

    2005-01-01

    Assessment of vascular compliance may be a useful measurement of the clinical effects of antihypertensive treatment. Both angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers are known to improve vascular elasticity. A study was performed to test the hypothesis that combined therapy with an ACE inhibitor and a calcium channel blocker would have additive benefits on vascular compliance at similar levels of blood pressure (BP), as compared with monotherapy with an ACE inhibitor. This 12-week, double-blind study was a substudy of a larger clinical hypertension study conducted in patients with hypertension and type 2 diabetes. Subjects (N = 20) were randomized to either a fixed-dose combination of amlodipine besylate/benazepril HCl or to enalapril monotherapy. BP, heart rate, large- and small-vessel compliance, systemic vascular resistance, and urinary microalbumin excretion were assessed at baseline and after treatment. Both treatments were similarly effective in lowering BP, reducing systemic vascular resistance, and decreasing urinary microalbumin excretion. Improvement in large-vessel compliance was significantly greater among subjects who received ACE-inhibitor/calcium channel blocker combination therapy (52%) as compared with those who received ACE-inhibitor monotherapy (32%; p < 0.05). No significant change in small-vessel compliance was observed with either treatment. Greater improvement in large-vessel compliance with combination therapy was independent of BP lowering.

  12. Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

    Directory of Open Access Journals (Sweden)

    Alberto F Rubio-Guerra

    2009-11-01

    Full Text Available Alberto F Rubio-Guerra1, David Castro-Serna2, Cesar I Elizalde Barrera2, Luz M Ramos-Brizuela21Metabolic and Research Clinic, 2Internal Medicine Department, Hospital General de Ticomán SS DF, MéxicoAbstract: Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.Keywords: hypertension, calcium channel blockers, renin-angiotensin-aldosterone system inhibitors, fixed-dose combination, adherence

  13. L—type calcium channel blockers inhibit the development but not the expression of sensitization to morphine in mice

    Institute of Scientific and Technical Information of China (English)

    ZhanQ; ZhenJW

    2002-01-01

    The relationship between opioid actions and L-type calcium channel blockers has been well documented.However,there is no report relevant to L-type calcium channel blockers and morphinesensitization,which is suggested to be an analog of behaviors that are the characteristics of drug addiction.Here the effects of three L-type calcium channel blockers,nimodipine,nifedipine and verapamil,on morphine-induced locomotor activity,the development and the expression of sensitization to morphine were studied systematically.The results showed that both nimodipine and verapamil attenuated,while nifedipine had only a tendency to decrease morphine-induced locomotor activity.All the three drugs inhibited the development of sensitization to morphine.However,none of them showed any effects on the expression of morphine sensitization.These results indicate that blocking L-tpye calcium channel attenuates the locomotor stimulating effects of morphine and inhibits the development but not the expression of morphine-sensitization.

  14. THE ROLE OF S-AMLODIPINE IN ARTERIAL HYPERTENSION THERAPY WITH COMBINATION OF CALCIUM CHANNEL BLOCKERS AND BETA-BLOCKERS

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    M. A. Maksimova

    2013-01-01

    Full Text Available Aim. To study efficacy and safety of calcium channel blocker, S-amlodipine, in combination with β-blocker, atenolol, in patients with arterial hypertension (HT 1-2 degree com- pared to fixed combination of racemic amlodipine and atenolol.Material and methods. Patients (n=31, 7 men and 24 women with HT 1–2 degree were included into the study. The patients were randomized into two groups by the com- binations sequence. Treatment with each combination lasted 4 weeks. Office blood pressure (BP was assessed at baseline and at the end of the treatment periods, possible side effects were registered.Results. All patients completed the study. Both combination of S-amlodipine+atenolol and fixed combination of racemic amlodipine+atenolol reduced systolic (in average, -15.9 and -12.7 mm Hg, respectively and diastolic (in average, -7.3 and -5.3 mmHg, respectively BP significantly. Heart rate also decreased during therapy (in average, -3 and -4 bt/min, respectively. The differences between combinations BP and heart rate effects were not significant. 8 and 16 adverse events were registered during S-amlodipine+atenolol and racemic amlodipine+atenolol therapies, respectively Conclusion. Combination of S-amlodipine+atenolol, as well as combination of racemic amlodipine+atenolol are effective in the treatment of patients with HT 1-2 degree, however combination with S-amlodipine has less number of adverse events.

  15. Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic

    Directory of Open Access Journals (Sweden)

    Volpe M

    2012-06-01

    Full Text Available Massimo Volpe,1,2 Giuliano Tocci21Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome, Sapienza, Sant'Andrea Hospital, Rome, 2IRCCS Neuromed, Pozzilli, ItalyAbstract: Hypertension is a growing global health problem, and is predicted to affect 1.56 billion people by 2025. Treatment remains suboptimal, with control of blood pressure achieved in only 20%–35% of patients, and the majority requiring two or more antihypertensive drugs to achieve recommended blood pressure goals. To improve blood pressure control, the European hypertension guidelines recommend that angiotensin II receptor blockers (ARBs or angiotensin-converting enzyme inhibitors (ACEIs are combined with calcium channel blockers (CCBs and/or thiazide diuretics. The rationale for this strategy is based, in part, on their different effects on the renin-angiotensin system, which improves antihypertensive efficacy. Data from a large number of trials support the efficacy of ACEIs or ARBs in combination with CCBs and/or hydrochlorothiazide (HCTZ. Combining two different classes of antihypertensive drugs has an additive effect on lowering of blood pressure, and does not increase adverse events, with the ARBs showing a tolerability advantage over the ACEIs. Among the different ARBs, olmesartan medoxomil is available as a dual fixed-dose combination with either amlodipine or HCTZ, and the increased blood pressure-lowering efficacy of these two combinations is proven. Triple therapy is required in 15%–20% of treated uncontrolled hypertensive patients, with a renin-angiotensin system blocker, CCB, and thiazide diuretic considered to be a rational combination according to the European guidelines. Olmesartan, amlodipine, and HCTZ are available as a triple fixed-dose combination, and significant blood pressure reductions have been observed with this regimen compared with the possible dual combinations. The availability of these fixed-dose combinations should

  16. Degradation kinetics and pathways of three calcium channel blockers under UV irradiation.

    Science.gov (United States)

    Zhu, Bing; Zonja, Bozo; Gonzalez, Oscar; Sans, Carme; Pérez, Sandra; Barceló, Damia; Esplugas, Santiago; Xu, Ke; Qiang, Zhimin

    2015-12-01

    Calcium channel blockers (CCBs) are a group of pharmaceuticals widely prescribed to lower blood pressure and treat heart diseases. They have been frequently detected in wastewater treatment plant (WWTP) effluents and downstream river waters, thus inducing a potential risk to aquatic ecosystems. However, little is known about the behavior and fate of CCBs under UV irradiation, which has been adopted as a primary disinfection method for WWTP effluents. This study investigated the degradation kinetics and pathways of three commonly-used CCBs, including amlodipine (AML), diltiazem (DIL), and verapamil (VER), under UV (254 nm) irradiation. The chemical structures of transformation byproducts (TBPs) were first identified to assess the potential ecological hazards. On that basis, a generic solid-phase extraction method, which simultaneously used four different cartridges, was adopted to extract and enrich the TBPs. Thereafter, the photo-degradation of target CCBs was performed under UV fluences typical for WWTP effluent disinfection. The degradation of all three CCBs conformed to the pseudo-first-order kinetics, with rate constants of 0.031, 0.044 and 0.011 min(-1) for AML, DIL and VER, respectively. By comparing the MS(2) fragments and the evolution (i.e., formation or decay) trends of identified TBPs, the degradation pathways were proposed. In the WWTP effluent, although the target CCBs could be degraded, several TBPs still contained the functional pharmacophores and reached peak concentrations under UV fluences of 40-100 mJ cm(-2).

  17. Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization.

    Science.gov (United States)

    Lee, Hyang-Ae; Hyun, Sung-Ae; Park, Sung-Gurl; Kim, Ki-Suk; Kim, Sung Joon

    2016-01-01

    Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca(2+) channel current (I Ca) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K(+) channel currents (I Kr, I Ks) and voltage-gated Na(+) channel current (I Na). The concentration-dependent inhibition of Ca(2+) channel currents (I Ca) was examined in rat cardiomyocytes; these CCBs have similar potency on I Ca channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 µM whereas NIC and AML shortened APD50 but not APD90 up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited I Kr and I Ks while ISR had only partial inhibitory effects (NIC and AML could compensate for the AP shortening effects due to the block of I Ca.

  18. The omega-atracotoxins: selective blockers of insect M-LVA and HVA calcium channels.

    Science.gov (United States)

    Chong, Youmie; Hayes, Jessica L; Sollod, Brianna; Wen, Suping; Wilson, David T; Hains, Peter G; Hodgson, Wayne C; Broady, Kevin W; King, Glenn F; Nicholson, Graham M

    2007-08-15

    The omega-atracotoxins (omega-ACTX) are a family of arthropod-selective peptide neurotoxins from Australian funnel-web spider venoms (Hexathelidae: Atracinae) that are candidates for development as biopesticides. We isolated a 37-residue insect-selective neurotoxin, omega-ACTX-Ar1a, from the venom of the Sydney funnel-web spider Atrax robustus, with high homology to several previously characterized members of the omega-ACTX-1 family. The peptide induced potent excitatory symptoms, followed by flaccid paralysis leading to death, in acute toxicity tests in house crickets. Using isolated smooth and skeletal nerve-muscle preparations, the toxin was shown to lack overt vertebrate toxicity at concentrations up to 1 microM. To further characterize the target of the omega-ACTXs, voltage-clamp analysis using the whole-cell patch-clamp technique was undertaken using cockroach dorsal unpaired median neurons. It is shown here for the first time that omega-ACTX-Ar1a, and its homolog omega-ACTX-Hv1a from Hadronyche versuta, reversibly block both mid-low- (M-LVA) and high-voltage-activated (HVA) insect calcium channel (Ca(v)) currents. This block occurred in the absence of alterations in the voltage-dependence of Ca(v) channel activation, and was voltage-independent, suggesting that omega-ACTX-1 family toxins are pore blockers rather than gating modifiers. At a concentration of 1 microM omega-ACTX-Ar1a failed to significantly affect global K(v) channel currents. However, 1 microM omega-ACTX-Ar1a caused a modest 18% block of insect Na(v) channel currents, similar to the minor block of Na(v) channels reported for other insect Ca(v) channel blockers such as omega-agatoxin IVA. These findings validate both M-LVA and HVA Ca(v) channels as potential targets for insecticides.

  19. Effects of calcium channel blockers on proteinuria in patients with diabetic nephropathy.

    Science.gov (United States)

    Toto, Robert D; Tian, Min; Fakouhi, Kaffa; Champion, Annette; Bacher, Peter

    2008-10-01

    Diabetic nephropathy management should include the use of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker with additional antihypertensive medications to reduce proteinuria and cardiovascular events. Some studies suggest that adding a nondihydropyridine rather than a dihydropyridine calcium channel blocker (CCB) may more effectively lower proteinuria. We hypothesized that a trandolapril/verapamil SR (T/V) fixed-dose combination (FDC) was superior to a benazepril/amlodipine (B/A) FDC for reducing albuminuria in 304 hypertensive diabetic nephropathy patients when treated for 36 weeks. No statistically significant differences were observed between groups in the primary end point; adjusted percentage change in urinary albumin/creatinine ratio (UACR), which increased (mean T/V, 29.29%; mean B/A, 8.49%; difference, 20.80%; P=.34); or in change in absolute UACR, which decreased (mean [g/g] T/V, -0.11; mean [g/g] B/A, -0.08; difference -0.03; P=.78). There were significant reductions in log UACR (mean change in T/V, -0.28; P<.01; mean change in B/A, -0.31; P<.001) and diastolic blood pressure in both groups and in systolic blood pressure in the B/A group. T/V was not superior to B/A for reducing UACR. Both ACEI/CCB FDCs may reduce albuminuria; in the case of T/V, this appears to be independent of systolic blood pressure reduction in patients who had previously been treated and had baseline blood pressure levels of 142/77 mm Hg.

  20. Calcium Channel Blockers, More than Diuretics, Enhance Vascular Protective Effects of Angiotensin Receptor Blockers in Salt-Loaded Hypertensive Rats

    Science.gov (United States)

    Yamamoto, Eiichiro; Kataoka, Keiichiro; Dong, Yi-Fei; Koibuchi, Nobutaka; Toyama, Kensuke; Sueta, Daisuke; Katayama, Tetsuji; Yasuda, Osamu; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2012-01-01

    The combination therapy of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB) or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 6 groups, and they were orally administered (1) vehicle, (2) olmesartan, an ARB, (3) azelnidipine, a CCB, (4) hydrochlorothiazide, a diuretic, (5) olmesartan combined with azelnidipine, or (6) olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS) pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB. PMID:22720058

  1. Calcium channel blockers, more than diuretics, enhance vascular protective effects of angiotensin receptor blockers in salt-loaded hypertensive rats.

    Directory of Open Access Journals (Sweden)

    Eiichiro Yamamoto

    Full Text Available The combination therapy of an angiotensin receptor blocker (ARB with a calcium channel blocker (CCB or with a diuretic is favorably recommended for the treatment of hypertension. However, the difference between these two combination therapies is unclear. The present work was undertaken to examine the possible difference between the two combination therapies in vascular protection. Salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP were divided into 6 groups, and they were orally administered (1 vehicle, (2 olmesartan, an ARB, (3 azelnidipine, a CCB, (4 hydrochlorothiazide, a diuretic, (5 olmesartan combined with azelnidipine, or (6 olmesartan combined with hydrochlorothiazide. Olmesartan combined with either azelnidipine or hydrochlorothiazide ameliorated vascular endothelial dysfunction and remodeling in SHRSP more than did monotherapy with either agent. However, despite a comparable blood pressure lowering effect between the two treatments, azelnidipine enhanced the amelioration of vascular endothelial dysfunction and remodeling by olmesartan to a greater extent than did hydrochlorothiazide in salt-loaded SHRSP. The increased enhancement by azelnidipine of olmesartan-induced vascular protection than by hydrochlorothiazide was associated with a greater amelioration of vascular nicotinamide adenine dinucleotide phosphate (NADPH oxidase activation, superoxide, mitogen-activated protein kinase activation, and with a greater activation of the Akt/endothelial nitric oxide synthase (eNOS pathway. These results provided the first evidence that a CCB potentiates the vascular protective effects of an ARB in salt-sensitive hypertension, compared with a diuretic, and provided a novel rationale explaining the benefit of the combination therapy with an ARB and a CCB.

  2. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

    Science.gov (United States)

    Graudins, Andis; Lee, Hwee Min; Druda, Dino

    2016-03-01

    Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock.

  3. Statin, Calcium Channel Blocker and Beta Blocker Therapy May Decrease the Incidence of Tuberculosis Infection in Elderly Taiwanese Patients with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Mei-Yueh Lee

    2015-05-01

    Full Text Available Background: It is well known that diabetes mellitus impairs immunity and therefore is an independent risk factor for tuberculosis. However, the influence of associated metabolic factors, such as hypertension, dyslipidemia and gout has yet to be confirmed. This study aimed to investigate whether the strong association between tuberculosis and diabetes mellitus is independent from the influence of hypertension and dyslipidemia, and its treatment in elderly Taiwanese patients. Methods: A total of 27,958 patients aged more than 65 years were identified from the National Health Insurance Research Database (NIHRD in 1997 and were followed from 1998 to 2009. The demographic characteristics between the patients with and without diabetes were analyzed using the χ2 test. A total of 13,981 patients with type 2 diabetes were included in this study. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risk of tuberculosis. Results: After adjusting for age, sex, other co-morbidities and medications, calcium channel blocker, beta blocker and statin users had a lower independent association, with risk ratios of 0.76 (95% CI, 0.58–0.98, 0.72 (95% CI, 0.58–0.91 and 0.76 (95% CI, 0.60–0.97, respectively. Conclusion: Calcium channel blocker, beta blocker and statin therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes.

  4. Effects of calcium ion, calpains, and calcium channel blockers on retinitis pigmentosa.

    Science.gov (United States)

    Nakazawa, Mitsuru

    2011-01-01

    Recent advances in molecular genetic studies have revealed many of the causative genes of retinitis pigmentosa (RP). These achievements have provided clues to the mechanisms of photoreceptor degeneration in RP. Apoptosis is known to be a final common pathway in RP and, therefore, a possible therapeutic target for photoreceptor rescue. However, apoptosis is not a single molecular cascade, but consists of many different reactions such as caspase-dependent and caspase-independent pathways commonly leading to DNA fractionation and cell death. The intracellular concentration of calcium ions is also known to increase in apoptosis. These findings suggest that calpains, one of the calcium-dependent proteinases, play some roles in the process of photoreceptor apoptosis and that calcium channel antagonists may potentially inhibit photoreceptor apoptosis. Herein, the effects of calpains and calcium channel antagonists on photoreceptor degeneration are reviewed.

  5. Effects of Calcium Ion, Calpains, and Calcium Channel Blockers on Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Mitsuru Nakazawa

    2011-01-01

    Full Text Available Recent advances in molecular genetic studies have revealed many of the causative genes of retinitis pigmentosa (RP. These achievements have provided clues to the mechanisms of photoreceptor degeneration in RP. Apoptosis is known to be a final common pathway in RP and, therefore, a possible therapeutic target for photoreceptor rescue. However, apoptosis is not a single molecular cascade, but consists of many different reactions such as caspase-dependent and caspase-independent pathways commonly leading to DNA fractionation and cell death. The intracellular concentration of calcium ions is also known to increase in apoptosis. These findings suggest that calpains, one of the calcium-dependent proteinases, play some roles in the process of photoreceptor apoptosis and that calcium channel antagonists may potentially inhibit photoreceptor apoptosis. Herein, the effects of calpains and calcium channel antagonists on photoreceptor degeneration are reviewed.

  6. Potentiation of Opioid-Induced Analgesia by L-Type Calcium Channel Blockers: Need for Clinical Trial in Cancer Pain

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    S Basu Ray

    2008-01-01

    Full Text Available Previous reports indicate that the analgesic effect of opioids is due to both closure of specific voltage-gated calcium channels (N- and P/Q-types and opening of G protein-coupled inwardly rectifying potassium channels (GIRKs in neurons concerned with transmission of pain. However, administration of opioids leads to unacceptable levels of side effects, particularly at high doses. Thus, current research is directed towards simultaneously targeting other voltage-gated calcium channels (VGCCs like the L-type VGCCs or even other cell signaling mechanisms, which would aug-ment opioid-mediated analgesic effect without a concurrent increase in the side effects. Unfortunately, the results of these studies are often conflicting considering the different experimental paradigms (variable drug selection and their doses and also the specific pain test used for studying analgesia adopted by researchers. The present review focuses on some of the interesting findings regarding the analgesic effect of Opioids + L-VGCC blockers and suggests that time has come for a clinical trial of this combination of drugs in the treatment of cancer pain.

  7. Neuroprotective effect of gadolinium: a stretch-activated calcium channel blocker in mouse model of ischemia-reperfusion injury.

    Science.gov (United States)

    Gulati, Puja; Muthuraman, Arunachalam; Jaggi, Amteshwar S; Singh, Nirmal

    2013-03-01

    The present study was designed to investigate the potential of gadolinium, a stretch-activated calcium channel blocker in ischemic reperfusion (I/R)-induced brain injury in mice. Bilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was given to induce cerebral injury in male Swiss mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using Morris water maze test and motor incoordination was evaluated using rota-rod, lateral push, and inclined beam walking tests. In addition, total calcium, thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were also estimated in brain tissue. I/R injury produced a significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Furthermore, I/R injury also produced a significant increase in levels of TBARS, total calcium, AChE activity, and a decrease in GSH levels. Pretreatment of gadolinium significantly attenuated I/R-induced infarct size, behavioral and biochemical changes. On the basis of the present findings, we can suggest that opening of stretch-activated calcium channel may play a critical role in ischemic reperfusion-induced brain injury and that gadolinium has neuroprotective potential in I/R-induced injury.

  8. Calcium-channel blockers and other factors influencing delayed function in renal allografts.

    Science.gov (United States)

    Ferguson, C J; Hillis, A N; Williams, J D; Griffin, P J; Salaman, J R

    1990-01-01

    A retrospective analysis was undertaken to examine the influence of calcium-channel blocking drugs on early renal allograft function. Delayed function was defined as the need for dialysis or a reduction in serum creatinine of less than 15% within 4 days of transplantation. The drug histories of 172 patients were examined. After exclusions, the data from 138 patients were analysed. No patient was taking any calcium-channel blocking drug other than nifedipine. Thirty-one patients were taking nifedipine at the time of transplantation and these had a delayed function rate of 16% compared with 40% for 107 patients not taking nifedipine (chi 2, P less than 0.05). Delayed function occurred in 61% of cases when the donor age was over 50 years compared with 29% with younger donors (chi 2, P less than 0.05). A total ischaemic time of longer than 24 h and administration of inotropic support to the donor were associated with delayed function (chi 2, P less than 0.05). Administration to the donor of mannitol, steroids, phenoxybenzamine and heparin had no effect on the rate of delayed function. Recipients treated with low-dose dopamine in the perioperative period had no advantage. Elevated trough whole blood concentrations of cyclosporin in the first week after transplant were associated with delayed function (Mann-Whitney U, P less than 0.05).

  9. Calcium-channel blockers do not alter the clinical efficacy of clopidogrel after myocardial infarction: a nationwide cohort study

    DEFF Research Database (Denmark)

    Olesen, Jonas B; Gislason, Gunnar H; Charlot, Mette G

    2011-01-01

    Objectives The purpose of this study was to determine the risk of adverse cardiovascular events associated with concomitant use of clopidogrel and calcium-channel blockers (CCBs) in patients with myocardial infarction (MI). Background CCBs inhibit a variety of cytochrome P-450 enzymes, some...... of which contribute to clopidogrel metabolic activation. This interaction may diminish the efficacy of clopidogrel. Methods All patients surviving 30 days after a first-time MI in the period 2000 to 2006 in Denmark were identified by individual-level linkage of nationwide administrative registers....... The cohort was divided into patients treated with and without clopidogrel and followed for 1 year after discharge. The risk of a composite of cardiovascular death, MI, or stroke and the risk of the individual components of the composite end point and all-cause death associated with CCBs were analyzed...

  10. Non-cardiogenic pulmonary edema and life-threatening shock due to calcium channel blocker overdose: a case report and clinical review.

    Science.gov (United States)

    Siddiqi, Tauseef Afaq; Hill, Jennifer; Huckleberry, Yvonne; Parthasarathy, Sairam

    2014-02-01

    Calcium channel blockers (CCBs) overdose can be life-threatening when manifest as catastrophic shock and non-cardiogenic pulmonary edema. We describe a case of massive overdose of multiple medications, including sustained-release verapamil, which was resistant to conventional support. Initial treatment for CCB overdose is primarily supportive, and includes fluid resuscitation. The mechanism of non-cardiogenic pulmonary edema is not well known, and reported cases have been successfully treated with mechanical ventilation. Circulatory shock may fail to respond to atropine, glucagon, and calcium in severely poisoned patients, and vasopressors are usually required. Attempting to overcome calcium-channel antagonism with the supra-therapeutic doses of calcium salts is clinically indicated to reverse hypotension and bradycardia. There is evidence that hyperinsulinemia-euglycemia therapy is superior to other therapies for CCB poisoning, and the mechanism is thought to be the insulin-mediated active transport of glucose into the cells, which counters the CCB-induced intra-cellular carbohydrate-deficient state. Conventional decontamination measures are ineffective in accelerating clearance of CCB. Experience with intravenous lipid emulsion for lipophilic drug overdose, such as verapamil, is limited, but has been proposed as a rescue therapy and might improve cardiac inotropy through intravascular sequestration of the lipophilic CCB.

  11. Calcium Channel Blockers and Esophageal Sclerosis: Should We Expect Exacerbation of Interstitial Lung Disease

    Directory of Open Access Journals (Sweden)

    Charalampos Seretis

    2012-01-01

    Full Text Available Esophageal sclerosis is the most common visceral manifestation of systemic sclerosis, resulting in impaired esophageal clearance and retention of ingested food; in addition, co-existence of lung fibrosis with esophageal scleroderma is not uncommon. Both the progression of generalized connective tissue disorders and the damaging effect of chronic aspiration due to esophageal dysmotility appear to be involved in this procedure of interstitial fibrosis. Nifedipine is a widely prescribed calcium antagonist in a significant percentage of rheumatologic patients suffering from Raynaud syndrome, in order to inhibit peripheral vasospasm. Nevertheless, blocking calcium channels has proven to contribute to exacerbation of gastroesophageal reflux, which consequently can lead to chronic aspiration. We describe the case of severe exacerbation of interstitial lung disease in a 76-year-old female with esophageal sclerosis who was treated with oral nifedipine for Raynaud syndrome.

  12. Calcium channel blocker prevents stress-induced activation of renin and aldosterone in conscious pig

    Energy Technology Data Exchange (ETDEWEB)

    Ceremuzynski, L.K.; Klos, J.; Barcikowski, B.; Herbaczynska-Cedro, K. (Department of Cardiology, Postgraduate Medical School, Warsaw (Poland))

    1991-06-01

    A considerable amount of data suggest the involvement of calcium-mediated processes in the activation of the renin-angiotensin-aldosterone (RAA) cascade. To investigate the effect of calcium-channel inhibition on the RAA system, the authors studied 21 conscious pigs. Blood renin and aldosterone levels increased by subjecting animals to 24 hours of immobilization stress. Renin and aldosterone levels were repeatedly measured by radioimmunoassay in blood samples taken periodically over 24 hours from a chronically implanted arterial cannula. Pretreatment of the animals (N = 11) with nisoldipine, 2 {times} 20 mg p.o. daily for 2 days before and on the day of immobilization, transiently attenuated the stress-induced increase of plasma renin activity and completely prevented the rise of aldosterone, as compared to nontreated controls (N = 10). The finding that nisoldipine suppresses RAA activation induced by a nonpharmacologic stimulus in the conscious intact animal may have clinical implications.

  13. Lipid Rescue Therapy and High-Dose insulin Euglycemic Therapy are Effective for Severe Refractory Calcium Channel Blocker Overdose: Case Report and Review of Literature

    Directory of Open Access Journals (Sweden)

    Niko Bekjarovski

    2013-09-01

    How to cite this article: Bekjarovski NG. Lipid Rescue Therapy and High-Dose insulin Euglycemic Therapy are Effective for Severe Refractory Calcium Channel Blocker Overdose: Case Report and Review of Literature. Asia Pac J Med Toxicol 2013;2:114-6.

  14. Inhibitory effects of calcium channel blockers on thyroid hormone uptake in neonatal rat cardiomyocytes

    NARCIS (Netherlands)

    F.A. Verhoeven; E.P.C.M. Moerings (Ellis); J.M.J. Lamers (Jos); G. Hennemann; T.J. Visser (Theo); M.E. Everts (Maria)

    2001-01-01

    textabstractThe effects of the Ca2+ channel blockers verapamil, nifedipine, and diltiazem on triiodothyronine (T3) and thyroxine (T4) uptake were tested in cultured cardiomyocytes from 2-day-old rats. Experiments were performed at 37 degrees C in medium with 0.5% BSA for [125I]T3 (

  15. Effect of subclinical, clinical and supraclinical doses of calcium channel blockers on models of drug-induced hepatotoxicity in rats.

    Science.gov (United States)

    Okwa, Iniviefien B; Akindele, Abidemi J; Agbaje, Esther O; Oshinuga, Oladoyin T; Anunobi, Chidozie C; Adeyemi, Olufunmilayo O

    2013-01-01

    Drug-related hepatotoxicity is the leading cause of acute liver failure, and hepatic problems are responsible for a significant number of liver transplantations and deaths worldwide. Calcium has been associated with various metabolic processes that lead to cell death and apoptosis, and increased cytosolic Ca(2+) has been implicated in hepatotoxicity. This study was designed to investigate the effects of calcium channel blockers (CCBs) on isoniazid-rifampicin, zidovudine and erythromycin-induced hepatotoxicity in rats. Treatment groups comprised control, hepatotoxicant, hepatotoxicant along with each of silymarin, nifedipine, verapamil and diltiazem at subclinical, clinical and supraclinical doses. A day to the end of treatment for each model, rats were subjected to the hexobarbitone-induced hypnosis test. On the last days of treatment, blood samples were collected and serum was analyzed for relevant biochemical parameters. Animals were sacrificed after blood collection and livers were harvested, and samples obtained for in vivo antioxidant indices assay and histopathology. The hepatotoxicants significantly increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as duration of sleep in the hypnosis test. These drugs significantly reduced the hepatic levels of reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and increased the level of malondialdehyde (MDA). The CCBs at the various doses significantly reversed the effects of isoniazid-rifampicin, zidovudine and erythromycin. The results obtained in this study suggest that the CCBs possess hepatoprotective activity in drug-induced hepatotoxicity and may be beneficial at the subclinical and clinical doses.

  16. Investigation of Calcium Channel Blockers as Antiprotozoal Agents and Their Interference in the Metabolism of Leishmania (L. infantum

    Directory of Open Access Journals (Sweden)

    Juliana Quero Reimão

    2016-01-01

    Full Text Available Leishmaniasis and Chagas disease are neglected parasitic diseases endemic in developing countries; efforts to find new therapies remain a priority. Calcium channel blockers (CCBs are drugs in clinical use for hypertension and other heart pathologies. Based on previous reports about the antileishmanial activity of dihydropyridine-CCBs, this work aimed to investigate whether the in vitro anti-Leishmania infantum and anti-Trypanosoma cruzi activities of this therapeutic class would be shared by other non-dihydropyridine-CCBs. Except for amrinone, our results demonstrated antiprotozoal activity for fendiline, mibefradil, and lidoflazine, with IC50 values in a range between 2 and 16 μM and Selectivity Index between 4 and 10. Fendiline demonstrated depolarization of mitochondrial membrane potential, with increased reactive oxygen species production in amlodipine and fendiline treated Leishmania, but without plasma membrane disruption. Finally, in vitro combinations of amphotericin B, miltefosine, and pentamidine against L. infantum showed in isobolograms an additive interaction when these drugs were combined with fendiline, resulting in overall mean sum of fractional inhibitory concentrations between 0.99 and 1.10. These data demonstrated that non-dihydropyridine-CCBs present antiprotozoal activity and could be useful candidates for future in vivo efficacy studies against Leishmaniasis and Chagas’ disease.

  17. Investigation into in vitro anti-leishmanial combinations of calcium channel blockers and current anti-leishmanial drugs

    Directory of Open Access Journals (Sweden)

    Juliana Quero Reimão

    2011-12-01

    Full Text Available The need for drug combinations to treat visceral leishmaniasis (VL arose because of resistance to antimonials, the toxicity of current treatments and the length of the course of therapy. Calcium channel blockers (CCBs have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania chagasi using promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs, sum of FICs (ΣFICs and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimodipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.

  18. Cost containment for treating hypertension in African Americans: impact of a combined ACE inhibitor-calcium channel blocker.

    Science.gov (United States)

    Kountz, D S

    1997-07-01

    The use of calcium channel blockers (CCBs) and angiotensin-converting enzyme (ACE) inhibitors has increased dramatically over the last 10 years and now accounts for 60% to 70% of all new antihypertensive prescriptions. Even though these two classes are efficacious, they are costly. Combined ACE inhibitor/CCB therapy (amlodipine-benazepril) was introduced in 1995. An analysis was done to assess the potential financial impact of substituting this agent for patients being treated with on ACE inhibitor/CCB combination. A pharmaceutical profile review of prescriptions during October 1995 was performed on 219 randomly selected patients enrolled in a Medicaid managed care program. Eighty-four profiles were analyzed; 24% of patients were on a combination ACE inhibitor/CCB regimen with an average monthly cost of $135. If the single agent amlodipine-benazepril with an average monthly cost of $45 (all strengths) was substituted, the savings would be considerable: $1080 per patient per year and $1,080,000 annualized for the calculated number of hypertensives on combination therapy in our network of 15,000 patients. Therapeutic substitution is one method of achieving cost containment in managed care. The cost differential between separately prescribed CCBs and ACE inhibitors and amlodipine-benazepril is significant. Compliance also should be enhanced as the patient would need to take only one pill daily. Once a patient has been maintained on a stable dose of a CCB/ACE inhibitor, substitution with amlodipine-benazepril should be considered.

  19. Effects of the long-acting calcium channel blocker barnidipine hydrochloride on 24-h ambulatory blood pressure.

    Science.gov (United States)

    Kuwajima, Iwao; Abe, Keishi

    2002-02-01

    The effect of the long acting calcium channel blocker, barnidipine hydrochloride (barnidipine) on 24-h ambulatory blood pressure (ABP) was evaluated in J-MUBA (Japanese Multicentre Study on Barnidipine with Ambulatory Blood Pressure Monitoring). Following an observation period of two weeks, antihypertensive treatment with barnidipine was continued for at least six months. At the end of each period, ABP were measured. The patients were divided into high- and low-range groups based on ABP measurement. Throughout the 24 h, barnidipine exerted an excellent antihypertensive effect in the high-range group, but not in the low-range group. Barnidipine had comparable effects in the daytime and nighttime in inverted dippers and non-dippers, but it was more effective on daytime ABP than on nighttime ABP in dippers and in extreme dippers. Morning blood pressure before and after waking was evaluated before and after barnidipine administration in 233 patients. Barnidipine inhibited increases in blood pressure before and after waking, especially in surge-type patients whose blood pressure increased rapidly after waking. A positive correlation among 24-h ABP, daytime and night time ABP, morning blood pressure, and clinic blood pressure during the observation period and the antihypertensive effect of barnidipine was observed, with barnidipine exhibiting stronger antihypertensive effects in patients with persistently high blood pressure. It was concluded that the antihypertensive effects of barnidipine are maintained for 24 h but it has no excessive hypotensive effects on lower blood pressure and is thus a safe antihypertensive agent.

  20. Dose calcium channel blocker verapamil decrease urinary VMA levels in sympathoadrenal hyperactive patients with posttraumatic stress disorder?

    Institute of Scientific and Technical Information of China (English)

    Munawar Alam Ansari; Shahida PAhmed; Zahida Memon

    2008-01-01

    Objective:The majority of the patients with posttraumatic stress disorders (PTSD)embrace augmented urina-ry flow of Vanillylmandelic Acid (VMA)than normal subjects owing to superior sympathetic doings,which steer to cardiovascular catastrophe.Urinary flow of VMA was evaluated as sympathoadrenal bustle marker in patients with posttraumatic stress disorder.Calcium ion shows a noteworthy dependability in nervousness owing to its special effects on brain synaptosomes.So this study was conducted to explore the effects of Verapamil on sympathoadrenal motion in patients with PTSD.Methods:Placebo controlled clinical tryout was conducted. At first hundred (100)PTSD patients were chosen and enrolled in the study,from department of Psychological Medicine Dow University of Health Sciences,Karachi.Verapamil 120 mg/day was specified in divided doses to group-I (n =50)patients and group-II (n =50)patients received placebo therapy on a daily basis for nine weeks.Each and every patient was monitored weekly,all the way through extent of study.Results:Under-neath the posttraumatic stress disorder,urinary excretion of VMA was greater.Calcium channel blocker vera-pamil additionally abolished the embellished retort in urinary flow of VMA appreciably in patients with PTSD. Conclusion:Verapamil was experiential to be exceedingly effectual treatment.It reduces VMA levels in u-rine,and on the whole cardiovascular threat in PTSD patients.

  1. Efficacy and Safety of Combination Therapy Consisting of Angiotensin II Type 1 Receptor Blocker, Calcium Channel Blocker and Hydrochlorothiazide in Patients With Hypertension

    Science.gov (United States)

    Shiga, Yuhei; Miura, Shin-ichiro; Motozato, Kota; Yoshimine, Yuka; Norimatsu, Kenji; Arimura, Tadaaki; Koyoshi, Rie; Morii, Joji; Kuwano, Takashi; Inoue, Ken; Shirotani, Tetsuro; Fujisawa, Kazuaki; Matsunaga, Eiyu; Saku, Keijiro

    2017-01-01

    Background Many patients continue to have high blood pressure (BP) even after treatment with high-dose (H)-angiotensin II type 1 receptor blocker (ARB)/calcium channel blocker (CCB) or middle-dose (M)-ARB/CCB/hydrochlorothiazide (HCTZ). Methods Thirty-two hypertensive patients who had the use of H-ARB/CCB or M-ARB/CCB/HCTZ were enrolled in this study. We applied a changeover with a switch to H-ARB (telmisartan 80 mg/day)/CCB (amlodipine 5 mg/day or nifedipine CR 40 mg/day)/HCTZ (12.5 mg/day). Results Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased in all patients and in the H-ARB/CCB and M-ARB/CCB/HCTZ groups after 3 months. Percentage (%) of patients who reached the target BP after 3 months (72%) in all patients was significantly higher than that at 0 months (19%). There were no serious adverse effects in any of the patients. Conclusions Combination therapy with H-ARB/CCB/HCTZ was associated with a significant reduction of BP. PMID:28090225

  2. Parathyroid Hormone and the Use of Diuretics and Calcium-Channel Blockers: The Multi-Ethnic Study of Atherosclerosis.

    Science.gov (United States)

    Zaheer, Sarah; de Boer, Ian; Allison, Matthew; Brown, Jenifer M; Psaty, Bruce M; Robinson-Cohen, Cassianne; Ix, Joachim H; Kestenbaum, Bryan; Siscovick, David; Vaidya, Anand

    2016-06-01

    Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine-sensitive calcium channels are expressed on parathyroid cells and may play a role in parathyroid hormone (PTH) regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n = 1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared with non-TZ use (44.4 versus 46.9 pg/mL, p = 0.02), whereas the use of LD and CCBs was associated with higher PTH when compared with non-users of each medication class (LD: 60.7 versus 45.5 pg/mL, p < 0.0001; CCB: 49.5 versus. 44.4 pg/mL, p < 0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (β = -3.2 pg/mL, p = 0.0007), and LD or CCB use and higher PTH (LD: β = +12.0 pg/mL, p < 0.0001; CCB: +3.7 pg/mL, p < 0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (β = +5.0 pg/mL, p < 0.0001), whereas non-dihydropyridine use was not (β = +0.58 pg/mL, p = 0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these

  3. Preadmission Use of Calcium Channel Blockers and Outcomes After Hospitalization With Pneumonia: A Retrospective Propensity-Matched Cohort Study.

    Science.gov (United States)

    Zheng, Lin; Hunter, Krystal; Gaughan, John; Poddar, Sameer

    In sepsis, an overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Pneumonia is the leading cause of sepsis. In animal septic models, sepsis could induce uncontrolled calcium (Ca) leaking, raising cytosolic Ca to a toxic level, causing irreversible cellular injuries and organ failure. All types of calcium channel blockers (CCBs), by inhibiting Ca influx, have been shown to decrease overall mortality in various septic animal models. However, to our best knowledge, no clinical study had been conducted to investigate the beneficial effect(s) of CCBs in sepsis. We conducted a retrospective propensity-matched cohort study after screening 2214 patients hospitalized for pneumonia from year 2012 to 2014 at our institution. We identified 387 preadmission CCB users and 387 nonusers by propensity score matching. Logistic regression analysis was then used to determine the association between preadmission CCB use and outcomes in pneumonia. Our study showed that the odds for development of severe sepsis was significantly lower in the CCB user group [odds ratio (OR), 0.466; 95% confidence interval (CI), 0.311-0.697; P = 0.002]. Preadmission CCB use was associated with a lower risk of contracting bacteremia (OR, 0.498; 95% CI, 0.262-0.99; P = 0.0327), lower risk of acute respiratory insufficiency (OR, 0.573; 95% CI, 0.412-0.798; P = 0.001), lower risk of intensive care unit admission (OR, 0.602; 95% CI, 0.432-0.840; P = 0.0028). In conclusion, our study suggested preadmission CCB use was associated with a reduction in the risks of development of respiratory insufficiency, bacteremia, and severe sepsis in patients admitted to the hospital with pneumonia.

  4. The calcium channel blocker amlodipine exerts its anti-proliferative action via p21(Waf1/Cip1) gene activation.

    Science.gov (United States)

    Ziesche, Rolf; Petkov, Ventzislav; Lambers, Christopher; Erne, Paul; Block, Lutz-Henning

    2004-10-01

    Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, we demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. We show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.

  5. Quantitative Structure-Activity Relationship Studies of 4-Imidazolyl- 1,4-dihydropyridines as Calcium Channel Blockers

    Directory of Open Access Journals (Sweden)

    Farzin Hadizadeh

    2013-08-01

    Conclusion: The predictive ability of the model was found to be satisfactory and could be used for designing a similar group of 1,4- dihydropyridines , based on a pyridine structure core which can block calcium channels.

  6. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Nishida Yayoi

    2012-05-01

    Full Text Available Abstract Background Both angiotensin II type I receptor blockers (ARBs and calcium channel blockers (CCBs are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601 and propensity-score matched new CCB users (n = 601, with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG, total cholesterol (TC, non-fasting blood glucose, hemoglobin A1c (HbA1c, sodium, potassium, creatinine, alanine aminotransferase (ALT, aspartate aminotransferase (AST, gamma-glutamyltransferase (GGT, hemoglobin and hematocrit, and white blood cell (WBC, red blood cell (RBC and platelet (PLT counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and

  7. Regression of glomerular and tubulointerstitial injuries by dietary salt reduction with combination therapy of angiotensin II receptor blocker and calcium channel blocker in Dahl salt-sensitive rats.

    Directory of Open Access Journals (Sweden)

    Kazi Rafiq

    Full Text Available A growing body of evidence indicates that renal tissue injuries are reversible. We investigated whether dietary salt reduction with the combination therapy of angiotensin II type 1 receptor blocker (ARB plus calcium channel blocker (CCB reverses renal tissue injury in Dahl salt-sensitive (DSS hypertensive rats. DSS rats were fed a high-salt diet (HS; 4% NaCl for 4 weeks. Then, DSS rats were given one of the following for 10 weeks: HS diet; normal-salt diet (NS; 0.5% NaCl, NS + an ARB (olmesartan, 10 mg/kg/day, NS + a CCB (azelnidipine, 3 mg/kg/day, NS + olmesartan + azelnidipine or NS + hydralazine (50 mg/kg/day. Four weeks of treatment with HS diet induced hypertension, proteinuria, glomerular sclerosis and hypertrophy, glomerular podocyte injury, and tubulointerstitial fibrosis in DSS rats. A continued HS diet progressed hypertension, proteinuria and renal tissue injury, which was associated with inflammatory cell infiltration and increased proinflammatory cytokine mRNA levels, NADPH oxidase activity and NADPH oxidase-dependent superoxide production in the kidney. In contrast, switching to NS halted the progression of hypertension, renal glomerular and tubular injuries. Dietary salt reduction with ARB or with CCB treatment further reduced blood pressure and partially reversed renal tissues injury. Furthermore, dietary salt reduction with the combination of ARB plus CCB elicited a strong recovery from HS-induced renal tissue injury including the attenuation of inflammation and oxidative stress. These data support the hypothesis that dietary salt reduction with combination therapy of an ARB plus CCB restores glomerular and tubulointerstitial injury in DSS rats.

  8. [Clinical efficacy of calcium channel blockers slow the third generation of lercanidipine in the treatment of patients with arterial hypertension and metabolic disorders (review)].

    Science.gov (United States)

    Tabidze, G A; Gezeli, T D; Tsibadze, T A; Dolidze, N M

    2015-02-01

    Arterial hypertension is the most common risk factor in patients with metabolic disorders. In the selection of antihypertensive therapy it is necessary to consider not only the anti-hypertensive and organoprotective effects of drugs and their metabolic effects, which has prognostic value. Calcium antaginists, along. Lercanidipine related to the third generation dihydripyridine calcium antagonist, has been much more selective for the so-called slow calcium channels of vascular smooth muscle cells, which is associated with a good hypertensive, organo and metabolic action. Combination therapy with an ACE inhibitor and a calcium channel blocker is also a justified tactic for the management of patients with high-risk cardiovascular and metabolic disorders. Attention is paid new fixed combinations, including angiotensin converting enzyme inhibitors and calcium antagonists.

  9. Efficacy and safety of calcium channel blockers in heart failure : Focus on recent trials with second-generation dihydropyridines

    NARCIS (Netherlands)

    de Vries, RJM; van Veldhuisen, DJ; Dunselman, PHJM

    2000-01-01

    Background Chronic heart failure (CHF) has high morbidity and mortality rates despite treatment with angiotensin-converting-enzyme inhibitors, diuretics, and digoxin. Adjunctive-vasodilation through calcium channel blockade has been suggested as potentially useful, However, the first-generation calc

  10. Synthesis and Effects of Novel Dihydropyridines as Dual Calcium Channel Blocker and Angiotensin Antagonist on Isolated Rat Aorta

    Directory of Open Access Journals (Sweden)

    Farzin Hadizadeh

    2010-01-01

    Full Text Available Four novel losartan analogues 5a-d were synthesized by connecting a dihydropyridine nucleus to imidazole ring. The effects of 5a and 5b on angiotensin receptors (AT1 and L-type calcium channels were investigated on isolated rat aorta. Materials and MethodsAortic rings were pre-contracted with 1 µM Angiotensin II or 80 mM KCl and relaxant effects of losartan, nifedipine, 5a and 5b were evaluated by cumulative addition of these drugs to the bath solution.ResultsThe results showed that compounds 5a and 5b have both L-type calcium channel and AT1 receptor blocking activity. Their effects on AT1 receptors are 1000 and 100,000 times more than losartan respectively. The activity of compound 5b on L-type calcium channel is significantly less than nifedipine but compound 5a has comparable effect with nifedipine. ConclusionFinally we concluded that these two new Compounds can be potential candidates to be used as effective antihypertensive agents.

  11. Study on combined antiepileptic effect of Topmax(TPM) and Calcium channel blockers(CCB)%CCB辅助TPM抗痫的探讨

    Institute of Scientific and Technical Information of China (English)

    程百学; 高唯一; 张新华; 赵宗彦; 李文浩; 邢玉栋

    2002-01-01

    目的:观察钙通道阻滞剂(Calcium channel blocker,CCB)辅助妥泰(Topmax,TPM)抗癫痫的效果.方法:将服用TPM治疗癫痫的患者分为TPM组及TPM加CCB组,观察癫痫发作频率的变化及不良反应发生率.结果:西比灵、尼莫地平辅助TPM组临床癫痫控制率(76.15%)明显优于未用CCB组(18.18%);不良反应发生率TPM加CCB组(10.09%)低于TPM组(33.3%).结论:CCB辅助TPM可提高癫痫控制率、降低TPM的不良反应发生率.

  12. In vivo and ex vivo evaluation of L-type calcium channel blockers on acid beta-glucosidase in Gaucher disease mouse models.

    Directory of Open Access Journals (Sweden)

    Ying Sun

    Full Text Available Gaucher disease is a lysosomal storage disease caused by mutations in acid beta-glucosidase (GCase leading to defective hydrolysis and accumulation of its substrates. Two L-type calcium channel (LTCC blockers-verapamil and diltiazem-have been reported to modulate endoplasmic reticulum (ER folding, trafficking, and activity of GCase in human Gaucher disease fibroblasts. Similarly, these LTCC blockers were tested with cultured skin fibroblasts from homozygous point-mutated GCase mice (V394L, D409H, D409V, and N370S with the effect of enhancing of GCase activity. Correspondingly, diltiazem increased GCase protein and facilitated GCase trafficking to the lysosomes of these cells. The in vivo effects of diltiazem on GCase were evaluated in mice homozygous wild-type (WT, V394L and D409H. In D409H homozygotes diltiazem (10 mg/kg/d via drinking water or 50-200 mg/kg/d intraperitoneally had minor effects on increasing GCase activity in brain and liver (1.2-fold. Diltiazem treatment (10 mg/kg/d had essentially no effect on WT and V394L GCase protein or activity levels (<1.2-fold in liver. These results show that LTCC blockers had the ex vivo effects of increasing GCase activity and protein in the mouse fibroblasts, but these effects did not translate into similar changes in vivo even at very high drug doses.

  13. Short-term exposure to L-type calcium channel blocker, verapamil, alters the expression pattern of calcium-binding proteins in the brain of goldfish, Carassius auratus.

    Science.gov (United States)

    Palande, Nikhil V; Bhoyar, Rahul C; Biswas, Saikat P; Jadhao, Arun G

    2015-01-01

    The influx of calcium ions (Ca(2+)) is responsible for various physiological events including neurotransmitter release and synaptic modulation. The L-type voltage dependent calcium channels (L-type VDCCs) transport Ca(2+) across the membrane. Calcium-binding proteins (CaBPs) bind free cytosolic Ca(2+) and prevent excitotoxicity caused by sudden increase in cytoplasmic Ca(2+). The present study was aimed to understand the regulation of expression of neuronal CaBPs, namely, calretinin (CR) and parvalbumin (PV) following blockade of L-type VDCCs in the CNS of Carassius auratus. Verapamil (VRP), a potent L-type VDCC blocker, selectively blocks Ca(2+) entry at the plasma membrane level. VRP present in the aquatic environment at a very low residual concentration has shown ecotoxicological effects on aquatic animals. Following acute exposure for 96h, median lethal concentration (LC50) for VRP was found to be 1.22mg/L for goldfish. At various doses of VRP, the behavioral alterations were observed in the form of respiratory difficulty and loss of body balance confirming the cardiovascular toxicity caused by VRP at higher doses. In addition to affecting the cardiovascular system, VRP also showed effects on the nervous system in the form of altered expression of PV. When compared with controls, the pattern of CR expression did not show any variations, while PV expression showed significant alterations in few neuronal populations such as the pretectal nucleus, inferior lobes, and the rostral corpus cerebellum. Our result suggests possible regulatory effect of calcium channel blockers on the expression of PV.

  14. Characterisation of marrubenol, a diterpene extracted from Marrubium vulgare, as an L-type calcium channel blocker.

    Science.gov (United States)

    El-Bardai, Sanae; Wibo, Maurice; Hamaide, Marie-Christine; Lyoussi, Badiaa; Quetin-Leclercq, Joelle; Morel, Nicole

    2003-12-01

    1. The objective of the present study was to investigate the mechanism of the relaxant activity of marrubenol, a diterpenoid extracted from Marrubium vulgare. In rat aorta, marrubenol was a more potent inhibitor of the contraction evoked by 100 mM KCl (IC50: 11.8+/-0.3 microM, maximum relaxation: 93+/-0.6%) than of the contraction evoked by noradrenaline (maximum relaxation: 30+/-1.5%). 2. In fura-2-loaded aorta, marrubenol simultaneously inhibited the Ca2+ signal and the contraction evoked by 100 mM KCl, and decreased the quenching rate of fura-2 fluorescence by Mn2+. 3. Patch-clamp data obtained in aortic smooth muscle cells (A7r5) indicated that marrubenol inhibited Ba2+ inward current in a voltage-dependent manner (KD: 8+/-2 and 40+/-6 microM at holding potentials of -50 and -100 mV, respectively). 4. These results showed that marrubenol inhibits smooth muscle contraction by blocking L-type calcium channels.

  15. Effects of first and second generation calcium channel blockers on diastolic function of the failing hamster heart: relationship with coronary flow changes.

    Science.gov (United States)

    Beaucage, Pierre; Massicotte, Julie; Boileau, Jean-François; Dumont, Louis

    2003-07-01

    Calcium channel blockers (CCBs) have variable efficacy in the treatment of heart failure. We hypothesized that modulation of left ventricular diastolic pressure (LVDP) may play a role in the variable efficacy of CCBs in this condition. Isolated perfused hearts from 200- to 250-day-old UM-X7.1 cardiomyopathic hamsters (failing hearts) and age-matched Syrian hamsters (normal hearts) were studied. After recording of heart rate, coronary flow (CF), LVDP and left ventricular systolic pressure (LVSP), hearts were exposed either to verapamil or diltiazem (1 nM-10 microM), mibefradil (1 nM-1 microM) or clentiazem (1 nM-10 microM). Mechanical increase in CF (+2 to +10 ml/min) was carried out using a roller pump. Mechanically-augmented flow led to an increase in coronary perfusion pressure (+40 to +90 mm Hg), LVSP (+5 to +40 mm Hg) and LVDP (+5 to +25 mm Hg). CCBs-induced increment of coronary flow led to a difference in their cardiac response. In normal hearts, the negative inotropic response was more important with diltiazem and verapamil. Failing hearts did not demonstrate increased inotropic sensitivity to first-generation CCBs. On the contrary, at clinically relevant concentrations, verapamil resulted in the most pronounced impairment of LVDP followed by diltiazem while mibefradil and clentiazem, at clinically relevant concentrations, preserved LVDP. Such findings provide an additional explanation for the variable efficacy of CCBs in heart failure.

  16. Simultaneous determination of a novel diphenylpiperazine calcium channel blocker and its four metabolites in rat liver microsomes by liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Guo, Wei; Kong, Dezhi; Du, Yingfeng; Shi, Xiaowei; Wang, Wei; Wang, Yongli

    2012-01-01

    Dipfluzine hydrochloride (Dip), a novel diphenylpiperazine calcium channel blocker, has revealed the characteristics of a promising candidate for the treatment of cerebral vascular diseases in preclinical studies. Our research identified and quantified Dip and its 4 metabolites (M1, M2, M4 and M5) in rat liver microsomes by liquid chromatography tandem mass spectrometry. The results showed that Dip was firstly metabolized to M1 and M5 by 1- and 4-dealkylation from a piperazine nitrogen, and then the latter was subsequently metabolized to M2 and M4. The concentrations of Dip, M1, M2 and M5 were 557.3 ± 26.3, 854.3 ± 46.0, 2796.7± 126.9, 2473.3 ± 82.6 and 4.0 ± 0.4, 2.4 ± 0.1, 318.2 ± 8.7 and 27.4 ± 1.5 ng/ml in male and female rats, respectively. M4 (404.2 ± 22.2 ng/ml) was detected only in males not in females, suggesting that there is gender difference in the metabolism of Dip.

  17. Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis.

    Science.gov (United States)

    Lu, Z; Chen, Y; Li, L; Wang, G; Xue, H; Tang, W

    2017-01-01

    Many randomized clinical trials (RCTs) have investigated the efficacy and safety of renin-angiotensin system inhibitors (RASIs) plus calcium channel blockers (CCBs), compared with other two-drug combinations, but systematic assessment in this aspect is still lacking. We carried out the present meta-analysis of randomized controlled trials to evaluate the long-term effect and safety of RASIs plus CCBs. Literatures were searched in MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials in September 2014. A fixed-effect model was used to estimate the pooled effect of trials identified. Thirty-four trials with 41 694 patients were included. Compared with RASIs plus diuretics, RASIs plus CCBs decreased total cardiovascular (CV) events (relative risk (RR) 0.82, 95% confidence interval (CI): 0.75, 0.91, adjusted RR (ARR) 1.7%) and withdrawals due to adverse effect (WDAE) (RR 0.87, 95% CI: 0.80, 0.94, ARR 1.3%). Compared with CCBs plus diuretics, RASIs plus CCBs decreased WDAE (RR 0.63, 95% CI: 0.45, 0.90, ARR 1.1%). Our meta-analysis indicates that RASIs plus CCBs provide a superior safety and prevention of CV events to RASIs plus diuretics, whereas this combination is also safer than CCBs plus diuretics. We also raise a new hypothesis. More high-quality RCTs focused on hard end points with CV, cerebrovascular and renal events are needed to confirm the hypothesis we have brought out.

  18. Optical isomers of dihydropyridine calcium channel blockers display enantiospecific effects on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450.

    Science.gov (United States)

    Štěpánková, Martina; Krasulová, Kristýna; Dořičáková, Aneta; Kurka, Ondřej; Anzenbacher, Pavel; Dvořák, Zdeněk

    2016-11-16

    Dihydropyridine calcium channel blockers (CCBs) are used as anti-hypertensives and in the treatment of angina pectoris. Structurally, CCBs have at least one chiral center in the molecule, thereby existing in two or more different enantiomers. In the current paper we examined effects of benidipine, felodipine and isradipine enantiomers on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450. All CCBs dose-dependently activated aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), as revealed by gene reporter assays. Activation of AhR, but not PXR, was enantiospecific. Consistently, CCBs induced CYP1A1 and CYP1A2 mRNAs, but not protein, in human hepatocytes and HepG2 cells, with following pattern: benidipine (-)>(+), isradipine (-)>(+) and felodipine (+)>(-). All CCBs induced CYP2A6, CYP2B6 and CYP3A4 mRNA and protein in human hepatocytes, and there were not differences between the enantiomers. All CCBs transformed AhR in its DNA-binding form, as revealed by electromobility shift assay. Tested CCBs inhibited enzyme activities of CYP3A4 (benidipine (+)>(-); felodipine (-)>(+); isradipine (-)-(+)) and CYP2C9 (benidipine (-)>(+); felodipine (+)>(-); isradipine (-)>(+)). The data presented here might be of toxicological and clinical importance.

  19. The effects of a sodium and a calcium channel blocker on lethality of mice injected with the yellow scorpion (Leiurus quinquestriatus venom

    Directory of Open Access Journals (Sweden)

    A. R. Al-Shanawani

    2005-06-01

    Full Text Available Scorpion venom toxins generally produce similar effects by mainly acting on sodium channels, and to a lesser extent, on potassium, calcium, and chloride channels. This leads to increased release of neurotransmitters and mediators, resulting in a cascade of pathological events, involving the central nervous system, the autonomic nervous system, the cardiovascular and the respiratory system, eventually leading to death. The objective of this paper was to discover whether a sodium channel blocker, lidocaine, or a calcium channel blocker, verapamil, would prolong the survival of mice injected with the venom from the common yellow scorpion Leiurus quinquestriatus quinquestriatus (LQQ. For this purpose, mice were divided into 2 groups, each injected with a different venom dose (250 or 300 µg.kg-1, s.c.. Subgroups (n=10 from each group were given venom alone; different doses of lidocaine (4, 10, 15, or 20 mg.kg-1; or several doses of verapamil (0.01, 0.03, 0.1, 0.3, or 1 mg.kg-1. All doses of lidocaine and verapamil were intravenously administered 3 minutes before, 1, 5, and 15 minutes after venom injection. Percent surviving after 24 hours was recorded in addition to the time of death. In general, lidocaine significantly prolonged survival at the dose of 10 mg.kg-1 (P<0.05 and P<0.01, versus low and high dose of venom, respectively or 15 mg.kg-1 (P<0.01 and P<0.001, versus low and high dose of venom, respectively; Covariance Wilcoxon survival statistics, especially when injected before the venom or in the early stages of envenomation. On the other hand, in all doses administered, verapamil was either toxic or showed non-significant results. Lidocaine, the sodium channel blocker, appears to play an important role in the protection from lethality of mice injected with LQQ venom, and significantly prolonged the survival time of mice whether injected before or in the early stages of envenomation.

  20. Extent of use of immediate-release formulations of calcium channel blockers as antihypertensive monotherapy by primary care physicians: multicentric study from Bahrain.

    Directory of Open Access Journals (Sweden)

    Sequeira R

    2002-07-01

    Full Text Available BACKGROUND: The issue of cardiovascular safety of calcium channel blockers (CCBs has been widely debated in view of reflex increase in sympathetic activity induced by immediate release (IR / short acting formulations. It is generally agreed that such CCBs should not be used alone in the management of hypertension. AIMS: We have determined the extent to which primary care physicians prescribe CCBs as monotherapy, especially the immediate release formulations, in the management of uncomplicated hypertension and diabetic hypertension - with an emphasis upon the age of the patients. SETTING, DESIGN AND METHODS: A retrospective prescription-based study was carried out in seven out of 18 Health Centres in Bahrain. The study involved a registered population of 229,300 representing 46% of registered individuals, and 35 physicians representing 43% of all primary care physicians. The data was collected between November 1998 and January 1999 using chronic dispensing cards. RESULTS: In all categories CCBs were the third commonly prescribed antihypertensive as monotherapy, with a prescription rate of 11.1% in uncomplicated hypertension, 18% in diabetic hypertension and 20.1% in elderly patients above 65 years of age. Nifedipine formulations were the most extensively prescribed CCBs. Almost half of the CCB-treated patients were on IR-nifedipine, whereas IR-diltiazem and IR-verapamil, and amlodipine were infrequently prescribed. CONCLUSION: Prescription of IR-formulations of CCBs as monotherapy by primary care physicians does not conform with recommended guidelines. In view of concerns about the safety of such practice, measures to change the prescribing pattern are required.

  1. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response.

    Science.gov (United States)

    Harmsze, Ankie M; Robijns, Karen; van Werkum, Jochem W; Breet, Nicoline J; Hackeng, Christian M; Ten Berg, Jurrien M; Ruven, Hendrik J T; Klungel, Olaf H; de Boer, Anthonius; Deneer, Vera H M

    2010-05-01

    Clopidogrel is a prodrug that has to be converted in vivo to its active metabolite by cytochrome (CYP)P450 iso-enzymes. As calcium channel blockers (CCBs) are inhibitors of CYP3A4, concomitant use of these drugs might play a role in the wide inter-individual variability in the response to clopidogrel. However, some CCBs also have strong inhibitory effects on the drug transporter P-glycoprotein (Pgp), which mediates clopidogrel's intestinal absorption. It was the aim of this study to evaluate the effect of co-administration of Pgp-inhibiting and non-Pgp-inhibiting CCBs on on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective percutaneous coronary intervention (PCI). In a total of 623 consecutive patients undergoing elective PCI treated with clopidogrel and aspirin, platelet reactivity to 5 and 20 muM adenosine diphospate (ADP) and clopidogrel poor-response (defined as > 70% platelet aggregation to 20 muM ADP) were evaluated by light transmittance aggregometry. A total of 222 patients (35.6%) were on CCB treatment, of which 98 used Pgp-inhibiting CCBs (verapamil, nifedipine, diltiazem, barnidipine) and 124 patients used the non-Pgp-inhibiting CCB amlodipine. Adjusted mean ADP-induced on-clopidogrel platelet reactivity was significantly higher in both users of Pgp-inhibiting CCBs and amlodipine as compared to CCB non-users (all p<0.05). However, only the use of amlodipine was significantly associated with a 2.3-fold increased risk of clopidogrel poor-response. This study demonstrates that concomitant use of Pgp-inhibiting CCBs and amlodipine increases on-clopidogrel platelet reactivity. Only amlodipine was associated with clopidogrel poor-response. The drug-drug interaction between clopidogrel and amlodipine might be more clinically relevant as compared to P-glycoprotein-inhibiting CCBs.

  2. Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Rong-Shuang Huang; Yi-Ming Cheng; Xiao-Xi Zeng; Sehee Kim; Ping Fu

    2016-01-01

    Background:Renin-angiotensin system inhibitor and calcium channel blocker (CCB) are widely used in controlling blood pressure (BP) in patients with chronic kidney disease (CKD).We carried out a meta-analysis to compare the renoprotective effect of the combination of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and CCB (i.e.,ACEI/ARB + CCB) with ACEI/ ARB monotherapy in patients with hypertension and CKD.Methods:Publications were identified from PubMed,Embase,Medline,and Cochrane databases.Only randomized controlled trials (RCTs) of BP lowering treatment for patients with hypertension and CKD were considered.The outcomes of end-stage renal disease (ESRD),cardiovascular events,BP,urinary protein measures,estimated glomerular filtration rate (GFR),and adverse events were extracted.Results:Based on seven RCTs with 628 patients,ACEI/ARB + CCB did not show additional benefit for the incidence of ESRD (risk ratio [RR] =0.84;95% confidence interval [CI]:0.52-1.33) and cardiovascular events (RR =0.58;95% CI:0.21-1.63) significantly,compared with ACEI/ARB monotherapy.There were no significant differences in change from baseline to the end points in diastolic BP (weighted mean difference [WMD] =-1.28 mmHg;95% CI:-3.18 to-0.62),proteinuria (standard mean difference =-0.55;95% CI:-1.41 to-0.30),GFR (WMD =-0.32 ml/min;95% CI:-1.53 to-0.89),and occurrence of adverse events (RR =1.05;95% CI:0.72-1.53).However,ACEI/ARB + CCB showed a greater reduction in systolic BP (WMD =-4.46 mmHg;95% CI:-6.95 to-1.97),compared with ACEI/ARB monotherapy.Conclusion:ACEI/ARB + CCB had no additional renoprotective benefit beyond than what could be achieved with ACEI/ARB monotherapy.

  3. Phenylalkylamines as calcium channel blockers

    Indian Academy of Sciences (India)

    Anamika Awasthi; Arpita Yadav

    2007-09-01

    In this study we present ab initio Hartree Fock molecular orbital calculations with complete geometry optimizations on some phenylalkylamines (PAAs) that are clinically used as antiarrhythmic drugs. Pharmacophoric features of PAAs have been derived. An explanation of potency regulation in PAAs has been suggested based on ion capturing vs. ion holding by the drug. Ion capturing by the drug is always electrostatically highly favourable but has to be analysed in terms of conformational changes required and physiological accessibility of the situation. Our results also seem to offer an explanation for inhibitory effect of Ca2+ ion concentration on binding affinity of PAAs.

  4. 钙通道阻滞剂对神经损伤后瘢痕处血管分布的影响%Effects of calcium channel blockers on the distribution of blood vessels around the scar after nerve injury

    Institute of Scientific and Technical Information of China (English)

    刘冲; 刘晓峰; 陈涛平; 王云飞; 任宝; 郭召; 薛金伟; 刘双立

    2015-01-01

    目的:探讨钙通道阻滞剂对大鼠坐骨神经损伤后瘢痕处血管分布的实验研究。方法选用SD大鼠96只,随机4组,每组24只,制作大鼠坐骨神经损伤模型,实验组及对照组每天分别给予腹腔注射维拉帕米和生理盐水(4 mg/kg),分别于术后第4、8周进行免疫组化染色及血管灌注,观察损伤后瘢痕处血管分布情况。结果术后4、8周实验组瘢痕处血管数量多、密度高,血管分布较均匀,血管走形较规律。对照组血管数量少,密度低,血管分布不均,血管走形紊乱。结论钙通道阻滞剂能够改变损伤处血管分布状况,改善损伤处神经组织的血液供应。%Objective To investigate the correlation between the calcium channel blockers on the distribution of blood vessels scar after sciatic nerve injury in rats.Methods 96 SD rats were divided into 4 group at random, 24 rats in each group. The experimental rats were made sciatic nerve injury model, the experimental group and control group were given respectively a intraperitoneal injection of verapamil and physiological saline(4 mg/kg), in 4, 8 weeks after surgery immunohistochemical staining and vascular perfusion were conducted to observe the scar after injury of vascular distribution.Results In 4, 8 weeks after surgery, the blood vessel numbers were increased and the density of the nerve lesions became higher, the vascular distributions were more uniform in the rats of the experimental group. However, the results of the controls indicated that the blood vessels numbers were decreased, the density of the nerve lesions became lower, the vascular distributions were in the state of disorder.Conclusion Calcium channel blockers can be used to reduce the formation of collagen ifbers to soften the scars, and thus improve the distribution of the lesions of blood vessels and promote the blood supply of nerve tissue damage, and make the damaged nerve bundle membrane and blood

  5. Rational application of antihypertensive calcium channel blockers in renal diseases%钙离子拮抗剂类降压药在肾脏病中的合理应用

    Institute of Scientific and Technical Information of China (English)

    王伟铭; 徐丽梨

    2014-01-01

    中国人群高血压发病率较高,其中继发性高血压第一位的病因就是慢性肾脏病(CKD)。对于CKD高血压患者首选血管紧张素转换酶抑制剂(ACEI)或血管紧张素II 受体拮抗剂(ARB)类药物,而单药治疗往往血压控制不佳,需联合其它降压药物治疗。钙离子拮抗剂(CCB)是一线降压药物,既往考虑其对肾脏副作用而较少应用于CKD患者。随着研究进展及新型制剂的研发, CCB类药物在CKD高血压治疗中亦有一定地位及优势,合理的应用可改善肾脏病预后,给患者带来益处。%The incidence of hypertension is high in the Chinese population.And the first cause of secondary hypertension is chronic kidney disease (CKD).To control the hypertension in CKD patients, angiotensin converting enzyme inhibitor (ACEI)or angiotensin receptor blocker (ARB)is the first choice. However,as single drug use of ACEI or ARB does not have satisfactory effect in controlling the hypertension of CKD patients,combination of other antihypertensive drugs is usually needed.Calcium channel blockers (CCB)are first-line antihypertensive drugs,but were less used in CKD patients previously due to their adverse effects.With the research progress and the development of new preparations,CCB have their certain places and advantages in treatment of hypertension patients with CKD.Rational application of CCB can improve prognosis of the kidney so as to benefit the patients.

  6. An open-label, randomized, controlled, 4-week comparative clinical trial of barnidipine hydrochloride, a calcium-channel blocker, and benazepril, an angiotensin-converting enzyme inhibitor, in Chinese patients with renal parenchymal hypertension.

    Science.gov (United States)

    Chen, X; Zheng, F; Chen, P; Tang, L; Wei, R; Yu, Y; Su, Y; Kikkawa, T; Yamamoto, M

    2006-01-01

    This study compared barnidipine, a calcium-channel blocker, and benazepril, an angiotensin-converting enzyme inhibitor, in 85 Chinese patients with renal parenchymal hypertension (diastolic blood pressure range 95 - 110 mmHg). Patients were randomly assigned to receive either 10 mg barnidipine or 10 mg benazepril orally daily for 4 weeks. In patients with diastolic blood pressure > 90 mmHg after 2 weeks of treatment, the dose of barnidipine or benazepril was increased by 5 or 10 mg, respectively. Both the barnidipine-treated group (n = 43) and the benazepril-treated group (n = 42) showed significant mean reductions from baseline in sitting systolic and diastolic blood pressures. The decrease in diastolic blood pressure with benazepril was significantly greater than with barnidipine treatment. Sitting heart rate was not changed by either drug. There was no significant difference in adverse events between the two groups. Barnidipine is similar to benazepril for the treatment of renal parenchymal hypertension.

  7. Angiotensin System Blockade Combined With Calcium Channel Blockers Is Superior to Other Combinations in Cardiovascular Protection With Similar Blood Pressure Reduction: A Meta-Analysis in 20,451 Hypertensive Patients.

    Science.gov (United States)

    Chi, Chen; Tai, Chenhui; Bai, Bin; Yu, Shikai; Karamanou, Marianna; Wang, Jiguang; Protogerou, Athanase; Blacher, Jacques; Safar, Michel E; Zhang, Yi; Xu, Yawei

    2016-08-01

    The authors aimed to investigate the superiority of angiotensin system blockade (angiotensin-converting enzyme [ACE] inhibitor/angiotensin receptor blocker [ARB]) plus a calcium channel blocker (CCB) (A+C) over other combination therapies in antihypertensive treatment. A meta-analysis in 20,451 hypertensive patients from eight randomized controlled trials was conducted to compare the A+C treatment with other combination therapies in terms of blood pressure (BP) reduction, clinical outcomes, and adverse events. The results showed that BP reduction did not differ significantly among the A+C therapy and other combination therapies in systolic and diastolic BP (P=.87 and P=.56, respectively). However, A+C therapy, compared with other combination therapies, achieved a significantly lower incidence of cardiovascular composite endpoints, including cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.70-0.91; Pother combinations (Pother combination therapies (P=.34) but presented a significantly lower incidence of serious adverse events (RR, 0.85; 95% CI, 0.73-0.98; P=.03). In conclusion, A+C therapy is superior to other combinations of antihypertensive treatment as it shows a lower incidence of cardiovascular events and adverse events, while it has similar effects in lowering BP and preserving renal function.

  8. Application of ab initio theory to QSAR study of 1,4-dihydropyridine-based calcium channel blockers using GA-MLR and PC-GA-ANN procedures.

    Science.gov (United States)

    Hemmateenejad, Bahram; Safarpour, Mohammad A; Miri, Ramin; Taghavi, Fariba

    2004-09-01

    The usefulness of the quantum chemical descriptors, calculated at the level of the RHF theory using 6-31G basis set for QSAR study of 1,4-dihydropyridine-based calcium channel antagonist was examined. A data set containing 45 dihydropyridine derivatives with known activity was used. Multiple linear regressions combined with genetic algorithm for variable selection and an artificial neural network model combined with principal component analysis for dimension reduction and genetic algorithm for factor selection (PC-GA-ANN) were employed. Some multiparametric MLR equations with good statistical quality were obtained for different classes of dihydropyridine derivatives. The resulting equations suggest that the electronic properties of the atoms belonging to the backbone of the molecules as well as the conformation of the molecules affect the binding of these molecules with their receptor. In the PC-GA-ANN, The principal components of the descriptors data matrix were used as the input of the neural network and then genetic algorithm was applied to select the most relevant set of principal components. Two ANN models with five selected principal components were obtained. These models, which have high statistical qualities, can predict the activity of the molecules with prediction errors lower than +/-5%.

  9. 钙离子拮抗剂致药物性牙龈增生的危险因素分析%Analysis of risk factors for gingival hyperplasia induced by calcium channel blockers

    Institute of Scientific and Technical Information of China (English)

    李行懿; 陈娜

    2012-01-01

    目的 调查高血压患者服用钙离子拮抗剂后引起药物性牙龈增生的患病率,并分析其危险因素.方法 将北京医院心血管内科的681例高血压或冠心病患者纳入本研究,其中330例服用钙离子拮抗剂(CCB组),351例未服用钙离子拮抗剂(对照组).记录患者的性别、年龄、用药种类、持续时间、剂量、是否联合用药.临床检查牙龈出血指数(BI)、菌斑指数(PLI)、牙龈增生指数(HI).结果 服用钙离子拮抗剂组牙龈增生的患病率为4l.21%,显著高于对照组4.84%(P <0.05).对调查的各种因素进行Logistic回归分析,结果显示:BI(OR=2.17,95%可信区间:1.60-2.94)PLI(OR=1.99,95%可信区间:1.38-2.87)是患者出现牙龈增生的危险因素.结论 口腔卫生状况和牙龈炎症反应是药物性牙龈增生的危险因素.%Objective Tu investigate the prevalence and risk factors of calcium channel blockers induced gingival overgrowth in hypertensive patients. Methods A cross-sectional survey was conducted in 681 hypertensive patients. Among them 330 patients took calcium channel blockers and 351 patients who had never received calcium channel bloclers were recruited as controls. The pharmacological and demographic data fnr each subject were recorded. Degree of gingival hyperplasia、plaque index and probing bleeding index were studied Results The prevalence of gingival overgrowth was 41.21% in CCB group which was statistically higher than that (4.84%) in the control group. By Logistic regression analysis BI ( OR=2.17,95% CI:1.60-2.94 ) and PL1 ( OR=1.99,95% CI:1.38-2.87 ) were found to be risk factors. Conclusion The gingivaJ inflammation and oral hygiene are important risk factors for the occurrence of gingival hyperplasia induced by calciun channel blockers.

  10. The effects of calcium channel blockers in the prevention of stroke in adults with hypertension: a meta-analysis of data from 273,543 participants in 31 randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Gui Jv Chen

    Full Text Available BACKGROUND: Hypertension is a major risk factor for the development of stroke. It is well known that lowering blood pressure decreases the risk of stroke in people with moderate to severe hypertension. However, the specific effects of calcium channel blockers (CCBs against stroke in patients with hypertension as compared to no treatment and other antihypertensive drug classes are not known. METHODS AND FINDINGS: This systematic review and meta-analysis of randomized controlled trials (RCTs evaluated CCBs effect on stroke in patients with hypertension in studies of CCBs versus placebo, angiotensin-converting-enzyme inhibitors (ACEIs, β-adrenergic blockers, and diuretics. The PUBMED, MEDLINE, EMBASE, OVID, CNKI, MEDCH, and WANFANG databases were searched for trials published in English or Chinese during the period January 1, 1996 to July 31, 2012. A total of 177 reports were collected, among them 31 RCTs with 273,543 participants (including 130,466 experimental subjects and 143,077 controls met the inclusion criteria. In these trials a total of 9,550 stroke events (4,145 in experimental group and 5,405 in control group were reported. CCBs significantly decreased the incidence of stroke compared with placebo (OR = 0.68, 95% CI 0.61-0.75, p<1×10(-5, β-adrenergic blockers combined with diuretics (OR = 0.89, 95% CI 0.83-0.95, p = 7×10(-5 and β-adrenergic blockers (OR = 0.79, 95% CI 0.72-0.87, p<1×10(-5, statistically significant difference was not found between CCBs and ACEIs (OR = 0.92, 95% CI 0.8-1.02, p = 0.12 or diuretics (OR = 0.95, 95% CI 0.84-1.07, p = 0.39. CONCLUSION: In a pooled analysis of data of 31 RCTs measuring the effect of CCBs on stroke, CCBs reduced stroke more than placebo and β-adrenergic blockers, but were not different than ACEIs and diuretics. More head to head RCTs are warranted.

  11. Effects of calcium channel blockers on growth cone and their clinical implications%钙离子通道调节剂在神经元的生长锥的作用及临床意义

    Institute of Scientific and Technical Information of China (English)

    Ji-Sun KIM; Vivian Y SZETO; 冯中平

    2016-01-01

    钙是神经发育过程中重要的信号分子,其生物学功能通过众多的钙离子通道、交换蛋白及钙结合蛋白来实现。在神经发育过程中,神经元的生长锥利用钙离子的浓度差来进行正确爬行,并最终引导轴突向正确的方向生长。然而,如果钙离子通道出现功能障碍,将会引起生长锥错误地爬行,从而导致神经发育相关疾病的发生。了解特异性表达于生长锥的钙通道,并获得能调控这些钙通道的调节剂对于治疗神经发育相关疾病至关重要。这些调节剂可能已广泛用于其他组织病变,如心血管疾病的治疗。但它们对生长锥上钙通道的调控仍有待进一步研究。最近的研究表明,离子通道调节剂可以作为治疗神经发育相关疾病的药物靶标。本文讨论钙通道调节剂在生长锥引导轴突生长过程中的潜在作用。%Calcium signaling is a critical component of neuronal development, and is mediated by numerous calcium channels, exchangers and calcium-binding proteins. Growth cones use calcium gradient as a tool to pathfind correctly, ultimately directing the appropriate growth of axons. Conse⁃quently, dysfunctions of calcium channels could lead to incorrect pathfinding, thus resulting in develop⁃mental disorders. It is important to understand the pharmacological modulators of the calcium channels present in the growth cone-some already widely used in other tissue pathologies, like cardiovascular disease. Further, L-type channel blockers such as dihydropyridines have been instrumental in under⁃standing the properties of L-type channels as well as their heterogeneous nature. Investigation of channel property often uses pharmacological inhibition to reveal their functionality. Recent studies show the channel modulators as promising drug targets in the treatment of neurodevelopmental disorders. The goal of this article is to discuss the potential effects of

  12. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011 (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011 (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

    2009-07-24

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}). Although nifedipine did not affect expression levels of PPAR-{gamma}, it increased the PPAR-{gamma} transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-{gamma} activation.

  13. Meta Analysis of the Effects of Calcium Channel Blockers or Renin-Angiotensin System Blockers on Arterial Stiffness in Hypertension%钙离子拮抗剂和肾素-血管紧张素系统阻断剂对高血压动脉僵硬度作用差异的荟萃分析

    Institute of Scientific and Technical Information of China (English)

    张艺军; 裴静娴; 王月刚; 吴平生

    2012-01-01

    目的 系统评价钙离子拮抗剂和肾素-血管紧张素系统阻断剂在高血压治疗中,动脉僵硬度变化的差异.方法 按循证医学的要求,制定相应的纳入、排除标准及其检索策略.通过PubMed、EMBASE、Ovid EMBReviews、中周期刊全文数据库、中文科技期刊全文数据库、万方数据库检索相关的随机对照临床研究,计算机检索时间从各数据库建库至2012年1月;同时辅助其他检索,纳入经过钙离子拮抗剂和肾素-血管紧张素系统阻断剂治疗原发性高血压患者的随机对照试验,治疗时间至少12周.采用RevMan5.0软件进行统计分析.结果 纳入7篇随机对照研究,共计524例高血压患者.荟萃分析结果显示:肾素-血管紧张素系统阻断剂在改善动脉僵硬度方面优于钙离子拮抗剂(均数差=160.15,95%可信区间57.10~263.21),差异有统计学意义.但是在降低收缩压(均数差=-2.94,95%可信区间-4.59~-1.29)和舒张压(均数差=-6.63,95%可信区间-9.56~-3.70)方面,较钙离子拮抗剂弱,在降低脉压差(均数差=-6.12,95%可信区间-2.3~14.55)方面与钙离子拮抗剂相比无显著性差异.结论 肾素-血管紧张素系统阻断剂在改善高血压患者动脉僵硬度方面优于钙离子拮抗剂,该作用与其降压作用无关.%Objective To evaluate the differences of the changes of pulse wave velocity(PWV) of hypertension patients with the treatment of calcium channel blockers or Renin-angiotensin system blockers. Methods Based on the principles of evidence-based medicine, corresponding inclusion and exclusion criteria, along with search strategies were developed. We searched the Ovid EMB Reviews, PubMed, EMBASE, Chinese Biomedical Literature Database, Chinese Scientific Journal Full-text Database, and Chinese Journal Full-text Database up to January 2012 to identify randomized controlled trials comparing the effects of calcium channel hlockers with that of Renin

  14. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.

    Science.gov (United States)

    Leenen, Frans H H; Nwachuku, Chuke E; Black, Henry R; Cushman, William C; Davis, Barry R; Simpson, Lara M; Alderman, Michael H; Atlas, Steven A; Basile, Jan N; Cuyjet, Aloysius B; Dart, Richard; Felicetta, James V; Grimm, Richard H; Haywood, L Julian; Jafri, Syed Z A; Proschan, Michael A; Thadani, Udho; Whelton, Paul K; Wright, Jackson T

    2006-09-01

    The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker-initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.

  15. 钙通道阻滞剂在危重烧伤脓毒症防治中的应用%Study of calcium channel blockers on prevention and treatment of patients with severe burn sepsis

    Institute of Scientific and Technical Information of China (English)

    吴祖煌; 宋斌; 陈国养; 王光毅

    2010-01-01

    (t = 2.20,2.17,2.19,2.17,2.61) (P <0.01 or 0.05). Plasma Ca2+ and iCa2+ levels were decreased. However,MAP were increased in the two groups, although no difference was found between the two group(P >0.05). Conclusions Early applying of calcium channel blockers (CCB) can markedly inhibit the degree of inflammatory medium in serum, thereby preventing the development of excessive inflammation response and subsequent multiple organ dysfunction syndrome associated with severely burned sepsis. It can effectively inhibit intracellular Ca2+ overload caused by myocadial infection injury,which may contribute to the effect of acupuncture in reducing myocardial injury and protecting myocardial performance and improving prognosis.%目的 探讨尼莫地平在危重烧伤脓毒症防治中的作用.方法 将28例危重烧伤脓毒症病例随机分为2组:治疗组(n=14)和对照组(n=14).2组除实施相同的脓毒症综合治疗方案外,治疗组应用微量泵持续给予生理盐水+尼莫地平注射液15 μg/(kg·h)进行治疗,对照组给予相同剂量的生理盐水治疗.观察2组血浆肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)、C-反应蛋白(CRP)、前降钙素(PCT)、脑钠肽(BNP)、血钙、离子钙水平变化和血流动力学变化.结果 ①血流动力学指标明显改善(ABF、ACC、LVET、TSVR对照组治疗前后t值分别为3.93、3.37、3.75、7.02,治疗组治疗前后t值分别为6.46、4.98、6.29、4.60,P<0.01或P<0.05),平均动脉压无明显变化(P>0.05).与对照组比较,治疗组主动脉血流量(ABF)、左心室血流最大流速(ACC)、左心室射血分数时间(LVET)、外周血管阻力(TSVR)改善更为明显(t值分别为2.29、2.07、2.23、2.14,P<0.01或P<0.05).②血浆TNF-α、IL-6、CRP浓度明显下降(TNF-α、IL-6、CRP对照组治疗前后t值分别为2.38、2.29、2.45,治疗组治疗前后t值分别为4.04、4.04、2.56,P<0.01或P<0.05).PCT、BNP治疗组更明显(PCT、BNP治疗

  16. Effects of calcium channel on 3-morpholinosydnonimine-induced rat hippocampal neuronal apoptosis

    Institute of Scientific and Technical Information of China (English)

    Quanzhong Chang; Shuling Zhang; Yuanyin Zheng; Lijuan Xu; Jinbao Yin; Shining Cai

    2011-01-01

    Previous studies have demonstrated that increased chloride channel activity plays a role in nitric oxide-induced neuronal apoptosis in the rat hippocampus.The present study investigated the effects of the broad-spectrum calcium channel blocker CdC12 on survival rate, percentage of apoptosis, and morphological changes in hippocampal neurons cultured in vitro, as well as the effects of calcium channels on neuronal apoptosis.The chloride channel blockers 4-acetamido-4'-isothiocyanatostilbene-2, 2'-disulfonic acid (SITS) or 4, 4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) increased the survival rate of 3-morpholinosydnonimine (SIN-1)-treated neurons and suppressed SIN-1-induced neuronal apoptosis.The calcium channel blocker CdC12 did not increase the survival rate of neurons and did not affect SIN-1-induced apoptosis or SITS- or DIDS-suppressed neuronal apoptosis.Results demonstrated that calcium channels did not significantly affect neuronal apoptosis.

  17. The genetic background affects the vascular response in T-type calcium channels 3.2 deficient mice

    DEFF Research Database (Denmark)

    Svenningsen, Per; Hansen, Pernille B L

    2016-01-01

    Voltage-gated calcium channels (Cav ) are important regulators of vascular tone and are attractive targets for pharmacological treatment of hypertension. The clinical used calcium blockers are often not selective for one channel but affect several types of calcium channels (Hansen 2015). L...

  18. 3种长效钙拮抗剂对血压季节变异的影响%Effect of three long-acting calcium channel blockers on the seasonal variability of blood pressure

    Institute of Scientific and Technical Information of China (English)

    曹平良; 唐琼珍; 陈早芳; 卢寅辉; 刘建萍; 邱元芝; 葛郁芝

    2011-01-01

    of cardiovascular events independent of mean blood pressure, and it has become an attentional focus. The seasonal blood pressure variability is closely related to cardiovascular events, but there are few studies about the effects of an-tihypertensive medications on its variability at home and abroad. Objective To explore the effect of three types of long-acting calcium channel blockers on seasonal variability of blood pressure. Methods One hundred fifty-nine patients with mild-to-moderate essential hypertension were randomly treated with felodipine extended-release tablet 5 mg/d(FEL group, n=53), nifedipine controlled-release tablet 30 mg/d(NIF group, n = 53) or amlodipine besylate tablet 5 mg/d( AML group, rc=53). All subjects were recruited in the same autumn. Office blood pressures was detected two to four times monthly and the daily mean temperature was recorded contemporarily for 12 months. 24 h ambulatory blood-pressure monitoring was also performed in summer and winter. Results The office mean systolic blood pressure (oSBP), 24 hours mean systolic blood pressure (24hSBP), diurnal mean systolic blood pressure (dSBP) and nocturnal mean systolic blood pressure (nSBP) in the three groups were significantly higher in winter than those in summer, and the variations between summer and winter were more obvious in group FEL[(8. 6i 3.7), (9.8 + 3.3), (10.9 + 3.6), (7.5 + 2.7) mm Hg] and group NIF [(7. 5±2. 8), (9.0 + 2.9), (10.2±3. 3), (7. 1±2. 5) mm Hg] than those in group AML [(4. 6 +1. 3), (5.4 + 1.9), (6. 2±2. 4), (4.9 + 1. 7)mm Hg] (all P<0. 05). In winter, the attainment rates of office and diurnal BP were higher in group AML (60.0%, 72. 2% )than those in group FEL (40.0%, 42.2%) and group NIF (38.3%, 44. 1%) (all P < 0. 05 ) , respectively. The standard deviations and variation coefficients of visit-to-visit office systolic and diastolic blood pressure were significantly lower in group AML than those in group FEL and group NIF (all P<0. 05). The office

  19. Effect of magnesium sulfate combined with calcium channel blockers on cystatin C,uric acid, alpha fetal protein and urinary transferrin levels in patients with hypertension pregnancy%硫酸镁联合钙离子通道拮抗剂对妊娠期高血压患者血清胱抑素C、尿酸、甲胎蛋白及尿转铁蛋白水平的影响

    Institute of Scientific and Technical Information of China (English)

    蔡安利; 宋飞銮; 秦洁; 戴洁; 潘倩若; 吕杰强

    2015-01-01

    目的:探讨硫酸镁联合钙离子通道拮抗剂对妊娠期高血压患者血清胱抑素C( cystatin C)、尿酸、甲胎蛋白( alpha fetal protein,AFP)及尿转铁蛋白( transferrin,TRF)水平的影响及意义。方法选取温州医科大学附属第三医院2013年1月~2014年10月产科收治的75例妊娠期高血压患者,随机分为2组,对照组37例行临床常规治疗;实验组38例,在对照组基础上加用硫酸镁和钙离子通道拮抗剂治疗。检测2组患者血清胱抑素C、尿酸、甲胎蛋白及尿转铁蛋白水平变化,比较2组临床疗效。结果与对照组比较,实验组Cys C、尿酸水平较低(P<0.05),血清AFP水平、尿TRF水平较低(P<0.05),血清血细胞比容、血液粘度及红细胞聚集指数较低(P<0.05),总有效率明显高于对照组(P<0.05)。结论硫酸镁联合钙离子通道拮抗剂对妊娠期高血压疾病患者治疗有较好的临床疗效,能有效改善血液粘度,降低血清Cys C、尿酸、AFP和尿TRF水平。%Objective To explore the effect of magnesium sulfate combined with calcium channel blockers on cystatin C, uric acid, alpha fetal protein and urinary transferrin in patients with hypertension pregnancy.Methods 75 cases with hypertension of pregnancy were selected and divided into two groups, control group(n=37) were treated with conventional therapy, experiment group(n=38) were treated with magnesium sulfate combined with calcium channel blockers on the basis of control group.Cystatin C, uric acid, alpha fetal protein and urinary transferrin were compared after treatment between two groups.Results Compared with control group, Cys C, uric acid, serum AFP l, urinary TRF levels were all lower in experiment group( P<0.05), serum hematocrit, whole blood viscosity and erythrocyte aggregation index were all lower in experiment group(P<0.05).The total efficiency of experiment group was significantly higher than

  20. 维拉帕米联合5-氟脲嘧啶腹腔内化疗对荷肝癌大鼠的抗肿瘤作用%Antineoplastic Effect of Calcium Channel Blocker-Verapamil and 5-Fluorouracil Intraperitoneal Chemotherapy on Hepatocarcinoma-Bearing Rats

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Department of General Surgery, Huadu District People's Hospital, Guangzhou 510800, ChinaObjective To study the antineoplastic effect of the calcium channel blocker verapamil and 5-fluorouracil intraperitoneal chemotherapy on hepatocarcinoma-bearing rats, and examine the action between calcium channel blockers and cytotoxic drugs.Methods We adopted the method of subcapsular implantation of carcinoma tissues of walker-256 in the left liver lobe as a model of liver carcinoma-bearing rats. All experimental animals were divided into four groups. On the sixth day post implantation, in group A (control group) 6 ml of saline was injected intraperitoneally once a day for 3 days. In group B (single chemotherapy group) 6 ml of 5-Fu 75 mg/kg was injected intraperitoneally once a day for 3 days. In group C (combination of treatment group) both 5-Fu (75 mg/kg) and verapamil (25 mg/kg) were administered simultaneously as in A and B. In group D (simple verapamil group) only 6 ml of verapamil (25 mg/kg) was administered as above.Results Compared with groups A, B and D, The volume of cancer and the contents of liver cancer DNA and protein were significantly reduced. The rates of inhibiting cancer (89.9% in group C and 35.4% in group B) were significantly increased in group C. Group C had significantly long survival time compared to groups A, B and D (P<0.05). By light microscopy, a number of focal necroses were found in cancer tissue in group C.Conclusion Calcium channel blockers can enhance the antineoplastic effect of 5-Fu intraperitoneal chemotherapy to liver cancer ; The use of verapamil can not increase the toxicity of 5-Fu.%目的 探讨钙拮抗剂与腹腔内化疗联合应用对荷肝癌大鼠的作用及 钙拮抗剂与细胞毒药物的相互作用。方法 采用肝被膜下植入法建立肝癌动物模型,将荷瘤大鼠分成四 组:A组(对照组),腹腔内注射6ml生理盐水,每天1次,连续3天;B组(单纯化疗组),腹腔内注射5Fu

  1. Role of L-type calcium-channel modulation in nonconvulsive epilepsy in rats

    NARCIS (Netherlands)

    Luijtelaar, E.L.J.M. van; Ates, N.; Coenen, A.M.L.

    1995-01-01

    Old male Wistar rats spontaneously showing hundreds of spike-wave discharges daily were used to investigate the role of calcium ions in nonconvulsive epilepsy. The effects of the L-type calcium channel blocker nimodipine and the L-type channel opener BAY K 8644 on number and duration of these spike-

  2. Store-Operated Calcium Channels.

    Science.gov (United States)

    Prakriya, Murali; Lewis, Richard S

    2015-10-01

    Store-operated calcium channels (SOCs) are a major pathway for calcium signaling in virtually all metozoan cells and serve a wide variety of functions ranging from gene expression, motility, and secretion to tissue and organ development and the immune response. SOCs are activated by the depletion of Ca(2+) from the endoplasmic reticulum (ER), triggered physiologically through stimulation of a diverse set of surface receptors. Over 15 years after the first characterization of SOCs through electrophysiology, the identification of the STIM proteins as ER Ca(2+) sensors and the Orai proteins as store-operated channels has enabled rapid progress in understanding the unique mechanism of store-operate calcium entry (SOCE). Depletion of Ca(2+) from the ER causes STIM to accumulate at ER-plasma membrane (PM) junctions where it traps and activates Orai channels diffusing in the closely apposed PM. Mutagenesis studies combined with recent structural insights about STIM and Orai proteins are now beginning to reveal the molecular underpinnings of these choreographic events. This review describes the major experimental advances underlying our current understanding of how ER Ca(2+) depletion is coupled to the activation of SOCs. Particular emphasis is placed on the molecular mechanisms of STIM and Orai activation, Orai channel properties, modulation of STIM and Orai function, pharmacological inhibitors of SOCE, and the functions of STIM and Orai in physiology and disease.

  3. Calcium channel antagonists in hypertension.

    Science.gov (United States)

    Ambrosioni, E; Borghi, C

    1989-02-01

    The clinical usefulness of calcium entry-blockers for the treatment of high blood pressure is related to their capacity to act upon the primary hemodynamic derangement in hypertension: the increased peripheral vascular resistance. They can be used alone or in combination with other antihypertensive agents for the treatment of various forms of hypertensive disease. The calcium entry-blockers appear to be the most useful agents for the treatment of hypertension in the elderly and for the treatment of hypertension associated with ischemic heart disease, pulmonary obstructive disease, peripheral vascular disease, and supraventricular arrhythmias. They are effective in reducing blood pressure in pregnancy-associated hypertension and must be considered as first-line therapy for the treatment of hypertensive crisis.

  4. Barnidipine: a new calcium channel blocker for hypertension treatment.

    Science.gov (United States)

    Liau, Chiau-Suong

    2005-03-01

    Although it is commonly agreed that all antihypertensive medications have similar efficacy, there are important differences related to safety, tolerability, patient adherence, cost effectiveness and effects on the prevention or retardation of associated disease progression. It is desirable for antihypertensives to have a long duration of action so that once-daily dosing is possible. In addition, antihypertensive medication must be able to be administered concomitantly with other drugs likely to be taken by the patients. This is particularly critical in the elderly population. Barnidipine, a novel, long-acting calcium antagonist, has met these challenges of modern pharmacotherapy. Its once-daily dosing, good tolerability and durable antihypertensive effect contribute to excellent patient adherence and make this drug a valuable addition to the antihypertensive formulary.

  5. Inhibition of N-Type Calcium Channels by Fluorophenoxyanilide Derivatives

    Directory of Open Access Journals (Sweden)

    Ellen C. Gleeson

    2015-04-01

    Full Text Available A set of fluorophenoxyanilides, designed to be simplified analogues of previously reported ω-conotoxin GVIA mimetics, were prepared and tested for N-type calcium channel inhibition in a SH-SY5Y neuroblastoma FLIPR assay. N-type or Cav2.2 channel is a validated target for the treatment of refractory chronic pain. Despite being significantly less complex than the originally designed mimetics, up to a seven-fold improvement in activity was observed.

  6. Magnesium: Effect on ocular health as a calcium channel antagonist

    Directory of Open Access Journals (Sweden)

    Şafak Korkmaz

    2013-06-01

    Full Text Available Magnesium is the physiologic calcium channel blocker,involving in many different metabolic processes by maintainingcell membrane function, modulating smooth musclecontraction and influencing enzymatic activities. Magnesiumhas been shown to increase blood flow to tissuesby modifying endothelial function via endothelin-1 (ET-1and nitric Oxide (NO pathways. Magnesium also exhibitsneuroprotective role by blocking N-methyl-D-aspartate(NMDA receptor related calcium influx and by inhibitingthe release of glutamate, hence protects the cell againstoxidative stress and apoptosis. Both increase in bloodflow and its neuroprotective effect make magnesium agood candidate for glaucoma studies. Magnesium hasbeen shown to decrease oxidative stress and apoptosisin retinal tissue and to have retinal ganglion cell sparingeffect. A series of studies has been conducted aboutmagnesium could decrease insulin resistance in diabeticpatients, ease glycemia control and prevent diabetic retinopathy.Magnesium is found to be critically important inmaintaining normal ionic homeostasis of lens. Magnesiumdeficiency has been shown to cause increased lenticularoxidative stress and ionic imbalance in the lens so triggercataractogenesis. J Clin Exp Invest 2013; 4 (2: 244-251Key words: Magnesium, calcium channel blockage,glaucoma, neuroprotection, diabetic retinopathy, cataract

  7. Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma

    Energy Technology Data Exchange (ETDEWEB)

    Bevilacqua, M.; Vago, T.; Norbiato, G. (Servizio di Endocrinologia, Milano, (Italy))

    1991-02-01

    Propionyl-L-carnitine (PC) protects perfused rat hearts against damage by ischemia-reperfusion. Activation of L-type calcium channel play a role on ischemia-reperfusion damage. Therefore, we studied the effect of PC on some properties of L-type calcium channels in an in vitro preparation from human myocardium sarcolemma (from patients with idiopathic dilated cardiomyopathy). Binding of the L-type calcium channel blockers isradipine ({sup 3}H)-PN 200-110 (PN) to plasma membrane preparations revealed a single population of binding sites (total number: Bmax = 213 +/- 34 fM/mg protein and affinity: Kd = 152 +/- 19 nM; n = 6). The characteristics of these binding sites were evaluated in the presence and in the absence of Ca{sup 2}{sup +} and of calcium blockers (D-888, a verapamillike drug, and diltiazem). Incubation in a Ca{sup 2}{sup +}-containing buffer increased the affinity of PN binding sites. Binding sites for PN were modulated by organic calcium channel blockers; in competition isotherms at 37{degree}C, D-888 (desmethoxyverapamil) decreased the PN binding, whereas diltiazem increased it. These results strongly suggest that the site labelled by PN is the voltage-operated calcium channel of the human myocardium. The addition of PC (1 mM) to plasma membranes labelled with PN at 37{degree}C decreased the affinity of the binding; this effect was counteracted by the addition of Ca{sup 2}{sup +} to the medium. This result was consistent with a competition between Ca{sup 2}{sup +} and PC. The effect of PC incubation at 4{degree}C was the opposite; at this temperature PC increased the affinity of the binding sites and the effect was obscured by Ca{sup 2}{sup +}.

  8. Endothelin induces two types of contractions of rat uterus: phasic contractions by way of voltage-dependent calcium channels and developing contractions through a second type of calcium channels

    Energy Technology Data Exchange (ETDEWEB)

    Kozuka, M.; Ito, T.; Hirose, S.; Takahashi, K.; Hagiwara, H.

    1989-02-28

    Effects of endothelin on nonvascular smooth muscle have been examined using rat uterine horns and two modes of endothelin action have been revealed. Endothelin (0.3 nM) caused rhythmic contractions of isolated uterus in the presence of extracellular calcium. The rhythmic contractions were completely inhibited by calcium channel antagonists. These characteristics of endothelin-induced contractions were very similar to those induced by oxytocin. Binding assays using /sup 125/I-endothelin showed that endothelin and the calcium channel blockers did not compete for the binding sites. However, endothelin was unique in that it caused, in addition to rhythmic contractions, a slowly developing monophasic contraction that was insensitive to calcium channel blockers. This developing contraction became dominant at higher concentrations of endothelin and was also calcium dependent.

  9. Chronic use of the calcium channel blocker nifedipine effected on bone metabolism in elder with coronary heart disease%老年冠心病患者长期应用硝苯地平对骨代谢及功能的影响

    Institute of Scientific and Technical Information of China (English)

    陈斌

    2013-01-01

    目的:硝苯地平(NIF)临床广泛用于调节心率,本文主要研究年冠心病患者长期应用NIF对骨代谢及功能的影响。探讨NIF应用1年后对碱性磷酸酶(ALP)活性、骨钙蛋白(OCN)和钙离子水平的影响,为治疗骨代谢性疾病提供理论性的依据。方法:本研究筛选160名老年冠心病患者,均参加NIF治疗临床跟踪随访1年,观测并评价NIF的疗效及对骨代谢及功能。结果:本研究所有病例用药前与用药后,男性和女性体内的钙离子水平均显著升高(P0.05)。结论:对于长期使用NIF的老年患者,应当及时监测骨骼代谢水平以及骨骼发育状况评价指标,提前预防骨质疏松。%Calcium channel blockers have been reported to have such diverse effects as reduction in protein synthesis, diminished incorporation of proline into new col agen, and decreased hormone release in vitro. The study screened 160 elderly patients with coronary heart disease, are members of nifedipine treatment of clinical fol ow-up 1 year, observation and evaluation of nifedipine and its effect on bone metabolism and function. Results: In this study, al cases before treatment and after treatment, the average male and female body calcium ion water was significantly higher (P 0.05). Conclusion: In patients with long-term use of nifedipine should be timely monitoring of bone metabolism and bone development status evaluation, prevention of osteoporosis in advance. In summary, chronic nifedipine use in males is associated with adverse effect on bone metabolism in elder with coronary heart disease.

  10. The role of L-type calcium channels in the development and expression of behavioral sensitization to ethanol.

    Science.gov (United States)

    Broadbent, Julie

    2013-10-11

    Behavioral sensitization is thought to play a significant role in drug addiction. L-type calcium channels have been implicated in sensitization to stimulant and opiate drugs but it is unclear if these channels also contribute to sensitization to ethanol. The effects of three L-type calcium channel blockers, nifedipine (1-7.5 mg/kg), diltiazem (12.5-50 mg/kg), and verapamil (12.5 and 25 mg/kg), on sensitization to ethanol (2 g/kg) were examined in DBA/2J mice. All three blockers reduced but did not prevent expression of sensitization. Only nifedipine blocked acquisition of sensitization. Nifedipine and verapamil decreased blood ethanol levels. The current findings suggest L-type calcium channels do not play a substantial role in sensitization to ethanol and that the neural mechanisms underlying sensitization to ethanol are distinct from those mediating sensitization to stimulants and opiates.

  11. Functional Importance of L- and P/Q-Type Voltage-Gated Calcium Channels in Human Renal Vasculature

    DEFF Research Database (Denmark)

    Hansen, Pernille B; Poulsen, Christian B; Walter, Steen

    2011-01-01

    in kidney function. It was hypothesized that human renal vascular excitation-contraction coupling involves different subtypes of channels. In human renal artery and dissected intrarenal blood vessels from nephrectomies, PCR analysis showed expression of L-type (Ca(v) 1.2), P/Q-type (Ca(v) 2.1), and T-type......, and L- and P/Q-type channels are of functional importance for the depolarization-induced vasoconstriction. The contribution of P/Q-type channels to contraction in the human vasculature is a novel mechanism for the regulation of renal blood flow and suggests that clinical treatment with calcium blockers......Calcium channel blockers are widely used for treatment of hypertension, because they decrease peripheral vascular resistance through inhibition of voltage-gated calcium channels. Animal studies of renal vasculature have shown expression of several types of calcium channels that are involved...

  12. Voltage-Gated Calcium Channels in Nociception

    Science.gov (United States)

    Yasuda, Takahiro; Adams, David J.

    Voltage-gated calcium channels (VGCCs) are a large and functionally diverse group of membrane ion channels ubiquitously expressed throughout the central and peripheral nervous systems. VGCCs contribute to various physiological processes and transduce electrical activity into other cellular functions. This chapter provides an overview of biophysical properties of VGCCs, including regulation by auxiliary subunits, and their physiological role in neuronal functions. Subsequently, then we focus on N-type calcium (Cav2.2) channels, in particular their diversity and specific antagonists. We also discuss the role of N-type calcium channels in nociception and pain transmission through primary sensory dorsal root ganglion neurons (nociceptors). It has been shown that these channels are expressed predominantly in nerve terminals of the nociceptors and that they control neurotransmitter release. To date, important roles of N-type calcium channels in pain sensation have been elucidated genetically and pharmacologically, indicating that specific N-type calcium channel antagonists or modulators are particularly useful as therapeutic drugs targeting chronic and neuropathic pain.

  13. Tryptophan hydroxylase is modulated by L-type calcium channels in the rat pineal gland.

    Science.gov (United States)

    Barbosa, Roseli; Scialfa, Julieta Helena; Terra, Ilza Mingarini; Cipolla-Neto, José; Simonneaux, Valérie; Afeche, Solange Castro

    2008-02-27

    Calcium is an important second messenger in the rat pineal gland, as well as cAMP. They both contribute to melatonin synthesis mediated by the three main enzymes of the melatonin synthesis pathway: tryptophan hydroxylase, arylalkylamine N-acetyltransferase and hydroxyindole-O-methyltransferase. The cytosolic calcium is elevated in pinealocytes following alpha(1)-adrenergic stimulation, through IP(3)-and membrane calcium channels activation. Nifedipine, an L-type calcium channel blocker, reduces melatonin synthesis in rat pineal glands in vitro. With the purpose of investigating the mechanisms involved in melatonin synthesis regulation by the L-type calcium channel, we studied the effects of nifedipine on noradrenergic stimulated cultured rat pineal glands. Tryptophan hydroxylase, arylalkylamine N-acetyltransferase and hydroxyindole-O-methyltransferase activities were quantified by radiometric assays and 5-hydroxytryptophan, serotonin, N-acetylserotonin and melatonin contents were quantified by HPLC with electrochemical detection. The data showed that calcium influx blockaded by nifedipine caused a decrease in tryptophan hydroxylase activity, but did not change either arylalkylamine N-acetyltransferase or hydroxyindole-O-methyltransferase activities. Moreover, there was a reduction of 5-hydroxytryptophan, serotonin, N-acetylserotonin and melatonin intracellular content, as well as a reduction of serotonin and melatonin secretion. Thus, it seems that the calcium influx through L-type high voltage-activated calcium channels is essential for the full activation of tryptophan hydroxylase leading to melatonin synthesis in the pineal gland.

  14. Iron overload and apoptosis of HL-1 cardiomyocytes: effects of calcium channel blockade.

    Directory of Open Access Journals (Sweden)

    Mei-pian Chen

    Full Text Available Iron overload cardiomyopathy that prevails in some forms of hemosiderosis is caused by excessive deposition of iron into the heart tissue and ensuing damage caused by a raise in labile cell iron. The underlying mechanisms of iron uptake into cardiomyocytes in iron overload condition are still under investigation. Both L-type calcium channels (LTCC and T-type calcium channels (TTCC have been proposed to be the main portals of non-transferrinic iron into heart cells, but controversies remain. Here, we investigated the roles of LTCC and TTCC as mediators of cardiac iron overload and cellular damage by using specific Calcium channel blockers as potential suppressors of labile Fe(II and Fe(III ingress in cultured cardiomyocytes and ensuing apoptosis.Fe(II and Fe(III uptake was assessed by exposing HL-1 cardiomyocytes to iron sources and quantitative real-time fluorescence imaging of cytosolic labile iron with the fluorescent iron sensor calcein while iron-induced apoptosis was quantitatively measured by flow cytometry analysis with Annexin V. The role of calcium channels as routes of iron uptake was assessed by cell pretreatment with specific blockers of LTCC and TTCC.Iron entered HL-1 cardiomyocytes in a time- and dose-dependent manner and induced cardiac apoptosis via mitochondria-mediated caspase-3 dependent pathways. Blockade of LTCC but not of TTCC demonstrably inhibited the uptake of ferric but not of ferrous iron. However, neither channel blocker conferred cardiomyocytes with protection from iron-induced apoptosis.Our study implicates LTCC as major mediators of Fe(III uptake into cardiomyocytes exposed to ferric salts but not necessarily as contributors to ensuing apoptosis. Thus, to the extent that apoptosis can be considered a biological indicator of damage, the etiopathology of cardiosiderotic damage that accompanies some forms of hemosiderosis would seem to be unrelated to LTCC or TTCC, but rather to other routes of iron ingress present in

  15. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Amigo, M

    1988-04-13

    The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.

  16. P-type calcium channels are blocked by the alkaloid daurisoline.

    Science.gov (United States)

    Lu, Y M; Fröstl, W; Dreessen, J; Knöpfel, T

    1994-07-21

    IN looking for a structurally defined non-peptide P-channel blocker we have tested the alkaloid daurisoline which has been isolated from traditional Chinese medicinal herb (Menispermum dauricum) used for the treatment of epilepsy, hypertension and asthma. We have found that daurisoline is an inhibitor of omega-Aga-IVA sensitive barium currents in cerebellar Purkinje cells and of excitatory postsynaptic potentials evoked in Purkinje cells by stimulating parallel fibres in acutely prepared cerebellar slices. Daurisoline did not significantly affect omega-Aga-IVA-insensitive barium currents recorded from granule cells freshly isolated from rat cerebellum. Daurisoline passes the blood-brain barrier and will, therefore, facilitate the functional characterization of brain calcium channels as well as the exploration of P-type calcium channels as possible drug targets.

  17. Disease causing mutations of calcium channels.

    Science.gov (United States)

    Lorenzon, Nancy M; Beam, Kurt G

    2008-01-01

    Calcium ions play an important role in the electrical excitability of nerve and muscle, as well as serving as a critical second messenger for diverse cellular functions. As a result, mutations of genes encoding calcium channels may have subtle affects on channel function yet strongly perturb cellular behavior. This review discusses the effects of calcium channel mutations on channel function, the pathological consequences for cellular physiology, and possible links between altered channel function and disease. Many cellular functions are directly or indirectly regulated by the free cytosolic calcium concentration. Thus, calcium levels must be very tightly regulated in time and space. Intracellular calcium ions are essential second messengers and play a role in many functions including, action potential generation, neurotransmitter and hormone release, muscle contraction, neurite outgrowth, synaptogenesis, calcium-dependent gene expression, synaptic plasticity and cell death. Calcium ions that control cell activity can be supplied to the cell cytosol from two major sources: the extracellular space or intracellular stores. Voltage-gated and ligand-gated channels are the primary way in which Ca(2+) ions enter from the extracellular space. The sarcoplasm reticulum (SR) in muscle and the endoplasmic reticulum in non-muscle cells are the main intracellular Ca(2+) stores: the ryanodine receptor (RyR) and inositol-triphosphate receptor channels are the major contributors of calcium release from internal stores.

  18. 钙通道阻滞剂改善内质网应激抑制压力过负荷高血压大鼠的心肌重构%Protective effect of calcium channel blocker on hypertensive rat myocardial remodeling of pressure overload induced by endoplasmic reticulum stress

    Institute of Scientific and Technical Information of China (English)

    槐勇; 赵连友; 李炜; 郑强荪; 刘静; 郭丽; 丁璐

    2012-01-01

    目的:研究在压力过负荷应激状态下钙通道阻滞剂拉西地平对内质网应激(endoplasmic reticulum stress,ERS)分子钙网蛋白(calreticulin,CRT)和细胞凋亡效应分子-12(caspase-12)在大鼠心肌组织中的表达及对心肌重构的影响.方法:将30只雄性Sprague-Dawly(SD)大鼠随机分为3组,即假手术组(Sham组)、腹主动脉缩窄组(TAC组)及TAC+拉西地平干预组(简称拉西地平组),每组10只.通过颈动脉插管测定各组大鼠的血流动力学,心脏超声心动图检查左心室的形态结构.采用免疫组化染色法检测大鼠心肌中CRT及caspase-12蛋白的表达水平,TUNEL荧光染色法检测心肌细胞的凋亡率.结果:与Sham组相比较,TAC组大鼠的平均动脉压(MAP)、室间隔厚度(IVST)、左室后壁厚度(LVPWT)、左室质量指数(LVWI)、CRT和caspase-12蛋白表达水平及心肌细胞的凋亡率比较,均有显著升高(P<0.01).拉西地平组大鼠MAP、IVST、LVPWT、LVWI、CRT和caspase-12蛋白的表达水平及心肌细胞的凋亡率较TAC组明显下降(P<0.05).结论:内质网应激可能参与了压力过负荷高血压大鼠心肌重构的过程.钙通道阻滞剂拉西地平可能通过降低CRT及caspase-12的表达及减少心肌细胞的凋亡干预ERS介导的压力负荷所致高血压大鼠心肌肥厚的信号通路,从而通过改善内质网应激发挥对心脏的保护作用.%AIM: To investigate the influence of calcium channel blocker lacidipine on the expression of calreticulin (CRT) and caspase-12 in rat cardiac myocytes and the effects of lacidipine against myocardium remodeling under pressure overload conditions. METHODS: Thirty male Sprague Dawley rats were randomly divided into TAC group (transverse aortic constriction) , control group ( sham group) and TAC + lacidipine group with ten rats in each group. Invasive hemodynamics were measured through carotid cannulation and left ventricular morphology was monitored by echocardiography

  19. Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels.

    Science.gov (United States)

    Arispe, Nelson; Diaz, Juan Carlos; Simakova, Olga; Pollard, Harvey B

    2008-02-19

    Digitoxin and other cardiac glycosides are important, centuries-old drugs for treating congestive heart failure. However, the mechanism of action of these compounds is still being elucidated. Calcium is known to potentiate the toxicity of these drugs, and we have hypothesized that digitoxin might mediate calcium entry into cells. We report here that digitoxin molecules mediate calcium entry into intact cells. Multimers of digitoxin molecules also are able to form calcium channels in pure planar phospholipid bilayers. These digitoxin channels are blocked by Al(3+) and La(3+) but not by Mg(2+) or the classical l-type calcium channel blocker, nitrendipine. In bilayers, we find that the chemistry of the lipid affects the kinetics of the digitoxin channel activity, but not the cation selectivity. Antibodies against digitoxin promptly neutralize digitoxin channels in both cells and bilayers. We propose that these digitoxin calcium channels may be part of the mechanism by which digitoxin and other active cardiac glycosides, such as digoxin, exert system-wide actions at and above the therapeutic concentration range.

  20. Synthesis, QSAR and calcium channel modulator activity of new hexahydroquinoline derivatives containing nitroimidazole.

    Science.gov (United States)

    Miri, Ramin; Javidnia, Katayoun; Mirkhani, Hossein; Hemmateenejad, Bahram; Sepeher, Zahra; Zalpour, Masomeh; Behzad, Taherh; Khoshneviszadeh, Mehdi; Edraki, Najmeh; Mehdipour, Ahmad R

    2007-10-01

    The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.

  1. Voltage-gated Calcium Channels and Autism Spectrum Disorders.

    Science.gov (United States)

    Breitenkamp, Alexandra F; Matthes, Jan; Herzig, Stefan

    2015-01-01

    Autism spectrum disorder is a complex-genetic disease and its etiology is unknown for the majority of cases. So far, more than one hundred different susceptibility genes were detected. Voltage-gated calcium channels are among the candidates linked to autism spectrum disorder by results of genetic studies. Mutations of nearly all pore-forming and some auxiliary subunits of voltage gated calcium channels have been revealed from investigations of autism spectrum disorder patients and populations. Though there are only few electrophysiological characterizations of voltage-gated calcium channel mutations found in autistic patients these studies suggest their functional relevance. In summary, both genetic and functional data suggest a potential role of voltage-gated calcium channels in autism spectrum disorder. Future studies require refinement of the clinical and systems biological concepts of autism spectrum disorder and an appropriate holistic approach at the molecular level, e.g. regarding all facets of calcium channel functions.

  2. Calcium channels, neuromuscular synaptic transmission and neurological diseases.

    Science.gov (United States)

    Urbano, Francisco J; Pagani, Mario R; Uchitel, Osvaldo D

    2008-09-15

    Voltage-dependent calcium channels are essential in neuronal signaling and synaptic transmission, and their functional alterations underlie numerous human disorders whether monogenic (e.g., ataxia, migraine, etc.) or autoimmune. We review recent work on Ca(V)2.1 or P/Q channelopathies, mostly using neuromuscular junction preparations, and focus specially on the functional hierarchy among the calcium channels recruited to mediate neurotransmitter release when Ca(V)2.1 channels are mutated or depleted. In either case, synaptic transmission is greatly compromised; evidently, none of the reported functional replacements with other calcium channels compensates fully.

  3. Calcium channel as a potential anticancer agent.

    Science.gov (United States)

    Kriazhev, L

    2009-11-01

    Anticancer treatment in modern clinical practices includes chemotherapy and radiation therapy with or without surgical interventions. Efficiency of both methods varies greatly depending on cancer types and stages. Besides, chemo- and radiotherapy are toxic and damaging that causes serious side effects. This fact prompts the search for alternative methods of antitumor therapy. It is well known that prolonged or high increase of intracellular calcium concentration inevitably leads to the cell death via apoptosis or necrosis. However, stimulation of cell calcium level by chemical agents is hardly achievable because cells have very sophisticated machinery for maintaining intracellular calcium in physiological ranges. This obstacle can be overridden, nevertheless. It was found that calcium channels in so called calcium cells in land snails are directly regulated by extracellular calcium concentration. The higher the concentration the higher the calcium intake is through the channels. Bearing in mind that extracellular/intracellular calcium concentration ratio in human beings is 10,000-12,000 fold the insertion of the channel into cancer cells would lead to fast and uncontrollable by the cells calcium intake and cell death. Proteins composing the channel may be extracted from plasma membrane of calcium cells and sequenced by mass-spectrometry or N-terminal sequencing. Either proteins or corresponding genes could be used for targeted delivery into cancer cells.

  4. Role of low voltage activated calcium channels in neuritogenesis and active migration of embryonic neural progenitor cells.

    Science.gov (United States)

    Louhivuori, Lauri M; Louhivuori, Verna; Wigren, Henna-Kaisa; Hakala, Elina; Jansson, Linda C; Nordström, Tommy; Castrén, Maija L; Akerman, Karl E

    2013-04-15

    The central role of calcium influx and electrical activity in embryonic development raises important questions about the role and regulation of voltage-dependent calcium influx. Using cultured neural progenitor cell (NPC) preparations, we recorded barium currents through voltage-activated channels using the whole-cell configuration of the patch-clamp technique and monitored intracellular free calcium concentrations with Fura-2 digital imaging. We found that NPCs as well as expressing high-voltage-activated (HVA) calcium channels express functional low-threshold voltage-dependent calcium channels in the very early stages of differentiation (5 h to 1 day). The size of the currents recorded at -50 versus -20 mV after 1 day in differentiation was dependent on the nature of the charge carrier. Peak currents measured at -20 mV in the presence 10 mM Ca2+ instead of 10 mM Ba2+ had a tendency to be smaller, whereas the nature of the divalent species did not influence the amplitude measured at -50 mV. The T-type channel blockers mibefradil and NNC 55-0396 significantly reduced the calcium responses elicited by depolarizing with extracellular potassium, while the overall effect of the HVA calcium channel blockers was small at differentiation day 1. At differentiation day 20, the calcium responses were effectively blocked by nifedipine. Time-lapse imaging of differentiating neurospheres cultured in the presence of low-voltage-activated (LVA) blockers showed a significant decrease in the number of active migrating neuron-like cells and neurite extensions. Together, these data provide evidence that LVA calcium channels are involved in the physiology of differentiating and migrating NPCs.

  5. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  6. Mechanism underlying blockade of voltage-gated calcium channels by agmatine in cultured rat hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Jian-quan ZHENG; Xie-chuan WENG; Xiao-dan GAI; Jin LI; Wen-bin XIAO

    2004-01-01

    AIM: To investigate whether agmatine could selectively block a given type of the voltage-gated calcium channels (VGCC) and whether related receptors are involved in the blocking effect of agmatine on VGCC. METHODS: The whole-cell patch recording technique was performed to record VGCC currents in the cultured neonatal rat hippocampal neurons. RESULTS: Verapamil (100 μmol/L), a selective blocker of L-type calcium channel, significantly inhibited VGCC current by 80 %± 7 %. Agmatine (100 μmol/L) could further depress the remained currents by 25 %±6 %. The α2-adrenoceptor antagonist yohimbine (10 μmol/L) and the I2 imidazoline receptor antagonist idazoxon (10 and 40 μmol/L) had no significant effect on VGCC currents when used respectively. When the mixture of yohimbine and agmatine was applied, VGCC currents were still depressed remarkably. However, the blocking effect of agmatine was decreased by 29 %± 8 % in the presence of idazoxon (10 μmol/L). The effect of idazoxon did not increase at a higher concentration (40 μmol/L). CONCLUSION: Agmatine could block the L- and other types of VGCC currents in the cultured rat hippocampal neurons. Blocking effect of agmatine on VGCC was partially related to I2 imidazoline receptor and had no relationship with α2-adrenoceptors.

  7. Voltage-dependent calcium channels from brain incorporated into planar lipid bilayers

    Science.gov (United States)

    Nelson, Mark T.; French, Robert J.; Krueger, Bruce K.

    1984-03-01

    Many important physiological processes, including neurotransmitter release and muscle contraction1-3, are regulated by the concentration of Ca2+ ions in the cell. Levels of cytoplasmic Ca2+ can be elevated by the entry of Ca2+ ions through voltage-dependent channels which are selective for Ca2+, Ba2+ and Sr2+ ions4-14. We have measured currents through single, voltage-dependent calcium channels from rat brain that have been incorporated into planar lipid bilayers. Channel gating was voltage-dependent: membrane depolarization increased the channel open times and decreased the closed times. The channels were selective for divalent cations over monovalent ions. The well-known calcium channel blockers, lanthanum and cadmium, produced a concentration-dependent reduction of the apparent single-channel conductance. Contrary to expectations14, the nature of the divalent cation carrying current through the channel affected not only the single-channel conductance, but also the channel open times, with mean open times being shortest for barium.

  8. Clinical Pharmacology of Alpha-1 Blockers Improving Drug-profile through Novel Formulations.

    Science.gov (United States)

    Nerurkar, Rajan P; Ved, Jignesh K

    2014-09-01

    Clinical pharmacology is an essential consideration in chronic therapies, and may play a significant role in modifying the pharmacological characteristics of drug formulations. Improvement in drug formulations may ensure their safe and effective use over a period of time. This has been particularly observed with α-1 adrenergic blockers in hypertension management. Advancements in formulations like prazosin GITS, have resulted in improvement in tolerability profile and smoother, more effective blood pressure control, which reasonably translate into improvement in patient compliance and better clinical outcomes.

  9. Hydrogen sulfide-induced itch requires activation of Cav3.2 T-type calcium channel in mice

    Science.gov (United States)

    Wang, Xue-Long; Tian, Bin; Huang, Ya; Peng, Xiao-Yan; Chen, Li-Hua; Li, Jun-Cheng; Liu, Tong

    2015-01-01

    The contributions of gasotransmitters to itch sensation are largely unknown. In this study, we aimed to investigate the roles of hydrogen sulfide (H2S), a ubiquitous gasotransmitter, in itch signaling. We found that intradermal injection of H2S donors NaHS or Na2S, but not GYY4137 (a slow-releasing H2S donor), dose-dependently induced scratching behavior in a μ-opioid receptor-dependent and histamine-independent manner in mice. Interestingly, NaHS induced itch via unique mechanisms that involved capsaicin-insensitive A-fibers, but not TRPV1-expressing C-fibers that are traditionally considered for mediating itch, revealed by depletion of TRPV1-expressing C-fibers by systemic resiniferatoxin treatment. Moreover, local application of capsaizapine (TRPV1 blocker) or HC-030031 (TRPA1 blocker) had no effects on NaHS-evoked scratching. Strikingly, pharmacological blockade and silencing of Cav3.2 T-type calcium channel by mibefradil, ascorbic acid, zinc chloride or Cav3.2 siRNA dramatically decreased NaHS-evoked scratching. NaHS induced robust alloknesis (touch-evoked itch), which was inhibited by T-type calcium channels blocker mibefradil. Compound 48/80-induced itch was enhanced by an endogenous precursor of H2S (L-cysteine) but attenuated by inhibitors of H2S-producing enzymes cystathionine γ-lyase and cystathionine β-synthase. These results indicated that H2S, as a novel nonhistaminergic itch mediator, may activates Cav3.2 T-type calcium channel, probably located at A-fibers, to induce scratching and alloknesis in mice. PMID:26602811

  10. David J. Triggle: Medicinal chemistry, to pharmacology, calcium channels, and beyond.

    Science.gov (United States)

    Walker, Michael J A

    2015-11-15

    David Triggle's scientific career began as a chemist, went through medicinal chemistry into pharmacology, and finally on to somewhat more philosophical interests in later years. It was a career marked by many contributions to all of those aspects of science. Chief amongst his many contributions, in addition to those in medicinal chemistry, was his work on the drugs known as calcium ion channel blockers or (calcium antagonists). In the calcium ion channel field he was a particularly instrumental figure in sorting out the mechanisms, actions and roles of the class of calcium channel blockers, known chemical and pharmacologically as the dihydropyridines (DHPs) in particular, as well as other calcium blockers of diverse structures. During the course of a long career, and extensive journeys into medicinal chemistry and pharmacology, he published voluminously in terms of papers, reviews, conference proceedings and books. Notably, many of his papers often had limited authorship where, as senior author it reflected his deep involvement in all aspects of the reported work. His work always helped clarify the field while his incisive reviews, together with his role in coordinating and running scientific meetings, were a great help in clarifying and organizing various fields of study. He has had a long and illustrious career, and is wellknown in the world of biomedical science; his contributions are appreciated, and well recognized everywhere. The following article attempts to chart a path through his work and contributions to medicinal chemistry, pharmacology, science, academia and students.

  11. P/Q-type and T-type voltage-gated calcium channels are involved in the contraction of mammary and brain blood vessels from hypertensive patients

    DEFF Research Database (Denmark)

    Thuesen, A D; Lyngsø, K S; Rasmussen, L

    2017-01-01

    AIM: Calcium channel blockers are widely used in cardiovascular diseases. Besides L-type channels, T- and P/Q-type calcium channels are involved in the contraction of human renal blood vessels. It was hypothesized that T- and P/Q-type channels are involved in the contraction of human brain...... and mammary blood vessels. METHODS: Internal mammary arteries from bypass surgery patients and cerebral arterioles from patients with brain tumours with and without hypertension were tested in a myograph and perfusion set-up. PCR and immunohistochemistry were performed on isolated blood vessels. RESULTS......: The P/Q-type antagonist ω-agatoxin IVA (10(-8) mol L(-1) ) and the T-type calcium blocker mibefradil (10(-7) mol L(-1) ) inhibited KCl depolarization-induced contraction in mammary arteries from hypertensive patients with no effect on blood vessels from normotensive patients. ω-Agatoxin IVA decreased...

  12. Influence of bupropion and calcium channel antagonists on the nicotine-induced memory-related response of mice in the elevated plus maze.

    Science.gov (United States)

    Biała, Grazyna; Kruk, Marta

    2009-01-01

    In this study, we investigated the effects of acute administration of nicotine on memory-related behavior in mice using the elevated plus maze test. In this test, the time necessary for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. Our results revealed that nicotine (0.035 and 0.175 mg/kg, base, sc) shortened the transfer latency relative to the saline-treated group. Moreover, we investigated the effects of bupropion (10, 20 and 40 mg/kg, ip) and L-type voltage-dependent calcium channel antagonists (nimodipine, flunarizine, verapamil, diltiazem - 5, 10 and 20 mg/kg, ip) on memory-related behavior. At all tested doses, bupropion, did not significantly affect transfer latency. However, flunarizine and verapamil (both at 10 mg/kg) resulted in a slight decrease in transfer latency, whereas nimodipine (10 mg/kg) increased transfer latency. Interestingly, both bupropion (20 mg/kg) and calcium channel blockers (5 mg/kg) attenuated the improvement of memory induced by nicotine. Our findings indicate that the cholinergic nicotinic system may play an important role in memory consolidation, and that neural calcium-dependent mechanisms can be involved in the modulation of memory-related responses induced by nicotine. The results of these studies have revealed neuronal mechanisms that are important for nicotinic modulation of cognition and will be useful for the treatments of human disorders in which cholinergic pathways have been implicated, such as psychiatric disorders and addiction.

  13. CNTF-ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through upregulating L-type calcium channel activity.

    Science.gov (United States)

    Sun, Meiqun; Liu, Hongli; Xu, Huanbai; Wang, Hongtao; Wang, Xiaojing

    2016-09-01

    A specialized culture medium termed ciliary neurotrophic factor-treated astrocyte-conditioned medium (CNTF-ACM) allows investigators to assess the peripheral effects of CNTF-induced activated astrocytes upon cultured neurons. CNTF-ACM has been shown to upregulate neuronal L-type calcium channel current activity, which has been previously linked to changes in mitochondrial respiration and oxidative stress. Therefore, the aim of this study was to evaluate CNTF-ACM's effects upon mitochondrial respiration and oxidative stress in rat cortical neurons. Cortical neurons, CNTF-ACM, and untreated control astrocyte-conditioned medium (UC-ACM) were prepared from neonatal Sprague-Dawley rat cortical tissue. Neurons were cultured in either CNTF-ACM or UC-ACM for a 48-h period. Changes in the following parameters before and after treatment with the L-type calcium channel blocker isradipine were assessed: (i) intracellular calcium levels, (ii) mitochondrial membrane potential (ΔΨm), (iii) oxygen consumption rate (OCR) and adenosine triphosphate (ATP) formation, (iv) intracellular nitric oxide (NO) levels, (v) mitochondrial reactive oxygen species (ROS) production, and (vi) susceptibility to the mitochondrial complex I toxin rotenone. CNTF-ACM neurons displayed the following significant changes relative to UC-ACM neurons: (i) increased intracellular calcium levels (p ACM (p ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through elevating L-type calcium channel activity.

  14. BETA-BLOCKERS IN THE TREATMENT OF ARTERIAL HYPERTENSION: EVIDENCE BASED DATA AND REAL PRACTICE

    Directory of Open Access Journals (Sweden)

    M. V. Leonova

    2012-01-01

    Full Text Available Data of the largest meta-analyzes of beta-blockers use in arterial hypertension is presented. The role of beta-blockers among other basic groups of antihypertensive drugs (thiazide diuretics, calcium channel blockers, ACE inhibitors is evaluated. Special considerations of beta-blockers use in hypertensive patients with diabetes mellitus and chronic heart failure are discussed. Special attention is paid to bisoprolol.

  15. BETA-BLOCKERS IN THE TREATMENT OF ARTERIAL HYPERTENSION: EVIDENCE BASED DATA AND REAL PRACTICE

    Directory of Open Access Journals (Sweden)

    M. V. Leonova

    2015-12-01

    Full Text Available Data of the largest meta-analyzes of beta-blockers use in arterial hypertension is presented. The role of beta-blockers among other basic groups of antihypertensive drugs (thiazide diuretics, calcium channel blockers, ACE inhibitors is evaluated. Special considerations of beta-blockers use in hypertensive patients with diabetes mellitus and chronic heart failure are discussed. Special attention is paid to bisoprolol.

  16. Analytical models of calcium binding in a calcium channel

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jinn-Liang [Department of Applied Mathematics, National Hsinchu University of Education, Hsinchu 300, Taiwan (China); Eisenberg, Bob [Department of Molecular Biophysics and Physiology, Rush University, Chicago, Illinois 60612 (United States)

    2014-08-21

    The anomalous mole fraction effect of L-type calcium channels is analyzed using a Fermi like distribution with the experimental data of Almers and McCleskey [J. Physiol. 353, 585 (1984)] and the atomic resolution model of Lipkind and Fozzard [Biochemistry 40, 6786 (2001)] of the selectivity filter of the channel. Much of the analysis is algebraic, independent of differential equations. The Fermi distribution is derived from the configuration entropy of ions and water molecules with different sizes, different valences, and interstitial voids between particles. It allows us to calculate potentials and distances (between the binding ion and the oxygen ions of the glutamate side chains) directly from the experimental data using algebraic formulas. The spatial resolution of these results is comparable with those of molecular models, but of course the accuracy is no better than that implied by the experimental data. The glutamate side chains in our model are flexible enough to accommodate different types of binding ions in different bath conditions. The binding curves of Na{sup +} and Ca{sup 2+} for [CaCl{sub 2}] ranging from 10{sup −8} to 10{sup −2} M with a fixed 32 mM background [NaCl] are shown to agree with published Monte Carlo simulations. The Poisson-Fermi differential equation—that includes both steric and correlation effects—is then used to obtain the spatial profiles of energy, concentration, and dielectric coefficient from the solvent region to the filter. The energy profiles of ions are shown to depend sensitively on the steric energy that is not taken into account in the classical rate theory. We improve the rate theory by introducing a steric energy that lumps the effects of excluded volumes of all ions and water molecules and empty spaces between particles created by Lennard-Jones type and electrostatic forces. We show that the energy landscape varies significantly with bath concentrations. The energy landscape is not constant.

  17. Potential L-Type Voltage-Operated Calcium Channel Blocking Effect of Drotaverine on Functional Models.

    Science.gov (United States)

    Patai, Zoltán; Guttman, András; Mikus, Endre G

    2016-12-01

    Drotaverine is considered an inhibitor of cyclic-3',5'-nucleotide-phophodiesterase (PDE) enzymes; however, published receptor binding data also support the potential L-type voltage- operated calcium channel (L-VOCC) blocking effect of drotaverine. Hence, in this work, we focus on the potential L-VOCC blocking effect of drotaverine by using L-VOCC-associated functional in vitro models. Accordingly, drotaverine and reference agents were tested on KCl-induced guinea pig tracheal contraction. Drotaverine, like the L-VOCC blockers nifedipine or diltiazem, inhibited the KCl-induced inward Ca(2+)- induced contraction in a concentration- dependent fashion. The PDE inhibitor theophylline had no effect on the KCl-evoked contractions, indicating its lack of inhibition on inward Ca(2+) flow. Drotaverine was also tested on the L-VOCC-mediated resting Ca(2+) refill model. In this model, the extracellular Ca(2+) enters the cells to replenish the emptied intracellular Ca(2+) stores. Drotaverine and L-VOCC blocker reference molecules inhibited Ca(2+) replenishment of Ca(2+)-depleted preparations detected by agonist-induced contractions in post-Ca(2+) replenishment Ca(2+)-free medium. Theophylline did not modify the Ca(2+) store replenishment after contraction. It seems that drotaverine, but not theophylline, inhibits inward Ca(2+) flux. The addition of CaCl2 to Ca(2+)-free medium containing the agonist induced inward Ca(2+) flow and subsequent contraction of Ca(2+)-depleted tracheal preparations. Drotaverine, similar to the L-VOCC blockers, inhibited inward Ca(2+) flow and blunted the slope of CaCl2-induced contraction in agonist containing Ca(2+)-free medium with Ca(2+)-depleted tracheal preparations. These results show that drotaverine behaves like L-VOCC blockers but, unlike PDE inhibitors using L-VOCC associated in vitro experimental models.

  18. Calcium Channel Blockade and Peroxisome Proliferator Activated Receptor γ Agonism Diminish Cognitive Loss and Preserve Endothelial Function During Diabetes Mellitus.

    Science.gov (United States)

    Jain, Swati; Sharma, B M; Sharma, Bhupesh

    2016-01-01

    Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia (VaD) by experimental diabetes. This study investigates the efficacy of a nifedipine, a calcium channel blocker and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent VaD in rats. Attentional set shifting (ASST) and Morris water-maze (MWM) test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of nifedipine and pioglitazone significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that nifedipine, a calcium channel blocker may be considered as a potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent VaD.

  19. Effects of in vitro and in vivo lead exposure on voltage-dependent calcium channels in central neurons of Lymnaea stagnalis.

    Science.gov (United States)

    Audesirk, G

    1987-01-01

    Currents through calcium channels of members of an identified cluster of neurons (B cells) in the pond snail Lymnaea stagnalis were studied under voltage clamp. The normal physiological saline was modified to maximize the visibility of voltage-dependent calcium currents and minimize contamination by other currents. Barium was used as the charge carrier for the calcium channels. Depolarizing voltage steps induce an inward current, the magnitude of which varies with the barium concentration. In brains taken from animals not exposed in vivo to lead, in vitro addition of lead acetate to the recording medium (0.25 to 14 microM) inhibits the barium current by 59 +/- 14% (mean +/- s.d.), in a manner that is independent of the lead concentration. The magnitude of the residual current still varies with the barium concentration. The voltage dependence of the current appears to be unaffected by lead. In contrast to some other calcium-channel blockers, such as cobalt, the inhibition of barium currents by in vitro lead exposure is irreversible, at least in short-term experiments. Contrary to expectations based on these in vitro results, barium currents in B cells of animals exposed to 5 microM lead for 6 to 12 weeks in vivo were approximately twice as large as barium currents in B cells from unexposed controls, when both were recorded in lead-free saline. It is possible that chronic in vivo lead exposure causes an increase in the number of calcium channels in these neurons.

  20. Heterogeneity of Calcium Channel/cAMP-Dependent Transcriptional Activation.

    Science.gov (United States)

    Kobrinsky, Evgeny

    2015-01-01

    The major function of the voltage-gated calcium channels is to provide the Ca(2+) flux into the cell. L-type voltage-gated calcium channels (Cav1) serve as voltage sensors that couple membrane depolarization to many intracellular processes. Electrical activity in excitable cells affects gene expression through signaling pathways involved in the excitation-transcription (E-T) coupling. E-T coupling starts with activation of the Cav1 channel and results in initiation of the cAMP-response element binding protein (CREB)-dependent transcription. In this review we discuss the new quantitative approaches to measuring E-T signaling events. We describe the use of wavelet transform to detect heterogeneity of transcriptional activation in nuclei. Furthermore, we discuss the properties of discovered microdomains of nuclear signaling associated with the E-T coupling and the basis of the frequency-dependent transcriptional regulation.

  1. Regulation of voltage gated calcium channels by GPCRs and post-translational modification.

    Science.gov (United States)

    Huang, Junting; Zamponi, Gerald W

    2016-10-18

    Calcium entry via voltage gated calcium channels mediates a wide range of physiological functions, whereas calcium channel dysregulation has been associated with numerous pathophysiological conditions. There are myriad cell signaling pathways that act on voltage gated calcium channels to fine tune their activities and to regulate their cell surface expression. These regulatory mechanisms include the activation of G protein-coupled receptors and downstream phosphorylation events, and their control over calcium channel trafficking through direct physical interactions. Calcium channels also undergo post-translational modifications that alter both function and density of the channels in the plasma membrane. Here we focus on select aspects of these regulatory mechanisms and highlight recent developments.

  2. Effects of acute and chronic nicotine on elevated plus maze in mice: involvement of calcium channels.

    Science.gov (United States)

    Biala, Grazyna; Budzynska, Barbara

    2006-05-30

    The current experiments examined the anxiety-related effects of acute and repeated nicotine administration using the elevated plus maze test in mice. Nicotine (0.1 mg/kg s.c., 5 and 30 min after injection; 0.5 mg/kg, s.c., 5 min after injection) had an anxiogenic effect, shown by specific decreases in the percentage of time spent on the open arms and in the percentage of open arm entries. Tolerance developed to this anxiogenic action after 6 days of daily nicotine administration (0.1 mg/kg, s.c.). Five minutes after the seventh injection, an anxiolytic effect was observed, i.e., specific increases in the percentage of time spent on the open arms and in the percentage of open arm entries. L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5, 10, 20 mg/kg) and diltiazem (5, 10, 20 mg/kg, i.p.) were also injected prior to an acute low dose of nicotine or to each injection of chronic nicotine. Our results revealed that calcium channel blockers dose-dependently attenuated both an anxiogenic effect of nicotine as well as the development of tolerance to this effect. Our results suggest that neural calcium-dependent mechanisms are involved in the anxiety-related responses to acute and chronic nicotine injection that may ultimately lead to addiction and smoking relapse in human smokers.

  3. Diltiazem and verapamil preferentially block inactivated cardiac calcium channels.

    Science.gov (United States)

    Kanaya, S; Arlock, P; Katzung, B G; Hondeghem, L M

    1983-02-01

    Diltiazem has been proposed to act by blocking calcium channels of cardiac and smooth muscle since it has pharmacological [12-14] and clinical [10] effects that resemble those of verapamil, an agent that has been shown to block these channels [3]. However, block of the slow inward current by diltiazem has not been directly demonstrated. In fact, it has been suggested that diltiazem has an entirely different mechanism of action [7]. We therefore studied the blocking effects of diltiazem and verapamil on cardiac calcium channels by measuring the slow inward current in voltage-clamped ferret myocardium. Both drugs blocked the slow inward current in a use-dependent fashion, i.e. the block was enhanced by increased frequency of activating clamps and by more positive holding potentials. However, we found that short single activating clamps resulted in minimal block, whereas prolonging the clamp step progressively enhanced the blockade. Thus, a single long clamp caused as much blockade as a train of shorter pulses. These results demonstrate that diltiazem and verapamil block the slow inward current by binding to calcium channels in a state-dependent fashion, i.e. inactivated channels have a high affinity for the drugs, while rested and open channels have a lower affinity.

  4. 以钙拮抗剂为基础的联合降压对高血压患者中心动脉压和脉搏波传导速度的对比研究%Comparison of different calcium channel blocker-based combination therapies on central blood pressure and pulse wave velocity in hypertensive patients

    Institute of Scientific and Technical Information of China (English)

    孙尚文; 路方红; 孙颖; 赵颖馨; 刘振东; 王舒健

    2012-01-01

    in baseline, after 12 and 24 months of treatment respectively. Results Central systolic blood pressure, diastolic blood pressure, pulse pressure, augmentation index and crPWV all significantly decreased after 12 months therapy in two groups. The crPWV [(8. 9 + 2. 0) vs (9. 5±2. 2)m/s, P<0. 05] in group B further reduced in 24 months, but there was no change in group A with time prolonged(P>0. 05). Treatment for 12 and 24 months, the decreases of crPWV in group B [12 months ( -3. 5 + 2. L)m/s; 24 months(-4. 1 + 2. 3)m/s] were markedly significant compared with group A [12 months ( - 2. 3± 1. 6)m/s; 24 months ( - 2. 5±1. 8)m/s, P<0. 01]. Conclusion CAP, AI and crPWV in hypertensive patients could be significantly reduced by the treatment with amlodipine/amiloride or amlodipine/telmisartan whereas amlodipine/telmisartan therapy shows more effective in the improvement of arterial flexibility than amlodipine/amiloride.

  5. Support for calcium channel gene defects in autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Lu Ake Tzu-Hui

    2012-12-01

    Full Text Available Abstract Background Alternation of synaptic homeostasis is a biological process whose disruption might predispose children to autism spectrum disorders (ASD. Calcium channel genes (CCG contribute to modulating neuronal function and evidence implicating CCG in ASD has been accumulating. We conducted a targeted association analysis of CCG using existing genome-wide association study (GWAS data and imputation methods in a combined sample of parent/affected child trios from two ASD family collections to explore this hypothesis. Methods A total of 2,176 single-nucleotide polymorphisms (SNP (703 genotyped and 1,473 imputed covering the genes that encode the α1 subunit proteins of 10 calcium channels were tested for association with ASD in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP. SNP imputation using IMPUTE2 and a combined reference panel from the HapMap3 and the 1,000 Genomes Project increased coverage density of the CCG. Family-based association was tested using the FBAT software which controls for population stratification and accounts for the non-independence of siblings within multiplex families. The level of significance for association was set at 2.3E-05, providing a Bonferroni correction for this targeted 10-gene panel. Results Four SNPs in three CCGs were associated with ASD. One, rs10848653, is located in CACNA1C, a gene in which rare de novo mutations are responsible for Timothy syndrome, a Mendelian disorder that features ASD. Two others, rs198538 and rs198545, located in CACN1G, and a fourth, rs5750860, located in CACNA1I, are in CCGs that encode T-type calcium channels, genes with previous ASD associations. Conclusions These associations support a role for common CCG SNPs in ASD.

  6. A calcium channel mutant mouse model of hypokalemic periodic paralysis

    OpenAIRE

    Wu, Fenfen; Mi, Wentao; Hernández-Ochoa, Erick O.; Burns, Dennis K.; Fu, Yu; Gray, Hillery F; Struyk, Arie F.; Martin F Schneider; Cannon, Stephen C.

    2012-01-01

    Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K+). HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (CaV1.1) or a sodium channel (NaV1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between CaV1.1 mutations and the ictal loss of muscle excitability during an attack of weakness in Hy...

  7. The molecular choreography of a store-operated calcium channel.

    Science.gov (United States)

    Lewis, Richard S

    2007-03-15

    Store-operated calcium channels (SOCs) serve essential functions from secretion and motility to gene expression and cell growth. A fundamental mystery is how the depletion of Ca2+ from the endoplasmic reticulum (ER) activates Ca2+ entry through SOCs in the plasma membrane. Recent studies using genetic approaches have identified genes encoding the ER Ca2+ sensor and a prototypic SOC, the Ca2+-release-activated Ca2+ (CRAC) channel. New findings reveal a unique mechanism for channel activation, in which the CRAC channel and its sensor migrate independently to closely apposed sites of interaction in the ER and the plasma membrane.

  8. Effects of calcium channel blocker, nifedipine, on antidepressant activity of fluvoxamine, venlafaxine and tianeptine in mice

    Directory of Open Access Journals (Sweden)

    Ashok K. Sharma

    2015-02-01

    Conclusions: Nifedipine, fluvoxamine, venlafaxine and tianeptine possess antidepressant activity and nifedipine exhibits synergistic antidepressant activity with fluvoxamine, venlafaxine and tianeptine. [Int J Basic Clin Pharmacol 2015; 4(1.000: 82-88

  9. L-type calcium channel blockers enhance 5-HTP-induced antinociception in mice

    Institute of Scientific and Technical Information of China (English)

    Jian-hui LIANG; Jun-xu LI; Xu-hua WANG; Bi CHEN; Ying LU; Pan ZHANG; Rong HAN; Xiang-feng YE

    2004-01-01

    AIM: To investigate the involvement of L-type Ca2+ channels in antinociceptive action induced by the 5-HT precursor,5-hydroxytryptophan (5-HTP). METHODS: Female Kunming mice were treated with either 5-HTP (20-80 mg/kg,ip) alone, or the combination of 5-HTP and fluoxetine (2-8 mg/kg, ip), pargyline (15-60 mg/kg, ip), nimodipine (2.5-10 mg/kg, ip), nifedipine (2.5-10 mg/kg, ip), verapamil (2.5-10 mg/kg, ip), CaC12 (5-20 mmol/L, icv), or EGTA (0.5-3 mmol/L, icv) prior to the hot-plate test (55 ℃, hind-paw licking latency). In addition, locomotor activity in mice treated with 5-HTP alone was measured using an ambulometer with five activity boxes. RESULTS: Ip injection of 5-HTP alone had no influence on the spontaneous locomotor activity, whereas dose-dependently increased the latency to licking hind-paw in the hot-plate test in mice. The inhibitory effects of 5-HTP on nociceptive response were significantly enhanced by fluoxetine in the mouse hot-plate test. At a sub-effective dose, pargyline could cause a leftward shift in the dose-response curve of 5-HTP-induced antinociception. Co-administration with 5-HTP and nimodipine, nifedipine, or verapamil obviously potentiated the antinociceptive effects elicited by 5-HTP.Interestingly, 5-HTP-induced antinociception was antagonized by CaC12 and enhanced by EGTA injected icv in the mouse hot-plate test. CONCLUSION: These findings suggest that systemic administration of 5-HTP may yield the antinociceptive effects, which are related to Ca2+ influx from extracellular fluid through L-type Ca2+ channels.

  10. Pharmacokinetics of barnidipine hydrochloride, a new dihydropyridine calcium channel blocker, in the rat, dog and human.

    Science.gov (United States)

    Teramura, T; Watanabe, T; Higuchi, S; Hashimoto, K

    1995-11-01

    1. The pharmacokinetics of a new calcium antagonist barnidipine hydrochloride, a stereochemically pure enantiomer, was studied after intravenous and oral dosing to the rat and dog, and oral to man. 2. After intravenous dosing, plasma concentrations of barnidipine hydrochloride declined bi-exponentially with the terminal half-lives of 0.6 h in the rat and 4.1 h in the dog. The blood clearance was 5.2 l/h/kg in the rat and 3.3 l/h/kg in the dog, and was comparable with hepatic blood flow in both species. 3. After oral dosing, plasma concentrations of barnidipine hydrochloride peaked rapidly (0.3-0.4 h in the rat and dog, 1.0-1.6 h in man). Cmax and AUC rose non-linearly with increasing doses in all three species. 4. The absolute bioavailability was low (11-18% in the rat and 6-9% in the dog), suggesting a marked first-pass metabolism.

  11. Calcium binding protein-mediated regulation of voltage-gated calcium channels linked to human diseases

    Institute of Scientific and Technical Information of China (English)

    Nasrin NFJATBAKHSH; Zhong-ping FENG

    2011-01-01

    Calcium ion entry through voltage-gated calcium channels is essential for cellular signalling in a wide variety of cells and multiple physiological processes. Perturbations of voltage-gated calcium channel function can lead to pathophysiological consequences. Calcium binding proteins serve as calcium sensors and regulate the calcium channel properties via feedback mechanisms. This review highlights the current evidences of calcium binding protein-mediated channel regulation in human diseases.

  12. Newer calcium channel antagonists and the treatment of hypertension.

    Science.gov (United States)

    Cummins, D F

    1999-07-01

    Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.

  13. Effects and mechanisms of store-operated calcium channel blockade on hepatic ischemia-reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Li-Jie Pan; Zi-Chao Zhang; Zhen-Ya Zhang; Wen-Jun Wang; Yue Xu; Zong-Ming Zhang

    2012-01-01

    AIM: To further investigate the important role of storeoperated calcium channels (SOCs) in rat hepatocytes and to explore the effects of SOC blockers on hepatic ischemia-reperfusion injury (HIRI). METHODS: Using freshly isolated hepatocytes from a rat model of HIRI (and controls), we measured cytosolic free Ca2+ concentration (by calcium imaging), net Ca2+ fluxes (by a non-invasive micro-test technique), the SOC current (ISOC; by whole-cell patch-clamp recording), and taurocholate secretion [by high-performance liquid chromatography and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays]. RESULTS: Ca2+ oscillations and net Ca2+ fluxes mediated by Ca2+ entry via SOCs were observed in rat hepatocytes. ISOC was significantly higher in HIRI groups than in controls (57.0 ± 7.5 pA vs 31.6 ± 2.7 pA, P <0.05) and was inhibited by La3+. Taurocholate secretion by hepatocytes into culture supernatant was distinctly lower in HIRI hepatocytes than in controls, an effect reversed by SOC blockers. CONCLUSION: SOCs are pivotal in HIRI. SOC blockers protected against HIRI and assisted the recovery of secretory function in hepatocytes. Thus, they are likely to become a novel class of effective drugs for prevention or therapy of HIRI patients in the future.

  14. R-type calcium channels are crucial for semaphorin 3A-induced DRG axon growth cone collapse.

    Directory of Open Access Journals (Sweden)

    Rimantas Treinys

    Full Text Available Semaphorin 3A (Sema3A is a secreted protein involved in axon path-finding during nervous system development. Calcium signaling plays an important role during axonal growth in response to different guidance cues; however it remains unclear whether this is also the case for Sema3A. In this study we used intracellular calcium imaging to figure out whether Sema3A-induced growth cone collapse is a Ca2+ dependent process. Intracellular Ca2+ imaging results using Fura-2 AM showed Ca2+ increase in E15 mice dorsal root ganglia neurons upon Sema3A treatment. Consequently we analyzed Sema3A effect on growth cones after blocking or modifying intracellular and extracellular Ca2+ channels that are expressed in E15 mouse embryos. Our results demonstrate that Sema3A increased growth cone collapse rate is blocked by the non-selective R- and T- type Ca2+ channel blocker NiCl2 and by the selective R-type Ca2+ channel blocker SNX482. These Ca2+ channel blockers consistently decreased the Sema3A-induced intracellular Ca2+ concentration elevation. Overall, our results demonstrate that Sema3A-induced growth cone collapses are intimately related with increase in intracellular calcium concentration mediated by R-type calcium channels.

  15. Clinical features of neuromuscular disorders in patients with N-type voltage-gated calcium channel antibodies

    Directory of Open Access Journals (Sweden)

    Andreas Totzeck

    2016-09-01

    Full Text Available Neuromuscular junction disorders affect the pre- or postsynaptic nerve to muscle transmission due to autoimmune antibodies. Members of the group like myasthenia gravis and Lambert-Eaton syndrome have pathophysiologically distinct characteristics. However, in practice, distinction may be difficult. We present a series of three patients with a myasthenic syndrome, dropped-head syndrome, bulbar and respiratory muscle weakness and positive testing for anti-N-type voltage-gated calcium channel antibodies. In two cases anti-acetylcholin receptor antibodies were elevated, anti-P/Q-type voltage-gated calcium channel antibodies were negative. All patients initially responded to pyridostigmine with a non-response in the course of the disease. While one patient recovered well after treatment with intravenous immunoglobulins, 3,4-diaminopyridine, steroids and later on immunosuppression with mycophenolate mofetil, a second died after restriction of treatment due to unfavorable cancer diagnosis, the third patient declined treatment. Although new antibodies causing neuromuscular disorders were discovered, clinical distinction has not yet been made. Our patients showed features of pre- and postsynaptic myasthenic syndrome as well as severe dropped-head syndrome and bulbar and axial muscle weakness, but only anti-N-type voltage-gated calcium channel antibodies were positive. When administered, one patient benefited from 3,4-diaminopyridine. We suggest that this overlap-syndrome should be considered especially in patients with assumed seronegative myasthenia gravis and lack of improvement under standard therapy.

  16. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate

    OpenAIRE

    Ivanov, Vadim; Ivanova, Svetlana; KALINOVSKY, TATIANA; NIEDZWIECKI, ALEKSANDRA; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition...

  17. Nifedipine improves immediate, and 6- and 12-month graft function in cyclosporin A (CyA) treated renal allograft recipients.

    Science.gov (United States)

    Harper, S J; Moorhouse, J; Veitch, P S; Horsburgh, T; Walls, J; Bell, P R; Donnelly, P K; Feehally, J

    1992-01-01

    To investigate the effect of oral nifedipine, a calcium channel blocker known not to modify cyclosporin A (CyA) pharmacokinetics, on immediate transplant function and CyA nephrotoxicity, 68 adult renal transplant recipients were pre-operatively randomized to one of three regimes: A (high-dose CyA, initial dose 17 mg/kg per day, maintenance dose 7 mg/kg per day); B (regime A plus oral nifedipine); C low-dose CyA, initial dose 10 mg/kg per day, maintenance 4 mg/kg per day plus azathioprine 1 mg/kg per day). All three groups received identical steroid regimes. Calcium channel blockers of all types were avoided in groups A and C. Delayed graft function (dialysis dependence by day 4) was seen least frequently in group B (P nifedipine significantly improves immediate and medium-term graft function.

  18. Influence of calcium blockers on the SPR of erythrocytes

    Science.gov (United States)

    Shynkarenko, Olena V.; Tril, Orest; Wojnarowska, Renata; Prohorenko, Sergiy; Shergii, E. M.

    2016-12-01

    One of the promising areas of research is the impact of calcium channel blockers (CB) of biological fluids. This paper shows that the CB impact on a biological fluid can be efficiently combine with the surface plasmon resonance (SPR). It is shown that the addition of CB at the SPR measurements affect the stability of membranes and acts differently on the kinetics of erythrocytes ligament in the different groups of people.

  19. Effects of calcium channel antagonists on the motivational effects of nicotine and morphine in conditioned place aversion paradigm.

    Science.gov (United States)

    Budzynska, Barbara; Polak, Piotr; Biala, Grazyna

    2012-03-01

    The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement-related process; thus, it is important to understand the mechanisms that mediate affective withdrawal behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative motivational symptoms of nicotine and morphine withdrawal using the conditioned place aversion (CPA) paradigm. Rats were chronically treated with nicotine (1.168 mg/kg, free base, s.c., 11 days, three times daily) or morphine (10 mg/kg,s.c., 11 days, twice daily). Then, during conditioning, rats pre-treated with nicotine or morphine received a nicotinic receptor antagonist mecamylamine (3.5 mg/kg) or an opioid receptor antagonist naloxone (1 mg/kg) to precipitate withdrawal in their initially preferred compartment, or saline in their non-preferred compartment. Our results demonstrated that after three conditioning sessions, mecamylamine induced a clear place aversion in rats that had previously received nicotine injections, and naloxone induced a significant place aversion in rats that had previously received morphine injections. Further, the major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (5 and 10 mg/kg, i.p.), injected before the administration of mecamylamine or naloxone, attenuated nicotine or morphine place aversion. As an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in aversive motivational component associated with nicotine a morphine withdrawal. We can suggest that calcium channel blockers have potential for alleviating nicotine and morphine addiction by selectively decreasing the incentive motivational properties of both drugs, and may be beneficial as smoking cessation or opioid dependence pharmacotherapies.

  20. Calcium channel structural determinants of synaptic transmission between identified invertebrate neurons.

    Science.gov (United States)

    Spafford, J David; Munno, David W; Van Nierop, Pim; Feng, Zhong-Ping; Jarvis, Scott E; Gallin, Warren J; Smit, August B; Zamponi, Gerald W; Syed, Naweed I

    2003-02-01

    We report here that unlike what was suggested for many vertebrate neurons, synaptic transmission in Lymnaea stagnalis occurs independent of a physical interaction between presynaptic calcium channels and a functional complement of SNARE proteins. Instead, synaptic transmission in Lymnaea requires the expression of a C-terminal splice variant of the Lymnaea homolog to mammalian N- and P/Q-type calcium channels. We show that the alternately spliced region physically interacts with the scaffolding proteins Mint1 and CASK, and that synaptic transmission is abolished following RNA interference knockdown of CASK or after the injection of peptide sequences designed to disrupt the calcium channel-Mint1 interactions. Our data suggest that Mint1 and CASK may serve to localize the non-L-type channels at the active zone and that synaptic transmission in invertebrate neurons utilizes a mechanism for optimizing calcium entry, which occurs independently of a physical association between calcium channels and SNARE proteins.

  1. T-type calcium channel expression in cultured human neuroblastoma cells

    Institute of Scientific and Technical Information of China (English)

    Xianjie Wen; Shiyuan Xu; Lingling Wang; Hua Liang; Chengxiang Yang; Hanbing Wang; Hongzhen Liu

    2011-01-01

    Human neuroblastoma cells (SH-SY5Y) have similar structures and functions as neural cells and have been frequently used for cell culture studies of neural cell functions. Previous studies have revealed Land N-type calcium channels in SH-SY5Y cells. However, the distribution of the low -voltage activated calcium channel (namely called T-type calcium channel, including Cav3.1, Cav3.2, and Cav3.3) in SH-SY5Y cells remains poorly understood. The present study detected mRNA and protein expression of the T-type calcium channel (Cav3.1, Cav3.2, and Cav3.3) in cultured SH-SY5Y cells using real-time polymerase chain reaction (PCR) and western blot analysis. Results revealed mRNA and protein expression from all three T-type calcium channel subtypes in SH-SY5Y cells. Moreover,Cav3.1 was the predominant T-type calcium channel subtype in SH-SY5Y cells.

  2. Cilnidipine, but not amlodipine, ameliorates osteoporosis in ovariectomized hypertensive rats through inhibition of the N-type calcium channel.

    Science.gov (United States)

    Shimizu, Hideo; Nakagami, Hironori; Yasumasa, Natsuki; Mariana, Osako Kiomy; Kyutoku, Mariko; Koriyama, Hiroshi; Nakagami, Futoshi; Shimamura, Munehisa; Rakugi, Hiromi; Morishita, Ryuichi

    2012-01-01

    Both osteoporosis and high blood pressure are major diseases in aging populations. Recent studies demonstrated that some antihypertensive drugs reduced the risk of bone fracture in elderly patients. Although calcium channel blockers (CCB) are widely used as first-line antihypertensive agents, there is no evidence that they prevent osteoporosis. In this study, we investigated the effects of two types of CCB on bone metabolism: cilnidipine (L-/N-type CCB), which suppresses norepinephrine release from the sympathetic nerve, and amlodipine (L-type CCB). In ovariectomized female spontaneous hypertensive rats, administration of cilnidipine, but not amlodipine, resulted in a significant increase in the ratio of alkaline phosphatase to tartrate-resistant acid phosphatase (TRAP) and a decrease in the number of osteoclasts, as assessed by TRAP staining in the proximal tibia. Bone mineral density, moreover, was significantly higher in the cilnidipine group as compared with the amlodipine group and was associated with a significant decrease in a urinary collagen degradation product (deoxypyridinoline). The degree of prevention of osteoporosis by cilnidipine was similar to that of carvedilol (a β-blocker) because β-blockers reduce fracture risks though the inhibition of osteoclast activation. Interestingly, these effects cannot be attributed to the reduction of blood pressure because all three drugs significantly decreased blood pressure. In contrast, both cilnidipine and carvedilol, but not amlodipine, significantly decreased heart rate, indicating that both cilnidipine and carvedilol suppressed sympathetic nervous activity. Overall, our present data showed that cilnidipine (L-/N-type CCB) ameliorated osteoporosis in ovariectomized hypertensive rats. These pleiotropic effects of antihypertensive drugs such as cilnidipine and carvedilol might provide additional benefits in the treatment of hypertensive postmenopausal women.

  3. Wearing blue-blockers in the morning could improve sleep of workers on a permanent night schedule: a pilot study.

    Science.gov (United States)

    Sasseville, Alexandre; Benhaberou-Brun, Dalila; Fontaine, Charlotte; Charon, Marie-Claude; Hebert, Marc

    2009-07-01

    Night shiftworkers often complain of disturbed sleep during the day. This could be partly caused by morning sunlight exposure during the commute home, which tends to maintain the circadian clock on a daytime rhythm. The circadian clock is most sensitive to the blue portion of the visible spectrum, so our aim was to determine if blocking short wavelengths of light below 540 nm could improve daytime sleep quality and nighttime vigilance of night shiftworkers. Eight permanent night shiftworkers (32-56 yrs of age) of Quebec City's Canada Post distribution center were evaluated during summertime, and twenty others (24-55 yrs of age) during fall and winter. Timing, efficacy, and fragmentation of daytime sleep were analyzed over four weeks by a wrist activity monitor, and subjective vigilance was additionally assessed at the end of the night shift in the fall-winter group. The first two weeks served as baseline and the remaining two as experimental weeks when workers had to wear blue-blockers glasses, either just before leaving the workplace at the end of their shift (summer group) or 2 h before the end of the night shift (fall-winter group). They all had to wear the glasses when outside during the day until 16:00 h. When wearing the glasses, workers slept, on average +/-SD, 32+/-29 and 34+/-60 more min/day, increased their sleep efficacy by 1.95+/-2.17% and 4.56+/-6.1%, and lowered their sleep fragmentation by 1.74+/-1.36% and 4.22+/-9.16% in the summer and fall-winter group, respectively. Subjective vigilance also generally improved on Fridays in the fall-winter group. Blue-blockers seem to improve daytime sleep of permanent night-shift workers.

  4. Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology.

    Science.gov (United States)

    Dolphin, Annette C

    2016-10-01

    Voltage-gated calcium channels are essential players in many physiological processes in excitable cells. There are three main subdivisions of calcium channel, defined by the pore-forming α1 subunit, the CaV 1, CaV 2 and CaV 3 channels. For all the subtypes of voltage-gated calcium channel, their gating properties are key for the precise control of neurotransmitter release, muscle contraction and cell excitability, among many other processes. For the CaV 1 and CaV 2 channels, their ability to reach their required destinations in the cell membrane, their activation and the fine tuning of their biophysical properties are all dramatically influenced by the auxiliary subunits that associate with them. Furthermore, there are many diseases, both genetic and acquired, involving voltage-gated calcium channels. This review will provide a general introduction and then concentrate particularly on the role of auxiliary α2 δ subunits in both physiological and pathological processes involving calcium channels, and as a therapeutic target.

  5. CHARACTERIZING CALCIUM INFLUX VIA VOLTAGE- AND LIGAND-GATED CALCIUM CHANNELS IN EMBRYONIC ALLIGATOR NEURONS IN CULTURE

    Science.gov (United States)

    Ju, Weina; Wu, Jiang; Pritz, Michael B.; Khanna, Rajesh

    2013-01-01

    Vertebrate brains share many features in common. Early in development, both the hindbrain and diencephalon are built similarly. Only later in time do differences in morphology occur. Factors that could potentially influence such changes include certain physiological properties of neurons. As an initial step to investigate this problem, embryonic Alligator brain neurons were cultured and calcium responses were characterized. The present report is the first to document culture of Alligator brain neurons in artificial cerebrospinal fluid (ACSF) as well as in standard mammalian tissue culture medium supplemented with growth factors. Alligator brain neuron cultures were viable for at least 1 week with unipolar neurites emerging by 24 hours. Employing Fura-2 AM, robust depolarization-induced calcium influx, was observed in these neurons. Using selective blockers of the voltage-gated calcium channels, the contributions of N-, P/Q-, R-, T-, and L-type channels in these neurons were assessed and their presence documented. Lastly, Alligator brain neurons were challenged with an excitotoxic stimulus (glutamate + glycine) where delayed calcium deregulation could be prevented by a classical NMDA receptor antagonist. PMID:24260711

  6. Stimulation of protein kinase C recruits covert calcium channels in Aplysia bag cell neurons.

    Science.gov (United States)

    Strong, J A; Fox, A P; Tsien, R W; Kaczmarek, L K

    The modulation of voltage-activated calcium currents by protein kinases provides excitable cells with a mechanism for regulating their electrical behaviour. At the single channel level, modulation of calcium current has, to date, been characterized only in cardiac muscle, where beta-adrenergic agonists, acting through cyclic AMP-dependent protein kinase, enhance the calcium current by increasing channel availability and opening. We now report that enhancement of calcium current in the peptidergic bag cell neurons of Aplysia by protein kinase C occurs through a different mechanism, the recruitment of a previously covert class of calcium channel. Under control conditions, bag cell neurons contain only one class of voltage-activated calcium channel with a conductance of approximately 12 pS. After exposure to agents that activate protein kinase C, these neurons also express a second class of calcium channel with a different unitary conductance (approximately 24 pS) that is never seen in untreated cells.

  7. T-type voltage-gated calcium channels regulate the tone of mouse efferent arterioles

    DEFF Research Database (Denmark)

    Poulsen, Christian B; Al-Mashhadi, Rozh H; Cribbs, Leanne L;

    2011-01-01

    Voltage-gated calcium channels are important for the regulation of renal blood flow and the glomerular filtration rate. Excitation-contraction coupling in afferent arterioles is known to require activation of these channels and we studied their role in the regulation of cortical efferent arteriolar...... tone. We used microdissected perfused mouse efferent arterioles and found a transient vasoconstriction in response to depolarization with potassium; an effect abolished by removal of extracellular calcium. The T-type voltage-gated calcium channel antagonists mibefradil and nickel blocked this potassium....... Low concentrations of nickel, an agent that blocks Ca(v)3.2, had a similar effect. Thus, T-type voltage-gated calcium channels are functionally important for depolarization-induced vasoconstriction and subsequent dilatation in mouse cortical efferent arterioles.Kidney International advance online...

  8. Disruption of learned timing in P/Q calcium channel mutants.

    Directory of Open Access Journals (Sweden)

    Akira Katoh

    Full Text Available To optimize motor performance, both the amplitude and temporal properties of movements should be modifiable by motor learning. Here we report that the modification of movement timing is highly dependent on signaling through P/Q-type voltage-dependent calcium channels. Two lines of mutant mice heterozygous for P/Q-type voltage-dependent calcium channels exhibited impaired plasticity of eye movement timing, but relatively intact plasticity of movement amplitude during motor learning in the vestibulo-ocular reflex. The results thus demonstrate a distinction between the molecular signaling pathways regulating the timing versus amplitude of movements.

  9. Novel tacrine derivatives that block neuronal calcium channels.

    Science.gov (United States)

    de los Ríos, Cristóbal; Marco, José L; Carreiras, María D C; Chinchón, P M; García, Antonio G; Villarroya, Mercedes

    2002-06-01

    A new series of tacrine (9-amino-1,2,3,4-tetrahydroacridine) derivatives were synthesized and their effects on 45Ca(2+) entry into bovine adrenal chromaffin cells stimulated with dimethylphenylpiperazinium (DMPP) or K(+), studied. At 3 microM, compound 1 did not affect (45)Ca(2+) uptake evoked by DMPP. Compounds 14, 15 and 17 inhibited the effects of DMPP by 30%. Compounds 3, 9 and tacrine blocked the DMPP signal by about 50%. Compounds 5 and 12 were the most potent blockers of DMPP-stimulated 45Ca(2+) entry (90%); the rest of the compounds inhibited the effects of DMPP by 70-80%. Compounds 1, 3, 4, 8, 10, 11, 13, 16, 17 and tacrine inhibited 45Ca(2+) uptake induced by K(+) about 20%. Compounds 6, 14 and 15 inhibited the K(+) effects by 10% or less. Compounds 7, 9, 12 and 18 blocked the K(+) signal by 30% and, finally, compounds 2 and 5 inhibited the K(+)-induced 45Ca(2+) entry by 50%. None of the new compounds was as effective as diltiazem (IC(50)=0.03 microM) in causing relaxation of the rat aorta precontracted with 35 mM K(+); the most potent was compound 7 (IC(50)=0.3 microM). Compounds 5, 6, 8, 9, 10 and 13 had IC(50)s around 10 microM and compounds 3, 4, 11 and 12 around 20 microM. Blockade of Ca(2+) entry through neuronal voltage-dependent Ca(2+) channels, without concomitant blockade of vascular Ca(2+) channels, suggests that some of these compounds might exhibit neuroprotectant effects but not undesirable hemodynamic effects.

  10. [Discovering L-type calcium channels inhibitors of antihypertensive drugs based on drug repositioning].

    Science.gov (United States)

    Liang, Ying-xi; He, Yu-su; Jiang, Lu-di; Yue, Qiao-xin; Cui, Shuai; Bin, Li; Ye, Xiao-tong; Zhang, Xiao-hua; Zhang, Yang-ling

    2015-09-01

    This study was amid to construct the pharmacophore model of L-type calcium channel antagonist in the application of screening Drugbank and TCMD. This paper repositions the approved drugs resulting from virtual screening and discusses the relocation-based drug discovery methods, screening antihypertensive drugs with L-type calcium channel function from TCMD. Qualitative hypotheses wre generated by HipHop separately on the basis of 12 compounds with antagonistic action on L-type calcium channel expressed in rabbit cardiac muscle. Datebase searching method was used to evaluate the generated hypotheses. The optimum hypothesis was used to search Drugbank and TCMD. This paper repositions the approved drugs and evaluates the antihypertensive effect of the chemical constituent of traditional Chinese medicine resulting from virtual screening by the matching score and literature. The results showed that optimum qualitative hypothesis is with six features, which were two hydrogen-bond acceptors, four hydrophobic groups, and the CAI value of 2.78. Screening Drugbank achieves 93 approved drugs. Screening TCMD achieves 285 chemical constituents of traditional Chinese medicine. It was concluded that the hypothesis is reliable and can be used to screen datebase. The approved drugs resulting from virtual screening, such as pravastatin, are potentially L-type calcium channels inhibitors. The chemical constituents of traditional Chinese medicine, such as Arctigenin III and Arctigenin are potentially antihypertensive drugs. It indicates that Drug Repositioning based on hypothesis is possible.

  11. L-type Voltage-Gated Calcium Channels in Conditioned Fear: A Genetic and Pharmacological Analysis

    Science.gov (United States)

    McKinney, Brandon C.; Sze, Wilson; White, Jessica A.; Murphy, Geoffrey G.

    2008-01-01

    Using pharmacological approaches, others have suggested that L-type voltage-gated calcium channels (L-VGCCs) mediate both consolidation and extinction of conditioned fear. In the absence of L-VGCC isoform-specific antagonists, we have begun to investigate the subtype-specific role of LVGCCs in consolidation and extinction of conditioned fear…

  12. CaV1.2 calcium channels: just cut out to be regulated?

    Science.gov (United States)

    Groth, Rachel D; Tirko, Natasha N; Tsien, Richard W

    2014-06-04

    Tight regulation of calcium entry through the L-type calcium channel CaV1.2 ensures optimal excitation-response coupling. In this issue of Neuron, Michailidis et al. (2014) demonstrate that CaV1.2 activity triggers negative feedback regulation through proteolytic cleavage of the channel within the core of the pore-forming subunit.

  13. 5,6-EET potently inhibits T-type calcium channels

    DEFF Research Database (Denmark)

    Cazade, M.; Bidaud, I.; Hansen, Pernille B. Lærkegaard;

    2014-01-01

    T-type calcium channels (T-channels) are important actors in neuronal pacemaking, in heart rhythm, and in the control of the vascular tone. T-channels are regulated by several endogenous lipids including the primary eicosanoid arachidonic acid (AA), which display an important role in vasodilation...

  14. New Role of P/Q-type Voltage-gated Calcium Channels

    DEFF Research Database (Denmark)

    Hansen, Pernille B L

    2015-01-01

    Voltage-gated calcium channels are important for the depolarization-evoked contraction of vascular smooth muscle cells (SMCs), with L-type channels being the classical channel involved in this mechanism. However, it has been demonstrated that the CaV2.1 subunit, which encodes a neuronal isoform o...

  15. [Persistence in drug therapy of hypertension among different treatment groups and comparison between fixed-dose combinations of ara II + calcium channel blockers vs ace inhibitors + calcium channel blockers].

    Science.gov (United States)

    Waisman, Gabriel Dario; Garfi, Leonardo Guillermo; Izbizky, Gustavo Hernan; Tortella, Juan Jose

    2012-01-01

    La hipertensión arterial (HTA) es una enfermedad crónica, y prevalente, que requiere un tratamiento sostenido en el tiempo donde existen medidas farmacológicas y no farmacológicas para su control. La “persistencia” es la continuidad de los tratamientos farmacológicos. Conocer cual es la persistencia de los diferentes grupos terapéuticos antihipertensivos podría ayudar a priorizar aquellos con mejores resultados. El objetivo es describir la persistencia al tratamiento antihipertensivo en una cohorte de pacientes utilizando diferentes métodos y comparar la persistencia en los diferentes grupos farmacológicos utilizados para el tratamiento de la HTA. Materiales y Métodos: Estudio observacional, de cohorte retrospectiva utilizando bases de datos secundarias obtenidas durante la dispensación de medicamentos y de los registros hospitalarios electrónicos del Hospital Italiano de Buenos Aires. Población adulta con diagnóstico de HTA y seguimiento por 2 años. Resultados: Los diuréticos, betabloqueantes de primera generación e inhibidores de la enzima convertidora de angiotensina son los grupos con la caída más importante en la persistencia. Los antagonistas de la angiotensina en monoterapia o junto con diurético y los betabloqueantes de segunda generación demostraron los mejores resultados de persistencia. La persistencia nunca llegó al 60% de los pacientes tratados a los 2 años. Conclusión: Pese a haber realizado la medición de la persistencia a través de distintos métodos los resultados fueron similares y demostraron una baja persistencia al tratamiento antihipertensivo. No encontramos variables extra farmacológicas que pudieran explicar la diferente persistencia en los diferentes grupos terapéuticos.

  16. Characterisation of marrubenol, a diterpene extracted from Marrubium vulgare, as an L-type calcium channel blocker

    OpenAIRE

    El-Bardai, Sanae; Wibo, Maurice; Hamaide, Marie-Christine; Lyoussi, Badiaa; Quetin-Leclercq, Joëlle; Morel, Nicole

    2003-01-01

    1. The objective of the present study was to investigate the mechanism of the relaxant activity of marrubenol, a diterpenoid extracted from Marrubium vulgare. In rat aorta, marrubenol was a more potent inhibitor of the contraction evoked by 100 mM KCl (IC50: 11.8+/-0.3 microM, maximum relaxation: 93+/-0.6%) than of the contraction evoked by noradrenaline (maximum relaxation: 30+/-1.5%). 2. In fura-2-loaded aorta, marrubenol simultaneously inhibited the Ca2+ signal and the contraction evoked b...

  17. Effects of the 1, 4-dihydropyridine L-type calcium channel blocker benidipine on bone marrow stromal cells.

    Science.gov (United States)

    Ma, Zhong-ping; Liao, Jia-cheng; Zhao, Chang; Cai, Dao-zhang

    2015-08-01

    Osteoporosis (OP) often increases the risk of bone fracture and other complications and is a major clinical problem. Previous studies have found that high blood pressure is associated with bone formation abnormalities, resulting in increased calcium loss. We have investigated the effect of the antihypertensive drug benidipine on bone marrow stromal cell (BMSC) differentiation into osteoblasts and bone formation under osteoporotic conditions. We used a combination of in vitro and in vivo approaches to test the hypothesis that benidipine promotes murine BMSC differentiation into osteoblasts. Alkaline phosphatase (ALP), osteocalcin (OCN), runt-related transcription factor 2 (RUNX2), β-catenin, and low-density lipoprotein receptor-related protein 5 (LRP5) protein expression was evaluated in primary femoral BMSCs from C57/BL6 mice cultured under osteogenic conditions for 2 weeks to examine the effects of benidipine. An ovariectomized (OVX) mouse model was used to investigate the effect of benidipine treatment for 3 months in vivo. We found that ALP, OCN, and RUNX2 expression was up-regulated and WNT/β-catenin signaling was enhanced in vitro and in vivo. In OVX mice that were intragastrically administered benidipine, bone parameters (trabecular thickness, bone mineral density, and trabecular number) in the distal femoral metaphysis were significantly increased compared with control OVX mice. Consistently, benidipine promoted BMSC differentiation into osteoblasts and protected against bone loss in OVX mice. Therefore, benidipine might be a suitable candidate for the treatment of patients with postmenopausal osteoporosis and hypertension.

  18. Metabolism and pharmacokinetics of barnidipine hydrochloride, a calcium channel blocker, in man following oral administration of its sustained release formulation.

    Science.gov (United States)

    Teramura, T; Watanabe, T; Higuchi, S; Hashimoto, K

    1997-02-01

    1. The metabolism and pharmacokinetics of barnidipine hydrochloride, a 1, 4-dihydropyridine calcium antagonist were evaluated following single oral administration of a sustained release formulation (SR) capsule comprising of quick and slow release pellets to healthy male volunteers. 2. Various metabolites were identified and quantitated by newly established GC-MS analytical methods. Major metabolites were the hydrolyzed product of the benzyl-pyrrolidinyl ester (M-3) in plasma and its oxidized pyridine product (M-4) in plasma and urine. The pyridine form of unchanged barnidipine and the N-debenzylated product were observed as minor metabolites. Therefore, the primary metabolic pathways in man are (a) hydrolysis of the benzylpyrrolidine ester, (b) N-debenzylation, and (c) oxidation of the dihydropyridine ring. 3. When the SR and normal capsules were administered at a dose of 10 mg to six subjects in a crossover design, AUC 0-infinity of unchanged drug, M-3 and 4 in each subject receiving the SR were 97 +/- 15, 85 +/- 31 and 76 +/- 21% respectively of those subjects receiving the normal formulation. The sum of the excretion of urinary metabolites for the SR formulation was 65 +/- 6% of that for the normal formulation. These data suggest that the absorption of the SR formulation is slightly reduced but that its bioavailability is comparable to that of the normal formulation.

  19. Potentiation of anticonvulsant activity of phenytoin by calcium channel blockers (verapamil and amlodipine against maximal electroshock seizures in rats

    Directory of Open Access Journals (Sweden)

    Monika Sharma

    2014-08-01

    Conclusions: From the present investigation, it may be concluded that the dose of DPH may be reduced in an antiepileptic individual who is on verapamil and amlodipine therapy. [Int J Basic Clin Pharmacol 2014; 3(4.000: 608-610

  20. FIXED COMBINATION OF THE CALCIUM CHANNEL BLOCKER LERCANIDIPINE AND ANGIOTENSIN CONVERTING ENZYME INHIBITOR ENALAPRIL: POSSIBILITY OF USAGE

    Directory of Open Access Journals (Sweden)

    O. D. Ostroumova

    2013-01-01

    Full Text Available Data on the updated approach to the choice of two-component antihypertensive combinations for different clinical situations are presented. Advantages and indications for combination of an angiotensin converting enzyme (ACE inhibitor and dihydropyridine calcium antagonist are considered. Data on the efficacy and safety of the combination of calcium antagonist of the third generation, lercanidipine, and ACE inhibitor, enalapril, are presented.

  1. Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects.

    Science.gov (United States)

    Pall, Martin L

    2013-08-01

    The direct targets of extremely low and microwave frequency range electromagnetic fields (EMFs) in producing non-thermal effects have not been clearly established. However, studies in the literature, reviewed here, provide substantial support for such direct targets. Twenty-three studies have shown that voltage-gated calcium channels (VGCCs) produce these and other EMF effects, such that the L-type or other VGCC blockers block or greatly lower diverse EMF effects. Furthermore, the voltage-gated properties of these channels may provide biophysically plausible mechanisms for EMF biological effects. Downstream responses of such EMF exposures may be mediated through Ca(2+) /calmodulin stimulation of nitric oxide synthesis. Potentially, physiological/therapeutic responses may be largely as a result of nitric oxide-cGMP-protein kinase G pathway stimulation. A well-studied example of such an apparent therapeutic response, EMF stimulation of bone growth, appears to work along this pathway. However, pathophysiological responses to EMFs may be as a result of nitric oxide-peroxynitrite-oxidative stress pathway of action. A single such well-documented example, EMF induction of DNA single-strand breaks in cells, as measured by alkaline comet assays, is reviewed here. Such single-strand breaks are known to be produced through the action of this pathway. Data on the mechanism of EMF induction of such breaks are limited; what data are available support this proposed mechanism. Other Ca(2+) -mediated regulatory changes, independent of nitric oxide, may also have roles. This article reviews, then, a substantially supported set of targets, VGCCs, whose stimulation produces non-thermal EMF responses by humans/higher animals with downstream effects involving Ca(2+) /calmodulin-dependent nitric oxide increases, which may explain therapeutic and pathophysiological effects.

  2. Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, D V; Ploug, K B; Olesen, J

    2011-01-01

    Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are i...... releases CGRP, and the release is regulated by Ca2+ ions and voltage-gated calcium channels.......Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons...

  3. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants.

    Directory of Open Access Journals (Sweden)

    Giuseppe eGangarossa

    2014-03-01

    Full Text Available The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations.

  4. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Gaba, D.M.; Metz, S.; Maze, M.

    1985-05-01

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  5. Synaptic Ribbons Require Ribeye for Electron Density, Proper Synaptic Localization, and Recruitment of Calcium Channels

    Directory of Open Access Journals (Sweden)

    Caixia Lv

    2016-06-01

    Full Text Available Synaptic ribbons are structures made largely of the protein Ribeye that hold synaptic vesicles near release sites in non-spiking cells in some sensory systems. Here, we introduce frameshift mutations in the two zebrafish genes encoding for Ribeye and thus remove Ribeye protein from neuromast hair cells. Despite Ribeye depletion, vesicles collect around ribbon-like structures that lack electron density, which we term “ghost ribbons.” Ghost ribbons are smaller in size but possess a similar number of smaller vesicles and are poorly localized to synapses and calcium channels. These hair cells exhibit enhanced exocytosis, as measured by capacitance, and recordings from afferent neurons post-synaptic to hair cells show no significant difference in spike rates. Our results suggest that Ribeye makes up most of the synaptic ribbon density in neuromast hair cells and is necessary for proper localization of calcium channels and synaptic ribbons.

  6. New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.

    Science.gov (United States)

    Visentin, Sonja; Rolando, Barbara; Di Stilo, Antonella; Fruttero, Roberta; Novara, Monica; Carbone, Emilio; Roussel, Christian; Vanthuyne, Nicolas; Gasco, Alberto

    2004-05-06

    A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.

  7. Anti-Convulsant Activity of Boerhaavia diffusa: Plausible Role of Calcium Channel Antagonism

    OpenAIRE

    Mandeep Kaur; Rajesh Kumar Goel

    2011-01-01

    “Ethnopharmacological” use of roots of Boerhaavia diffusa (B. diffusa) in the treatment of epilepsy in Nigerian folk medicine and reports showing the presence of a calcium channel antagonistic compound “liriodendrin” in its roots, led us to undertake the present study. The study was designed to investigate the methanolic root extract of B. diffusa and its different fractions including liriodendrin-rich fraction for exploring the possible role of liriodendrin in its anti-convulsant activity. A...

  8. Lavender Oil-Potent Anxiolytic Properties via Modulating Voltage Dependent Calcium Channels

    OpenAIRE

    2013-01-01

    Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs) as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, bioc...

  9. Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

    OpenAIRE

    2008-01-01

    Digitoxin and other cardiac glycosides are important, centuries-old drugs for treating congestive heart failure. However, the mechanism of action of these compounds is still being elucidated. Calcium is known to potentiate the toxicity of these drugs, and we have hypothesized that digitoxin might mediate calcium entry into cells. We report here that digitoxin molecules mediate calcium entry into intact cells. Multimers of digitoxin molecules also are able to form calcium channels in pure plan...

  10. Expression of the apoptotic calcium channel P2X7 in the glandular epithelium.

    Science.gov (United States)

    Slater, Michael; Danieletto, Suzanne; Barden, Julian A

    2005-03-01

    In the current study, expression of the apoptotic calcium channel receptor P2X(7) and prostate-specific antigen (PSA) levels were studied in biopsy cores from 174 patients as well as 20 radical prostatectomy cases. In clinical biopsies, we have previously demonstrated that P2X(1 )and P2X(2) calcium channel receptors are absent from normal prostate epithelium that does not progress to prostate cancer within 5 years. In cases that did progress to prostate cancer however, P2X(1 )and P2X(2) labeling was observed in a stage-specific manner first in the nucleus, then the cytoplasm and finally on the apical epithelium, as prostate cancer developed. These markers were present up to 5 years before cancer was detectable by the usual morphological criteria (Gleason grading) as determined by H and E staining. In the current study, the apoptotic calcium channel receptor P2X(7) yielded similar results to that of P2X(1) and P2X(2). Using radical prostatectomy tissue sections as well as biopsies, these changes in calcium channel metabolism were noted throughout the prostate, indicating a field effect. This finding suggests that the presence of a prostate tumor could be detected without the need for direct sampling of tumor tissue, leading to detection of false negative cases missed by H or E stain. The reliability of PSA levels as a prognostic indicator has been questioned in recent years. In the current study, PSA levels were correlated with the P2X(7) labeling results. All patients who exhibited no P2X(7) labeling had a prostatic serum antigen (PSA) level of 2. This finding suggests that increasing PSA may be an accurate indicator of cancer development.

  11. Differential CaMKII regulation by voltage-gated calcium channels in the striatum.

    Science.gov (United States)

    Pasek, Johanna G; Wang, Xiaohan; Colbran, Roger J

    2015-09-01

    Calcium signaling regulates synaptic plasticity and many other functions in striatal medium spiny neurons to modulate basal ganglia function. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a major calcium-dependent signaling protein that couples calcium entry to diverse cellular changes. CaMKII activation results in autophosphorylation at Thr286 and sustained calcium-independent CaMKII activity after calcium signals dissipate. However, little is known about the mechanisms regulating striatal CaMKII. To address this, mouse brain slices were treated with pharmacological modulators of calcium channels and punches of dorsal striatum were immunoblotted for CaMKII Thr286 autophosphorylation as an index of CaMKII activation. KCl depolarization increased levels of CaMKII autophosphorylation ~2-fold; this increase was blocked by an LTCC antagonist and was mimicked by treatment with pharmacological LTCC activators. The chelation of extracellular calcium robustly decreased basal CaMKII autophosphorylation within 5min and increased levels of total CaMKII in cytosolic fractions, in addition to decreasing the phosphorylation of CaMKII sites in the GluN2B subunit of NMDA receptors and the GluA1 subunit of AMPA receptors. We also found that the maintenance of basal levels of CaMKII autophosphorylation requires low-voltage gated T-type calcium channels, but not LTCCs or R-type calcium channels. Our findings indicate that CaMKII activity is dynamically regulated by multiple calcium channels in the striatum thus coupling calcium entry to key downstream substrates.

  12. Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of D-amphetamine and nicotine in the mouse elevated plus maze test.

    Science.gov (United States)

    Biala, Grazyna; Kruk, Marta

    2008-01-01

    The purpose of the current experiments was to examine the anxiety-related effects of repeated amphetamine and nicotine administration using the mouse elevated plus maze (EPM). d-amphetamine was administered daily for 8 days (2 mg/kg, i.p.). On the 9th day, mice were challenged with amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.), and were tested 30 min after this last injection. Additionally, a distinct group of mice was pretreated with nicotine (0.1 mg/kg, s.c., 6 days). These mice were subjected to nicotine (0.1 mg/kg, s.c.) or amphetamine (2 mg/kg, i.p.) challenge on the seventh day to see if full crossover effects developed after the pretreatment of both psychostimulant drugs. Moreover, the L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5 and 10 mg/kg, i.p.) and diltiazem (5 and 10 mg/kg, i.p.) were injected prior to each injection of chronic d-amphetamine or nicotine. We observed cross-tolerance to the anxiogenic effects of d-amphetamine and nicotine that was blunted by a pretreatment with calcium channel blockers. Overall our findings imply that similar neural calcium-dependent mechanisms are involved in the anxiety-related responses to chronic amphetamine and nicotine injections. As anxiety seems to be an important factor for the development of psychostimulant dependence, the L-type VDCC antagonists can offer an interesting approach for the pharmacotherapy of addiction, including amphetamine and/or nicotine dependence.

  13. Deltamethrin Inhibits the Human T-type Voltage-Sensitive Calcium Channel (Cav3.2

    Directory of Open Access Journals (Sweden)

    Steven B. Symington

    2009-01-01

    Full Text Available The goal of this study was to determine the effect of deltamethrin, a pyrethroid insecticide, on CaV3.2, a human T-type voltage-sensitive calcium channel expressed in Xenopus laevis (X.laevis oocytes. Cav3.2 cDNA was transcribed into cRNA; the cRNA was then injected into X.laevis oocytes and electrophysiologically characterized using the two-electrode voltage clamp technique with Ba2+ as a charge carrier. Deltamethrin (10-7 M reduced peak current in a nonreversible manner compared to the untreated control, but had no effect on the voltagedependent activation and inactivation kinetics. These findings confirm that human CaV3.2 is a target for deltamethrin and quite possibly other pyrethroid insecticides. These studies provide insight into the molecular mechanisms of the effect that pyrethroids have on voltage-sensitive calcium channels in general. This information will allow a more complete understanding of the molecular and cellular nature of pyrethroid-induced toxicity and expand our knowledge of the structure-activity relationships of pyrethroids with regard to their action on voltage-sensitive calcium channels.

  14. Physiology and Regulation of Calcium Channels in Stomatal Guard Cells

    Energy Technology Data Exchange (ETDEWEB)

    Schroeder, Julian I.

    2007-05-02

    Stomatal pores in the epidermis of leaves regulate the diffusion of CO2 into leaves for photosynthetic carbon fixation and control water loss of plants during drought periods. Guard cells sense CO2, water status, light and other environmental conditions to regulate stomatal apertures for optimization of CO2 intake and plant growth under drought stress. The cytosolic second messenger calcium contributes to stomatal movements by transducing signals and regulating ion channels in guard cells. Studies suggest that both plasma membrane Ca2+ influx channels and vacuolar/organellar Ca2+ release channels contribute to ABA-induced Ca2+ elevations in guard cells. Recent research in the P.I.'s laboratory has led to identification of a novel major cation-selective Ca2+-permeable influx channel (Ica) in the plasma membrane of Arabidopsis guard cells. These advances will allow detailed characterization of Ica plasma membrane Ca2+ influx channels in guard cells. The long term goal of this research project is to gain a first detailed characterization of these novel plasma membrane Ca2+-permeable channel currents in Arabidopsis guard cells. The proposed research will investigate the hypothesis that Ica represents an important Ca2+ influx pathway for ABA and CO2 signal transduction in Arabidopsis guard cells. These studies will lead to elucidation of key signal transduction mechanisms by which plants balance CO2 influx into leaves and transpirational water loss and may contribute to future strategies for manipulating gas exchange for improved growth of crop plants and for biomass production.

  15. Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system: news from the world of knockout mice.

    Science.gov (United States)

    Hansen, Pernille B L

    2015-02-15

    Over the years, it has been discussed whether T-type calcium channels Cav3 play a role in the cardiovascular and renal system. T-type channels have been reported to play an important role in renal hemodynamics, contractility of resistance vessels, and pacemaker activity in the heart. However, the lack of highly specific blockers cast doubt on the conclusions. As new T-type channel antagonists are being designed, the roles of T-type channels in cardiovascular and renal pathology need to be elucidated before T-type blockers can be clinically useful. Two types of T-type channels, Cav3.1 and Cav3.2, are expressed in blood vessels, the kidney, and the heart. Studies with gene-deficient mice have provided a way to investigate the Cav3.1 and Cav3.2 channels and their role in the cardiovascular system. This review discusses the results from these knockout mice. Evaluation of the literature leads to the conclusion that Cav3.1 and Cav3.2 channels have important, but different, functions in mice. T-type Cav3.1 channels affect heart rate, whereas Cav3.2 channels are involved in cardiac hypertrophy. In the vascular system, Cav3.2 activation leads to dilation of blood vessels, whereas Cav3.1 channels are mainly suggested to affect constriction. The Cav3.1 channel is also involved in neointima formation following vascular damage. In the kidney, Cav3.1 regulates plasma flow and Cav3.2 plays a role setting glomerular filtration rate. In conclusion, Cav3.1 and Cav3.2 are new therapeutic targets in several cardiovascular pathologies, but the use of T-type blockers should be specifically directed to the disease and to the channel subtype.

  16. Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes

    Science.gov (United States)

    Fares, Hassan; DiNicolantonio, James J; O'Keefe, James H; Lavie, Carl J

    2016-01-01

    Objectives Hypertension is well established as a major risk factor for cardiovascular disease. Although there is undeniable evidence to support the beneficial effects of antihypertensive therapy on morbidity and mortality, adequate blood pressure management still remains suboptimal. Research into the treatment of hypertension has produced a multitude of drug classes with different efficacy profiles. These agents include β-blockers, diuretics, ACE inhibitors, angiotensin receptor blockers and calcium channel blockers. One of the oldest groups of antihypertensives, the calcium channel blockers are a heterogeneous group of medications. Methods This review paper will focus on amlodipine, a dihydropyridine calcium channel blockers, which has been widely used for 2 decades. Results Amlodipine has good efficacy and safety, in addition to strong evidence from large randomised controlled trials for cardiovascular event reduction. Conclusions Amlodipine should be considered a first-line antihypertensive agent.

  17. Role of Calcium Channels in the Protective Effect of Hydrogen Sulfide in Rat Cardiomyoblasts

    Directory of Open Access Journals (Sweden)

    Daniele Avanzato

    2014-04-01

    Full Text Available Background: Hydrogen sulfide contributes to the reduction of oxidative stress-related injury in cardiomyocytes but the underlying mechanism is still unclear. Aims: Here we investigated the role of voltage-operated calcium channels (VOCCs as mediators of the beneficial effect of H2S against oxidative stress in cultured rat cardiomyoblasts (H9c2. Methods: Intracellular calcium signals were measured by fluorimetric live cell imaging and cell viability by colorimetric assay. Results: Treatment with H2S donor (NaHS 10 µM or Nifedipine (10 µM decreased resting intracellular calcium concentration [Ca]i, suggesting that L-type VOCCs are negatively modulated by H2S. In the presence of Nifedipine H2S was still able to lower [Ca]i, while co-incubation with Nifedipine and Ni2+ 100 µM completely prevented H2S-dependent [Ca]i decrease, suggesting that both L-type and T-type VOCCs are inhibited by H2S. In addition, in the same experimental conditions, H2S triggered a slow increase of [Ca]i whose molecular nature remains to be clarified. Pretreatment of H9c2 with NaHS (10 µM significantly prevented cell death induced by H2O2. This effect was mimicked by pretreatment with L-Type calcium channel inhibitor Nifedipine (10 µM. Conclusions: The data provide the first evidence that H2S protects rat cardiomyoblasts against oxidative challenge through the inhibition of L-type calcium channels.

  18. Signal processing by T-type calcium channel interactions in the cerebellum

    Science.gov (United States)

    Engbers, Jordan D. T.; Anderson, Dustin; Zamponi, Gerald W.; Turner, Ray W.

    2013-01-01

    T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (IT) and hyperpolarization-activated cation current (IH) are activated during trains of inhibitory postsynaptic potentials. These currents have distinct, and yet synergistic, roles in the subthreshold domain with IT generating a rebound burst and IH controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing IH to increase the efficacy of IT and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect

  19. Drosophila mushroom body Kenyon cells generate spontaneous calcium transients mediated by PLTX-sensitive calcium channels.

    Science.gov (United States)

    Jiang, Shaojuan Amy; Campusano, Jorge M; Su, Hailing; O'Dowd, Diane K

    2005-07-01

    Spontaneous calcium oscillations in mushroom bodies of late stage pupal and adult Drosophila brains have been implicated in memory consolidation during olfactory associative learning. This study explores the cellular mechanisms regulating calcium dynamics in Kenyon cells, principal neurons in mushroom bodies. Fura-2 imaging shows that Kenyon cells cultured from late stage Drosophila pupae generate spontaneous calcium transients in a cell autonomous fashion, at a frequency similar to calcium oscillations in vivo (10-20/h). The expression of calcium transients is up regulated during pupal development. Although the ability to generate transients is a property intrinsic to Kenyon cells, transients can be modulated by bath application of nicotine and GABA. Calcium transients are blocked, and baseline calcium levels reduced, by removal of external calcium, addition of cobalt, or addition of Plectreurys toxin (PLTX), an insect-specific calcium channel antagonist. Transients do not require calcium release from intracellular stores. Whole cell recordings reveal that the majority of voltage-gated calcium channels in Kenyon cells are PLTX-sensitive. Together these data show that influx of calcium through PLTX-sensitive voltage-gated calcium channels mediates spontaneous calcium transients and regulates basal calcium levels in cultured Kenyon cells. The data also suggest that these calcium transients represent cellular events underlying calcium oscillations in the intact mushroom bodies. However, spontaneous calcium transients are not unique to Kenyon cells as they are present in approximately 60% of all cultured central brain neurons. This suggests the calcium transients play a more general role in maturation or function of adult brain neurons.

  20. Signal processing by T-type calcium channel interactions in the cerebellum

    Directory of Open Access Journals (Sweden)

    Jordan D.T. Engbers

    2013-11-01

    Full Text Available T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs. In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (IT and hyperpolarization-activated cation current (IH are activated during trains of IPSPs. These currents have distinct, and yet synergistic, roles in the subthreshold domain with IT generating a rebound burst and IH controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing IH to increase the efficacy of IT, and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect effects on

  1. Signal processing by T-type calcium channel interactions in the cerebellum.

    Science.gov (United States)

    Engbers, Jordan D T; Anderson, Dustin; Zamponi, Gerald W; Turner, Ray W

    2013-11-27

    T-type calcium channels of the Cav3 family are unique among voltage-gated calcium channels due to their low activation voltage, rapid inactivation, and small single channel conductance. These special properties allow Cav3 calcium channels to regulate neuronal processing in the subthreshold voltage range. Here, we review two different subthreshold ion channel interactions involving Cav3 channels and explore the ability of these interactions to expand the functional roles of Cav3 channels. In cerebellar Purkinje cells, Cav3 and intermediate conductance calcium-activated potassium (IKCa) channels form a novel complex which creates a low voltage-activated, transient outward current capable of suppressing temporal summation of excitatory postsynaptic potentials (EPSPs). In large diameter neurons of the deep cerebellar nuclei, Cav3-mediated calcium current (I T) and hyperpolarization-activated cation current (I H) are activated during trains of inhibitory postsynaptic potentials. These currents have distinct, and yet synergistic, roles in the subthreshold domain with I T generating a rebound burst and I H controlling first spike latency and rebound spike precision. However, by shortening the membrane time constant the membrane returns towards resting value at a faster rate, allowing I H to increase the efficacy of I T and increase the range of burst frequencies that can be generated. The net effect of Cav3 channels thus depends on the channels with which they are paired. When expressed in a complex with a KCa channel, Cav3 channels reduce excitability when processing excitatory inputs. If functionally coupled with an HCN channel, the depolarizing effect of Cav3 channels is accentuated, allowing for efficient inversion of inhibitory inputs to generate a rebound burst output. Therefore, signal processing relies not only on the activity of individual subtypes of channels but also on complex interactions between ion channels whether based on a physical complex or by indirect

  2. T-type calcium channel: a privileged gate for calcium entry and control of adrenal steroidogenesis

    Directory of Open Access Journals (Sweden)

    Michel Florian Rossier

    2016-05-01

    Full Text Available Intracellular calcium plays a crucial role in modulating a variety of functions such as muscle contraction, hormone secretion, gene expression or cell growth. Calcium signaling has been however shown to be more complex than initially thought. Indeed, it is confined within cell microdomains and different calcium channels are associated with different functions, as shown by various channelopathies.Sporadic mutations on voltage-operated L-type calcium channels in adrenal glomerulosa cells have been shown recently to be the second most prevalent genetic abnormalities present in human aldosterone-producing adenoma. The observed modification of the threshold of activation of the mutated channels not only provides an explanation for this gain of function but reminds us on the importance of maintaining adequate electrophysiological characteristics to make channels able to exert specific cellular functions. Indeed, the contribution to steroid production of the various calcium channels expressed in adrenocortical cells is not equal and the reason has been investigated for a long time. Given the very negative resting potential of these cells, and the small membrane depolarization induced by their physiological agonists, low threshold T-type calcium channels are particularly well suited for responding under these conditions and conveying calcium into the cell, at the right place for controlling steroidogenesis. In contrast, high threshold L-type channels are normally activated by much stronger cell depolarizations. The fact that dihydropyridine calcium antagonists, specific for L-type channels, are poorly efficient for reducing aldosterone secretion either in vivo or in vitro, strongly supports the view that these two types of channels differently affect steroid biosynthesis.Whether a similar analysis is transposable to fasciculata cells and cortisol secretion is one of the questions addressed in the present review. No similar mutations on L-type or T

  3. Follicle-stimulating hormone receptor-mediated uptake of sup 45 Ca sup 2+ by proteoliposomes and cultured rat sertoli cells: Evidence for involvement of voltage-activated and voltage-independent calcium channels

    Energy Technology Data Exchange (ETDEWEB)

    Grasso, P.; Reichert, L.E. Jr. (Albany Medical College, NY (USA))

    1989-12-01

    We have previously reported incorporation into liposomes of Triton X-100-solubilized FSH receptor-G-protein complexes derived from purified bovine calf testis membranes. In the present study we have used this model system to show that FSH induces flux of 45Ca2+ into such proteoliposomes in a hormone-specific concentration-dependent manner. FSH, inactivated by boiling, had no stimulatory effect on 45Ca2+ flux, nor did isolated alpha- or beta-subunits of FSH. Addition of GTP (or its analogs 5'-guanylylimidodiphosphate and guanosine-5'-O-(3-thiotriphosphate)) or sodium fluoride (in the presence or absence of GTP or its analogs) failed to induce 45Ca2+ flux into proteoliposomes, suggesting that the uptake of 45Ca2+ was receptor, and not G-protein, related. Voltage-independent (ruthenium red and gadolinium chloride) and voltage-activated (methyoxyverapamil and nifedipine) calcium channel-blocking agents reduced FSH-stimulated 45Ca2+ flux into proteoliposomes to control levels. FSH also induced uptake of 45Ca2+ by cultured rat Sertoli cells. Ruthenium red and gadolinium chloride had no effect on basal levels of 45Ca2+ uptake or estradiol secretion by cultured rat Sertoli cells, nor did methoxyverapamil or nifedipine. All four calcium channel blockers, however, were able to reduce FSH-induced 45Ca2+ uptake to basal levels and FSH-stimulated conversion of androstenedione to estradiol by up to 50%, indicating an involvement of Ca2+ in FSH-stimulated steroidogenesis. Our results suggest that the well documented changes in intracellular calcium levels consequent to FSH binding may be due, at least in part, to an influx of calcium through FSH receptor-regulated calcium channels.

  4. Combining other antihypertensive drugs with β-blockers in hypertension: a focus on safety and tolerability.

    Science.gov (United States)

    Richards, Tiffany R; Tobe, Sheldon W

    2014-05-01

    Combining multiple classes of antihypertensive drugs together is one of the most important factors for achieving blood pressure control in most hypertensive patients. The benefits of combination therapy in comparison with monotherapy include: a synergistic enhancement of each drug's hypertensive effects and a potential reduction of side effects if each drug is used at a lower dose. Although long-acting dihydropyridine calcium channel blockers and β-blockers are a good fit for combination therapy, because of the risk of atrioventricular block and bradycardia, the combination of verapamil and β-blockers is not advised. In addition, the combination of higher-dose diltiazem and β-blockers is also not advised. β-blockers and diuretic agents as initial lone combination therapy are not the preferred combination to be used in uncomplicated hypertension. Using an angiotensin-converting enzyme inhibitor as initial combination therapy with most β-blockers is not recommended because of a lack of antihypertensive efficacy. Nebivolol, however, appears different in this regard and might provide an opportunity for combining these 2 classes of agents with proven cardiovascular benefits for better blood pressure control. Adding an α-blocker to a β-blocker is an effective combination.

  5. Enhanced currents through L-type calcium channels in cardiomyocytes disturb the electrophysiology of the dystrophic heart.

    Science.gov (United States)

    Koenig, Xaver; Rubi, Lena; Obermair, Gerald J; Cervenka, Rene; Dang, Xuan B; Lukacs, Peter; Kummer, Stefan; Bittner, Reginald E; Kubista, Helmut; Todt, Hannes; Hilber, Karlheinz

    2014-02-15

    Duchenne muscular dystrophy (DMD), induced by mutations in the gene encoding for the cytoskeletal protein dystrophin, is an inherited disease characterized by progressive muscle weakness. Besides the relatively well characterized skeletal muscle degenerative processes, DMD is also associated with cardiac complications. These include cardiomyopathy development and cardiac arrhythmias. The current understanding of the pathomechanisms in the heart is very limited, but recent research indicates that dysfunctional ion channels in dystrophic cardiomyocytes play a role. The aim of the present study was to characterize abnormalities in L-type calcium channel function in adult dystrophic ventricular cardiomyocytes. By using the whole cell patch-clamp technique, the properties of currents through calcium channels in ventricular cardiomyocytes isolated from the hearts of normal and dystrophic adult mice were compared. Besides the commonly used dystrophin-deficient mdx mouse model for human DMD, we also used mdx-utr mice, which are both dystrophin- and utrophin-deficient. We found that calcium channel currents were significantly increased, and channel inactivation was reduced in dystrophic cardiomyocytes. Both effects enhance the calcium influx during an action potential (AP). Whereas the AP in dystrophic mouse cardiomyocytes was nearly normal, implementation of the enhanced dystrophic calcium conductance in a computer model of a human ventricular cardiomyocyte considerably prolonged the AP. Finally, the described dystrophic calcium channel abnormalities entailed alterations in the electrocardiograms of dystrophic mice. We conclude that gain of function in cardiac L-type calcium channels may disturb the electrophysiology of the dystrophic heart and thereby cause arrhythmias.

  6. Ryanodine Receptors Selectively Interact with L Type Calcium Channels in Mouse Taste Cells.

    Directory of Open Access Journals (Sweden)

    Michelle R Rebello

    Full Text Available WE REPORTED THAT RYANODINE RECEPTORS ARE EXPRESSED IN TWO DIFFERENT TYPES OF MAMMALIAN PERIPHERAL TASTE RECEPTOR CELLS: Type II and Type III cells. Type II cells lack voltage-gated calcium channels (VGCCs and chemical synapses. In these cells, ryanodine receptors contribute to the taste-evoked calcium signals that are initiated by opening inositol trisphosphate receptors located on internal calcium stores. In Type III cells that do have VGCCs and chemical synapses, ryanodine receptors contribute to the depolarization-dependent calcium influx.The goal of this study was to establish if there was selectivity in the type of VGCC that is associated with the ryanodine receptor in the Type III taste cells or if the ryanodine receptor opens irrespective of the calcium channels involved. We also wished to determine if the ryanodine receptors and VGCCs require a physical linkage to interact or are simply functionally associated with each other. Using calcium imaging and pharmacological inhibitors, we found that ryanodine receptors are selectively associated with L type VGCCs but likely not through a physical linkage.Taste cells are able to undergo calcium induced calcium release through ryanodine receptors to increase the initial calcium influx signal and provide a larger calcium response than would otherwise occur when L type channels are activated in Type III taste cells.

  7. Synergism of ochratoxin B and calcium-channel antagonist verapamil caused mitochondrial dysfunction.

    Science.gov (United States)

    Chatopadhyay, Pronobesh; Tariang, Banlumlang; Agnihotri, Amit; Veer, Vijay

    2014-09-01

    We examined the mechanism by which the ochratoxin B induced interaction with calcium-channel antagonist verapamil and mitochondrial dysfunction of the rat trachea in vitro experiment. The tracheas were cut into 2-3 mm wide rings and suspended in a tissue bath. Isometric tension was continuously measured with an isometric force transducer connected to a computer-based data acquisition system. Verapamil (1 × 10(-6) M) produced a concentration-dependent contraction response in rat's tracheal rings pre-contracted by acetylcholine. Incubation of rat's tracheal rings with the ochratoxin B significantly potentiated the contraction responses of verapamil. Verapamil and OTB accelerate the overloading of Ca(2+) in tracheal smooth muscle contributes the tissue toxicity as shown in electron microscopy and mitochondrial enzymes, through a mechanism that could involve perturbations of Ca(2+) homeostasis. These results proved that ochratoxin B is a potential vasoconstrictor mycotoxin with the presence of calcium-channel antagonist. In conclusion, disturbance of Ca(2+) homeostasis caused by OTA and plays a significant role in produces toxicity through mitochondrial enzyme inhibition.

  8. Genotypic to expression profiling of bovine calcium channel, voltage-dependent, alpha-2/delta subunit 1 gene, and their association with bovine mastitis among Frieswal (HFX Sahiwal) crossbred cattle of Indian origin.

    Science.gov (United States)

    Deb, Rajib; Singh, Umesh; Kumar, Sushil; Kumar, Arun; Singh, Rani; Sengar, Gyanendra; Mann, Sandeep; Sharma, Arjava

    2014-04-01

    Calcium channel, voltage-dependent, alpha-2/delta subunit 1 (CACNA2D1) gene is considered to be an important noncytokine candidate gene influencing mastitis. Scanty of reports are available until today regarding the role play of CACNA2D1 gene on the susceptibility of bovine mastitis. We interrogated the CACNA2D1 G519663A [A>G] SNP by PCR-RFLP among two hundreds Frieswal (HF X Sahiwal) crossbred cattle of Indian origin. Genotypic frequency of AA (51.5, n=101) was comparatively higher than AG (35, n=70) and GG (14.5, n=29). Association of Somatic cell score (SCS) with genotypes revealed that, GG genotypes showing lesser count (less susceptible to mastitis) compare to AA and AG. Relative expression of CACNA2D1 transcript (in milk samples) was significantly higher among GG than AG and AA. Further we have also isolated blood sample from the all groups and PBMCs were cultured from each blood sample as per the standard protocol. They were treated with Calcium channel blocker and the expression level of the CACNA2D1 gene was evaluated by Real Time PCR. Results show that expression level decline in each genotypic group after treatment and expression level of GG are again significantly higher than AA and AG. Thus, it may be concluded that GG genotypic animals are favorable for selecting disease resistant breeds.

  9. Three dimensional neuronal cell cultures more accurately model voltage gated calcium channel functionality in freshly dissected nerve tissue.

    Directory of Open Access Journals (Sweden)

    Yinzhi Lai

    Full Text Available It has been demonstrated that neuronal cells cultured on traditional flat surfaces may exhibit exaggerated voltage gated calcium channel (VGCC functionality. To gain a better understanding of this phenomenon, primary neuronal cells harvested from mice superior cervical ganglion (SCG were cultured on two dimensional (2D flat surfaces and in three dimensional (3D synthetic poly-L-lactic acid (PLLA and polystyrene (PS polymer scaffolds. These 2D- and 3D-cultured cells were compared to cells in freshly dissected SCG tissues, with respect to intracellular calcium increase in response to high K(+ depolarization. The calcium increases were identical for 3D-cultured and freshly dissected, but significantly higher for 2D-cultured cells. This finding established the physiological relevance of 3D-cultured cells. To shed light on the mechanism behind the exaggerated 2D-cultured cells' functionality, transcriptase expression and related membrane protein distributions (caveolin-1 were obtained. Our results support the view that exaggerated VGCC functionality from 2D cultured SCG cells is possibly due to differences in membrane architecture, characterized by uniquely organized caveolar lipid rafts. The practical implication of use of 3D-cultured cells in preclinical drug discovery studies is that such platforms would be more effective in eliminating false positive hits and as such improve the overall yield from screening campaigns.

  10. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development

    Science.gov (United States)

    Cipriani, A; Saunders, K; Attenburrow, M-J; Stefaniak, J; Panchal, P; Stockton, S; Lane, T A; Tunbridge, E M; Geddes, J R; Harrison, P J

    2016-01-01

    l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ‘brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes. PMID:27240535

  11. Regulation of L-type Voltage Gated Calcium Channel CACNA1S in Macrophages upon Mycobacterium tuberculosis Infection.

    Science.gov (United States)

    Antony, Cecil; Mehto, Subhash; Tiwari, Brijendra K; Singh, Yogendra; Natarajan, Krishnamurthy

    2015-01-01

    We demonstrated earlier the inhibitory role played by Voltage Gated Calcium Channels (VGCCs) in regulating Mycobacterium tuberculosis (M. tb) survival and pathogenesis. In this report, we investigated mechanisms and key players that regulate the surface expression of VGCC-CACNA1S by Rv2463 and M. tb infection in macrophages. Our earlier work identified Rv2463 to be expressed at early times post infection in macrophages that induced suppressor responses to dendritic cells and macrophages. Our results in this study demonstrate a role of MyD88 independent TLR pathway in mediating CACNA1S expression. Dissecting the role for second messengers, we show that calcium homeostasis plays a key role in CACNA1S expression during M. tb infection. Using siRNAs against molecular sensors of calcium regulation, we show an involvement of ER associated Stromal Interaction Molecules 1 and 2 (STIM1 and STIM2), and transcription factor pCREB, towards CACNA1S expression that also involved the MyD88 independent pathway. Interestingly, reactive oxygen species played a negative role in M. tb mediated CACNA1S expression. Further, a cross-regulation of ROS and pCREB was noted that governed CACNA1S expression. Characterizing the mechanisms governing CACNA1S expression would improve our understanding of the regulation of VGCC expression and its role in M. tb pathogenesis during M. tb infection.

  12. Reciprocal regulation of reactive oxygen species and phospho-CREB regulates voltage gated calcium channel expression during Mycobacterium tuberculosis infection.

    Directory of Open Access Journals (Sweden)

    Arti Selvakumar

    Full Text Available Our previous work has demonstrated the roles played by L-type Voltage Gated Calcium Channels (VGCC in regulating Mycobacterium tuberculosis (M. tb survival and pathogenesis. Here we decipher mechanisms and pathways engaged by the pathogen to regulate VGCC expression in macrophages. We show that M. tb and its antigen Rv3416 use phospho-CREB (pCREB, Reactive Oxygen Species (ROS, Protein Kinase C (PKC and Mitogen Activated Protein Kinase (MAPK to modulate VGCC expression in macrophages. siRNA mediated knockdown of MyD88, IRAK1, IRAK2 or TRAF6 significantly inhibited antigen mediated VGCC expression. Inhibiting Protein Kinase C (PKC or MEK-ERK1/2 further increased VGCC expression. Interestingly, inhibiting intracellular calcium release upregulated antigen mediated VGCC expression, while inhibiting extracellular calcium influx had no significant effect. siRNA mediated knockdown of transcription factors c-Jun, SOX5 and CREB significantly inhibited Rv3416 mediated VGCC expression. A dynamic reciprocal cross-regulation between ROS and pCREB was observed that in turn governed VGCC expression with ROS playing a limiting role in the process. Further dissection of the mechanisms such as the interplay between ROS and pCREB would improve our understanding of the regulation of VGCC expression during M. tb infection.

  13. Cav1.2, but not Cav1.3, L-type calcium channel subtype mediates nicotine-induced conditioned place preference in miceo.

    Science.gov (United States)

    Liu, Yudan; Harding, Meghan; Dore, Jules; Chen, Xihua

    2017-04-03

    Nicotine use is one of the most common forms of drug addiction. Although L-type calcium channels (LTCCs) are involved in nicotine addiction, the contribution of the two primary LTCC subtypes (Cav1.2 and 1.3) is unknown. This study aims to determine the contribution of these two LTCC subtypes to nicotine-induced conditioned place preference (CPP) responses by using transgenic mouse models that do not express Cav1.3 (Cav1.3(-/-)) or contain a mutation in the dihydropyridine (DHP) site of the Cav1.2 (Cav1.2DHP(-/-)). We found a hyperbolic dose dependent nicotine (0.1-1mg/kg; 0.5mg/kg optimum) effect on place preference in wild type (WT) mice, that could be prevented by the DHP LTCC blocker nifedipine pretreatment. Similarly, Cav1.3(-/-) mice showed nicotine-induced place preference which was antagonized by nifedipine. In contrast, nifedipine pretreatment of Cav1.2DHP(-/-) mice had no effect on nicotine-induced CPP responses, suggesting an involvement of Cav1.2 subtype in the nicotine-induced CPP response. Nifedipine alone failed to produce either conditioned place aversion or CPP in WT mice. These results collectively indicate Cav1.2, but not Cav1.3 LTCC subtype regulates, at least in part, the reinforcing effects of nicotine use.

  14. GABAA increases calcium in subventricular zone astrocyte-like cells through L- and T-type voltage-gated calcium channels

    Directory of Open Access Journals (Sweden)

    Stephanie Z Young

    2010-04-01

    Full Text Available In the adult neurogenic subventricular zone (SVZ, the behavior of astrocyte-like cells and some of their functions depend on changes in intracellular Ca2+ levels and tonic GABAA receptor activation. However, it is unknown whether, and if so how, GABAA receptor activity regulates intracellular Ca2+ dynamics in SVZ astrocytes. To monitor Ca2+ activity selectively in astrocyte-like cells, we used two lines of transgenic mice expressing either GFP fused to a Gq-coupled receptor or DsRed under the human glial fibrillary acidic protein (hGFAP promoter. GABAA receptor activation induced Ca2+ increases in 40-50% of SVZ astrocytes. GABAA-induced Ca2+ increases were prevented with nifedipine and mibefradil, blockers of L- and T-type voltage-gated calcium channels (VGCC. The L-type Ca2+ channel activator BayK 8644 increased the percentage of GABAA-responding astrocyte-like cells to 75%, suggesting that the majority of SVZ astrocytes express functional VGCCs. SVZ astrocytes also displayed spontaneous Ca2+ activity, the frequency of which was regulated by tonic GABAA receptor activation. These data support a role for ambient GABA in tonically regulating intracellular Ca2+ dynamics through GABAA receptors and VGCC in a subpopulation of astrocyte-like cells in the postnatal SVZ.

  15. Hypericum perforatum modulates apoptosis and calcium mobilization through voltage-gated and TRPM2 calcium channels in neutrophil of patients with Behcet's disease.

    Science.gov (United States)

    Nazıroğlu, Mustafa; Sahin, Mehmet; Ciğ, Bilal; Aykur, Mehmet; Erturan, Ijlal; Ugan, Yunus

    2014-03-01

    Behcet's disease (BD) is a chronic, inflammatory, and multisystemic condition although its pathogenesis is uncertain. Main component of St. John's wort (Hypericum perforatum, HP) is hyperforin and induces antiinflammatory and antioxidant properties. We aimed to investigate effects of HP on oxidative stress, apoptosis, and cytosolic-free Ca²⁺ [Ca²⁺](i) concentration in neutrophil of BD patients. Nine new-diagnosed active patients with BD and nine control subjects were included in the study. Disease activity was considered by clinical findings. Neutrophil samples were obtained from the patients and controls. The neutrophils from patients were divided into three subgroups and were incubated with HP, voltage-gated calcium channel (VGCC) blockers, (verapamil+dilitiazem) and non-specific TRPM2 channel blocker (2-aminoethyl diphenylborinate, 2-APB), respectively. The neutrophils were stimulated by fMLP as a Ca²⁺-concentration agonist and oxidative stress former. Caspase-3, caspase-9, apoptosis, lipid peroxidation, and [Ca²⁺](i) values were high in the patient groups, although cell viability, glutathione (GSH), and glutathione peroxidase (GSH-Px) values were low in patient group. However, the [Ca²⁺](i), caspase-3, and caspase-9 values decreased markedly in patient+HP group although GSH and GSH-Px values increased in the group. The [Ca²⁺](i) concentration was also decreased in the patient group by V+D, 2-APB, and HP incubations. In conclusion, we observed the importance of neutrophil Ca²⁺ entry, apoptosis, and oxidative stress through gating VGCC and TRPM2 channels in the neutrophils in the pathogenesis and activation of the patients with BD. HP induced protective effects on oxidative stress by modulating Ca²⁺ influx in BD patients.

  16. Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Zhi-ying LIN; Li-min CHEN; Jing ZHANG; Xiao-dong PAN; Yuan-gui ZHU; Qin-yong YE; Hua-pin HUANG; Xiao-chun CHEN

    2012-01-01

    Aim:To investigate the effect of ginsenoside Rb1 on voltage-gated calcium currents in cultured rat hippocampal neurons and the modulatory mechanism.Methods:Cultured hippocampal neurons were prepared from Sprague Dawley rat embryos.Whole-cell configuration of the patchclamp technique was used to record the voltage-gated calcium currents (VGCCs)from the hippocampal neurons,and the effect of Rb1 was examined.Results:Rb1 (2-100 μmol/L)inhibited VGCCs in a concentration-dependent manner,and the current was mostly recovered upon wash-out.The specific L-type Ca2+ channel inhibitor nifedipine (10 μmol/L)occluded Rb1-induced inhibition on VGCCs.Neither the selective N-type Ca2+ channel blocker ω-conotoxin-GVlA (1 μmoVL),nor the selective P/Q-type Ca2+ channel blocker ωo-agatoxin IVA (30 nmol/L)diminished Rb1-sensitive VGCCs.Rb1 induced a leftward shift of the steady-state inactivation curve of Ica to a negative potential without affecting its activation kinetics or reversal potential in the I-V curve.The inhibitory effect of Rb1 was neither abolished by the adenylyl cyclase activator forskolin (10 μmol/L),nor by the PKA inhibitor H-89 (10 μmol/L).Conclusion:Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels,without affecting the N-type or P/Q-type Ca2+ channels in hippocampal neurons,cAMP-PKA signaling pathway is not involved in this effect.

  17. Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4: Alpha blockers v calcium blockers to increase spontaneous passage of renal calculi.

    Science.gov (United States)

    Stewart, Alexander; Ferguson, Craig

    2013-02-01

    A short cut review was carried out to establish the administration of an alpha-1 receptor antagonist or a calcium channel blocker would facilitate the most rapid and successful expulsion of a stone from a patient with uncomplicated renal colic. 597 articles were found using the reported search, of which five trials were selected as providing the best evidence to answer this question. The authors, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. It is concluded that in a patient with an uncomplicated ureteric calculus tamsulosin is more effective than nifedipine in promoting speedy and successful expulsion of the stone.

  18. Long-Term Blocking of Calcium Channels in mdx Mice Results in Differential Effects on Heart and Skeletal Muscle

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Blain, Alison; Greally, Elizabeth;

    2011-01-01

    calcium ions to enter the cell. The objective of this study was to investigate the effect of chronically blocking calcium channels with the aminoglycoside antibiotic streptomycin from onset of disease in the mdx mouse model of Duchenne muscular dystrophy (DMD). Treatment in utero onwards delayed onset...... in older mice. However, streptomycin treatment did not show positive effects in diaphragm or heart muscle, and heart pathology was worsened. Thus, blocking calcium channels even before disease onset does not prevent dystrophy, making this an unlikely treatment for DMD. These findings highlight...

  19. Osteoblasts detect pericellular calcium concentration increase via neomycin-sensitive voltage gated calcium channels.

    Science.gov (United States)

    Sun, Xuanhao; Kishore, Vipuil; Fites, Kateri; Akkus, Ozan

    2012-11-01

    The mechanisms underlying the detection of critically loaded or micro-damaged regions of bone by bone cells are still a matter of debate. Our previous studies showed that calcium efflux originates from pre-failure regions of bone matrix and MC3T3-E1 osteoblasts respond to such efflux by an increase in the intracellular calcium concentration. The mechanisms by which the intracellular calcium concentration increases in response to an increase in the pericellular calcium concentration are unknown. Elevation of the intracellular calcium may occur via release from the internal calcium stores of the cell and/or via the membrane bound channels. The current study applied a wide range of pharmaceutical inhibitors to identify the calcium entry pathways involved in the process: internal calcium release from endoplasmic reticulum (ER, inhibited by thapsigargin and TMB-8), calcium receptor (CaSR, inhibited by calhex), stretch-activated calcium channel (SACC, inhibited by gadolinium), voltage-gated calcium channels (VGCC, inhibited by nifedipine, verapamil, neomycin, and ω-conotoxin), and calcium-induced-calcium-release channel (CICRC, inhibited by ryanodine and dantrolene). These inhibitors were screened for their effectiveness to block intracellular calcium increase by using a concentration gradient induced calcium efflux model which mimics calcium diffusion from the basal aspect of cells. The inhibitor(s) which reduced the intracellular calcium response was further tested on osteoblasts seeded on mechanically loaded notched cortical bone wafers undergoing damage. The results showed that only neomycin reduced the intracellular calcium response in osteoblasts, by 27%, upon extracellular calcium stimulus induced by concentration gradient. The inhibitory effect of neomycin was more pronounced (75% reduction in maximum fluorescence) for osteoblasts seeded on notched cortical bone wafers loaded mechanically to damaging load levels. These results imply that the increase in

  20. Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients.

    Science.gov (United States)

    Shimada, S; Nakajima, Y; Yamamoto, K; Sawada, Y; Iga, T

    1996-03-01

    The relationships between plasma drug concentration and antihypertensive effect of eight calcium channel antagonists (nicardipine, nifedipine, nilvadipine, benidipine, manidipine, barnidipine, nitrendipine and efonidipine) in Japanese essential hypertensive patients were analyzed. Based on the effect compartment model, we could explain the long duration of the pharmacological effect, and there was significant correlation (r = 0.876, p < 0.05) between estimated EC50 values and the dissociation constants (Kd) obtained from in vitro binding studies. We also developed the ion-channel binding model to understand the pharmacodynamics of long acting calcium antagonists. The model was also well fitted to antihypertensive effect data. A significant correlation between the apparent in vivo dissociation constants and in vitro Kd values was observed with a slope of 1.45 (r = 0.913), suggesting that the mechanism of long-lasting antihypertensive effect of newer developed calcium antagonists is due to their high binding affinity at ion-channel sites.

  1. Mechanism of Action of Novel Glibenclamide Derivatives on Potassium and Calcium Channels for Insulin Secretion.

    Science.gov (United States)

    Frederico, Marisa Jádson Silva; Castro, Allisson Jhonatan Gomes; Menegaz, Danusa; De Bernardis Murat, Cahuê; Mendes, Camila Pires; Mascarello, Alessandra; Nunes, Ricardo José; Silva, Fátima Regina Mena Barreto

    2016-06-14

    Glibenclamide is widely used and remains a cornerstone and an effective antihyperglycemic drug. After the casual discovery of its hypoglycemic potential, this compound was introduced for diabetes treatment. However, the long-term side effects reveal that glibenclamide should be replaced by new molecules able to maintain the health of β-cells, protecting them from hyperstimulation/hyperexcitability, hyperinsulinemia, functional failure and cell death. The aim of this review was to highlight the main mechanism of action of glibenclamide and the influence of its derivatives, such as acyl-hydrazones, sulfonamides and sulfonylthioureas on β-cells potassium and calcium channels for insulin secretion as well as the contribution of these new compounds to restore glucose homeostasis. Furthermore, the role of glibenclamide-based novel structures that promise less excitability of β-cell in a long-term treatment with effectiveness and safety for diabetes therapy was discussed.

  2. Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart

    NARCIS (Netherlands)

    Schultz, D; Mikala, G; Yatani, A; Engle, D B; Iles, D E; Segers, B; Sinke, R J; Weghuis, D O; Klöckner, U; Wakamori, M

    1993-01-01

    A unique structural variant of the cardiac L-type voltage-dependent calcium channel alpha 1 subunit cDNA was isolated from libraries derived from normal human heart mRNA. The deduced amino acid sequence shows significant homology to other calcium channel alpha 1 subunits. However, differences from t

  3. Correlated ions in a calcium channel model: a Poisson-Fermi theory.

    Science.gov (United States)

    Liu, Jinn-Liang; Eisenberg, Bob

    2013-10-10

    We derive a continuum model, called the Poisson-Fermi equation, of biological calcium channels (of cardiac muscle, for example) designed to deal with crowded systems in which ionic species and side chains nearly fill space. The model is evaluated in three dimensions. It includes steric and correlation effects and is derived from classical hard-sphere lattice models of configurational entropy of finite size ions and solvent molecules. The maximum allowable close packing (saturation) condition is satisfied by all ionic species with different sizes and valences in a channel system, as shown theoretically and numerically. Unphysical overcrowding ("divergence") predicted by the Gouy-Chapman diffuse model (produced by a Boltzmann distribution of point charges with large potentials) does not occur with the Fermi-like distribution. Using probability theory, we also provide an analytical description of the implicit dielectric model of ionic solutions that gives rise to a global and a local formula for the chemical potential. In this primitive model, ions are treated as hard spheres and solvent molecules are described as a dielectric medium. The Poisson-Fermi equation is a local formula dealing with different correlations at different places. The correlation effects are apparent in our numerical results. Our results show variations of dielectric permittivity from bath to channel pore described by a new dielectric function derived as an output from the Poisson-Fermi analysis. The results are consistent with existing theoretical and experimental results. The binding curve of Poisson-Fermi is shown to match Monte Carlo data and illustrates the anomalous mole fraction effect of calcium channels, an effective blockage of permeation of sodium ions by a tiny concentration (or number) of calcium ions.

  4. Changes of neuronal calcium channel following brain damage induced by injection of pertussis bacilli in rats

    Institute of Scientific and Technical Information of China (English)

    陈立华; 于嘉; 刘丽旭; 曹美鸿

    2002-01-01

    To explore changes of neuronal calcium channel following brain damage induced by injection of pertussis bacilli in rats, and to investigate the relationship between cytosolic free calcium concentration ( [ Ca2 + ] i ) in the synaptosome and Ca2 + -ATPase activities of mitochondria. Methods: The level of [ Ca2+ ]i in the synaptosome and Ca2+ -ATPase activities of mitochondria in the acute brain damage induced by injection of pertussis bacilli (PB)in rat was determined and nimodipine was administrated to show its effects on [ Ca2+ ]i in the synaptosome and on alteration of Ca2+ -ATPase activity in the mitochondria.Seventy-three rats were randomly divided into four groups,ie, normal control group (Group A ), sham-operation control group (Group B), PB group (Group C) and nimodipine treatment group (Group D). Results: The level of [ Ca2+ ]i was significantly increased in the PB-injected cerebral hemisphere in the Group C as compared with that in the Group A and the Group B at 30 minutes after injection of PB. The level of [ Ca2+ ]i was kept higher in the 4 hours and 24 hours subgroups after the injection in the Group C ( P < 0.05).In contrast, the Ca2+ -ATPase activities were decreased remarkably among all of the subgroups in the Group C.Nimodipine, which was administered after injection of PB,could significantly decrease the [ Ca2+ ]i and increase the activity of Ca2 + -ATPase ( P < 0.05 ). Conclusions: The neuronal calcium channel is opened after injection of PB. There is a negative correlation between activities of Ca2 +-ATPase and [ Ca2 + ]i.Nimodipine can reduce brain damage through stimulating the activities of Ca2+ -ATPase in the mitochondria, and decrease the level of [ Ca2+ ]i in the synaptosome.Treatment with nimodipine dramatically reduces the effects of brain damage induced by injection of PB.

  5. Anti-Convulsant Activity of Boerhaavia diffusa: Plausible Role of Calcium Channel Antagonism

    Directory of Open Access Journals (Sweden)

    Mandeep Kaur

    2011-01-01

    Full Text Available “Ethnopharmacological” use of roots of Boerhaavia diffusa (B. diffusa in the treatment of epilepsy in Nigerian folk medicine and reports showing the presence of a calcium channel antagonistic compound “liriodendrin” in its roots, led us to undertake the present study. The study was designed to investigate the methanolic root extract of B. diffusa and its different fractions including liriodendrin-rich fraction for exploring the possible role of liriodendrin in its anti-convulsant activity. Air-dried roots of B. diffusa were extracted with methanol by cold maceration. The methanol soluble fraction of extract thus obtained was successively extracted to obtain liriodendrin-rich fraction and two side fractions, that is, chloroform fraction and phenolic compound fraction. Anti-convulsant activity of methanolic extract (1000, 1500 and 2000 mg kg-1, intraperitoneally (i.p. and its different fractions, that is, liriodendrin-rich fraction (10, 20 and 40 mg kg-1, i.p., chloroform fraction (20 mg kg-1, i.p. and phenolic compound fraction (1 mg kg-1, i.p. were studied in pentylenetetrazol (PTZ-induced seizures (75 mg kg-1, i.p.. The crude methanolic extract of B. diffusa and only its liriodendrin-rich fraction showed a dose-dependent protection against PTZ-induced convulsions. The liriodendrin-rich fraction also showed significant protection against seizures induced by BAY k-8644. These findings reiterated the anti-convulsant activity of methanolic extract of B. diffusa roots. Furthermore, it can be concluded that the observed anti-convulsant activity was due to its calcium channel antagonistic action as this activity was retained only in the liodendrin-rich fraction, which has additionally been confirmed by significant anti-convulsant activity of liriodendrin-rich fraction in BAY k-8644-induced seizures.

  6. Anti-Convulsant Activity of Boerhaavia diffusa: Plausible Role of Calcium Channel Antagonism.

    Science.gov (United States)

    Kaur, Mandeep; Goel, Rajesh Kumar

    2011-01-01

    "Ethnopharmacological" use of roots of Boerhaavia diffusa (B. diffusa) in the treatment of epilepsy in Nigerian folk medicine and reports showing the presence of a calcium channel antagonistic compound "liriodendrin" in its roots, led us to undertake the present study. The study was designed to investigate the methanolic root extract of B. diffusa and its different fractions including liriodendrin-rich fraction for exploring the possible role of liriodendrin in its anti-convulsant activity. Air-dried roots of B. diffusa were extracted with methanol by cold maceration. The methanol soluble fraction of extract thus obtained was successively extracted to obtain liriodendrin-rich fraction and two side fractions, that is, chloroform fraction and phenolic compound fraction. Anti-convulsant activity of methanolic extract (1000, 1500 and 2000 mg kg(-1), intraperitoneally (i.p.)) and its different fractions, that is, liriodendrin-rich fraction (10, 20 and 40 mg kg(-1), i.p., chloroform fraction (20 mg kg(-1), i.p.) and phenolic compound fraction (1 mg kg(-1), i.p.) were studied in pentylenetetrazol (PTZ)-induced seizures (75 mg kg(-1), i.p.). The crude methanolic extract of B. diffusa and only its liriodendrin-rich fraction showed a dose-dependent protection against PTZ-induced convulsions. The liriodendrin-rich fraction also showed significant protection against seizures induced by BAY k-8644. These findings reiterated the anti-convulsant activity of methanolic extract of B. diffusa roots. Furthermore, it can be concluded that the observed anti-convulsant activity was due to its calcium channel antagonistic action as this activity was retained only in the liodendrin-rich fraction, which has additionally been confirmed by significant anti-convulsant activity of liriodendrin-rich fraction in BAY k-8644-induced seizures.

  7. Lavender oil-potent anxiolytic properties via modulating voltage dependent calcium channels.

    Science.gov (United States)

    Schuwald, Anita M; Nöldner, Michael; Wilmes, Thomas; Klugbauer, Norbert; Leuner, Kristina; Müller, Walter E

    2013-01-01

    Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs) as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, biochemical, and electrophysiological experiments were investigated in physiological concentrations in the nanomolar range, which correlate to a single dosage of 80 mg/d in humans that was used in clinical trials. We show for the first time that lavender oil bears some similarities with the established anxiolytic pregabalin. Lavender oil inhibits VOCCs in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines in the same range such as pregabalin. Interestingly, Silexan does not primarily bind to P/Q type calcium channels such as pregabalin and does not interact with the binding site of pregabalin, the α2δ subunit of VOCCs. Lavender oil reduces non-selectively the calcium influx through several different types of VOCCs such as the N-type, P/Q-type and T-type VOCCs. In the hippocampus, one brain region important for anxiety disorders, we show that inhibition by lavender oil is mainly mediated via N-type and P/Q-type VOCCs. Taken together, we provide a pharmacological and molecular rationale for the clinical use of the oral application of lavender oil in patients suffering from anxiety.

  8. Lavender oil-potent anxiolytic properties via modulating voltage dependent calcium channels.

    Directory of Open Access Journals (Sweden)

    Anita M Schuwald

    Full Text Available Recent clinical data support the clinical use of oral lavender oil in patients suffering from subsyndromal anxiety. We identified the molecular mechanism of action that will alter the perception of lavender oil as a nonspecific ingredient of aromatherapy to a potent anxiolytic inhibiting voltage dependent calcium channels (VOCCs as highly selective drug target. In contrast to previous publications where exorbitant high concentrations were used, the effects of lavender oil in behavioral, biochemical, and electrophysiological experiments were investigated in physiological concentrations in the nanomolar range, which correlate to a single dosage of 80 mg/d in humans that was used in clinical trials. We show for the first time that lavender oil bears some similarities with the established anxiolytic pregabalin. Lavender oil inhibits VOCCs in synaptosomes, primary hippocampal neurons and stably overexpressing cell lines in the same range such as pregabalin. Interestingly, Silexan does not primarily bind to P/Q type calcium channels such as pregabalin and does not interact with the binding site of pregabalin, the α2δ subunit of VOCCs. Lavender oil reduces non-selectively the calcium influx through several different types of VOCCs such as the N-type, P/Q-type and T-type VOCCs. In the hippocampus, one brain region important for anxiety disorders, we show that inhibition by lavender oil is mainly mediated via N-type and P/Q-type VOCCs. Taken together, we provide a pharmacological and molecular rationale for the clinical use of the oral application of lavender oil in patients suffering from anxiety.

  9. The cardiac L-type calcium channel distal carboxy terminus autoinhibition is regulated by calcium.

    Science.gov (United States)

    Crump, Shawn M; Andres, Douglas A; Sievert, Gail; Satin, Jonathan

    2013-02-01

    The L-type calcium channel (LTCC) provides trigger Ca(2+) for sarcoplasmic reticulum Ca-release, and LTCC function is influenced by interacting proteins including the LTCC distal COOH terminus (DCT) and calmodulin. DCT is proteolytically cleaved and reassociates with the LTCC complex to regulate calcium channel function. DCT reduces LTCC barium current (I(Ba,L)) in reconstituted channel complexes, yet the contribution of DCT to LTCC Ca(2+) current (I(Ca,L)) in cardiomyocyte systems is unexplored. This study tests the hypothesis that DCT attenuates cardiomyocyte I(Ca,L). We measured LTCC current and Ca(2+) transients with DCT coexpressed in murine cardiomyocytes. We also heterologously coexpressed DCT and Ca(V)1.2 constructs with truncations corresponding to the predicted proteolytic cleavage site, Ca(V)1.2Δ1801, and a shorter deletion corresponding to well-studied construct, Ca(V)1.2Δ1733. DCT inhibited I(Ba,L) in cardiomyocytes, and in human embryonic kidney (HEK) 293 cells expressing Ca(V)1.2Δ1801 and Ca(V)1.2Δ1733. Ca(2+)-CaM relieved DCT block in cardiomyocytes and HEK cells. The selective block of I(Ba,L) combined with Ca(2+)-CaM effects suggested that DCT-mediated blockade may be relieved under conditions of elevated Ca(2+). We therefore tested the hypothesis that DCT block is dynamic, increasing under relatively low Ca(2+), and show that DCT reduced diastolic Ca(2+) at low stimulation frequencies but spared high frequency Ca(2+) entry. DCT reduction of diastolic Ca(2+) and relief of block at high pacing frequencies and under conditions of supraphysiological bath Ca(2+) suggests that a physiological function of DCT is to increase the dynamic range of Ca(2+) transients in response to elevated pacing frequencies. Our data motivate the new hypothesis that DCT is a native reverse use-dependent inhibitor of LTCC current.

  10. The involvement of the Mid1/Cch1/Yvc1 calcium channels in Aspergillus fumigatus virulence.

    Directory of Open Access Journals (Sweden)

    Patrícia Alves de Castro

    Full Text Available Aspergillus fumigatus is a major opportunistic pathogen and allergen of mammals. Calcium homeostasis and signaling is essential for numerous biological processes and also influences A. fumigatus pathogenicity. The presented study characterized the function of the A. fumigatus homologues of three Saccharomyces cerevisiae calcium channels, voltage-gated Cch1, stretch-activated Mid1 and vacuolar Yvc1. The A. fumigatus calcium channels cchA, midA and yvcA were regulated at transcriptional level by increased calcium levels. The YvcA::GFP fusion protein localized to the vacuoles. Both ΔcchA and ΔmidA mutant strains showed reduced radial growth rate in nutrient-poor minimal media. Interestingly, this growth defect in the ΔcchA strain was rescued by the exogenous addition of CaCl2. The ΔcchA, ΔmidA, and ΔcchA ΔmidA strains were also sensitive to the oxidative stress inducer, paraquat. Restriction of external Ca(2+ through the addition of the Ca(2+-chelator EGTA impacted upon the growth of the ΔcchA and ΔmidA strains. All the A. fumigatus ΔcchA, ΔmidA, and ΔyvcA strains demonstrated attenuated virulence in a neutropenic murine model of invasive pulmonary aspergillosis. Infection with the parental strain resulted in a 100% mortality rate at 15 days post-infection, while the mortality rate of the ΔcchA, ΔmidA, and ΔyvcA strains after 15 days post-infection was only 25%. Collectively, this investigation strongly indicates that CchA, MidA, and YvcA play a role in A. fumigatus calcium homeostasis and virulence.

  11. Beta-blockers

    DEFF Research Database (Denmark)

    Arboe, Bente; Ulrik, Charlotte Suppli

    2013-01-01

    Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.......Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma....

  12. Functional and pharmacological consequences of the distribution of voltage-gated calcium channels in the renal blood vessels

    DEFF Research Database (Denmark)

    Hansen, P B L

    2013-01-01

    -type is usually associated with vascular contractility. However, the L-, T- and P-/Q-types of calcium channels are present in the renal vasculature and are differentially involved in controlling vascular contractility, thereby contributing to regulation of kidney function and blood pressure. In the preglomerular...

  13. Dopamine Induces LTP Differentially in Apical and Basal Dendrites through BDNF and Voltage-Dependent Calcium Channels

    Science.gov (United States)

    Navakkode, Sheeja; Sajikumar, Sreedharan; Korte, Martin; Soong, Tuck Wah

    2012-01-01

    The dopaminergic modulation of long-term potentiation (LTP) has been studied well, but the mechanism by which dopamine induces LTP (DA-LTP) in CA1 pyramidal neurons is unknown. Here, we report that DA-LTP in basal dendrites is dependent while in apical dendrites it is independent of activation of L-type voltage-gated calcium channels (VDCC).…

  14. Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system

    DEFF Research Database (Denmark)

    Amrutkar, D V; Ploug, K B; Olesen, J;

    2011-01-01

    Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are i...

  15. The effects of S4 segments on the voltage-dependence of inactivation for Cav3.1 calcium channels

    Institute of Scientific and Technical Information of China (English)

    LI JunYing

    2007-01-01

    T-type calcium channels exhibit fast voltage-dependent inactivation,for which the underlying structure-function relationship still remains unclear.To investigate the roles of S4 segments in voltage-dependent inactivation of T-type calcium channels,we created S4 replacement chimeras between Cav3.1 calcium channels(fast voltage-dependent inactivation)and Cav1.2 calcium channels(little oltage-dependent inactivation)by replacing S4s in Cav3.1 with the corresponding regions in Cav1.2.Wild type and chimeric channels were expressed in Xenopus oocytes and channel currents were recorded with two-electrode voltage-clamp.We showed that replacing S4 region in domain I shifted voltage-dependence for inactivation of Cav3.1 to the left,and the V0.5 inact and kinact value were significantly changed.However replacing S4s in domains Ⅱ-Ⅳ had no effects on the voltage-dependent inactivation properties.These results suggest that the roles of S4 segments in domains Ⅰ-Ⅳ are different,and S4 in domain I is likely to be involved in voltage-dependent Inactivation process.Its movement during membrane depolarization may trigger a conformational change in the inactivation gate.

  16. Immunogenicity of P/Q-type calcium channel in small cell lung cancer: investigation of alpha1 subunit polyglutamine expansion.

    Science.gov (United States)

    Black, J L; Nelson, T R; Snow, K; Lennon, V A

    1999-12-01

    The ectopic expression of neuronal P/Q-type voltage-gated calcium channels in small cell lung carcinoma (SCLC) is thought to induce antisynaptic autoimmunity in the paraneoplastic Lambert-Eaton myasthenic syndrome. The gene CACNL1A4, encoding the principal (alpha1A) subunit of this calcium channel, is mutated in several inherited neurological disorders. One of these disorders (spinocerebellar ataxia, type 6, or SCA-6) involves the expansion of a trinucleotide (CAG) repeat unit. We hypothesized that a somatic CAG repeat instability of this gene in neoplastic cells might generate a non-self epitope capable of initiating autoimmunity to P/Q-type calcium channels. We therefore analyzed the CACNL1A4 gene in SCLC lines established from metastases derived from seven individual patients (four associated with Lambert-Eaton myasthenic syndrome, one associated with myasthenia gravis, and two not associated with neurological autoimmunity). We compared their CAG repeat numbers (determined by polymerase chain reaction (PCR) amplification followed by separation of products on a 6% polyacrylamide/8M urea gel) to published norms and to DNA from a patient with SCA-6. The number of CAG repeats in SCLC DNA fell within a normal range whether or not the neoplasm was complicated by neurological autoimmunity. Therefore, it is unlikely that somatically unstable CAG repeat units in the gene encoding the P/Q-type voltage-gated calcium channel account for this tumor protein's immunogenicity in the Lambert-Eaton myasthenic syndrome.

  17. A role for L-type calcium channels in the maturation of parvalbumin-containing hippocampal interneurons.

    Science.gov (United States)

    Jiang, M; Swann, J W

    2005-01-01

    While inhibitory interneurons are well recognized to play critical roles in the brain, relatively little is know about the molecular events that regulate their growth and differentiation. Calcium ions are thought to be important in neuronal development and L-type voltage gated Ca(+2) channels have been implicated in activity-dependent mechanisms of early-life. However, few studies have examined the role of these channels in the maturation of interneurons. The studies reported here were conducted in hippocampal slice cultures and indicate that the L-type Ca(+2) channel agonists and antagonists accelerate and suppress respectively the growth of parvalbumin-containing interneurons. The effects of channel blockade were reversible suggesting they are not the result of interneuronal cell death. Results from immunoblotting showed that these drugs have similar effects on the expression of the GABA synthetic enzymes, glutamic acid decarboxylase65, glutamic acid decarboxylase67 and the vesicular GABA transporter. This suggests that L-type Ca(+2) channels regulate not only parvalbumin expression but also interneuron development. These effects are likely mediated by actions on the interneurons themselves since the alpha subunits of L-type channels, voltage-gated calcium channel subunit 1.2 and voltage-gated calcium channel subunit 1.3 were found to be highly expressed in neonatal mouse hippocampus and co-localized with parvalbumin in interneurons. Results also showed that while these interneurons can contain either subunit, voltage-gated calcium channel subunit 1.3 was more widely expressed. Taken together results suggest that an important subset of developing interneurons expresses L-type Ca(+2) channels alpha subunits, voltage-gated calcium channel subunit 1.2 and especially voltage-gated calcium channel subunit 1.3 and that these channels likely regulate the development of these interneurons in an activity-dependent manner.

  18. Brain death provokes very acute alteration in myocardial morphology detected by echocardiography: preventive effect of beta-blockers.

    Science.gov (United States)

    Ferrera, René; Hadour, Guylaine; Tamion, Fabienne; Henry, Jean-Paul; Mulder, Paul; Richard, Vincent; Thuillez, Christian; Ovize, Michel; Derumeaux, Geneviève

    2011-03-01

    Our objective was to evaluate immediate acute changes in myocardial function during the autonomic storm of brain death (BD). Wistar rats were divided into four groups (n = 8/group): controls without any treatment, β-blocker (Esmolol®, 10 mg/kg), calcium channel blocker (Diltiazem®, 10 mg/kg), or alpha-blocker (Prazosin®, 0.3 mg/kg). Treatments were administered intravenously 5 min before BD induction. Echocardiography (ATL-5000, 8 MHz) was performed to measure left ventricular (LV) dimensions and fractional shortening at baseline, during BD induction and 5 min and 15 min after BD. In controls, BD was immediately associated with an increase in wall thickness and a decrease in LV cavity dimension. This myocardial wall hypertrophy was completely prevented by β-blockers, but not with calcium- and alpha-blockers. Extensive myocardial interstitial edema was found in all groups, except in the β-blocker group. Myocardial wall hypertrophy was also prevented during a longer follow-up of 180 min after BD in β-blocker group as opposed to controls. In conclusion, BD is associated with an immediate and severe myocardial damage related to an important interstitial edema which is prevented by β-blockers.

  19. Defining the role of calcium channel antagonists in heart failure due to systolic dysfunction.

    Science.gov (United States)

    Mahé, Isabelle; Chassany, Olivier; Grenard, Anne-Sophie; Caulin, Charles; Bergmann, Jean-François

    2003-01-01

    Calcium channel antagonists (CCAs) may either be divided into the dihydropyridines (e.g. amlodipine, felodipine, isradipine, lacidipine, nilvadipine, nifedipine, nicardipine etc.), the phenylalkylamines (e.g. verapamil) and the benzothiazepines (e.g. diltiazem) according to their chemical structure, or into first generation agents (nifedipine, verapamil and diltiazem) and second generation agents (subsequently developed dihydropyridine-derivatives). Second generation CCAs are characterized by greater selectivity for calcium channels in vascular smooth muscle cells than the myocardium, a longer duration of action and a small trough-to-peak variation in plasma concentrations. Heart failure is characterized by decreased cardiac output resulting in inadequate oxygen delivery to peripheral tissues. Although the accompanying neurohormonal activation, leading to vasoconstriction and increased blood pressure, is initially beneficial in increasing tissue perfusion, prolonged activation is detrimental because it increases afterload and further reduces cardiac output. At the level of the myocyte, heart failure is associated with increased intracellular calcium levels which are thought to impair diastolic function. These changes indicate that the CCAs would be beneficial in patients with heart failure. There has been a strong interest and increasing experience in the use of CCAs in patients with heart failure. Despite potential beneficial effects in initial small trials, findings from larger trials suggest that CCA may have detrimental effects upon survival and cardiovascular events. However, this may not necessarily be a 'class b' effect of the CCAs as there is considerable heterogeneity in the chemical structure of individual agents. Clinical experience with different CCAs in patients with heart failure includes trials that evaluated their effects on hemodynamic parameters, exercise tolerance and on symptomatology. However, the most relevant results are those from randomized

  20. NALCN ion channels have alternative selectivity filters resembling calcium channels or sodium channels.

    Directory of Open Access Journals (Sweden)

    Adriano Senatore

    Full Text Available NALCN is a member of the family of ion channels with four homologous, repeat domains that include voltage-gated calcium and sodium channels. NALCN is a highly conserved gene from simple, extant multicellular organisms without nervous systems such as sponges and placozoans and mostly remains a single gene compared to the calcium and sodium channels which diversified into twenty genes in humans. The single NALCN gene has alternatively-spliced exons at exons 15 or exon 31 that splices in novel selectivity filter residues that resemble calcium channels (EEEE or sodium channels (EKEE or EEKE. NALCN channels with alternative calcium, (EEEE and sodium, (EKEE or EEKE -selective pores are conserved in simple bilaterally symmetrical animals like flatworms to non-chordate deuterostomes. The single NALCN gene is limited as a sodium channel with a lysine (K-containing pore in vertebrates, but originally NALCN was a calcium-like channel, and evolved to operate as both a calcium channel and sodium channel for different roles in many invertebrates. Expression patterns of NALCN-EKEE in pond snail, Lymnaea stagnalis suggest roles for NALCN in secretion, with an abundant expression in brain, and an up-regulation in secretory organs of sexually-mature adults such as albumen gland and prostate. NALCN-EEEE is equally abundant as NALCN-EKEE in snails, but is greater expressed in heart and other muscle tissue, and 50% less expressed in the brain than NALCN-EKEE. Transfected snail NALCN-EEEE and NALCN-EKEE channel isoforms express in HEK-293T cells. We were not able to distinguish potential NALCN currents from background, non-selective leak conductances in HEK293T cells. Native leak currents without expressing NALCN genes in HEK-293T cells are NMDG(+ impermeant and blockable with 10 µM Gd(3+ ions and are indistinguishable from the hallmark currents ascribed to mammalian NALCN currents expressed in vitro by Lu et al. in Cell. 2007 Apr 20;129(2:371-83.

  1. Microdamage induced calcium efflux from bone matrix activates intracellular calcium signaling in osteoblasts via L-type and T-type voltage-gated calcium channels.

    Science.gov (United States)

    Jung, Hyungjin; Best, Makenzie; Akkus, Ozan

    2015-07-01

    Mechanisms by which bone microdamage triggers repair response are not completely understood. It has been shown that calcium efflux ([Ca(2+)]E) occurs from regions of bone undergoing microdamage. Such efflux has also been shown to trigger intracellular calcium signaling ([Ca(2+)]I) in MC3T3-E1 cells local to damaged regions. Voltage-gated calcium channels (VGCCs) are implicated in the entry of [Ca(2+)]E to the cytoplasm. We investigated the involvement of VGCC in the extracellular calcium induced intracellular calcium response (ECIICR). MC3T3-E1 cells were subjected to one dimensional calcium efflux from their basal aspect which results in an increase in [Ca(2+)]I. This increase was concomitant with membrane depolarization and it was significantly reduced in the presence of Bepridil, a non-selective VGCC inhibitor. To identify specific type(s) of VGCC in ECIICR, the cells were treated with selective inhibitors for different types of VGCC. Significant changes in the peak intensity and the number of [Ca(2+)]I oscillations were observed when L-type and T-type specific VGCC inhibitors (Verapamil and NNC55-0396, respectively) were used. So as to confirm the involvement of L- and T-type VGCC in the context of microdamage, cells were seeded on devitalized notched bone specimen, which were loaded to induce microdamage in the presence and absence of Verapamil and NNC55-0396. The results showed significant decrease in [Ca(2+)]I activity of cells in the microdamaged regions of bone when L- and T-type blockers were applied. This study demonstrated that extracellular calcium increase in association with damage depolarizes the cell membrane and the calcium ions enter the cell cytoplasm by L- and T-type VGCCs.

  2. Voltage gated calcium channels negatively regulate protective immunity to Mycobacterium tuberculosis.

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    Shashank Gupta

    Full Text Available Mycobacterium tuberculosis modulates levels and activity of key intracellular second messengers to evade protective immune responses. Calcium release from voltage gated calcium channels (VGCC regulates immune responses to pathogens. In this study, we investigated the roles of VGCC in regulating protective immunity to mycobacteria in vitro and in vivo. Inhibiting L-type or R-type VGCC in dendritic cells (DCs either using antibodies or by siRNA increased calcium influx in an inositol 1,4,5-phosphate and calcium release calcium activated channel dependent mechanism that resulted in increased expression of genes favoring pro-inflammatory responses. Further, VGCC-blocked DCs activated T cells that in turn mediated killing of M. tuberculosis inside macrophages. Likewise, inhibiting VGCC in infected macrophages and PBMCs induced calcium influx, upregulated the expression of pro-inflammatory genes and resulted in enhanced killing of intracellular M. tuberculosis. Importantly, compared to healthy controls, PBMCs of tuberculosis patients expressed higher levels of both VGCC, which were significantly reduced following chemotherapy. Finally, blocking VGCC in vivo in M. tuberculosis infected mice using specific antibodies increased intracellular calcium and significantly reduced bacterial loads. These results indicate that L-type and R-type VGCC play a negative role in M. tuberculosis infection by regulating calcium mobilization in cells that determine protective immunity.

  3. Antischistosomal activity of a calcium channel antagonist on schistosomula and adult Schistosoma mansoni worms

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    Vanessa Silva-Moraes

    2013-08-01

    Full Text Available Current schistosomiasis control strategies are largely based on chemotherapeutic agents and a limited number of drugs are available today. Praziquantel (PZQ is the only drug currently used in schistosomiasis control programs. Unfortunately, this drug shows poor efficacy in patients during the earliest infection phases. The effects of PZQ appear to operate on the voltage-operated Ca2+channels, which are located on the external Schistosoma mansoni membrane. Because some Ca2+channels have dihydropyridine drug class (a class that includes nifedipine sensitivity, an in vitro analysis using a calcium channel antagonist (clinically used for cardiovascular hypertension was performed to determine the antischistosomal effects of nifedipine on schistosomula and adult worm cultures. Nifedipine demonstrated antischistosomal activity against schistosomula and significantly reduced viability at all of the concentrations used alone or in combination with PZQ. In contrast, PZQ did not show significant efficacy when used alone. Adult worms were also affected by nifedipine after a 24 h incubation and exhibited impaired motility, several lesions on the tegument and intense contractility. These data support the idea of Ca2+channels subunits as drug targets and favour alternative therapeutic schemes when drug resistance has been reported. In this paper, strong arguments encouraging drug research are presented, with a focus on exploring schistosomal Ca2+channels.

  4. Emerging roles of L-type voltage gated and other calcium channels in T lymphocytes.

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    Abdallah eBadou

    2013-08-01

    Full Text Available In T lymphocytes, calcium ion controls a variety of biological processes including development, survival, proliferation, and effector functions. These distinct and specific roles are regulated by different calcium signals, which are generated by various plasma membrane calcium channels. The repertoire of calcium-conducting proteins in T lymphocytes includes store-operated CRAC channels, transient receptor potential (TRP channels, P2X channels, and L-type voltage-gated calcium (Cav1 channels. In this paper, we will focus mainly on the role of the Cav1 channels found expressed by T lymphocytes, where these channels appear to operate in a TCR stimulation-dependent and voltage-sensor independent manner. We will review their expression profile at various differentiation stages of CD4 and CD8 T lymphocytes. Then, we will present crucial genetic evidence in favor of a role of these Cav1 channels and related regulatory proteins in both CD4 and CD8 T cell functions such as proliferation, survival, cytokine production and cytolysis. Finally, we will provide evidence and speculate on how these voltage-gated channels might function in the T lymphocyte, a non-excitable cell.

  5. In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

    Science.gov (United States)

    Tomlinson, Susan E; Tan, S Veronica; Burke, David; Labrum, Robyn W; Haworth, Andrea; Gibbons, Vaneesha S; Sweeney, Mary G; Griggs, Robert C; Kullmann, Dimitri M; Bostock, Hugh; Hanna, Michael G

    2016-02-01

    Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development.

  6. T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex.

    Science.gov (United States)

    Deleuze, Charlotte; David, François; Béhuret, Sébastien; Sadoc, Gérard; Shin, Hee-Sup; Uebele, Victor N; Renger, John J; Lambert, Régis C; Leresche, Nathalie; Bal, Thierry

    2012-08-29

    The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.

  7. BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis.

    Science.gov (United States)

    Béguin, Pascal; Nagashima, Kazuaki; Mahalakshmi, Ramasubbu N; Vigot, Réjan; Matsunaga, Atsuko; Miki, Takafumi; Ng, Mei Yong; Ng, Yu Jin Alvin; Lim, Chiaw Hwee; Tay, Hock Soon; Hwang, Le-Ann; Firsov, Dmitri; Tang, Bor Luen; Inagaki, Nobuya; Mori, Yasuo; Seino, Susumu; Launey, Thomas; Hunziker, Walter

    2014-04-28

    Voltage-gated calcium channels (VGCCs) are key regulators of cell signaling and Ca(2+)-dependent release of neurotransmitters and hormones. Understanding the mechanisms that inactivate VGCCs to prevent intracellular Ca(2+) overload and govern their specific subcellular localization is of critical importance. We report the identification and functional characterization of VGCC β-anchoring and -regulatory protein (BARP), a previously uncharacterized integral membrane glycoprotein expressed in neuroendocrine cells and neurons. BARP interacts via two cytosolic domains (I and II) with all Cavβ subunit isoforms, affecting their subcellular localization and suppressing VGCC activity. Domain I interacts at the α1 interaction domain-binding pocket in Cavβ and interferes with the association between Cavβ and Cavα1. In the absence of domain I binding, BARP can form a ternary complex with Cavα1 and Cavβ via domain II. BARP does not affect cell surface expression of Cavα1 but inhibits Ca(2+) channel activity at the plasma membrane, resulting in the inhibition of Ca(2+)-evoked exocytosis. Thus, BARP can modulate the localization of Cavβ and its association with the Cavα1 subunit to negatively regulate VGCC activity.

  8. The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor Function

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    Amaury François

    2015-01-01

    Full Text Available The T-type calcium channel Cav3.2 emerges as a key regulator of sensory functions, but its expression pattern within primary afferent neurons and its contribution to modality-specific signaling remain obscure. Here, we elucidate this issue using a unique knockin/flox mouse strain wherein Cav3.2 is replaced by a functional Cav3.2-surface-ecliptic GFP fusion. We demonstrate that Cav3.2 is a selective marker of two major low-threshold mechanoreceptors (LTMRs, Aδ- and C-LTMRs, innervating the most abundant skin hair follicles. The presence of Cav3.2 along LTMR-fiber trajectories is consistent with critical roles at multiple sites, setting their strong excitability. Strikingly, the C-LTMR-specific knockout uncovers that Cav3.2 regulates light-touch perception and noxious mechanical cold and chemical sensations and is essential to build up that debilitates allodynic symptoms of neuropathic pain, a mechanism thought to be entirely A-LTMR specific. Collectively, our findings support a fundamental role for Cav3.2 in touch/pain pathophysiology, validating their critic pharmacological relevance to relieve mechanical and cold allodynia.

  9. Differential expression of T- and L-type voltage-dependent calcium channels in renal resistance vessels

    DEFF Research Database (Denmark)

    Hansen, Pernille B. Lærkegaard; Jensen, Boye L.; Andreasen, D;

    2001-01-01

    .2 protein was demonstrated by immunochemical labeling of rat preglomerular vasculature and juxtamedullary efferent arterioles and vasa recta. Cortical efferent arterioles were not immunopositive. Recordings of intracellular calcium concentration with digital fluorescence imaging microscopy showed......The distribution of voltage-dependent calcium channels in kidney pre- and postglomerular resistance vessels was determined at the molecular and functional levels. Reverse transcription-polymerase chain reaction analysis of microdissected rat preglomerular vessels and cultured smooth muscle cells...... showed coexpression of mRNAs for T-type subunits (Ca(V)3.1, Ca(V)3.2) and for an L-type subunit (Ca(V)1.2). The same expression pattern was observed in juxtamedullary efferent arterioles and outer medullary vasa recta. No calcium channel messages were detected in cortical efferent arterioles. Ca(V)1...

  10. RGS12 interacts with the SNARE-binding region of the Cav2.2 calcium channel.

    Science.gov (United States)

    Richman, Ryan W; Strock, Jesse; Hains, Melinda D; Cabanilla, Nory Jun; Lau, King-Kei; Siderovski, David P; Diversé-Pierluissi, María

    2005-01-14

    Activation of GABAB receptors in chick dorsal root ganglion (DRG) neurons inhibits the Cav2.2 calcium channel in both a voltage-dependent and voltage-independent manner. The voltage-independent inhibition requires activation of a tyrosine kinase that phosphorylates the alpha1 subunit of the channel and thereby recruits RGS12, a member of the "regulator of G protein signaling" (RGS) proteins. Here we report that RGS12 binds to the SNARE-binding or "synprint" region (amino acids 726-985) in loop II-III of the calcium channel alpha1 subunit. A recombinant protein encompassing the N-terminal PTB domain of RGS12 binds to the synprint region in protein overlay and surface plasmon resonance binding assays; this interaction is dependent on tyrosine phosphorylation and yet is within a sequence that differs from the canonical NPXY motif targeted by other PTB domains. In electrophysiological experiments, microinjection of DRG neurons with synprint-derived peptides containing the tyrosine residue Tyr-804 altered the rate of desensitization of neurotransmitter-mediated inhibition of the Cav2.2 calcium channel, whereas peptides centered about a second tyrosine residue, Tyr-815, were without effect. RGS12 from a DRG neuron lysate was precipitated using synprint peptides containing phosphorylated Tyr-804. The high degree of conservation of Tyr-804 in the SNARE-binding region of Cav2.1 and Cav2.2 calcium channels suggests that this region, in addition to the binding of SNARE proteins, is also important for determining the time course of the modulation of calcium current via tyrosine phosphorylation.

  11. Synthesis and Calcium Channel Blocking Activity of 1, 4-Dihydropyridine Derivatives Containing Ester Substitute and Phenyl Carbamoyl Group

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    Bassem Sadek

    2011-01-01

    Full Text Available Problem statement: Several studies on the synthesis of new nifedipine analogs have been carried out, but the literature reveled that no study on the synthesis and calcium channel blocking activity of the substituted ester with an amide (5-phenylcarbamoyl moiety has been reported. Approach: Six new derivatives of m-nifedipine have been successfully synthesized by substituting an ester moiety with an amide (5-phenylcarbamoyl moiety, using a modified Hantzsch reactions and tested for their pharmacological activities. The nifedipine analogs 1-6 were characterized and confirmed using elemental analysis, Infrared spectroscopy (IR, Nuclear Magnetic Resonance (1H NMR and Mass spectroscopy. The purity of the compounds was ascertained by melting point and TLC. The in vitro calcium channel blocking activities were evaluated using the high K+ concentration of Porcine Coronary Artery Smooth Muscles (PCASM assay. Results: The compounds (1-2 failed to exhibit any blocking activity (IC50 = 10−7 to 10−5 M range, while the compounds 3-6 relaxed precontracted porcine coronary artery smooth muscles with pEC50 values ranging between 4.37±0.10 (compound 3 and 6.46±0.07 (compound 5, indicating that compounds 3-6 exhibit comparable potencies in blocking calcium channels to reference drug varapamil (6.97±0.15 and m-nifedipine (6.48±0.05. Conclusion: The results of this study showed that some of the developed new compounds possess maximal calcium channel blocking effects comparable to m-nifedipine. The developed compounds in the present study will predicatively show an increased metabolic stability and consequently longer duration of actions compared to m-nifedipine and could be, therefore, suitable candidates for further optimization to be evaluated as a new class of antihypertensive drugs.

  12. Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function.

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    Alexandra F S Breitenkamp

    Full Text Available Autism Spectrum Disorders (ASD are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction. Dysregulation of cellular calcium homeostasis might be involved in ASD pathogenesis, and genes coding for the L-type calcium channel subunits CaV1.2 (CACNA1C and CaVβ2 (CACNB2 were recently identified as risk loci for psychiatric diseases. Here, we present three rare missense mutations of CACNB2 (G167S, S197F, and F240L found in ASD-affected families, two of them described here for the first time (G167S and F240L. All these mutations affect highly conserved regions while being absent in a sample of ethnically matched controls. We suggest the mutations to be of physiological relevance since they modulate whole-cell Ba2+ currents through calcium channels when expressed in a recombinant system (HEK-293 cells. Two mutations displayed significantly decelerated time-dependent inactivation as well as increased sensitivity of voltage-dependent inactivation. In contrast, the third mutation (F240L showed significantly accelerated time-dependent inactivation. By altering the kinetic parameters, the mutations are reminiscent of the CACNA1C mutation causing Timothy Syndrome, a Mendelian disease presenting with ASD. In conclusion, the results of our first-time biophysical characterization of these three rare CACNB2 missense mutations identified in ASD patients support the hypothesis that calcium channel dysfunction may contribute to autism.

  13. Expression and cellular localization of the voltage-gated calcium channel α2δ3 in the rodent retina.

    Science.gov (United States)

    Pérez de Sevilla Müller, Luis; Sargoy, Allison; Fernández-Sánchez, Laura; Rodriguez, Allen; Liu, Janelle; Cuenca, Nicolás; Brecha, Nicholas

    2015-07-01

    High-voltage-activated calcium channels are hetero-oligomeric protein complexes that mediate multiple cellular processes, including the influx of extracellular Ca(2+), neurotransmitter release, gene transcription, and synaptic plasticity. These channels consist of a primary α(1) pore-forming subunit, which is associated with an extracellular α(2)δ subunit and an intracellular β auxiliary subunit, which alter the gating properties and trafficking of the calcium channel. The cellular localization of the α(2)δ(3) subunit in the mouse and rat retina is unknown. In this study using RT-PCR, a single band at ∼ 305 bp corresponding to the predicted size of the α(2)δ(3) subunit fragment was found in mouse and rat retina and brain homogenates. Western blotting of rodent retina and brain homogenates showed a single 123-kDa band. Immunohistochemistry with an affinity-purified antibody to the α(2)δ(3) subunit revealed immunoreactive cell bodies in the ganglion cell layer and inner nuclear layer and immunoreactive processes in the inner plexiform layer and the outer plexiform layer. α(2)δ(3) immunoreactivity was localized to multiple cell types, including ganglion, amacrine, and bipolar cells and photoreceptors, but not horizontal cells. The expression of the α(2)δ(3) calcium channel subunit to multiple cell types suggests that this subunit participates widely in Ca-channel-mediated signaling in the retina.

  14. Effects of calcium channel antagonists on the induction of nitric oxide synthase in cultured cells by immunostimulants.

    Science.gov (United States)

    Hattori, Y; Kasai, K; So, S; Hattori, S; Banba, N; Shimoda, S

    1995-01-01

    We investigated whether calcium channel antagonists would alter the induction of nitric oxide (NO) synthesis by bacterial lipopolysaccharide (LPS) alone or in combination with interferon-gamma (IFN gamma) in cultured J774 macrophages, rat vascular smooth muscle cells, rat renal mesangial cells, and rat cardiac myocytes. The induction of NO synthesis was determined by measuring nitrite, the stable end-product. The dihydropyridine calcium channel antagonists, nifedipine, manidipine, nitrendipine, benidipine, barnidipine, perdipine, and nilvadipine all reduced the LPS-induced nitrite production in a dose-dependent manner, each with a differing half-maximal inhibitory concentration, in cultured J774 macrophages. Nifedipine also inhibited nitrite production in vascular smooth muscle cells, mesangial cells, and cardiac myocytes. The half-maximal inhibitory concentrations of nifedipine were ranked as follows: smooth muscle cells < mesangial cells < cardiac myocytes. Diltiazem, at nontoxic concentrations, had no effect on the nitrite formation in the three cell types. Verapamil markedly increased the formation of nitrite in cardiac myocytes in response to LPS and IFN gamma, but not in vascular smooth muscle or mesangial cells. Exposure of cardiac myocytes to LPS and IFN gamma caused the expression of NO synthase mRNA that was significantly increased by verapamil. Thus, certain calcium channel antagonists modulate NO synthesis by altering the induction of NO synthase.

  15. Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease

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    Satoshi Umemura

    2013-07-01

    Full Text Available An altered ambulatory blood pressure (BP and heart rate (HR profile is related to chronic kidney disease (CKD and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18 or the benazepril add-on group (n = 18. Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

  16. Raised activity of L-type calcium channels renders neurons prone to form paroxysmal depolarization shifts.

    Science.gov (United States)

    Rubi, Lena; Schandl, Ulla; Lagler, Michael; Geier, Petra; Spies, Daniel; Gupta, Kuheli Das; Boehm, Stefan; Kubista, Helmut

    2013-09-01

    Neuronal L-type voltage-gated calcium channels (LTCCs) are involved in several physiological functions, but increased activity of LTCCs has been linked to pathology. Due to the coupling of LTCC-mediated Ca(2+) influx to Ca(2+)-dependent conductances, such as KCa or non-specific cation channels, LTCCs act as important regulators of neuronal excitability. Augmentation of after-hyperpolarizations may be one mechanism that shows how elevated LTCC activity can lead to neurological malfunctions. However, little is known about other impacts on electrical discharge activity. We used pharmacological up-regulation of LTCCs to address this issue on primary rat hippocampal neurons. Potentiation of LTCCs with Bay K8644 enhanced excitatory postsynaptic potentials to various degrees and eventually resulted in paroxysmal depolarization shifts (PDS). Under conditions of disturbed Ca(2+) homeostasis, PDS were evoked frequently upon LTCC potentiation. Exposing the neurons to oxidative stress using hydrogen peroxide also induced LTCC-dependent PDS. Hence, raising LTCC activity had unidirectional effects on brief electrical signals and increased the likeliness of epileptiform events. However, long-lasting seizure-like activity induced by various pharmacological means was affected by Bay K8644 in a bimodal manner, with increases in one group of neurons and decreases in another group. In each group, isradipine exerted the opposite effect. This suggests that therapeutic reduction in LTCC activity may have little beneficial or even adverse effects on long-lasting abnormal discharge activities. However, our data identify enhanced activity of LTCCs as one precipitating cause of PDS. Because evidence is continuously accumulating that PDS represent important elements in neuropathogenesis, LTCCs may provide valuable targets for neuroprophylactic therapy.

  17. Hypothyroid state reduces calcium channel function in 18-day pregnant rat uterus.

    Science.gov (United States)

    Parija, S C; Mishra, S K; Raviprakash, V

    2006-01-01

    Hypothyroidism significantly reduced the mean amplitude and increased the mean frequency of spontaneous rhythmic contractions in 18 day pregnant rat uterus. Nifedipine (10(-12)-10(-9) M) and diltiazem (10(-10)-10(-6) M) caused concentration related inhibition of the myogenic responses of the uterine strips obtained from both pregnant and hypothyroid state. However, nifedipine was less potent (IC50:2.11 x 10(-11) M) in pregnant hypothyroid state as compared to pregnant control (IC50: 3.1 x 10(-12) M). Similarly, diltiazem was less potent (IC50: 3.72 x 10(-9) M) in inhibiting the uterine spontaneous contractions in hypothyroid than in pregnant rat uterus (IC50:5.37 x 10(-10) M). A similar decrease in the sensitivity to nifedipine and diltiazem for reversal of K+ (100 mM)-induced tonic contraction and K(+)-stimulated 45Ca2+ influx was observed with these calcium channel antagonists in uterus obtained from hypothyroid pregnant rats compared to the controls. Nifedipine-sensitive influx of 45Ca(2+)-stimulated either by K+ (100 mM) or by Bay K8644 (1,4-dihydro-2,6-methyl-5-nitro-4-[2'-(trifluromethyl)phenyl]-3-pyridine carboxylic acid methyl ester) (10(-9) M) was significantly less in uterine strips from hypothyroid rats compared to controls. The results suggest that the inhibition of uterine rhythmic contractions may be attributable to a reduction in rat myometrial Ca2+ channel function in the hypothyroid state.

  18. Possible roles of exceptionally conserved residues around the selectivity filters of sodium and calcium channels.

    Science.gov (United States)

    Tikhonov, Denis B; Zhorov, Boris S

    2011-01-28

    In the absence of x-ray structures of sodium and calcium channels their homology models are used to rationalize experimental data and design new experiments. A challenge is to model the outer-pore region that folds differently from potassium channels. Here we report a new model of the outer-pore region of the NaV1.4 channel, which suggests roles of highly conserved residues around the selectivity filter. The model takes from our previous study (Tikhonov, D. B., and Zhorov, B. S. (2005) Biophys. J. 88, 184-197) the general disposition of the P-helices, selectivity filter residues, and the outer carboxylates, but proposes new intra- and inter-domain contacts that support structural stability of the outer pore. Glycine residues downstream from the selectivity filter are proposed to participate in knob-into-hole contacts with the P-helices and S6s. These contacts explain the adapted tetrodotoxin resistance of snakes that feed on toxic prey through valine substitution of isoleucine in the P-helix of repeat IV. Polar residues five positions upstream from the selectivity filter residues form H-bonds with the ascending-limb backbones. Exceptionally conserved tryptophans are engaged in inter-repeat H-bonds to form a ring whose π-electrons would facilitate passage of ions from the outer carboxylates to the selectivity filter. The outer-pore model of CaV1.2 derived from the NaV1.4 model is also stabilized by the ring of exceptionally conservative tryptophans and H-bonds between the P-helices and ascending limbs. In this model, the exceptionally conserved aspartate downstream from the selectivity-filter glutamate in repeat II facilitates passage of calcium ions to the selectivity-filter ring through the tryptophan ring. Available experimental data are discussed in view of the models.

  19. Exposure to extremely low-frequency electromagnetic fields inhibits T-type calcium channels via AA/LTE4 signaling pathway.

    Science.gov (United States)

    Cui, Yujie; Liu, Xiaoyu; Yang, Tingting; Mei, Yan-Ai; Hu, Changlong

    2014-01-01

    Extremely low-frequency electromagnetic fields (ELF-EMF) causes various biological effects through altering intracellular calcium homeostasis. The role of high voltage-gated (HVA) calcium channels in ELF-EMF induced effects has been extensively studied. However, the effect of ELF-EMF on low-voltage-gated (LVA) T-type calcium channels has not been reported. In this study, we test the effect of ELF-EMF (50Hz) on human T-type calcium channels transfected in HEK293 cells. Conversely to its stimulant effects on HVA channels, ELF-EMF exposure inhibited all T-type (Cav3.1, Cav3.2 and Cav3.3) channels. Neither the protein expression nor the steady-state activation and inactivation kinetics of Cav3.2 channels were altered by ELF-EMF (50Hz, 0.2mT) exposure. Exposure to ELF-EMF increased both arachidonic acid (AA) and leukotriene E4 (LTE4) levels in HEK293 cells. CAY10502 and bestatin, which block the increase of AA and LTE4 respectively, abrogated the ELF-EMF inhibitory effect on Cav3.2 channels. Exogenous LTE4 mimicked the ELF-EMF inhibition of T-type calcium channels. ELF-EMF (50Hz) inhibits native T-type calcium channels in primary cultured mouse cortical neurons via LTE4. We conclude that 50Hz ELF-EMF inhibits T-type calcium channels through AA/LTE4 signaling pathway.

  20. Effect of testosterone on calcium channels and cardiac function%睾酮对钙离子通道和心脏功能的影响

    Institute of Scientific and Technical Information of China (English)

    周玉文; 曹雪滨; 徐鹏; 张燕; 江明宏

    2012-01-01

    Testosterone has important effects on human body metabolism, physiology and cardiac pathology. Higher concentrations of testosterone or its chronic effects can increase T- and L-type calcium channel density and lower concentrations or acute effects can block T- and L-type calcium channels, reduce male Q-Tc period and improve sensitivity to insulin and lipid metabolism. Testosterone can increase calcium regulatory proteins and expression of beta-2 receptor, enhance calcium transit rate and reduce calcium overload in case of increase of intracellular calcium concentration. Appropriate concentration of testosterone can sustain a certain vascular tension, improve cardiac conduction or dilate coronary arteries, reduce insulin resistance and incidence of metabolic syndrome, improve myocardial ischemia, reduce apoptosis and myocardial cell fibrosis, protect the heart and enhance cardiac diastolic efficiency.%睾酮对人体的全身代谢、心脏的生理和病理均有着重要的影响.较高浓度的睾酮或其慢性作用可以提高T型、L型钙离子通道的密度,较低浓度或急性作用可以阻滞T型、L型钙离子通道,缩短男性Q-Tc间期,提高对胰岛素的敏感性及改善血脂代谢.睾酮可上调钙调节蛋白、β2受体的表达,在提高细胞内钙离子浓度的情况下,可增加钙瞬变的幅度,减少钙超载.一定浓度的睾酮可以维持血管的一定张力,改善心脏传导或扩张冠脉;减少胰岛素抵抗、代谢综合征的发生,改善心肌缺血、减少心肌细胞凋亡及纤维化,保护心脏,改善心脏收缩舒张效率.

  1. Adding thiazide to a rennin-angiotensin blocker regimen to improve left ventricular relaxation in diabetes and nondiabetes patients with hypertension

    Directory of Open Access Journals (Sweden)

    Takami T

    2012-09-01

    0.144; P = 0.0257 and between changes in estimated glomerular filtration rate and changes in the E/e′ ratio (r = –0.130; P = 0.0436. Among patients without DM, there was a significant relationship between changes in high-sensitivity C-reactive protein (hs-CRP and changes in E/e′ (r = 0.205; P = 0.0010. Multivariate analysis demonstrated changes in hemoglobin A1c levels as one of the determinants of change of e′ and E/e′ in patients with DM, whereas hs-CRP was the determinant of change of e′ among patients without DM. These data suggest that improvement in LV diastolic function is associated with an improvement of DM and a concomitant reduction in UACR among DM patients, and with a reduction of hs-CRP in patients without DM when thiazide is added to a renin–angiotensin blocker treatment regimen.Keywords: diastolic dysfunction, diabetes, urinary albumin to creatinine ratio, losartan, HCTZ

  2. BIN1 localizes the L-type calcium channel to cardiac T-tubules.

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    Ting-Ting Hong

    2010-02-01

    Full Text Available The BAR domain protein superfamily is involved in membrane invagination and endocytosis, but its role in organizing membrane proteins has not been explored. In particular, the membrane scaffolding protein BIN1 functions to initiate T-tubule genesis in skeletal muscle cells. Constitutive knockdown of BIN1 in mice is perinatal lethal, which is associated with an induced dilated hypertrophic cardiomyopathy. However, the functional role of BIN1 in cardiomyocytes is not known. An important function of cardiac T-tubules is to allow L-type calcium channels (Cav1.2 to be in close proximity to sarcoplasmic reticulum-based ryanodine receptors to initiate the intracellular calcium transient. Efficient excitation-contraction (EC coupling and normal cardiac contractility depend upon Cav1.2 localization to T-tubules. We hypothesized that BIN1 not only exists at cardiac T-tubules, but it also localizes Cav1.2 to these membrane structures. We report that BIN1 localizes to cardiac T-tubules and clusters there with Cav1.2. Studies involve freshly acquired human and mouse adult cardiomyocytes using complementary immunocytochemistry, electron microscopy with dual immunogold labeling, and co-immunoprecipitation. Furthermore, we use surface biotinylation and live cell confocal and total internal fluorescence microscopy imaging in cardiomyocytes and cell lines to explore delivery of Cav1.2 to BIN1 structures. We find visually and quantitatively that dynamic microtubules are tethered to membrane scaffolded by BIN1, allowing targeted delivery of Cav1.2 from the microtubules to the associated membrane. Since Cav1.2 delivery to BIN1 occurs in reductionist non-myocyte cell lines, we find that other myocyte-specific structures are not essential and there is an intrinsic relationship between microtubule-based Cav1.2 delivery and its BIN1 scaffold. In differentiated mouse cardiomyocytes, knockdown of BIN1 reduces surface Cav1.2 and delays development of the calcium transient

  3. Gynura procumbens Merr. decreases blood pressure in rats by vasodilatation via inhibition of calcium channels

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    See-Ziau Hoe

    2011-01-01

    Full Text Available INTRODUCTION: Gynura procumbens has been shown to decrease blood pressure via inhibition of the angiotensinconverting enzyme. However, other mechanisms that may contribute to the hypotensive effect have not been studied. OBJECTIVES: To investigate the cardiovascular effects of a butanolic fraction of Gynura procumbens in rats. METHODS: Anaesthetized rats were given intravenous bolus injections of butanolic fraction at doses of 2.5-20 mg/kg in vivo. The effect of butanolic fraction on vascular reactivity was recorded in isolated rat aortic rings in vitro. RESULTS: Intravenous administrations of butanolic fraction elicited significant (p<0.001 and dose-dependent decreases in the mean arterial pressure. However, a significant (p<0.05 decrease in the heart rate was observed only at the higher doses (10 and 20 mg/kg. In isolated preparations of rat aortic rings, phenylephrine (1×10-6 M- or potassium chloride (8×10-2 M-precontracted endothelium-intact and -denuded tissue; butanolic fraction (1×10-6-1×10-1 g/ml induced similar concentration-dependent relaxation of the vessels. In the presence of 2.5×10-3 and 5.0×10-3 g/ml butanolic fraction, the contractions induced by phenylephrine (1×10-9-3×10-5 M and potassium chloride (1×10-2-8×10-2 M were significantly antagonized. The calcium-induced vasocontractions (1×10-4-1×10-2 M were antagonized by butanolic fraction concentration-dependently in calcium-free and high potassium (6×10-2 M medium, as well as in calcium- and potassium-free medium containing 1×10-6 M phenylephrine. However, the contractions induced by noradrenaline (1×10-6 M and caffeine (4.5×10-2 M were not affected by butanolic fraction. CONCLUSION: Butanolic fraction contains putative hypotensive compounds that appear to inhibit calcium influx via receptor-operated and/or voltage-dependent calcium channels to cause vasodilation and a consequent fall in blood pressure.

  4. Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling

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    Hurley Joyce H

    2008-04-01

    Full Text Available Abstract Background The aberrant release of the neurotransmitters, glutamate and calcitonin-gene related peptide (CGRP, from trigeminal neurons has been implicated in migraine. The voltage-gated P/Q-type calcium channel has a critical role in controlling neurotransmitter release and has been linked to Familial Hemiplegic Migraine. Therefore, we examined the importance of voltage-dependent calcium channels in controlling release of glutamate and CGRP from trigeminal ganglion neurons isolated from male and female rats and grown in culture. Serotonergic pathways are likely involved in migraine, as triptans, a class of 5-HT1 receptor agonists, are effective in the treatment of migraine and their effectiveness may be due to inhibiting neurotransmitter release from trigeminal neurons. We also studied the effect of serotonin receptor activation on release of glutamate and CGRP from trigeminal neurons grown in culture. Results P/Q-, N- and L-type channels each mediate a significant fraction of potassium-stimulated release of glutamate and CGRP. We determined that 5-HT significantly inhibits potassium-stimulated release of both glutamate and CGRP. Serotonergic inhibition of both CGRP and glutamate release can be blocked by pertussis toxin and NAS-181, a 5-HT1B/1D antagonist. Stimulated release of CGRP is unaffected by Y-25130, a 5-HT3 antagonist and SB 200646, a 5-HT2B/2C antagonist. Conclusion These data suggest that release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling in a pertussis-toxin dependent manner and probably via 5-HT1 receptor signaling. This is the first characterization of glutamate release from trigeminal neurons grown in culture.

  5. Lung adenocarcinoma with Lambert–Eaton myasthenic syndrome indicated by voltage-gated calcium channel: a case report

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    Arai Hiromasa

    2012-09-01

    Full Text Available Abstract Introduction Lambert–Eaton myasthenic syndrome is a rare disorder and it is known as a paraneoplastic neurological syndrome. Small cell lung cancer often accompanies this syndrome. Lambert–Eaton myasthenic syndrome associated with lung adenocarcinoma is extremely rare; there are only a few reported cases worldwide. Case presentation A 75-year-old Japanese man with a past history of chronic rheumatoid arthritis and Sjögren syndrome was diagnosed with Lambert–Eaton myasthenic syndrome by electromyography and serum anti-P/Q-type voltage-gated calcium channel antibody level preceding the diagnosis of lung cancer. A chest computed tomography to screen for malignant lesions revealed an abnormal shadow in the lung. Although a histopathological examination by bronchoscopic study could not reveal the malignancy, lung cancer was mostly suspected after the results of a chest computed tomography and [18F]-fluorodeoxyglucose positron emission tomography. An intraoperative diagnosis based on the frozen section obtained by tumor biopsy was adenocarcinoma so the patient underwent a lobectomy of the right lower lobe and lymph node dissection with video-assisted thoracoscopic surgery. The permanent pathological examination was the same as the frozen diagnosis (pT2aN1M0: Stage IIa: TNM staging 7th edition. Immunohistochemistry revealed that most of the cancer cells were positive for P/Q-type voltage-gated calcium channel. Conclusions Our case is a rare combination of Lambert–Eaton myasthenic syndrome associated with lung adenocarcinoma, rheumatoid arthritis and Sjögren syndrome, and to the best of our knowledge it is the first report that indicates the presence of voltage-gated calcium channel in lung adenocarcinoma by immunostaining.

  6. The coupling of acetylcholine-induced BK channel and calcium channel in guinea pig saccular type II vestibular hair cells.

    Science.gov (United States)

    Kong, Wei-Jia; Guo, Chang-Kai; Zhang, Xiao-Wen; Chen, Xiong; Zhang, Song; Li, Guan-Qiao; Li, Zhi-Wang; Van Cauwenberge, Paul

    2007-01-19

    Molecular biological studies and electrophysiological data have demonstrated that acetylcholine (ACh) is the principal cochlear and vestibular efferent neurotransmitter among mammalians. However, the functional roles of ACh in type II vestibular hair cells (VHCs II) among mammalians are still unclear, with the exception of the well-known alpha9-containing nicotinic ACh receptor (alpha9-containing nAChR)-activated small conductance, calcium-dependent potassium current (SK) in cochlear hair cells and frog saccular hair cells. The activation of SK current was necessary for the calcium influx through the alpha9-containing nAChR. Recently, we have demonstrated that ACh-induced big conductance, calcium-dependent potassium current (BK) was present in VHCs II of the vestibular end-organ of guinea pig. In this study, the nature of calcium influx for the activation of ACh-induced BK current in saccular VHCs II of guinea pig was investigated. Following extracellular perfusion of ACh, saccular VHCs II displayed a sustained outward current, which was sensitive to iberiotoxin (IBTX). High concentration of apamin failed to inhibit the current amplitude of ACh-induced outward current. Intracellular application of Cs(+) completely abolished the current evoked by ACh. ACh-induced current was potently inhibited by nifedipine, nimodipine, Cd(2+) and Ni(2+), respectively. The inhibition potency of these four calcium channel antagonists was nimodipine>nifedipine>cadmium>nickel. The L-type Ca(2+) channels agonist, (-)-Bay-K 8644 mimicked the effect of ACh and activated an IBTX-sensitive current. In addition, partial VHCs II displayed a biphasic waveform. In conclusion, the present data showed that in the guinea pig saccular VHCs II, ACh-induced BK channel was coupled with the calcium channel, but not the receptor. The perfusion of ACh will drive the opening of calcium channels; the influx of calcium ions will then activate the BK current.

  7. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure

    DEFF Research Database (Denmark)

    Mookerjee, Rajeshwar P; Pavesi, Marco; Thomsen, Karen Louise

    2016-01-01

    BACKGROUND AND AIMS: Non-selective beta-blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute on chronic liver failure (ACLF...

  8. Comparison of seven electronic healthcare databases in EU countries using a standardized methodology: a descriptive study on the exposure to calcium-channel blockers (CCBs).

    NARCIS (Netherlands)

    Groot, M.C.H. de; Ham, R. van den; Bruin, M. de; Huerta Alvarez, C.; Gil, M.; Afonso, A.; Requena, G.; Hesse, U.; Ronn, P.F.; Souverein, P.C.; Alvarez, Y.; Slattery, J.; Rottenkolber, M.; Schmiedl, S.; Dijk, L. van; Schlienger, R.; Reynolds, R.; Klungel, O.H.; Grimaldi-Bensouda, L.

    2013-01-01

    Background: Information on prevalence of CCB prescribing is scarce in the literature and differs considerably among European countries due to differences in type of data sources, time periods, population distributions, and methodology used. Objectives: To measure and investigate sources of variation

  9. [Evaluation of the antihypertensive effect and tolerability of a new delayed-action calcium channel blocker: nitrendipine, prescribed as a single daily dose of 20 mg].

    Science.gov (United States)

    Herpin, D; Amiel, A; Boutaud, P; Ciber, M A; Demange, J

    1986-11-01

    The authors have studied the effects of Nitrendipine, orally given in a dose of 20 mg, once a day for 30 days, in patients with mild to moderate hypertension. Twelve patients initially entered the study but four of them discontinued the treatment during the first week, because of unwanted side-effects: headaches, palpitation, sensations of burning skin. The remaining eight patients underwent a comparative evaluation at the end of a placebo period (DO) and at the end of the active treatment (D30), including successively: an automatic blood pressure recording with a Bard-Sentron device for 3 hours, then a determination of plasma renin activity, aldosterone and catecholamines, and finally a measurement of the blood pressure with a mercury manometer, at rest and during a standardized exercise on an ergometric bicycle. At D30, the Nitrendipine tablet was given one hour after the beginning of the automatic recording. The blood pressure measured with the mercury manometer (i.e. approximately 2 hours after the dose of Nitrendipine) significantly decreased from D0 to D30, at rest and during exercise, respectively from 161.5/104.6 to 132.8/82.5 mmHg and from 210.0/116.8 to 190.0/95.6 mmHg. The automatic recording provided, at D0, a mean blood pressure value of 152.4/90.6 mmHg; at D30, this mean value was as high as 142.6/90.7 mmHg during the hour preceding the dose of Nitrendipine (NS) and as high as 129.2/78.6 mmHg during the 2nd hour following the intake of the tablet (p less than 0.01). Plasma aldosterone and plasma renin activity significantly (p less than 0.05) increased from D0 to D30, whereas catecholamines did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Rapid changes in skeletal muscle calcium uptake induced in vitro by 1,25-dihydroxyvitamin D/sub 3/ are suppressed by calcium channel blockers

    Energy Technology Data Exchange (ETDEWEB)

    de Boland, A.R.; Boland, R.L.

    1987-05-01

    Previous investigations have shown that 1,25-dihydroxyvitamin D/sub 3/ (1,25-(OH)/sub 2/D/sub 3/) stimulates muscle Ca uptake through a nuclear mechanism. The possibility that 1,25-(OH)/sub 2/D/sub 3/ would induce rapid changes in muscle Ca fluxes independent of de novo protein synthesis was investigated in the present work. In vitro preparations of soleus muscles obtained from vitamin D-deficient chicks were used. A significant increase in /sup 45/Ca labeling of the tissue was already observed after 3-min treatment with 2.4 X 10(-10) M 1,25-(OH)/sub 2/D/sub 3/. This early stimulation in muscle Ca uptake became maximal at 10-15 min. Cycloheximide (50 microM) did not block the effect of the metabolite at 15 and 30 min. However, the antibiotic effectively blocked the increase in Ca uptake induced by 1,25-(OH)/sub 2/D/sub 3/ after 1-h treatment. The rapid 1,25-(OH)/sub 2/D/sub 3/-dependent stimulation of /sup 45/Ca labeling of soleus muscle was not associated to changes in lipid synthesis as assessed by measurements of /sup 3/H-glycerol incorporation into the tissue lipids. However, the calcium antagonists verapamil and nifedipine (50 microM) abolished the stimulation in Ca uptake produced by 1,25-(OH)/sub 2/D/sub 3/ in 5 min. These results suggest that 1,25-(OH)/sub 2/D/sub 3/ can act directly at the muscle membrane level affecting Ca fluxes through Ca channels.

  11. Management of cardiac fibrosis in diabetic rats; the role of peroxisome proliferator activated receptor gamma (PPAR-gamma and calcium channel blockers (CCBs

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    Mohamad Hoda E

    2011-03-01

    Full Text Available Abstract Background Diabetes mellitus (DM and hypertension (HTN are accused of being responsible for the development of the cardiac fibrosis due to severe cardiomyopathy. Methods Blood glucose (BG test was carried out, lipid concentrations, tumor necrosis factor alpha (TNF-α, transforming growth factor beta (TGF-β, matrix metalloproteinase (MMP-2, collagen-I and collagen-III were measured in male Albino rats weighing 179-219 g. The rats were divided into five groups, kept on either control diet or high fat diet (HFD, and simultaneously treated with rosiglitazone (PPAR-gamma only for one group with 3 mg/kg/day via oral route for 30 days, and with rosiglitazone and felodipine combination for another group with 3 mg/kg/day and 5 mg/kg/day, respectively via oral route for 30 days. Results Diabetic hypertensive (DH rats which fed on a HFD, injected with streptozotocin (STZ (i.p. and obstruction for its right kidney was occurred develop hyperglycemia, hypertension, cardiac fibrosis, hypertriglyceridemia, hypercholesterolemia, increased TNF-α, increased TGF-β, decreased MMP-2, increased collagen-I and increased collagen-III, when compared to rats fed on control diet. Treating the DH rats with rosiglitazone only causes a significant decrease for BG levels by 52.79%, triglycerides (TGs by 24.05%, total cholesterol (T-Chol by 30.23%, low density lipoprotein cholesterol (LDL-C by 40.53%, TNF-α by 20.81%, TGF-β by 46.54%, collagen-I by 48.11% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 272.73%. Moreover, Treating the DH rats with rosiglitazone and felodipine combination causes a significant decrease for BG levels by 61.08%, blood pressure (BP by 16.78%, TGs by 23.80%, T-Chol by 33.27%, LDL-C by 45.18%, TNF-α by 22.82%, TGF-β by 49.31%, collagen-I by 64.15% and collagen-III by 53.85% but causes a significant increase for MMP-2 by 290.91%. Rosiglitazone alone failed to decrease the BP in DH rats in the current dosage and duration. Conclusion Our results indicate that the co-existence of diabetes and hypertension could induce cardiomyopathy which could further result in cardiac fibrosis, and that combination treatment with rosiglitazone and felodipine has a great protective role against the metabolic abnormalities, meanwhile, the treatment with rosiglitazone alone has a protective role with a minimal effect against these abnormalities and has no effect on decreasing BP in these cases which may lead to coronary artery diseases (CADs in future.

  12. Epileptic seizure-induced hypertension and its prevention by calcium channel blockers: a real-time study in conscious telemetered rats.

    Science.gov (United States)

    Beig, Mirza Irfan; Chandra, Ramesh; Talwar, Anita; Fahim, Mohammad; Katyal, Anju

    2009-07-01

    Epileptic seizures are accompanied by changes in autonomic function that in turn influence the cardiovascular system (hypertension and bradyarrhythmia). We have studied possible cardioprotective activity (during the ictal state in conscious animals) of valproic acid, nifedipine, and verapamil, alone and in combination, during pentylenetetrazole (PTZ)-induced seizures. Telemetry system was used for recording EEG, blood pressure, and heart rate in conscious, freely moving rats during seizures. We observed that PTZ-induced seizures were accompanied by hypertension and bradyarrhythmia. Pretreatment with valproic acid did not block seizure-induced hypertension and bradyarrhythmia. Nifedipine alone and in combination with valproic acid blocked seizure-induced hypertension and bradyarrhythmia significantly. We also observed that pretreatment with verapamil alone and in combination with valproic acid did not block seizure-induced hypertension and bradyarrhythmia significantly. Our results suggest that pretreatment with nifedipine alone or in combination with valproic acid provides protection against seizure-induced hypertension and bradyarrhythmia.

  13. Examination of metabolic pathways and identification of human liver cytochrome P450 isozymes responsible for the metabolism of barnidipine, a calcium channel blocker.

    Science.gov (United States)

    Teramura, T; Fukunaga, Y; Van Hoogdalem, E J; Watanabe, T; Higuchi, S

    1997-09-01

    1. In a human liver microsomal system, barnidipine was converted into three primary metabolites, an N-debenzylated product (M-1), a hydrolyzed product of the benzyl-pyrrolidine ester (M-3) and an oxidized product of the dihydropyridine ring (M-8). 2. Involvement of CYP3A in the three primary metabolic pathways was revealed by the following studies: (a) inhibition of CYP3A, (b) a correlation study using 10 individual human liver microsomes and (c) cDNA-expression studies. The secondary metabolites, M-2 and M-4 (pyridine forms of M-1 and M-3), were most likely generated from M-8 but were unlikely from M-1 or M-3. Involvement of CYP3A in the secondary pathways of metabolism is also suggested. 3. The possibility of interactions between barnidipine and coadministered drugs was examined in vitro. The formation rate of the primary metabolites was little affected by warfarin, theophylline, phenytoin, diclofenac and amitriptyline at concentrations of 200 microM, but was inhibited by glibenclamide, simvastatin and cyclosporin A. IC50 for the latter drugs was estimated to be > 200, 200 and 20 microM respectively, which was roughly > 200, 6000 and 50 times higher than their respective therapeutic plasma levels, suggesting that interactions with cyclosporin A, a CYP3A inhibitor, are of possible clinical relevance.

  14. ADVANTAGES OF COMBINATION THERAPY OF HYPERTENSION WITH CALCIUM CHANNEL BLOCKER AND ANGIOTENSIN-CONVERTING ENZYME INHIBITOR IN PATIENTS WITH IMPAIRED RENAL FUNCTION

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    N. A. Dzhaiani

    2014-01-01

    Full Text Available Up-to-date data on combination therapy of arterial hypertension in patients with chronic kidney disease are presented. Special attention is paid to the fixed combination of calcium antagonist lercanidipine and angiotensin-converting enzyme inhibitor enalapril.

  15. Amino acid substitutions in the FXYD motif enhance phospholemman-induced modulation of cardiac L-type calcium channels.

    Science.gov (United States)

    Guo, Kai; Wang, Xianming; Gao, Guofeng; Huang, Congxin; Elmslie, Keith S; Peterson, Blaise Z

    2010-11-01

    We have found that phospholemman (PLM) associates with and modulates the gating of cardiac L-type calcium channels (Wang et al., Biophys J 98: 1149-1159, 2010). The short 17 amino acid extracellular NH(2)-terminal domain of PLM contains a highly conserved PFTYD sequence that defines it as a member of the FXYD family of ion transport regulators. Although we have learned a great deal about PLM-dependent changes in calcium channel gating, little is known regarding the molecular mechanisms underlying the observed changes. Therefore, we investigated the role of the PFTYD segment in the modulation of cardiac calcium channels by individually replacing Pro-8, Phe-9, Thr-10, Tyr-11, and Asp-12 with alanine (P8A, F9A, T10A, Y11A, D12A). In addition, Asp-12 was changed to lysine (D12K) and cysteine (D12C). As expected, wild-type PLM significantly slows channel activation and deactivation and enhances voltage-dependent inactivation (VDI). We were surprised to find that amino acid substitutions at Thr-10 and Asp-12 significantly enhanced the ability of PLM to modulate Ca(V)1.2 gating. T10A exhibited a twofold enhancement of PLM-induced slowing of activation, whereas D12K and D12C dramatically enhanced PLM-induced increase of VDI. The PLM-induced slowing of channel closing was abrogated by D12A and D12C, whereas D12K and T10A failed to impact this effect. These studies demonstrate that the PFXYD motif is not necessary for the association of PLM with Ca(V)1.2. Instead, since altering the chemical and/or physical properties of the PFXYD segment alters the relative magnitudes of opposing PLM-induced effects on Ca(V)1.2 channel gating, PLM appears to play an important role in fine tuning the gating kinetics of cardiac calcium channels and likely plays an important role in shaping the cardiac action potential and regulating Ca(2+) dynamics in the heart.

  16. Comparative effects of sodium channel blockers in short term rat whole embryo culture

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    Nilsson, Mats F, E-mail: Mats.Nilsson@farmbio.uu.se [Department of Pharmaceutical Biosciences, Uppsala University (Sweden); Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma [AstraZeneca R and D Södertälje (Sweden); Cebers, Gvido [AstraZeneca R and D, iMed, 141 Portland Street, Cambridge, MA 02139 (United States); Hellmold, Heike; Gustafson, Anne-Lee [AstraZeneca R and D Södertälje (Sweden); Webster, William S [Department of Anatomy and Histology, University of Sydney (Australia)

    2013-10-15

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.

  17. Negative inotropic action of denbufylline through interfering with the calcium channel independently of its PDE IV inhibitory activity in guinea pig ventricle papillary muscles.

    Science.gov (United States)

    Sanae, F; Ohmae, S; Kobayashi, D; Takag, K; Miyamoto, K

    1996-04-01

    The inotropic actions of xanthine derivatives with long alkyl chains were investigated in guinea pig ventricular papillary muscle. A potent and nonselective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine, elicited a positive inotropy and inhibited the negative inotropic effects of calcium channel inhibitors, as did a selective PDE III inhibitor, amrinone, and these effects were canceled by a protein kinase inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89). However, 1,3-di-n-butyl-7-(2'oxopropyl)xanthine (denbufylline) and 1-n-butyl-3-n-propylxanthine (XT-044), which have potent and selective PDE IV-inhibitory activities, showed negative inotropic actions that became more potent in the presence of H-89. Denbufylline abolished the late restoration phase induced by ryanodine. This xanthine derivative attenuated the effects of both the calcium channel acting agents Bay K 8644 and verapamil, without interaction with caffeine and dihydropyridine calcium channel inhibitors, and denbufylline had little direct influence on the specific binding of [(3)H]azidopine and [(3)H]desmethoxyverapamil to cardiac membranes. A nonxanthine PDE IV inhibitor, Ro 20-1724, did not affect the inotropic actions of calcium channel inhibitors. The attenuation by denbufylline or XT-044 of the negative inotropic action of verapamil was not influenced by treatment with H-89. These results suggest that in the ventricular papillary muscle, these xanthine derivatives elicit negative inotropy by acting on a verapamil-sensitive site of the calcium channel without involving their PDE-inhibitory activity.

  18. Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation

    Science.gov (United States)

    He, Fengping; Xu, Xin; Yuan, Shuguo; Tan, Liangqiu; Gao, Lingjun; Ma, Shaochun; Zhang, Shebin; Ma, Zhanzhong; Jiang, Wei; Liu, Fenglian; Chen, Baofeng; Zhang, Beibei; Pang, Jungang; Huang, Xiuyan; Weng, Jiaqiang

    2016-08-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

  19. A genetic screen for dihydropyridine (DHP-resistant worms reveals new residues required for DHP-blockage of mammalian calcium channels.

    Directory of Open Access Journals (Sweden)

    Trevor C Y Kwok

    2008-05-01

    Full Text Available Dihydropyridines (DHPs are L-type calcium channel (Ca(v1 blockers prescribed to treat several diseases including hypertension. Ca(v1 channels normally exist in three states: a resting closed state, an open state that is triggered by membrane depolarization, followed by a non-conducting inactivated state that is triggered by the influx of calcium ions, and a rapid change in voltage. DHP binding is thought to alter the conformation of the channel, possibly by engaging a mechanism similar to voltage dependent inactivation, and locking a calcium ion in the pore, thereby blocking channel conductance. As a Ca(v1 channel crystal structure is lacking, the current model of DHP action has largely been achieved by investigating the role of candidate Ca(v1 residues in mediating DHP-sensitivity. To better understand DHP-block and identify additional Ca(v1 residues important for DHP-sensitivity, we screened 440,000 randomly mutated Caenorhabditis elegans genomes for worms resistant to DHP-induced growth defects. We identified 30 missense mutations in the worm Ca(v1 pore-forming (alpha(1 subunit, including eleven in conserved residues known to be necessary for DHP-binding. The remaining polymorphisms are in eight conserved residues not previously associated with DHP-sensitivity. Intriguingly, all of the worm mutants that we analyzed phenotypically exhibited increased channel activity. We also created orthologous mutations in the rat alpha(1C subunit and examined the DHP-block of current through the mutant channels in culture. Six of the seven mutant channels examined either decreased the DHP-sensitivity of the channel and/or exhibited significant residual current at DHP concentrations sufficient to block wild-type channels. Our results further support the idea that DHP-block is intimately associated with voltage dependent inactivation and underscores the utility of C. elegans as a screening tool to identify residues important for DHP interaction with mammalian

  20. Genetic Evidence for Possible Involvement of the Calcium Channel Gene CACNA1A in Autism Pathogenesis in Chinese Han Population.

    Directory of Open Access Journals (Sweden)

    Jun Li

    Full Text Available Autism spectrum disorders (ASD are a group of neurodevelopmental disorders. Recent studies suggested that calcium channel genes might be involved in the genetic etiology of ASD. CACNA1A, encoding an alpha-1 subunit of voltage-gated calcium channel, has been reported to play an important role in neural development. Previous study detected that a single nucleotide polymorphism (SNP in CACNA1A confers risk to ASD in Central European population. However, the genetic relationship between autism and CACNA1A in Chinese Han population remains unclear. To explore the association of CACNA1A with autism, we performed a family-based association study. First, we carried out a family-based association test between twelve tagged SNPs and autism in 239 trios. To further confirm the association, the sample size was expanded to 553 trios by recruiting 314 additional trios. In a total of 553 trios, we identified association of rs7249246 and rs12609735 with autism though this would not survive after Bonferroni correction. Our findings suggest that CACNA1A might play a role in the etiology of autism.

  1. Glucocorticoids specifically enhance L-type calcium current amplitude and affect calcium channel subunit expression in the mouse hippocampus.

    Science.gov (United States)

    Chameau, Pascal; Qin, Yongjun; Spijker, Sabine; Smit, August Benjamin; Smit, Guus; Joëls, Marian

    2007-01-01

    Previous studies have shown that corticosterone enhances whole cell calcium currents in CA1 pyramidal neurons, through a pathway involving binding of glucocorticoid receptor homodimers to the DNA. We examined whether glucocorticoids show selectivity for L- over N-type of calcium currents. Moreover, we addressed the putative gene targets that eventually lead to the enhanced calcium currents. Electrophysiological recordings were performed in nucleated patches that allow excellent voltage control. Calcium currents in these patches almost exclusively involve N- and L-type channels. We found that L- but not N-type calcium currents were largely enhanced after treatment with a high dose of corticosterone sufficient to activate glucocorticoid receptors. Voltage dependency and kinetic properties of the currents were unaffected by the hormone. Nonstationary noise analysis suggests that the increased current is not caused by a larger unitary conductance, but rather to a doubling of the number of functional channels. Quantitative real-time PCR revealed that transcripts of the Ca(v)1 subunits encoding for the N- or L-type calcium channels are not upregulated in the mouse CA1 area; instead, a strong, direct, and consistent upregulation of the beta4 subunit was observed. This indicates that the corticosteroid-induced increase in number of L-type calcium channels is not caused by a simple transcriptional regulation of the pore-forming subunit of the channels.

  2. Presynaptic calcium channels and α3-integrins are complexed with synaptic cleft laminins, cytoskeletal elements and active zone components.

    Science.gov (United States)

    Carlson, Steven S; Valdez, Gregorio; Sanes, Joshua R

    2010-11-01

    At chemical synapses, synaptic cleft components interact with elements of the nerve terminal membrane to promote differentiation and regulate function. Laminins containing the β2 subunit are key cleft components, and they act in part by binding the pore-forming subunit of a pre-synaptic voltage-gated calcium channel (Ca(v)α) (Nishimune et al. 2004). In this study, we identify Ca(v)α-associated intracellular proteins that may couple channel-anchoring to assembly or stabilization of neurotransmitter release sites called active zones. Using Ca(v)α-antibodies, we isolated a protein complex from Torpedo electric organ synapses, which resemble neuromuscular junctions but are easier to isolate in bulk. We identified 10 components of the complex: six cytoskeletal proteins (α2/β2 spectrins, plectin 1, AHNAK/desmoyokin, dystrophin, and myosin 1), two active zone components (bassoon and piccolo), synaptic laminin, and a calcium channel β subunit. Immunocytochemistry confirmed these proteins in electric organ synapses, and PCR analysis revealed their expression by developing mammalian motor neurons. Finally, we show that synaptic laminins also interact with pre-synaptic integrins containing the α3 subunit. Together with our previous finding that a distinct synaptic laminin interacts with SV2 on nerve terminals (Son et al. 2000), our results identify three paths by which synaptic cleft laminins can send developmentally important signals to nerve terminals.

  3. L-Type Calcium Channels Do Not Play a Critical Role in Chest Blow Induced Ventricular Fibrillation: Commotio Cordis

    Directory of Open Access Journals (Sweden)

    Christopher Madias

    2016-01-01

    Full Text Available Background. In a commotio cordis swine model, ventricular fibrillation (VF can be induced by a ball blow to the chest believed secondary to activation of mechanosensitive ion channels. The purpose of the current study is to evaluate whether stretch induced activation of the L-type calcium channel may cause intracellular calcium overload and underlie the VF in commotio cordis. Method and Results. Anesthetized juvenile swine received 6 chest wall strikes with a 17.9 m/s lacrosse ball timed to the vulnerable period for VF induction. Animals were randomized to IV verapamil (n=6 or placebo (n=6. There was no difference in the observed frequency of VF between verapamil (19/26: 73% and placebo (20/36: 56% treated animals (p=0.16. There was also no significant difference in the combined endpoint of VF or nonsustained VF (21/26: 81% in verapamil versus 24/36: 67% in controls, p=0.22. Conclusions. In this experimental model of commotio cordis, verapamil did not prevent VF induction. Thus, in commotio cordis it is unlikely that stretch activation of the L-type calcium channel with resultant intracellular calcium overload plays a prominent role.

  4. Mapping of dihydropyridine binding residues in a less sensitive invertebrate L-type calcium channel (LCa v 1).

    Science.gov (United States)

    Senatore, Adriano; Boone, Adrienne; Lam, Stanley; Dawson, Taylor F; Zhorov, Boris; Spafford, J David

    2011-01-01

    Invertebrate L-type calcium channel, LCa(v) 1, isolated from the pond snail Lymnaea stagnalis is nearly indistinguishable from mammalian Ca(v) 1.2 (α1C) calcium channel in biophysical characteristics observed in vitro. These L-type channels are likely constrained within a narrow range of biophysical parameters to perform similar functions in the snail and mammalian cardiovascular systems. What distinguishes snail and mammalian L-type channels is a difference in dihydropyridine sensitivity: 100 nM isradipine exhibits a significant block of mammalian Ca(v) 1.2 currents without effect on snail LCa(v)1 currents. The native snail channel serves as a valuable surrogate for validating key residue differences identified from previous experimental and molecular modeling work. As predicted, three residue changes in LCa(v)1 (N_3o18, F_3i10, and I_4i12) replaced with DHP-sensing residues in respective positions of Ca(v) 1.2, (Q_3o18, Y_3i10, and M_4i12) raises the potency of isradipine block of LCa(v)1 channels to that of mammalian Ca(v) 1.2. Interestingly, the single N_3o18_Q mutation in LCa(v) 1 channels lowers DHP sensitivity even further and the triple mutation bearing enhanced isradipine sensitivity, still retains a reduced potency of agonist, (S)-Bay K8644.

  5. Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells

    Science.gov (United States)

    Jorgensen, Niklas Rye; Teilmann, Stefan Cuoni; Henriksen, Zanne; Civitelli, Roberto; Sorensen, Ole Helmer; Steinberg, Thomas H.

    2003-01-01

    The propagation of mechanically induced intercellular calcium waves (ICW) among osteoblastic cells occurs both by activation of P2Y (purinergic) receptors by extracellular nucleotides, resulting in "fast" ICW, and by gap junctional communication in cells that express connexin43 (Cx43), resulting in "slow" ICW. Human osteoblastic cells transmit intercellular calcium signals by both of these mechanisms. In the current studies we have examined the mechanism of slow gap junction-dependent ICW in osteoblastic cells. In ROS rat osteoblastic cells, gap junction-dependent ICW were inhibited by removal of extracellular calcium, plasma membrane depolarization by high extracellular potassium, and the L-type voltage-operated calcium channel inhibitor, nifedipine. In contrast, all these treatments enhanced the spread of P2 receptor-mediated ICW in UMR rat osteoblastic cells. Using UMR cells transfected to express Cx43 (UMR/Cx43) we confirmed that nifedipine sensitivity of ICW required Cx43 expression. In human osteoblastic cells, gap junction-dependent ICW also required activation of L-type calcium channels and influx of extracellular calcium.

  6. Differential rescue of spatial memory deficits in aged rats by L-type voltage-dependent calcium channel and ryanodine receptor antagonism.

    Science.gov (United States)

    Hopp, S C; D'Angelo, H M; Royer, S E; Kaercher, R M; Adzovic, L; Wenk, G L

    2014-11-01

    Age-associated memory impairments may result as a consequence of neuroinflammatory induction of intracellular calcium (Ca(+2)) dysregulation. Altered L-type voltage-dependent calcium channel (L-VDCC) and ryanodine receptor (RyR) activity may underlie age-associated learning and memory impairments. Various neuroinflammatory markers are associated with increased activity of both L-VDCCs and RyRs, and increased neuroinflammation is associated with normal aging. In vitro, pharmacological blockade of L-VDCCs and RyRs has been shown to be anti-inflammatory. Here, we examined whether pharmacological blockade of L-VDCCs or RyRs with the drugs nimodipine and dantrolene, respectively, could improve spatial memory and reduce age-associated increases in microglia activation. Dantrolene and nimodipine differentially attenuated age-associated spatial memory deficits but were not anti-inflammatory in vivo. Furthermore, RyR gene expression was inversely correlated with spatial memory, highlighting the central role of Ca(+2) dysregulation in age-associated memory deficits.

  7. Structure-function of proteins interacting with the alpha1 pore-forming subunit of high voltage-activated calcium channel

    Directory of Open Access Journals (Sweden)

    Alan eNeely

    2014-06-01

    Full Text Available Openings of high-voltage-activated calcium channels lead to a transient increase in calcium concentration that in turn activate a plethora of cellular functions, including muscle contraction, secretion and gene transcription. To coordinate all these responses calcium channels form supramolecular assemblies containing effectors and regulatory proteins that couple calcium influx to the downstream signal cascades and to feedback elements. According to the original biochemical characterization of skeletal muscle Dihydropyridine receptors, high-voltage-activated calcium channels are multi-subunit protein complexes consisting of a pore-forming subunit (α1 associated with four additional polypeptide chains β, α2, δ and γ, often referred to as accessory subunits. Twenty-five years after the first purification of a high-voltage calcium channel, the concept of a flexible stoichiometry to expand the repertoire of mechanisms that regulate calcium channel influx has emerged. Several other proteins have been identified that associate directly with the α1-subunit, including calmodulin and multiple members of the small and large GTPase family. Some of these proteins only interact with a subset of α1-subunits and during specific stages of biogenesis. More strikingly, most of the α1-subunit interacting proteins, such as the β-subunit and small GTPases, regulate both gating and trafficking through a variety of mechanisms. Modulation of channel activity covers almost all biophysical properties of the channel. Likewise, regulation of the number of channels in the plasma membrane is performed by altering the release of the α1-subunit from the endoplasmic reticulum, by reducing its degradation or enhancing its recycling back to the cell surface. In this review, we discuss the structural basis, interplay and functional role of selected proteins that interact with the central pore-forming subunit of high-voltage-activated calcium channels.

  8. Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation

    OpenAIRE

    Fengping He; Xin Xu; Shuguo Yuan; Liangqiu Tan; Lingjun Gao; Shaochun Ma; Shebin Zhang; Zhanzhong Ma; Wei Jiang; Fenglian Liu; Baofeng Chen; Beibei Zhang; Jungang Pang; Xiuyan Huang; Jiaqiang Weng

    2016-01-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. ...

  9. Influence of acute or chronic calcium channel antagonists on the acquisition and consolidation of memory and nicotine-induced cognitive effects in mice.

    Science.gov (United States)

    Biala, Grazyna; Kruk-Slomka, Marta; Jozwiak, Krzysztof

    2013-07-01

    Nicotinic cholinergic receptors (nAChRs) form a heterogeneous family of ligand-gated ion channels found in the nervous system. The main objective of our research was to investigate the interaction between cholinergic nicotinic system and calcium homeostasis in cognitive processes using the modified elevated plus maze memory model in mice. The time each mouse took to move from the open arm to either of the enclosed arms on the retention trial (transfer latency, TL2) was used as an index of memory. Our results showed that a single injection of nicotine (0.035 and 0.175 mg/kg) shortened TL2 values, improving memory-related processes. Similarly, L-type calcium channel antagonists (CCAs), i.e., flunarizine, verapamil, amlodipine, nimodipine, nifedipine, and nicardipine (at the range of dose 5-20 mg/kg) administered before or after training, decreased TL2 value improving memory acquisition and/or consolidation. Interestingly, at the subthresold doses, flunarizine, nicardipine, amlodipine, verapamil, and bupropion, a nAChR antagonist, significantly reversed the nicotine improvement of memory acquisition, while flunarizine, verapamil, and bupropion attenuated the improvement of memory consolidation provoked by an acute injection of nicotine (0.035 mg/kg, s.c.). After subchronic administration (14 days, i.p.) of verapamil and amlodipine, two CCAs with the highest affinity for nAChRs, only verapamil (5 mg/kg) impaired memory acquisition and consolidation while both verapamil and amlodipine, at the subthresold, ineffective dose (2.5 mg/kg), significantly reversed the improvement of memory provoked by an acute injection of nicotine (0.035 mg/kg, s.c.). Our findings can be useful to better understand the interaction between cholinergic nicotinic receptors and calcium-related mechanisms in memory-related processes.

  10. Calcium signaling and T-type calcium channels in cancer cell cycling

    Institute of Scientific and Technical Information of China (English)

    James T Taylor; Xiang-Bin Zeng; Jonathan E Pottle; Kevin Lee; Alun R Wang; Stephenie G Yi; Jennifer A S Scruggs; Suresh S Sikka; Ming Li

    2008-01-01

    Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells,free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear;however, there is a growing body of evidence that suggests the T-type Ca2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel isminimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca2+ channels are not expressed in epithelial cells, selective T-type Ca2+ channel blockers may be useful in the treatment of certain types of cancers.

  11. First direct electron microscopic visualization of a tight spatial coupling between GABAA-receptors and voltage-sensitive calcium channels

    DEFF Research Database (Denmark)

    Hansen, Gert Helge; Belhage, B; Schousboe, A

    1992-01-01

    Using cerebellar granule neurons in culture it was demonstrated that exposure of the cells to the GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) leads to an increase in the number of voltage-gated calcium channels as revealed by quantitative preembedding indirect...... immunogold labelling using a monoclonal antibody specific for phenylalkylamine and dihydropyridine sensitive Ca2+ channels. Using the same technique and a monoclonal antibody (bd-17) to the beta 2/beta 3-subunit of the GABAA-receptor, double labelling of Ca2+ channels and GABAA-receptors with gold particles...... of THIP-treated cultures. This suggests that primarily low affinity GABAA-receptors are closely associated with Ca2+ channels and this may be important for the ability of these receptors to mediate an inhibitory action on transmitter release even under extreme depolarizing conditions....

  12. Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye; Teilmann, Stefan Cuoni; Henriksen, Zanne

    2003-01-01

    The propagation of mechanically induced intercellular calcium waves (ICW) among osteoblastic cells occurs both by activation of P2Y (purinergic) receptors by extracellular nucleotides, resulting in "fast" ICW, and by gap junctional communication in cells that express connexin43 (Cx43), resulting...... in "slow" ICW. Human osteoblastic cells transmit intercellular calcium signals by both of these mechanisms. In the current studies we have examined the mechanism of slow gap junction-dependent ICW in osteoblastic cells. In ROS rat osteoblastic cells, gap junction-dependent ICW were inhibited by removal...... of extracellular calcium, plasma membrane depolarization by high extracellular potassium, and the L-type voltage-operated calcium channel inhibitor, nifedipine. In contrast, all these treatments enhanced the spread of P2 receptor-mediated ICW in UMR rat osteoblastic cells. Using UMR cells transfected to express Cx...

  13. Long-term use of angiotensin receptor blockers and the risk of cancer.

    Directory of Open Access Journals (Sweden)

    Laurent Azoulay

    Full Text Available The association between angiotensin receptor blockers (ARBs and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs and 95% confidence intervals (CIs of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years. When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96-1.03 or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06-1.20 and RR: 1.19; 95% CI: 1.12-1.27, respectively. This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.

  14. Tolperisone-type drugs inhibit spinal reflexes via blockade of voltage-gated sodium and calcium channels.

    Science.gov (United States)

    Kocsis, Pál; Farkas, Sándor; Fodor, László; Bielik, Norbert; Thán, Márta; Kolok, Sándor; Gere, Anikó; Csejtei, Mónika; Tarnawa, István

    2005-12-01

    The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50-400 microM), eperisone, lanperisone, inaperisone, and silperisone (25-200 microM) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100-800 microM) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with tolperisone and its analogs in the [3H]batrachotoxinin A 20-alpha-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of tolperisone-type centrally acting muscle relaxant drugs. Furthermore, tolperisone, eperisone, and especially silperisone had a marked effect on voltage-gated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that tolperisone-type muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.

  15. Inhibitors of arachidonate-regulated calcium channel signaling suppress triggered activity induced by the late sodium current.

    Science.gov (United States)

    Wolkowicz, Paul; Umeda, Patrick K; Sharifov, Oleg F; White, C Roger; Huang, Jian; Mahtani, Harry; Urthaler, Ferdinand

    2014-02-05

    Disturbances in myocyte calcium homeostasis are hypothesized to be one cause for cardiac arrhythmia. The full development of this hypothesis requires (i) the identification of all sources of arrhythmogenic calcium and (ii) an understanding of the mechanism(s) through which calcium initiates arrhythmia. To these ends we superfused rat left atria with the late sodium current activator type II Anemonia sulcata toxin (ATXII). This toxin prolonged atrial action potentials, induced early afterdepolarization, and provoked triggered activity. The calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphon-amide) suppressed ATXII triggered activity but its inactive congener KN-92 (2-[N-(4-methoxy benzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) did not. Neither drug affected normal atrial contractility. Calcium entry via L-type channels or calcium leakage from sarcoplasmic reticulum stores are not critical for this type of ectopy as neither verapamil ((RS)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-(methyl)amino}-2-prop-2-ylpentanenitrile) nor ryanodine affected ATXII triggered activity. By contrast, inhibitors of the voltage independent arachidonate-regulated calcium (ARC) channel and the store-operated calcium channel specifically suppressed ATXII triggered activity without normalizing action potentials or affecting atrial contractility. Inhibitors of cytosolic calcium-dependent phospholipase A2 also suppressed triggered activity suggesting that this lipase, which generates free arachidonate, plays a key role in ATXII ectopy. Thus, increased left atrial late sodium current appears to activate atrial Orai-linked ARC and store operated calcium channels, and these voltage-independent channels may be unexpected sources for the arrhythmogenic calcium that underlies triggered activity.

  16. Sensitization of voltage activated calcium channel currents for capsaicin in nociceptive neurons by tumor-necrosis-factor-alpha.

    Science.gov (United States)

    Hagenacker, T; Czeschik, J C; Schäfers, M; Büsselberg, D

    2010-01-15

    It is known that application of tumor-necrosis-factor-alpha (TNF-alpha) sensitizes neuronal calcium channels for heat stimuli in rat models of neuropathic pain. This study examines whether TNF-alpha modulates the capsaicin-induced effects after transient receptor potential vanilloid (TRPV)-1 receptor activation on voltage activated calcium channel currents (I(Ca(V))). TRPV-1 receptors are activated by heat and play an important role in the pathogenesis of thermal hyperalgesia in neuropathic pain syndromes, while voltage activated channels are essential for transmission of neuronal signals. Eliciting I(Ca(V)) in DRG neurons of rats by a depolarization from the resting potential to 0 mV, TNF-alpha (100 ng/ml) reduces I(Ca(V)) by 16.9+/-2.2%, while capsaicin (0.1 microM) decreases currents by 27+/-4.3%. Pre-application of TNF-alpha (100 ng/ml) for 24h results in a sensitization of I(Ca(V)) to capsaicin (0.1 microM) with a reduction of 42.8+/-4.4% mediated by TRPV-1. While L-type (36.6+/-5.2%) and P/Q-type currents (35.6+/-4.1%) are also sensitized by TRPV-1 activation, N-type channel currents are most sensitive (74.5+/-7.3%). The capsaicin-induced shift towards the hyperpolarizing voltage range does not occur when TNF-alpha is applied. Summarizing, TNF-alpha sensitizes nociceptive neurons for capsaicin.

  17. T-type calcium channels promote predictive homeostasis of input-output relations in thalamocortical neurons of lateral geniculate nucleus.

    Science.gov (United States)

    Hong, Su Z; Kim, Haram R; Fiorillo, Christopher D

    2014-01-01

    A general theory views the function of all neurons as prediction, and one component of this theory is that of "predictive homeostasis" or "prediction error." It is well established that sensory systems adapt so that neuronal output maintains sensitivity to sensory input, in accord with information theory. Predictive homeostasis applies the same principle at the cellular level, where the challenge is to maintain membrane excitability at the optimal homeostatic level so that spike generation is maximally sensitive to small gradations in synaptic drive. Negative feedback is a hallmark of homeostatic mechanisms, as exemplified by depolarization-activated potassium channels. In contrast, T-type calcium channels exhibit positive feedback that appears at odds with the theory. In thalamocortical neurons of lateral geniculate nucleus (LGN), T-type channels are capable of causing bursts of spikes with an all-or-none character in response to excitation from a hyperpolarized potential. This "burst mode" would partially uncouple visual input from spike output and reduce the information spikes convey about gradations in visual input. However, past observations of T-type-driven bursts may have resulted from unnaturally high membrane excitability. Here we have mimicked within rat brain slices the patterns of synaptic conductance that occur naturally during vision. In support of the theory of predictive homeostasis, we found that T-type channels restored excitability toward its homeostatic level during periods of hyperpolarization. Thus, activation of T-type channels allowed two retinal input spikes to cause one output spike on average, and we observed almost no instances in which output count exceeded input count (a "burst"). T-type calcium channels therefore help to maintain a single optimal mode of transmission rather than creating a second mode. More fundamentally our results support the general theory, which seeks to predict the properties of a neuron's ion channels and

  18. The effects of inorganic lead on voltage-sensitive calcium channels differ among cell types and among channel subtypes.

    Science.gov (United States)

    Audesirk, G; Audesirk, T

    1993-01-01

    The whole-cell version of patch clamping was used to compare the effects of acute in vitro exposure to inorganic lead (Pb2+) on voltage-sensitive calcium channels in cultured N1E-115 mouse neuroblastoma cells and E18 rat hippocampal neurons. Free Pb2+ concentrations in salines with a high lead-buffering capacity were measured with a calibrated Pb(2+)-selective electrode. Previously, we found that N1E-115 neurons contain low voltage activated, rapidly inactivating (T) channels and high voltage activated, slowly inactivating (L) channels. Pb2+ inhibits both channel subtypes in N1E-115 cells, with some selectivity against L-type channels (IC50 approximately 700 nM free Pb2+ for L-type channels, 1300 nM free Pb2+ for T-type channels; Audesirk and Audesirk, 1991). In addition to T-type and L-type channels, cultured E18 rat hippocampal neurons have been reported to contain high voltage-activated, rapidly inactivating (N) channels. In our experiments with 5 to 20 day old cultures, almost all neurons showed substantial L-type current, approximately half showed significant N-type current, and fewer than 5% showed significant T-type current. We found that Pb2+ is somewhat selective against L-type channels (IC50 approximately 30 nM free Pb2+ in 10 mM Ba2+ as the charge carrier, 55 nM in 50 mM Ba2+) compared to N-channels (IC50 approximately 80 nM free Pb2+ in 10 mM Ba2+, 200 nM in 50 mM Ba2+). These results suggest that the effects of Pb2+ on calcium channels of vertebrate neurons vary both among cell types and among channel subtypes.

  19. Effects of inorganic lead on voltage-sensitive calcium channels in N1E-115 neuroblastoma cells.

    Science.gov (United States)

    Audesirk, G; Audesirk, T

    1991-01-01

    N1E-115 mouse neuroblastoma cells have been reported to possess two types of voltage-sensitive calcium channels: Low voltage activated, rapidly inactivating T-type (type I) and high voltage activated, slowly inactivating L-type (type II). We studied the effects of acute in vitro exposure to inorganic lead on these calcium channels, using the whole-cell variant of patch clamping. Using salines with a high lead-buffering capacity, we found that both T-type and L-type channels are reversibly inhibited in a dose-dependent manner at free Pb2+ concentrations ranging from 20 nM to 14 microM. L-type channels are somewhat more sensitive to Pb2+ than T-type channels are (L-type: IC50 approx. 0.7 microM; T-type: IC50 approx. 1.3 microM). Both channels show small but significant inhibition (approx. 10%) at 20 nM free Pb2+. Pb2+ affects neither activation nor inactivation of T-type channels, but enhances inactivation of L-type channels at holding potentials around -60 to -40 mV. A peculiar phenomenon was observed in cells exposed to 2.3 microM free Pb2+. T-type channels were inhibited in all 20 cells studied. In 15 cells, L-type channels were also inhibited, but in the remaining 5 cells, current flow through L-type channels was enhanced by Pb2+ exposure.

  20. Aberrant Splicing Promotes Proteasomal Degradation of L-type Ca v 1.2 Calcium Channels by Competitive Binding for CaV β Subunits in Cardiac Hypertrophy

    NARCIS (Netherlands)

    Hu, Zhenyu; Wang, Jiong Wei; Yu, Dejie; Soon, Jia Lin; De Kleijn, Dominique P V; Foo, Roger; Liao, Ping; Colecraft, Henry M.; Soong, Tuck Wah

    2016-01-01

    Decreased expression and activity of Ca V1.2 calcium channels has been reported in pressure overload-induced cardiac hypertrophy and heart failure. However, the underlying mechanisms remain unknown. Here we identified in rodents a splice variant of Ca V1.2 channel, named Ca V1.2 e21+22, that contain

  1. Nitric oxide and L-type calcium channel influences the changes in arterial blood pressure and heart rate induced by central angiotesin II

    Directory of Open Access Journals (Sweden)

    Guarda Ismael FMS

    2008-05-01

    Full Text Available Abstract We study the voltage dependent calcium channels and nitric oxide involvement in angiotensin II-induced pressor effect. The antipressor action of L-Type calcium channel antagonist, nifedipine, has been studied when it was injected into the third ventricle prior to angiotensin II. The influence of nitric oxide on nifedipine antipressor action has also been studied by utilizing NW-nitro-L-arginine methyl ester (LNAME (40 μg/0.2 μl a nitric oxide synthase inhibitor and L-arginine (20 μg/0.2 μl, a nitric oxide donor agent. Adult male Holtzman rats weighting 200–250 g, with cannulae implanted into the third ventricle were injected with angiotensin II. Angiotensin II produced an elevation in mean arterial pressure and a decreased in heart rate. Such effects were potentiated by the prior injection of LNAME. L-arginine and nifedipine blocked the effects of angiotensin II. These data showed the involvement of L-Type calcium channel and a free radical gas nitric oxide in the central control of angiotensin II-induced pressor effect. This suggested that L-Type calcium channel of the circunventricular structures of central nervous system participated in both short and long term neuronal actions of ANG II with the influence of nitrergic system.

  2. The L-Type Voltage-Gated Calcium Channel Ca[subscript v]1.3 Mediates Consolidation, but Not Extinction, of Contextually Conditioned Fear in Mice

    Science.gov (United States)

    McKinney, Brandon C.; Murphy, Geoffrey G.

    2006-01-01

    Using pharmacological techniques, it has been demonstrated that both consolidation and extinction of Pavlovian fear conditioning are dependent to some extent upon L-type voltage-gated calcium channels (LVGCCs). Although these studies have successfully implicated LVGCCs in Pavlovian fear conditioning, they do not provide information about the…

  3. Inhibition of voltage-gated calcium channels after subchronic and repeated exposure of PC12 cells to different classes of insecticides

    NARCIS (Netherlands)

    Meijer, Marieke; Brandsema, Joske A R; Nieuwenhuis, Desirée; Wijnolts, Fiona M J; Dingemans, Milou M L; Westerink, Remco H S

    2015-01-01

    We previously demonstrated that acute inhibition of voltage-gated calcium channels (VGCCs) is a common mode of action for (sub)micromolar concentrations of chemicals, including insecticides. However, since human exposure to chemicals is usually chronic and repeated, we investigated if selected insec

  4. Cloning and characterization of a novel calcium channel toxin-like gene BmCa1 from Chinese scorpion Mesobuthus martensii Karsch.

    Science.gov (United States)

    Zhijian, Cao; Yun, Xie; Chao, Dai; Shunyi, Zhu; Shijin, Yin; Yingliang, Wu; Wenxin, Li

    2006-06-01

    Many studies have been carried on peptides and genes encoding scorpion toxins from the venom of Mesobuthus martensii Karsch (synonym: Buthus martensii Karsch, BmK), such as Na+, K+ and Cl- channel modulators. In this study, a novel calcium channel toxin-like gene BmCa1 was isolated and characterized from the venom of Mesobuthus martensii Karsch. First, a partial cDNA sequence of the Ca2+ channel toxin-like gene was identified by random sequencing method from a venomous gland cDNA library of Mesobuthus martensii Karsch. The full-length sequence of BmCa1 was then obtained by 5'RACE technique. The peptide deduced from BmCa1 precursor nucleotide sequence contains a 27-residue signal peptide and a 37-residue mature peptide. Although BmCa1 and other scorpion toxins are different at the gene and protein primary structure levels, BmCa1 has the same precursor nucleotide organization and cysteine arrangement as that of the first subfamily members of calcium channel scorpion toxins. Genomic DNA sequence of BmCa1 was also cloned by PCR. Sequence analysis showed that BmCa1 gene consists of three exons separated by two introns of 72 bp and 1076 bp in length, respectively. BmCa1 is the first calcium channel toxin-like gene cloned from the venom of Mesobuthus martensii Karsch and potentially represents a novel class of calcium channel toxins in scorpion venoms.

  5. Effects of in vitro lead exposure on voltage-sensitive calcium channels differ among cell types in central neurons of Lymnaea stagnalis.

    Science.gov (United States)

    Audesirk, G; Audesirk, T

    1989-01-01

    The effects of acute in vitro lead exposure on slowly inactivating voltage-sensitive calcium channels in central neurons of the freshwater pond snail Lymnaea stagnalis were studied under voltage clamp. Three physiologically distinct cell types were used: two subsets of the B cell cluster (Bpos and Bneg) and the pedal giant neuron (RPeD1). In Bpos neurons, 5 nM free Pb2+ irreversibly inhibited current flow through calcium channels by 38 +/- 10%. In Bneg neurons, 5 nM free Pb2+ slightly inhibited inward currents (12 +/- 6%) and may have shifted their voltage dependence to more depolarized voltages. The inhibition and voltage shift were irreversible. In RPeD1 neurons, Pb2+ caused a small, statistically insignificant inhibition of inward current (5 nM free Pb2+; 18 +/- 19%; 30 nM free Pb2+: 31 +/- 23%). The effects of Pb2+ were fully reversible. These data indicate that (1) voltage-sensitive calcium channels in Lymnaea neurons are inhibited by nanomolar concentrations of free Pb2+; (2) there are multiple types of calcium channels in Lymnaea neurons; and (3) the effects of in vitro lead exposure differ qualitatively among channel types.

  6. Like Extinction, Latent Inhibition of Conditioned Fear in Mice Is Blocked by Systemic Inhibition of L-Type Voltage-Gated Calcium Channels

    Science.gov (United States)

    Blouin, Ashley M.; Cain, Chris K.; Barad, Mike

    2004-01-01

    Having recently shown that extinction of conditioned fear depends on L-type voltage-gated calcium channels (LVGCCs), we have been seeking other protocols that require this unusual induction mechanism. We tested latent inhibition (LI) of fear, because LI resembles extinction except that cue exposures precede, rather than follow, cue-shock pairing.…

  7. A study on separation of canine atrial myocytes and detection of their L-type calcium channel current%犬心房肌细胞分离及其L型钙通道电流检测的研究

    Institute of Scientific and Technical Information of China (English)

    邹帅; 龙毅; 范晋奇; 周亚南; 高大中; 殷跃辉

    2011-01-01

    目的 探讨一种稳定可靠的犬心房肌细胞的分离方法,提高膜片钳的实验成功率并检测L型钙通道电流.方法 采用改良Langderoff灌流系统行主动脉逆行灌注,采用选择性冠状动脉插管的方法,获得单个心房肌细胞.在显微镜下观察细胞形态,并应用膜片钳全细胞模式记录L型钙通道电流.结果 分离细胞存活率为70%~80%,复钙后细胞存活率为30%~40%,耐钙细胞形态呈杆状,折光性强,横纹清晰,并能稳定记录L型钙通道电流.结论 改良Langderoff技术有助于稳定分离出存活率高、具有正常电生理特性的犬心房肌细胞,能用于心房肌细胞离子通道的研究.%Objective To explore a stable and reliable method of canine atrial myocytes separation for improving the success rate of patch-clamp techniques and detecting the L-type calcium channel current. Methods Modified Langderoff perfusion system was adopted to perform retrograde aortic perfusion and selective coronary artery catheterization was used to obtain single atrial myot-cytes. Microscope was employed to observe the cellular morphology and the L-type calcium channel current was measured by whole-cell patch-clamp recording. Results The survival rate of separated cells was 70% to 80% ,and it was 30% to 40% after recalcifica-tion. A stable L-type calcium channel current could be recorded in calcium-tolerant cells which was rod-shaped with good refraction and clear horizontal stripe. Conclusion Modified Langderoff technique contribute to stable separation of canine atrial myocytes with high survival rate and normal electrophysiological properties,and can be used in the research of the iron channel of atrial myocytes.

  8. High affinity complexes of pannexin channels and L-type calcium channel splice-variants in human lung: Possible role in clevidipine-induced dyspnea relief in acute heart failure

    Directory of Open Access Journals (Sweden)

    Gerhard P. Dahl

    2016-08-01

    Research in Context: Clevidipine lowers blood pressure by inhibiting calcium channels in vascular smooth muscle. In patients with acute heart failure, clevidipine was shown to relieve breathing problems. This was only partially related to the blood pressure lowering actions of clevidipine and not conferred by another calcium channel inhibitor. We here found calcium channel variants in human lung that are more selectively inhibited by clevidipine, especially when associated with pannexin channels. This study gives a possible mechanism for clevidipine's relief of breathing problems and supports future clinical trials testing the role of clevidipine in the treatment of acute heart failure.

  9. Troponin T3 regulates nuclear localization of the calcium channel Cavβ1a subunit in skeletal muscle.

    Science.gov (United States)

    Zhang, Tan; Taylor, Jackson; Jiang, Yang; Pereyra, Andrea S; Messi, Maria Laura; Wang, Zhong-Min; Hereñú, Claudia; Delbono, Osvaldo

    2015-08-15

    The voltage-gated calcium channel (Cav) β1a subunit (Cavβ1a) plays an important role in excitation-contraction coupling (ECC), a process in the myoplasm that leads to muscle-force generation. Recently, we discovered that the Cavβ1a subunit travels to the nucleus of skeletal muscle cells where it helps to regulate gene transcription. To determine how it travels to the nucleus, we performed a yeast two-hybrid screening of the mouse fast skeletal muscle cDNA library and identified an interaction with troponin T3 (TnT3), which we subsequently confirmed by co-immunoprecipitation and co-localization assays in mouse skeletal muscle in vivo and in cultured C2C12 muscle cells. Interacting domains were mapped to the leucine zipper domain in TnT3 COOH-terminus (160-244 aa) and Cavβ1a NH2-terminus (1-99 aa), respectively. The double fluorescence assay in C2C12 cells co-expressing TnT3/DsRed and Cavβ1a/YFP shows that TnT3 facilitates Cavβ1a nuclear recruitment, suggesting that the two proteins play a heretofore unknown role during early muscle differentiation in addition to their classical role in ECC regulation.

  10. Metabotropic glutamate receptor 6 signaling enhances TRPM1 calcium channel function and increases melanin content in human melanocytes.

    Science.gov (United States)

    Devi, Sulochana; Markandeya, Yogananda; Maddodi, Nityanand; Dhingra, Anuradha; Vardi, Noga; Balijepalli, Ravi C; Setaluri, Vijayasaradhi

    2013-05-01

    Mutations in TRPM1, a calcium channel expressed in retinal bipolar cells and epidermal melanocytes, cause complete congenital stationary night blindness with no discernible skin phenotype. In the retina, TRPM1 activity is negatively coupled to metabotropic glutamate receptor 6 (mGluR6) signaling through Gαo and TRPM1 mutations result in the loss of responsiveness of TRPM1 to mGluR6 signaling. Here, we show that human melanocytes express mGluR6, and treatment of melanocytes with L-AP4, a type III mGluR-selective agonist, enhances Ca(2+) uptake. Knockdown of TRPM1 or mGluR6 by shRNA abolished L-AP4-induced Ca(2+) influx and TRPM1 currents, showing that TRPM1 activity in melanocytes is positively coupled to mGluR6 signaling. Gαo protein is absent in melanocytes. However, forced expression of Gαo restored negative coupling of TRPM1 to mGluR6 signaling, but treatment with pertussis toxin, an inhibitor of Gi /Go proteins, did not affect basal or mGluR6-induced Ca(2+) uptake. Additionally, chronic stimulation of mGluR6 altered melanocyte morphology and increased melanin content. These data suggest differences in coupling of TRPM1 function to mGluR6 signaling explain different cellular responses to glutamate in the retina and the skin.

  11. Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system

    DEFF Research Database (Denmark)

    Hansen, Pernille B L

    2015-01-01

    Over the years, it has been discussed whether T-type calcium channels Cav3 play a role in the cardiovascular and renal system. T-type channels have been reported to play an important role in renal hemodynamics, contractility of resistance vessels, and pacemaker activity in the heart. However...... to the conclusion that Cav3.1 and Cav3.2 channels have important, but different, functions in mice. T-type Cav3.1 channels affect heart rate, whereas Cav3.2 channels are involved in cardiac hypertrophy. In the vascular system, Cav3.2 activation leads to dilation of blood vessels, whereas Cav3.1 channels are mainly.......2, are expressed in blood vessels, the kidney, and the heart. Studies with gene-deficient mice have provided a way to investigate the Cav3.1 and Cav3.2 channels and their role in the cardiovascular system. This review discusses the results from these knockout mice. Evaluation of the literature leads...

  12. Effects of low-dose ionising radiation on pituitary adenoma: is there a role for L-type calcium channel?

    Energy Technology Data Exchange (ETDEWEB)

    Soares, Marcella Araugio; Santos, Raquel Gouvea dos [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN), Belo Horizonte, MG (Brazil). Lab. de Radiobiologia]. E-mail: santosr@cdtn.br

    2005-10-15

    Pituitary adenomas constitute about 6-18% of brain tumours in adults. Activation of voltage gated calcium currents can account for growth hormone over secretion in some GH-secreting pituitary adenomas that produce an acromegaly appearance and increase mortality. Ca{sup 2+} ions, as mediators of intracellular signalling, are crucial for the development of apoptosis. However, the role of [Ca{sup 2+}] in the development of apoptosis is ambiguous. In this study, the effects of low-dose ionising gamma radiation ({sup 60} Co) on rat pituitary adenoma cells survival and proliferation and the role of calcium channels on the apoptosis radio-induced were evaluated. Doses as low as 3 Gy were found to inhibit GH3 cell proliferation. Even though there was a significant number of live cells,168 hours following irradiation, they were not able to proliferate. The results indicate that the blockade of extracellular calcium influx through these channels does not interfere in the radiation-induced apoptosis in GH3 cells. (author)

  13. Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice.

    Directory of Open Access Journals (Sweden)

    Christian Schön

    Full Text Available Retinitis pigmentosa is an inherited blinding disorder characterized by progressive degeneration and loss of photoreceptors. The exact mechanism of degeneration and cell death of photoreceptors is not known, but is thought to involve disturbed Ca2+-signaling. Ca2+ can enter the photoreceptor cell via outer segment cyclic nucleotide-gated (CNG channels or synaptic Cav1.4 L-type voltage-gated calcium channels (VGCC. Previously, we have shown that genetic ablation of the Cngb1 gene encoding the B subunit of the rod CNG channel delays the fast progressing degeneration in the rd1 mutant mouse model of retinitis pigmentosa. In this study, we crossbred rd1 mice with the Cacna1f-deficient mouse lacking the Cav1.4 α1 subunit of the L-type VGCC. Longitudinal in vivo examinations of photoreceptor layer thickness by optical coherence tomography revealed a significant, but not sustained delay of retinal degeneration in Cacna1f x rd1 double mutant mice compared to rd1 mice. This was accompanied by a reduction of TUNEL positive cells in the early phase of rod degeneration. Remarkably, Cacna1f x rd1 double mutant mice displayed a strong decrease in the activation of the Ca2+-dependent protease calpain during photoreceptor loss. Our results show that genetic deletion of the synaptic Cav1.4 L-type VGCCs impairs calpain activation and leads to a short-term preservation of photoreceptors in the rd1 mouse.

  14. Commitment of Satellite Cells Expressing the Calcium Channel α2δ1 Subunit to the Muscle Lineage

    Directory of Open Access Journals (Sweden)

    Tammy Tamayo

    2012-01-01

    Full Text Available Satellite cells can maintain or repair muscle because they possess stem cell properties, making them a valuable option for cell therapy. However, cell transplants into skeletal muscle of patients with muscular dystrophy are limited by donor cell attachment, migration, and survival in the host tissue. Cells used for therapy are selected based on specific markers present in the plasma membrane. Although many markers have been identified, there is a need to find a marker that is expressed at different states in satellite cells, activated, quiescent, or differentiated cell. Furthermore, the marker has to be present in human tissue. Recently we reported that the plasma membrane α2δ1 protein is involved in cell attachment and migration in myoblasts. The α2δ1 subunit forms a part of the L-type voltage-dependent calcium channel in adult skeletal muscle. We found that the α2δ1 subunit is expressed in the majority of newly isolated satellite cells and that it appears earlier than the α1 subunits and at higher levels than the β or γ subunits. We also found that those cells that expressed α2δ1 would differentiate into muscle cells. This evidence indicates that the α2δ1 may be used as a marker of satellite cells that will differentiate into muscle.

  15. Science Signaling Podcast for 24 January 2017: Tissue-specific regulation of L-type calcium channels.

    Science.gov (United States)

    Hell, Johannes W; Navedo, Manuel F; VanHook, Annalisa M

    2017-01-24

    This Podcast features an interview with Johannes Hell and Manuel Navedo, senior authors of two Research Articles that appear in the 24 January 2017 issue of Science Signaling, about tissue-specific regulation of the L-type calcium channel CaV1.2. This channel is present in many tissues, including the heart, vasculature, and brain, and allows calcium to flow into cells when it is activated. Signaling through the β-adrenergic receptor (βAR) stimulates CaV1.2 activity in heart cells and neurons to accelerate heart rate and increase neuronal excitability, respectively. Using mouse models, Qian et al found that βAR-mediated enhancement of CaV1.2 activity in the brain required phosphorylation of Ser(1928), whereas βAR-mediated enhancement of CaV1.2 activity in the heart did not require phosphorylation of this residue. In a related study, Nystoriak et al demonstrated that phosphorylation of Ser(1928) in arterial myocytes was required for vasoconstriction during acute hyperglycemia and in diabetic mice. These findings demonstrate tissue-specific differences in CaV1.2 regulation and suggest that it may be possible to design therapies to target this channel in specific tissues.Listen to Podcast.

  16. Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels

    Science.gov (United States)

    Lee, Moon Young; Park, Chanjae; Ha, Se Eun; Park, Paul J.; Berent, Robyn M.; Jorgensen, Brian G.; Corrigan, Robert D.; Grainger, Nathan; Blair, Peter J.; Slivano, Orazio J.; Miano, Joseph M.; Ward, Sean M.; Smith, Terence K.; Sanders, Kenton M.

    2017-01-01

    Serum response factor (SRF) transcriptionally regulates expression of contractile genes in smooth muscle cells (SMC). Lack or decrease of SRF is directly linked to a phenotypic change of SMC, leading to hypomotility of smooth muscle in the gastrointestinal (GI) tract. However, the molecular mechanism behind SRF-induced hypomotility in GI smooth muscle is largely unknown. We describe here how SRF plays a functional role in the regulation of the SMC contractility via myotonic dystrophy protein kinase (DMPK) and L-type calcium channel CACNA1C. GI SMC expressed Dmpk and Cacna1c genes into multiple alternative transcriptional isoforms. Deficiency of SRF in SMC of Srf knockout (KO) mice led to reduction of SRF-dependent DMPK, which down-regulated the expression of CACNA1C. Reduction of CACNA1C in KO SMC not only decreased intracellular Ca2+ spikes but also disrupted their coupling between cells resulting in decreased contractility. The role of SRF in the regulation of SMC phenotype and function provides new insight into how SMC lose their contractility leading to hypomotility in pathophysiological conditions within the GI tract. PMID:28152551

  17. Modulation of MAA-induced apoptosis in male germ cells: role of Sertoli cell P/Q-type calcium channels

    Directory of Open Access Journals (Sweden)

    Aguanno Salvatore

    2005-04-01

    Full Text Available Abstract Spontaneous germ cell death by apoptosis occurs during normal spermatogenesis in mammals and is thought to play a role in the physiological mechanism limiting the clonal expansion of such cell population in the male gonad. In the prepubertal rat testis, the most conspicuous dying cells are pachytene spermatocytes, which are also the primary target of the apoptosis experimentally induced by the methoxyacetic acid (MAA. Since we have recently reported that Sertoli cells, the somatic component of the seminiferous epithelium, regulate not only germ cell viability and differentiation but also their death, we have further investigated the mechanism involved in such a control. In this paper we have used the protein clusterin, produced by Sertoli cells and associated with tissue damage or injury, as indicator of germ cell apoptosis in rat seminiferous tubules treated with MAA in the presence or in the absence of omega-agatoxin, a specific inhibitor of P/Q type voltage-operated calcium channels (VOCC's. We performed both a qualitative analysis of clusterin content and germ cell apoptosis by immunofluorescence experiments and a quantitative analysis by in situ end labelling of apoptotic germ cells followed by flow cytometry. The results obtained demonstrate that Sertoli cells modulate germ cell apoptosis induced by methoxyacetic acid also throughout the P/Q-type VOCC's.

  18. 甜菜碱促进小鼠脾淋巴细胞增殖作用的钙通道机制研究%Calcium channel mechanism by which betaine promotes proliferation of lymphocytes in mice

    Institute of Scientific and Technical Information of China (English)

    季宇彬; 高世勇; 冯小燕; 何立巍

    2009-01-01

    Objective: To study how the way in which betaine promotes the proliferation of mouse spleen lymphocytes is related to calcium channels. Method:BALB/c mice were used for this experiment. Mouse spleen lymphocytes were obtained through in vitro cultivation after they had been separated, and were divided into a negative control group, a ConA group, and 0. 04, 0. 4, 4, and 20 mmol·L~(-1) betaine groups. MTT was used to observe the effect of betaine on the proliferation of mouse spleen lymphocytes; flow cytometry was used to measure the changes in the cell cycle of mouse spleen lymphocytes; and laser confocal scanning microscopy was used to observe the changes in the intracellular [ Ca~(2+) ]; of mouse spleen lymphocytes after betaine or different calcium channel blockers were applied. Result; Betaine was found to promote the proliferation of mouse spleen lymphocytes 12 h after it had been applied in vitro in concentrations of 4 and 20 mmol·L~(-1). It was also found to promote the proliferation of mouse spleen lymphocytes 24 h and 48 h after it had been applied in vitro in concentrations of 0. 04, 0. 4, 4, and 20 mmol·L~(-1), with the effect being most marked for the 4 mmol·L~(-1) group 24 h after its application. It was found to facilitate the entry of mouse spleen lymphocytes from the G_0/G_1 to the S phase 4, 6, 18, and 24 h after it had been applied to mouse spleen lymphocytes in a concentration of 4 mmol·L~(-1) , with the effect being most marked at 18 h after its application. Intracellular [ Ca~(2+) ]; in mouse spleen lymphocytes increased significantly (P < 0.01 ) 6,12, 18 h after 4 mmol·L~(-1) betaine had acted on the lymphocytes, with the effect being most marked at 6 h. The calcium channel blockers nifidipine, dihiazem, mibefradil, and genistein had no effect on the increase of the intracellular [ Ca~(2+) ] ; in mouse spleen lymphocytes due to the application of betaine, while verapamil, mycifradin, heparin, and procaine could block such increase

  19. L-type calcium channels and calcium/calmodulin-dependent kinase II differentially mediate behaviors associated with nicotine withdrawal in mice.

    Science.gov (United States)

    Jackson, K J; Damaj, M I

    2009-07-01

    Smoking is a widespread health problem. Because the nicotine withdrawal syndrome is a major contributor to continued smoking and relapse, it is important to understand the molecular and behavioral mechanisms of nicotine withdrawal to generate more effective smoking cessation therapies. Studies suggest a role for calcium-dependent mechanisms, such as L-type calcium channels and calcium/calmodulin-dependent protein kinase II (CaMKII), in the effects of nicotine dependence; however, the role of these mechanisms in nicotine-mediated behaviors is unclear. Thus, the goal of this study was to elucidate the role of L-type calcium channels and CaMKII in nicotine withdrawal behaviors. Using both pharmacological and genetic methods, our results show that L-type calcium channels are involved in physical, but not affective, nicotine withdrawal behaviors. Although our data do provide evidence of a role for CaMKII in nicotine withdrawal behaviors, our pharmacological and genetic assessments yielded different results concerning the specific role of the kinase. Pharmacological data suggest that CaMKII is involved in somatic signs and affective nicotine withdrawal, and activity level is decreased after nicotine withdrawal, whereas the genetic assessments yielded results suggesting that CaMKII is involved only in the anxiety-related response, yet the kinase activity may be increased after nicotine withdrawal; thus, future studies are necessary to clarify the precise behavioral specifics of the relevance of CaMKII in nicotine withdrawal behaviors. Overall, our data show that L-type calcium channels and CaMKII are relevant in nicotine withdrawal and differentially mediate nicotine withdrawal behaviors.

  20. Chronic deficit in nitric oxide elicits oxidative stress and augments T-type calcium-channel contribution to vascular tone of rodent arteries and arterioles

    DEFF Research Database (Denmark)

    Howitt, Lauren; Kuo, Ivana Y; Ellis, Anthie;

    2013-01-01

    AIMS: As cardiovascular disease is characterized by reduced nitric oxide bioavailability, our aim was to determine the impact of this change on the mechanism underlying vascular tone of pressurized arteries in vitro and in vivo. METHODS AND RESULTS: We used pressurized cerebral and mesenteric......, by regulating the bioavailability of reactive oxygen species produced by NADPH oxidase. Our data provide evidence for a novel causal link between nitric oxide deficit, oxidative stress, and T-type calcium channel function....

  1. Cellular uptake of {sup 99m}TcN-NOET in human leukaemic HL-60 cells is related to calcium channel activation and cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Guillermet, Stephanie; Vuillez, Jean-Philippe; Caravel, Jean-Pierre; Marti-Batlle, Daniele; Fagret, Daniel [Universite de Grenoble, Radiopharmaceutiques Biocliniques, La Tronche (France); Fontaine, Eric [Universite de Grenoble, Laboratoire de Bioenergetique Fondamentale et Appliquee, Grenoble (France); Pasqualini, Roberto [Cis Bio International Schering SA, Gif-sur-Yvette (France)

    2006-01-01

    A major goal of nuclear oncology is the development of new radiolabelled tracers as proliferation markers. Intracellular calcium waves play a fundamental role in the course of the cell cycle. These waves occur in non-excitable tumour cells via store-operated calcium channels (SOCCs). Bis(N-ethoxy, N-ethyldithiocarbamato) nitrido technetium (V)-99m ({sup 99m}TcN-NOET) has been shown to interact with L-type voltage-operated calcium channels (VOCCs) in cultured cardiomyocytes. Considering the analogy between VOCCs and SOCCs, we sought to determine whether {sup 99m}TcN-NOET also binds to activated SOCCs in tumour cells in order to clarify the potential value of this tracer as a proliferation marker. Uptake kinetics of {sup 99m}TcN-NOET were measured in human leukaemic HL-60 cells over 60 min and the effect of several calcium channel modulators on 1-min tracer uptake was studied. The uptake kinetics of {sup 99m}TcN-NOET were compared both with the variations of cytosolic free calcium concentration measured by indo-1/AM and with the variations in the SG{sub 2}M cellular proliferation index. All calcium channel inhibitors significantly decreased the cellular uptake of {sup 99m}TcN-NOET whereas the activator thapsigargin induced a significant 10% increase. In parallel, SOCC activation by thapsigargin, as measured using the indo-1/AM probe, was inhibited by nicardipine. These results indicate that the uptake of {sup 99m}TcN-NOET is related to the activation of SOCCs. Finally, a correlation was observed between the tracer uptake and variations in the proliferation index SG{sub 2}M. The uptake of {sup 99m}TcN-NOET seems to be related to SOCC activation and to cell proliferation in HL-60 cells. These results indicate that {sup 99m}TcN-NOET might be a marker of cell proliferation. (orig.)

  2. Subthreshold membrane potential oscillations in inferior olive neurons are dynamically regulated by P/Q- and T-type calcium channels: a study in mutant mice.

    Science.gov (United States)

    Choi, Soonwook; Yu, Eunah; Kim, Daesoo; Urbano, Francisco J; Makarenko, Vladimir; Shin, Hee-Sup; Llinás, Rodolfo R

    2010-08-15

    The role of P/Q- and T-type calcium channels in the rhythmic oscillatory behaviour of inferior olive (IO) neurons was investigated in mutant mice. Mice lacking either the CaV2.1 gene of the pore-forming alpha1A subunit for P/Q-type calcium channel, or the CaV3.1 gene of the pore-forming alpha1G subunit for T-type calcium channel were used. In vitro intracellular recording from IO neurons reveals that the amplitude and frequency of sinusoidal subthreshold oscillations (SSTOs) were reduced in the CaV2.1-/- mice. In the CaV3.1-/- mice, IO neurons also showed altered patterns of SSTOs and the probability of SSTO generation was significantly lower (15%, 5 of 34 neurons) than that of wild-type (78%, 31 of 40 neurons) or CaV2.1-/- mice (73%, 22 of 30 neurons). In addition, the low-threshold calcium spike and the sustained endogenous oscillation following rebound potentials were absent in IO neurons from CaV3.1-/- mice. Moreover, the phase-reset dynamics of oscillatory properties of single neurons and neuronal clusters in IO were remarkably altered in both CaV2.1-/- and CaV3.1-/- mice. These results suggest that both alpha1A P/Q- and alpha1G T-type calcium channels are required for the dynamic control of neuronal oscillations in the IO. These findings were supported by results from a mathematical IO neuronal model that incorporated T and P/Q channel kinetics.

  3. Differential effect of T-type voltage-gated calcium channel disruption on renal plasma flow and glomerular filtration rate in vivo

    DEFF Research Database (Denmark)

    Thuesen, Anne D; Andersen, Henrik; Cardel, Majken

    2014-01-01

    Voltage-gated calcium channels (Cav) play an essential role in regulation of renal blood flow and GFR. Because T-type Cavs are differentially expressed in pre- and postglomerular vessels it was hypothesized that they impact renal blood flow and GFR differentially. The question was addressed by us...... contribute to renal vascular resistance. It is suggested that endothelial and nerve localization of Cav 3.2 and Cav 3.1, respectively, may account for the observed effects....

  4. Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons from Embryonic Mouse Brain

    Science.gov (United States)

    Chauvet, Sylvain; Jarvis, Louis; Chevallet, Mireille; Shrestha, Niroj; Groschner, Klaus; Bouron, Alexandre

    2016-01-01

    In the murine brain, the first post-mitotic cortical neurons formed during embryogenesis express store-operated channels (SOCs) sensitive to Pyr3, initially proposed as a blocker of the transient receptor potential channel of C type 3 (TRPC3 channel). However, Pyr3 does not discriminate between Orai and TRPC3 channels, questioning the contribution of TRPC3 in SOCs. This study was undertaken to clarify the molecular identity and the pharmacological profile of native SOCs from E13 cortical neurons. The mRNA expression of STIM1-2 and Orai1-3 was assessed by quantitative reverse transcription polymerase chain reaction. E13 cortical neurons expressed STIM1-2 mRNAs, with STIM2 being the predominant isoform. Only transcripts of Orai2 were found but no Orai1 and Orai3 mRNAs. Blockers of Orai and TRPC channels (Pyr6, Pyr10, EVP4593, SAR7334, and GSK-7975A) were used to further characterize the endogenous SOCs. Their activity was recorded using the fluorescent Ca2+ probe Fluo-4. Cortical SOCs were sensitive to the Orai blockers Pyr6 and GSK-7975A, as well as to EVP4593, zinc, copper, and gadolinium ions, the latter one being the most potent SOCs blocker tested (IC50 ∼10 nM). SOCs were insensitive to the TRPC channel blockers Pyr10 and SAR7334. In addition, preventing mitochondrial Ca2+ uptake inhibited SOCs which were unaffected by inhibitors of the Ca2+-independent phospholipase A2. Altogether, Orai2 channels are present at the beginning of the embryonic murine cortico-genesis and form the core component of native SOCs in the immature cortex. This Ca2+ route is likely to play a role in the formation of the brain cortex. PMID:28018223

  5. Types of voltage—dependent calcium channels involved in high potassium depolarization—induced amylase secretion in the exocrine pancreatic tumour cell line AR4—2J

    Institute of Scientific and Technical Information of China (English)

    CUIZONGJIE

    1998-01-01

    In the perifused fura-2 loaded exocrine pancreatic acinar cell line AR4-2J pulses of high potassium induced repetitive increases in intracellular calcium,Attached cells when stimulated with high potassium secreted large amount of amylase.High potassium-induced secretion was dependent both on the concentration of potassium and duration of stimulation.High potassium induced increases in intracellular calcium were inhibited by voltage-dependent calcium channel anatagonists with an order of potency as follows:nifedipine>ω-agatoxin IVA>ω-conotoxin GVIA.In contrast,the L-type calcium channel anatagonist nifedipine almost completely inhibited potassium-induced amylase secretion,whereas the N-type channel antagonist ω-conotoxin GVIA was without effect.The P-type channel antagonist ω-agatoxin IVA had a small inhibitory effect,but this inhibition was not significant at the level of amylase secretion.In conclusion,the AR4-2J cell line posesses different voltage-dependent calcium channels(L,P,N)with the L-type predominantly involved in depolarization induced amylase secretion.

  6. Genetic contribution to iron status: SNPs related to iron deficiency anaemia and fine mapping of CACNA2D3 calcium channel subunit.

    Science.gov (United States)

    Baeza-Richer, Carlos; Arroyo-Pardo, Eduardo; Blanco-Rojo, Ruth; Toxqui, Laura; Remacha, Angel; Vaquero, M Pilar; López-Parra, Ana M

    2015-12-01

    Numerous studies associate genetic markers with iron- and erythrocyte-related parameters, but few relate them to iron-clinical phenotypes. Novel SNP rs1375515, located in a subunit of the calcium channel gene CACNA2D3, is associated with a higher risk of anaemia. The aim of this study is to further investigate the association of this SNP with iron-related parameters and iron-clinical phenotypes, and to explore the potential role of calcium channel subunit region in iron regulation. Furthermore, we aim to replicate the association of other SNPs reported previously in our population. We tested 45 SNPs selected via systematic review and fine mapping of CACNA2D3 region, with haematological and biochemical traits in 358 women of reproductive age. Multivariate analyses include back-step logistic regression and decision trees. The results replicate the association of SNPs with iron-related traits, and also confirm the protective effect of both A allele of rs1800562 (HFE) and G allele of rs4895441 (HBS1L-MYB). The risk of developing anaemia is increased in reproductive age women carriers of A allele of rs1868505 (CACNA2D3) and/or T allele of rs13194491 (HIST1H2BJ). Association of SNPs from fine mapping with ferritin and serum iron suggests that calcium channels could be a potential pathway for iron uptake in physiological conditions.

  7. Design, Synthesis and Structure-activity of N-Glycosyl-1-pyridyl-1H-pyrazole-5-carboxamide as Inhibitors of Calcium Channels

    Institute of Scientific and Technical Information of China (English)

    ZHOU Yun-yun; LI Yu-xin; LI Yi-ming; YANG Xiao-ping; MAO Ming-zhen; LI Zheng-ming

    2013-01-01

    Carbohydrates,with broad-spectrum structures and biological functions,are key organic compounds in nature,along with nucleic acids and proteins.As part of our ongoing efforts to develop a new class of pesticides with novel mechanism of action,a series of novel N-glycosyl-l-pyridyl-lH-pyrazole-5-carboxamide was designed and synthesized via the reactions of glycosyl methanamides and pyridyl-pyrazole acid.The compounds were characterized by 1H NMR and 13C NMR.The bioassay results indicate that some of these compounds exhibit moderate insecticidal activities and assessed as potential inhibitors of calcium channels.The modulation of voltage-gated calcium channels by compounds 4a and 5a in the central neurons isolated from the third instar larvae of Spodoptera exigua was studied by whole-cell patch-clamp technique.In addition,compound 5a inhibits the recorded calcium currents reversible on washout.Experimental results also indicate that compound 5a did not release stored calcium from the Endoplasmic Reticulum.The present work demonstrates that N-glycosyl-l-pyridyl-lH-pyrazole-5-carboxamides cannot be used as possible inhibitors of calcium channels for developing novel pesticides.

  8. Co-localization of putative calcium channels (phenylalkylamine-binding sites) on oil bodies in protoplasts from dark-grown sunflower seedling cotyledons.

    Science.gov (United States)

    Vandana, Shweta; Bhatla, Satish C

    2009-07-01

    Oil bodies are spherical entities containing a triacylglycerol (TAG) matrix encased by a phospholipid monolayer, which is stabilized by oil body-specific proteins, principally oleosins. Biochemical investigations in the recent past have also demonstrated the expression of calcium-binding proteins, called caleosins, as a component of oil body membranes during seed germination. Using DM-Bodipy-phenylalkylamine (PAA; a fluorescent derivative of phenylalkylamine)-a fluorescent probe known to bind L-type calcium channel proteins, present investigations provide the first report on the localization and preferential accumulation of putative calcium channel proteins on/around oil bodies during peak lipolytic phase in protoplasts derived from dark-grown sunflower (Helianthus annuus L. cv Morden) seedling cotyledons. Specificity of DM-Bodipy-PAA labeling was confirmed by using bepridil, a non-fluorescent competitor of PAA while non-specific dye accumulation has been ruled out by using Bodipy-FL as control. Co-localization of fluorescence from DM-Bodipy-PAA binding sites (ex: 504 nm; em: 511 nm) and nile red fluorescing oil bodies (ex: 552 nm; em: 636 nm) has been undertaken by epifluorescence and confocal laser scanning microscopy (CLSM). It revealed the affinity of PAA-sensitive ion channels for the oil body surface. Findings from the current investigations highlight the significance of calcium and calcium channel proteins during oil body mobilization in sunflower.

  9. Kinetics of low threshold calcium channels of relay cells in cat lateral geniculate nucleus

    Institute of Scientific and Technical Information of China (English)

    罗茀荪; S.M.Sherman

    1996-01-01

    Kinetics of the low threshold T-type Ca2+ channel is studied with single electrode voltage damp technique on brain slices of the cat lateral geniculate nucleus (LGN). Space damp is dramatically improved by blocking various K+ and Na+ channels, decreasing Ca2+ current and selecting proper holding potentials. Results from this study are similar to those obtained from acutely dissociated LGN neurons of the rat, indicating that the kinetics of T-Ca2+ channels of the cat LGN neurons is the same as that of the rat LGN. The result reported previously on the cat LGN may result from a defect in space damp.

  10. The nociception role of Cav3.2 calcium channel%Cav3.2通道在伤害性感受中的作用

    Institute of Scientific and Technical Information of China (English)

    苏昊; 徐世元

    2015-01-01

    Background Some of the earliest detailed descriptions of biophysical properties of low voltage-activated or transient (T) type Calcium channels were done using in vitro preparation of primary sensory or dorsal root ganglion (DRG) neurons that are known for their functional role in processing pain signals.However, in spite of these early discoveries, T-type calcium channels were not implicated in sensory transmission in general and pain processing (nociception) in particular until recently.Objective To summarize the important role of peripheral T-type Calcium channels in boosting nociceptive transmission.Content T-type calcium channels in peripheral sensory neurons play important role under physiological conditions (e.g.acute nociceptive pain) and to pain processing under pathological conditions.Trend peripheral T-type Calcium channels in nociception and the value of these channels as cellular targets for potential drug developments.%背景 疼痛是危害人类健康,影响人类生存质量的重要因素,但目前可用于临床治疗的手段尚不能满足患者的无痛要求,且存在不同程度的副作用,其主要原因之一是目前对疼痛的产生机制尚未完全明了.最近的研究表明,T型钙通道Cav3.2亚型在疼痛信号转导中起重要作用. 目的 综述T型钙通道Cav3.2亚型在痛觉传导中的作用. 内容 阐述位于背根神经节(dorsal root ganglion,DRG)的T型钙通道参与传递生理性疼痛(疼痛感知)和病理性疼痛(神经病理性疼痛)伤害性刺激信号. 趋向 T型钙离子通道可调控疼痛伤害性刺激信号转导,并可作为可能的疼痛治疗靶点.

  11. Butanol isomers exert distinct effects on voltage-gated calcium channel currents and thus catecholamine secretion in adrenal chromaffin cells.

    Directory of Open Access Journals (Sweden)

    Sarah McDavid

    Full Text Available Butanol (C4H10OH has been used both to dissect the molecular targets of alcohols/general anesthetics and to implicate phospholipase D (PLD signaling in a variety of cellular functions including neurotransmitter and hormone exocytosis. Like other primary alcohols, 1-butanol is a substrate for PLD and thereby disrupts formation of the intracellular signaling lipid phosphatidic acid. Because secondary and tertiary butanols do not undergo this transphosphatidylation, they have been used as controls for 1-butanol to implicate PLD signaling. Recently, selective pharmacological inhibitors of PLD have been developed and, in some cases, fail to block cellular functions previously ascribed to PLD using primary alcohols. For example, exocytosis of insulin and degranulation of mast cells are blocked by primary alcohols, but not by the PLD inhibitor FIPI. In this study we show that 1-butanol reduces catecholamine secretion from adrenal chromaffin cells to a much greater extent than tert-butanol, and that the PLD inhibitor VU0155056 has no effect. Using fluorescent imaging we show the effect of these drugs on depolarization-evoked calcium entry parallel those on secretion. Patch-clamp electrophysiology confirmed the peak amplitude of voltage-gated calcium channel currents (I(Ca is inhibited by 1-butanol, with little or no block by secondary or tert-butanol. Detailed comparison shows for the first time that the different butanol isomers exert distinct, and sometimes opposing, effects on the voltage-dependence and gating kinetics of I(Ca. We discuss these data with regard to PLD signaling in cellular physiology and the molecular targets of general anesthetics.

  12. Butanol isomers exert distinct effects on voltage-gated calcium channel currents and thus catecholamine secretion in adrenal chromaffin cells.

    Science.gov (United States)

    McDavid, Sarah; Bauer, Mary Beth; Brindley, Rebecca L; Jewell, Mark L; Currie, Kevin P M

    2014-01-01

    Butanol (C4H10OH) has been used both to dissect the molecular targets of alcohols/general anesthetics and to implicate phospholipase D (PLD) signaling in a variety of cellular functions including neurotransmitter and hormone exocytosis. Like other primary alcohols, 1-butanol is a substrate for PLD and thereby disrupts formation of the intracellular signaling lipid phosphatidic acid. Because secondary and tertiary butanols do not undergo this transphosphatidylation, they have been used as controls for 1-butanol to implicate PLD signaling. Recently, selective pharmacological inhibitors of PLD have been developed and, in some cases, fail to block cellular functions previously ascribed to PLD using primary alcohols. For example, exocytosis of insulin and degranulation of mast cells are blocked by primary alcohols, but not by the PLD inhibitor FIPI. In this study we show that 1-butanol reduces catecholamine secretion from adrenal chromaffin cells to a much greater extent than tert-butanol, and that the PLD inhibitor VU0155056 has no effect. Using fluorescent imaging we show the effect of these drugs on depolarization-evoked calcium entry parallel those on secretion. Patch-clamp electrophysiology confirmed the peak amplitude of voltage-gated calcium channel currents (I(Ca)) is inhibited by 1-butanol, with little or no block by secondary or tert-butanol. Detailed comparison shows for the first time that the different butanol isomers exert distinct, and sometimes opposing, effects on the voltage-dependence and gating kinetics of I(Ca). We discuss these data with regard to PLD signaling in cellular physiology and the molecular targets of general anesthetics.

  13. Inhibition of voltage-gated calcium channels as common mode of action for (mixtures of) distinct classes of insecticides.

    Science.gov (United States)

    Meijer, Marieke; Dingemans, Milou M L; van den Berg, Martin; Westerink, Remco H S

    2014-09-01

    Humans are exposed to distinct structural classes of insecticides with different neurotoxic modes of action. Because calcium homeostasis is essential for proper neuronal function and development, we investigated the effects of insecticides from different classes (pyrethroid: (α-)cypermethrin; organophosphate: chlorpyrifos; organochlorine: endosulfan; neonicotinoid: imidacloprid) and mixtures thereof on the intracellular calcium concentration ([Ca(2+)]i). Effects of acute (20 min) exposure to (mixtures of) insecticides on basal and depolarization-evoked [Ca(2+)]i were studied in vitro with Fura-2-loaded PC12 cells and high resolution single-cell fluorescence microscopy. The data demonstrate that cypermethrin, α-cypermethrin, endosulfan, and chlorpyrifos concentration-dependently decreased depolarization-evoked [Ca(2+)]i, with 50% (IC50) at 78nM, 239nM, 250nM, and 899nM, respectively. Additionally, acute exposure to chlorpyrifos or endosulfan (10μM) induced a modest increase in basal [Ca(2+)]i, amounting to 68 ± 8nM and 53 ± 8nM, respectively. Imidacloprid did not disturb basal or depolarization-evoked [Ca(2+)]i at 10μM. Following exposure to binary mixtures, effects on depolarization-evoked [Ca(2+)]i were within the expected effect additivity range, whereas the effect of the tertiary mixture was less than this expected additivity effect range. These results demonstrate that different types of insecticides inhibit depolarization-evoked [Ca(2+)]i in PC12 cells by inhibiting voltage-gated calcium channels (VGCCs) in vitro at concentrations comparable with human occupational exposure levels. Moreover, the effective concentrations in this study are below those for earlier described modes of action. Because inhibition of VGCCs appears to be a common and potentially additive mode of action of several classes of insecticides, this target should be considered in neurotoxicity risk assessment studies.

  14. An L-type calcium channel agonist, bay K8644, extends the window of intervention against ischemic neuronal injury.

    Science.gov (United States)

    Hu, Hong-hai; Li, Shu-ji; Wang, Pu; Yan, Hua-cheng; Cao, Xiong; Hou, Feng-qin; Fang, Ying-ying; Zhu, Xin-hong; Gao, Tian-ming

    2013-02-01

    Our previous data indicate that the inhibition of L-type calcium channels (LTCCs) might be the cause of post-ischemic neuronal injury and that the activation of LTCCs can give rise to neuroprotection. In the present study, we aimed to profile the intervention window of Bay K8644, an LTCC agonist, and determine the involved mechanisms. The four vessel occlusion and oxygen-glucose deprivation models were employed to mimic ischemia/reperfusion damage in vivo and in vitro. Neuronal injury was analyzed using Nissl and Fluoro-Jade B staining in vivo and Hoechst 33342 and propidium iodide staining in vitro. The behavioral effects were tested using the Morris water maze. The phosphorylation of P38, Jun N-terminal kinase, and extracellular-regulated kinase (ERK) was detected by Western blotting. Our results show that Bay K8644 administered as late as 24 h after reperfusion prevented CA1 neuronal death and ameliorated the deficiencies in spatial learning performance induced by global ischemia. In oxygen-glucose deprivation (OGD), Bay K8644 delivered from 1 to 12 h after re-oxygenation reduced neuronal death. The decrease in p-ERK1/2 that was observed at 1 h after OGD was reversed by Bay K8644, and the effect of Bay K8644 was blocked by treatment with U0126 and MEK kinase dead transfection. Moreover, similar to Bay K8644, FPL 64176, another potent LTCC agonist, extends the window of intervention against neuronal injury in an in vitro model of ischemia. In conclusion, our data suggest that opening LTCCs may be a practicable approach for stroke therapy.

  15. EFFECT OF ELECTROACUPUNCTURE AND CALCIUM-CHANNEL INHIBITORS ON CYTOPLASMIC FREE CALCIUM CONCENTRATION OF MOUSE BRAIN CELLS

    Institute of Scientific and Technical Information of China (English)

    ZHANG Ming-mei; XIE Ji-min; CHEN Min; ZHANG Yan

    2005-01-01

    Objective: To study the effect of electroacupuncture (EA) and Verapamil and Nifedipine (calcium channel inhibitors) on free calcium concentrations of cells and intrasynaptosomes in hypothalamus (HT), periaqueductual grey matter (PAG) and hippocampus (HIP) of mice. Methods: The female ICR mice were randomly divided into control, EA, CaCl2 and CaCl2+EA groups (n=8 in each group). Pain threshold was detected by using radiation-heat irradiation-induced tail flick method. EA (8 Hz, a suitable stimulating strength, dense-sparse waves and duration of 30 min) was applied to"Shuigou" (水沟 GV 26) and "Chengjiang" (承浆CV 24). CaCl2 (10 μL, 0.2 μmol/L) was injected into the lateral cerebral ventricle of mice after EA. The concentrations of cytosolic free calcium ([Ca2+]i) in HIP, PAG, HT cell suspension specimen and hippocampal intrasynaptosome suspension of mice were determined by the fluorescent calcium indicator Fura-2-AM and a spectrofluorometer. Results: During EA analgesia, the intracellular free [Ca2+]i in HT and PAG specimens and intrsynaptosomal [Ca2+]i of the 3 cerebral regions decreased considerably (P<0.05~0.01), but that in hippocampal cell suspension increased significantly (P<0.01) in comparison with control group. The concentrations of hippocampal intrasynaptosomal free [Ca2+]i decreased significantly after adding Verapamil and Nifedipine to the extracted hippocampal intrasynaptosomal specimen. Microinjection of CaCl2 into lateral ventricle had no apparent influence on degree of analgesia (DA)% and intracellular and intrasynapsotomal [Ca2+]i, but significantly lower DA% and reduce changes of cytosolic and intrasynaptosomal [Ca2+]i induced by EA stimulation. Conclusion: Calcium ion in the neurons and intrasynaptosome of HT, PAG and HIP is involved in electroacupuncture analgesia.

  16. G(o) transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons.

    Science.gov (United States)

    Menon-Johansson, A S; Berrow, N; Dolphin, A C

    1993-11-01

    High-voltage-activated (HVA) calcium channel currents (IBa) were recorded from acutely replated cultured dorsal root ganglion (DRG) neurons. IBa was irreversibly inhibited by 56.9 +/- 2.7% by 1 microM omega-conotoxin-GVIA (omega-CTx-GVIA), whereas the 1,4-dihydropyridine antagonist nicardipine was ineffective. The selective gamma-aminobutyric acidB (GABAB) agonist, (-)-baclofen (50 microM), inhibited the HVA IBa by 30.7 +/- 5.4%. Prior application of omega-CTx-GVIA completely occluded inhibition of the HVA IBa by (-)-baclofen, indicating that in this preparation (-)-baclofen inhibits N-type current. To investigate which G protein subtype was involved, cells were replated in the presence of anti-G protein antisera. Under these conditions the antibodies were shown to enter the cells through transient pores created during the replating procedure. Replating DRGs in the presence of anti-G(o) antiserum, raised against the C-terminal decapeptide of the G alpha o subunit, reduced (-)-baclofen inhibition of the HVA IBa, whereas replating DRGs in the presence of the anti-Gi antiserum did not. Using anti-G alpha o antisera (1:2000) and confocal laser microscopy, G alpha o localisation was investigated in both unreplated and replated neurons. G alpha o immunoreactivity was observed at the plasma membrane, neurites, attachment plaques and perinuclear region, and was particularly pronounced at points of cell-to-cell contact. The plasma membrane G alpha o immunoreactivity was completely blocked by preincubation with the immunising G alpha o undecapeptide (1 microgram.ml-1) for 1 h at 37 degrees C. A similar treatment also blocked recognition of G alpha o in brain membranes on immunoblots.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Splice variants of the CaV1.3 L-type calcium channel regulate dendritic spine morphology

    Science.gov (United States)

    Stanika, Ruslan; Campiglio, Marta; Pinggera, Alexandra; Lee, Amy; Striessnig, Jörg; Flucher, Bernhard E.; Obermair, Gerald J.

    2016-01-01

    Dendritic spines are the postsynaptic compartments of glutamatergic synapses in the brain. Their number and shape are subject to change in synaptic plasticity and neurological disorders including autism spectrum disorders and Parkinson’s disease. The L-type calcium channel CaV1.3 constitutes an important calcium entry pathway implicated in the regulation of spine morphology. Here we investigated the importance of full-length CaV1.3L and two C-terminally truncated splice variants (CaV1.342A and CaV1.343S) and their modulation by densin-180 and shank1b for the morphology of dendritic spines of cultured hippocampal neurons. Live-cell immunofluorescence and super-resolution microscopy of epitope-tagged CaV1.3L revealed its localization at the base-, neck-, and head-region of dendritic spines. Expression of the short splice variants or deletion of the C-terminal PDZ-binding motif in CaV1.3L induced aberrant dendritic spine elongation. Similar morphological alterations were induced by co-expression of densin-180 or shank1b with CaV1.3L and correlated with increased CaV1.3 currents and dendritic calcium signals in transfected neurons. Together, our findings suggest a key role of CaV1.3 in regulating dendritic spine structure. Under physiological conditions it may contribute to the structural plasticity of glutamatergic synapses. Conversely, altered regulation of CaV1.3 channels may provide an important mechanism in the development of postsynaptic aberrations associated with neurodegenerative disorders. PMID:27708393

  18. Melanopsin Phototransduction Contributes to Light-Evoked Choroidal Expansion and Rod L-Type Calcium Channel Function In Vivo

    Science.gov (United States)

    Berkowitz, Bruce A.; Schmidt, Tiffany; Podolsky, Robert H.; Roberts, Robin

    2016-01-01

    Purpose In humans, rodents, and pigeons, the dark → light transition signals nonretinal brain tissue to increase choroidal thickness, a major control element of choroidal blood flow, and thus of photoreceptor and retinal pigment epithelium function. However, it is unclear which photopigments in the retina relay the light signal to the brain. Here, we test the hypothesis that melanopsin (Opn4)-regulated phototransduction modulates light-evoked choroidal thickness expansion in mice. Methods Two-month-old C57Bl/6 wild-type (B6), 4- to 5-month-old C57Bl/6/129S6 wild-type (B6 + S6), and 2-month-old melanopsin knockout (Opn4−/−) on a B6 + S6 background were studied. Retinal anatomy was evaluated in vivo by optical coherence tomography and MRI. Choroidal thickness in dark and light were measured by diffusion-weighted MRI. Rod cell L-type calcium channel (LTCC) function in dark and light (manganese-enhanced MRI [MEMRI]) was also measured. Results Opn4−/− mice did not show the light-evoked expansion of choroidal thickness observed in B6 and B6 + S6 controls. Additionally, Opn4−/− mice had lower than normal rod cell and inner retinal LTCC function in the dark but not in the light. These deficits were not due to structural abnormalities because retinal laminar architecture and thickness, and choroidal thickness in the Opn4−/− mice were similar to controls. Conclusions First time evidence is provided that melanopsin phototransduction contributes to dark → light control of murine choroidal thickness. The data also highlight a contribution in vivo of melanopsin phototransduction to rod cell and inner retinal depolarization in the dark. PMID:27727394

  19. Circadian profiles in the embryonic chick heart: L-type voltage-gated calcium channels and signaling pathways.

    Science.gov (United States)

    Ko, Michael L; Shi, Liheng; Grushin, Kirill; Nigussie, Fikru; Ko, Gladys Y-P

    2010-10-01

    Circadian clocks exist in the heart tissue and modulate multiple physiological events, from cardiac metabolism to contractile function and expression of circadian oscillator and metabolic-related genes. Ample evidence has demonstrated that there are endogenous circadian oscillators in adult mammalian cardiomyocytes. However, mammalian embryos cannot be entrained independently to light-dark (LD) cycles in vivo without any maternal influence, but circadian genes are well expressed and able to oscillate in embryonic stages. The authors took advantage of using chick embryos that are independent of maternal influences to investigate whether embryonic hearts could be entrained under LD cycles in ovo. The authors found circadian regulation of L-type voltage-gated calcium channels (L-VGCCs), the ion channels responsible for the production of cardiac muscle contraction in embryonic chick hearts. The mRNA levels and protein expression of VGCCα1C and VGCCα1D are under circadian control, and the average L-VGCC current density is significantly larger when cardiomyocytes are recorded during the night than day. The phosphorylation states of several kinases involved in insulin signaling and cardiac metabolism, including extracellular signal-regulated kinase (Erk), stress-activated protein kinase (p38), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK-3β), are also under circadian control. Both Erk and p38 have been implicated in regulating cardiac contractility and in the development of various pathological states, such as cardiac hypertrophy and heart failure. Even though both Erk and phosphoinositide 3-kinase (PI3K)-Akt signaling pathways participate in complex cellular processes regarding physiological or pathological states of cardiomyocytes, the circadian oscillators in the heart regulate these pathways independently, and both pathways contribute to the circadian regulation of L-VGCCs.

  20. The pre-synaptic blocker toosendanin does not inhibit secretion in exocrine cells

    Institute of Scientific and Technical Information of China (English)

    Zong-Jie Cui; Xue-Hui He

    2002-01-01

    AIM: Toosendanin is a pre-synaptic blocker at theneuromuscular junction and its inhibitory effect is dividedinto an initial facilitative/stimulatory phase followed by aprolonged inhibitory phase. The present study investigatedwhether the subsequent inhibitory phase was due toexhaustion of the secretory machinery as a result of extensivestimulation during the initial facilitative phase. Morespecifically, this paper examined whether toosendanin coulddirectly inhibit the secretory machinery in exocrine cells.METHODS: Rat pancreatic acinar cells were isolated bycollagenase digestion. Secretion was assessed by measuringthe amount of amylase released into the extracellular mediumas a percentage of the total present in the cells beforestimulation. Cholecystokinin (CCK)-induced increases inintracellular calcium in single cells were measured with fura-2 microfluorometry.RESULTS: Effects of toosendanin on CCK-induced amylasesecretion and calcium oscillations were investigated.Toosendanin of 87-870 tM had no effect on 10 pM-100 nMCCK-stimulated amylase secretion, nor did 8.7-870 μMtoosendanin inhibit 5 pM CCK-induced calcium oscillations.In contrast, 10 nM CCK1 receptor antagonist FK 480 completelyblocked 5 pM CCK-induced calcium oscillations.CONCLUSION: The pre-synaptic "blocker" toosendanin is aselective activator of the voltage-dependent calcium channels,but does not interfere with the secretory machinery itself.

  1. Acute effect of calcium blocker on renal hemodynamics in diabetic spontaneously hypertensive rat.

    Science.gov (United States)

    Kaizu, K; Ling, Q Y; Uriu, K; Ikeda, M; Eto, S

    1995-01-01

    This study was done to examine the acute effect of a calcium channel blocker on renal hemodynamics in the diabetic spontaneously hypertensive rat (SHR). Streptozotocin was used to induce diabetes, and barnidipine (B) was used as a calcium blocker. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate (PAH) and inulin, respectively. Rats were divided into two groups: nondiabetic SHR, N-SHR; diabetic SHR, DM-SHR. B increased RBF in N-SHR (7.44 +/- 1.99 versus 8.50 +/- 1.97 mL/min/g.kw) while there was no change in DM-SHR. B reduced renovascular resistance (RVR) in DM-SHR and N-SHR. B increased GFR in N-SHR (1.15 +/- 0.24 versus 1.34 +/- 0.25 mL/min/g.kw), in spite of no changes in DM-SHR. B did not modify filtration fraction (FF) in both groups. These results indicate (1) in SHR, B exerts beneficial effects on hypertensive renal damage by reducing mean arterial pressure (MAP), RVR, RBF, and GFR; (2) in diabetic SHR, B is less effective in restoring renal hyperfiltration in spite of reducing RVR.

  2. Effects of chloride channel blockers on hypotonicity-induced contractions of the rat trachea

    Science.gov (United States)

    Coelho, Roberta R; Souza, Emmanuel P; Soares, Pedro M G; Meireles, Ana Vaneska P; Santos, Geam C M; Scarparo, Henrique C; Assreuy, Ana Maria S; Criddle, David N

    2003-01-01

    We have investigated the inhibitory effects of blockers of volume-activated (Clvol) and calcium-activated (ClCa) chloride channels on hypotonic solution (HS)-induced contractions of rat trachea, comparing their effects with those of the voltage-dependent calcium channel (VDCC) blocker nifedpine. HS elicited large, stable contractions that were partially dependent on the cellular chloride gradient; a reduction to 41.45±7.71% of the control response was obtained when extracellular chloride was removed. In addition, HS-induced responses were reduced to 26.8±5.6% of the control by 1 μM nifedipine, and abolished under calcium-free conditions, indicating a substantial requirement for extracellular calcium entry, principally via VDCCs. The established Clvol blockers tamoxifen (⩽10 μM) and 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (1–100 μM), at concentrations previously reported to inhibit Clvol in smooth muscle, did not significantly inhibit HS-induced contractions. In contrast, the recognized ClCa blocker niflumic acid (NFA; 1–100 μM) produced a reversible, concentration-dependent inhibition of HS responses, with a reduction to 36.6±6.4% of control contractions at the highest concentration. The mixed Clvol and ClCa blocker, 5-nitro 2-(3-phenylpropylamine) benzoic acid (NPPB; 10–100 μM) also elicited concentration-related inhibition of HS-induced contractions, producing a decrease to 35.9±11.3% of the control at 100 μM. Our results show that HS induces reversible, chloride-dependent contractions of rat isolated trachea that were inhibited by NFA and NPPB, while exhibiting little sensitivity to recognized blockers of Clvol. The data support the possibility that opening of calcium-activated chloride channels under hypotonic conditions in respiratory smooth muscle may ultimately lead to VDCC-mediated calcium entry and contraction. PMID:14691057

  3. 17β-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons

    Science.gov (United States)

    Zhang, Chunguang; Bosch, Martha A.; Rick, Elizabeth A.; Kelly, Martin J.; Ronnekleiv, Oline K.

    2009-01-01

    T-type calcium channels are responsible for generating low-threshold spikes that facilitate burst firing and neurotransmitter release in neurons. GnRH neurons exhibit burst firing, but the underlying conductances are not known. Previously, we have found that 17β-estradiol (E2) increases T-type channel expression and excitability of hypothalamic arcuate nucleus neurons. Therefore, we used ovariectomized oil- or E2-treated EGFP-GnRH mice to explore the expression and E2-regulation of T-type channels in GnRH neurons. Based on single cell RT-PCR and real-time PCR quantification of the T-type channel α1-subunits, we found that all three subunits were expressed in GnRH neurons with Cav3.3≥Cav3.2>Cav3.1. The mRNA expression of the three subunits was increased with surge-inducing levels of E2 during the morning. During the afternoon, Cav3.3 mRNA expression remained elevated, whereas Cav3.1 and Cav3.2 were decreased. The membrane estrogen receptor agonist STX increased the expression of Cav3.3, but not Cav3.2 in GnRH neurons. Whole-cell patch recordings in GnRH neurons revealed that E2 treatment significantly augmented T-type current density at both time-points, and increased the rebound excitation during the afternoon. Although E2 regulated the mRNA expression of all three subunits in GnRH neurons, the increased expression combined with the slower inactivation kinetics of the T-type current indicates that Cav3.3 may be the most important for bursting activity associated with the GnRH/LH surge. The E2-induced increase in mRNA expression, which depends in part on membrane-initiated signaling, leads to increased channel function and neuronal excitability, and could be a mechanism by which E2 facilitates burst firing and cyclic GnRH neurosecretion. PMID:19710308

  4. Effects of low-dose ionising radiation on pituitary adenoma: is there a role for L-type calcium channel?

    Directory of Open Access Journals (Sweden)

    Marcella Araugio Soares

    2005-10-01

    Full Text Available Pituitary adenomas constitute about 6-18% of brain tumours in adults. Activation of voltage gated calcium currents can account for growth hormone oversecretion in some GH-secreting pituitary adenomas that produce an acromegaly appearance and increase mortality. Ca2+ ions, as mediators of intracellular signalling, are crucial for the development of apoptosis. However, the role of [Ca2+] in the development of apoptosis is ambiguous. In this study, the effects of low-dose ionising gamma radiation (60Co on rat pituitary adenoma cells survival and proliferation and the role of calcium channels on the apoptosis radio-induced were evaluated. Doses as low as 3 Gy were found to inhibit GH3 cell proliferation. Even though there was a significant number of live cells,168 hours following irradiation, they were not able to proliferate. The results indicate that the blockade of extracellular calcium influx through these channels does not interfere in the radiation-induced apoptosis in GH3 cells.Adenomas de pituitária constituem cerca de 6-18% dos tumores cerebrais em adultos. A ativação de correntes de cálcio dependentes de voltagem podem levar à super-excreção de hormônio do crescimento produzindo acromegalia e aumentando a mortalidade. Íons Ca2+ como mediadores de sinalização intracelular são cruciais no desenvolvimento da apoptose. No entanto, o papel da [Ca 2+] no desenvolvimento da apoptose é ambíguo. Neste estudo nós avaliamos os efeitos de baixas doses de radiação gama (60Co na sobrevivência e proliferação de células de adenoma de pituitária de rato e o papel do cálcio na apoptose radio-induzida. Nossos resultados mostraram que a dose de 3Gy foi suficiente para inibir a proliferação das células GH3. Apesar de existir um número significativo de células vivas após 168 horas do tratamento com radiação, elas não estavam aptas a proliferar. Nossos resultados também indicaram que bloqueio do influxo de cálcio extracelular n

  5. Influences of ramipril on L-type calcium channel in rats with diastolic heart failure%雷米普利对舒张性心力衰竭大鼠心房肌L型钙通道的影响

    Institute of Scientific and Technical Information of China (English)

    郭作兵; 孙淑娟

    2014-01-01

    目的:观察雷米普利对舒张性心力衰竭(DHF)大鼠模型心房肌细胞L型钙通道的影响。方法腹主动脉缩窄术建立DHF大鼠模型,随机分为DHF组及雷米普利大、中、小剂量组,另设对照组。全细胞膜片钳检测心房肌细胞L型钙通道电流(ICa-L);RT-PCR检测L型钙通道上Cav1.2 mRNA的表达;Western blot检测钙调控相关蛋白LTCC的表达。结果与对照组比较,DHF组大鼠心房肌细胞ICa-L电流密度峰值、Cav1.2 mRNA表达及钙调蛋白LTCC的表达明显降低(P<0.05);与DHF组比较,雷米普利组心房肌细胞ICa-L电流密度峰值明显增加、Cav1.2 mRNA及钙调控蛋白LTCC的表达增加(P<0.05),且剂量越大增加越明显。结论雷米普利能上调舒张性心力衰竭大鼠心房肌ICa-L电流密度峰值,增加Cav1.2 mRNA及钙调控蛋白LTCC的表达,对DHF大鼠有治疗作用,其机制与调控心房肌细胞L型钙通道的功能有关。%Objective To observe the influence of ramipril on L-type calcium channel in rats with diastolic heart fail-ure (DHF). Methods The rat model of DHF was established by using abdominal aortic coarctation,and then the rats were randomly divided into DHF group,high-dose,mid-dose and low-dose ramipril groups and control group.L-type calcium channel current (ICa-L) was investigated by using a whole cell patchclamp technique.The expression levels of Cav1.2 mRNA were measured by RT-PCR analysis.The expression levels of LTCC were measured by Wsetern blot analysis. Results Compared with control group,the peak density of atrial ICa-L,the expression levels of Cav1.2 mRNA and the expression levels of LTCC was lower in DHF group (P<0.05).Compared with the DHF group,the peak density of atrial ICa-L,the expression levels of Cav1.2 mRNA and the expression levels of LTCC increased in three ramipril groups (P<0.05).The more dose of ramipril,the more increasing in ramipril group. Conclusion Ramipril can improve the peak density of

  6. 17β-Estradiol Regulation of the mRNA Expression of T-type Calcium Channel subunits: Role of Estrogen Receptor α and Estrogen Receptor β

    Science.gov (United States)

    Bosch, Martha A.; Hou, Jingwen; Fang, Yuan; Kelly, Martin J.; Rønnekleiv., Oline K.

    2009-01-01

    Low voltage-activated (T-type) calcium channels are responsible for burst firing and transmitter release in neurons and are important for exocytosis and hormone secretion in pituitary cells. T-type channels contain an α1 subunit, of which there are three subtypes, Cav3.1, 3.2 and 3.3, and each subtype has distinct kinetic characteristics. Although 17β-estradiol modulates T-type calcium channel expression and function, little is known about the molecular mechanisms involved. Presently, we used real-time PCR quantification of RNA extracted from hypothalamic nuclei and pituitary in vehicle and E2-treated C57BL/6 mice to elucidate E2-mediated regulation of Cav3.1, 3.2 and 3.3 subunits. The three subunits were expressed in both the hypothalamus and the pituitary. E2 treatment increased the mRNA expression of Cav3.1 and 3.2, but not Cav3.3, in the medial preoptic area and the arcuate nucleus. In the pituitary, Cav3.1 was increased with E2-treatment and Cav3.2 and 3.3 were decreased. In order to examine whether the classical estrogen receptors (ERs) were involved in the regulation, we used ERα- and ERβ-deficient C57BL/6 mice and explored the effects of E2 on T-type channel subtypes. Indeed, we found that the E2-induced increase in Cav3.1 in the hypothalamus was dependent on ERα, whereas the E2 effect on Cav3.2 was dependent on both ERα and ERβ. However, the E2-induced effects in the pituitary were dependent on only the expression of ERα. The robust E2-regulation of the T-type calcium channels could be an important mechanism by which E2 increases the excitability of hypothalamic neurons and modulates pituitary secretion. PMID:19003958

  7. Beta-blockers: friend or foe in asthma?

    Directory of Open Access Journals (Sweden)

    Arboe B

    2013-07-01

    Full Text Available Bente Arboe, Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Hvidovre, DenmarkBackground and aim: Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.Method: Systematic literature review.Results: No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1 following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma.Conclusion: The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not

  8. An oral Na(V)1.8 blocker improves motor function in mice completely deficient of myelin protein P-0

    DEFF Research Database (Denmark)

    Rosberg, Mette R.; Alvarez Herrero, Susana; Krarup, Christian

    2016-01-01

    -/-, a CMT model with a much more severe neuropathy. We found that the progressive impairment of motor performance from 1 to 4 months of age in P0-/- could be acutely reversed by C31 treatment. The effect was associated with an improvement of the amplitude of the plantar CMAP evoked by tibial nerve...... stimulation. The corresponding motor nerve excitability studies by “threshold tracking” showed changes after C31 consistent with attenuation of a resting membrane depolarization. Our data suggest that the depolarizing motor conduction failure in P0-/- could be acutely improved by C31. This provides proof......Mice deficient of myelin protein P0 are established models of demyelinating Charcot-Marie-Tooth (CMT) disease. Dysmyelination in these mice is associated with an ectopic expression of the sensory neuron specific sodium channel isoform NaV1.8 on motor axons. We reported that in P0+/−, a model of CMT...

  9. COOH-terminal association of human smooth muscle calcium channel Ca(v)1.2b with Src kinase protein binding domains: effect of nitrotyrosylation.

    Science.gov (United States)

    Kang, Minho; Ross, Gracious R; Akbarali, Hamid I

    2007-12-01

    The carboxyl terminus of the calcium channel plays an important role in the regulation of calcium entry, signal transduction, and gene expression. Potential protein-protein interaction sites within the COOH terminus of the L-type calcium channel include those for the SH3 and SH2 binding domains of c-Src kinase that regulates calcium currents in smooth muscle. In this study, we examined the binding sites involved in Src kinase-mediated phosphorylation of the human voltage-gated calcium channel (Ca(v)) 1.2b (hCav1.2b) and the effect of nitrotyrosylation. Cotransfection of human embryonic kidney (HEK)-293 cells with hCa(v)1.2b and c-Src resulted in tyrosine phosphorylation of the calcium channel, which was prevented by nitration of tyrosine residues by peroxynitrite. Whole cell calcium currents were reduced by 58 + 5% by the Src kinase inhibitor PP2 and 64 + 6% by peroxynitrite. Nitrotyrosylation prevented Src-mediated regulation of the currents. Glutathione S-transferase fusion protein of the distal COOH terminus of hCa(v)1.2b (1809-2138) bound to SH2 domain of Src following tyrosine phosphorylation, while binding to SH3 required the presence of the proline-rich motif. Site-directed mutation of Y(2134) prevented SH2 binding and resulted in reduced phosphorylation of hCa(v)1.2b. Within the distal COOH terminus, single, double, or triple mutations of Y(1837), Y(1861), and Y(2134) were constructed and expressed in HEK-293 cells. The inhibitory effects of PP2 and peroxynitrite on calcium currents were significantly reduced in the double mutant Y(1837-2134F). These data demonstrate that the COOH terminus of hCa(v)1.2b contains sites for the SH2 and SH3 binding of Src kinase. Nitrotyrosylation of these sites prevents Src kinase regulation and may be importantly involved in calcium influx regulation during inflammation.

  10. 穿孔膜片钳方法记录L型钙通道及脱氢紫堇碱对其影响的研究%Recording L-type calcium channel current by perforated patch clamp and effect of dehydrocorydaline on L-type calcium channel

    Institute of Scientific and Technical Information of China (English)

    孟红旭; 王宝; 刘建勋

    2011-01-01

    Aim To observe the difference of recording L-type calcium channel currents over time through by whole cell patch clamp and perforated patch clamp method and the effect of dehydrocorydaline on L-type calcium channel by perforated patch clamp method.Methods Whole cell patch clamp and perforated patch clamp were used to record L-type calcium channel current in acutely isolated rat ventricular myocytes.Results The L-type calcium channel current peak recorded by whole cell patch clamp decayed of the ( 34 ±23 )% ( n =10 ) within 15 minutes, while using perforated patch clamp, L-type calcium channel current peak attenuated ( 2. 7 ±3. 4 )% ( n =9 ) within 15 minutes; The inhibitory effect of ginsenoside Re( 100μmol · L-1 ) could be clearlv recorded by perforated patch clamp method. while the current decaying produced by whole cell patch clamp almost completely overshadowed the effects of ginsenoside Re. Dehydrocorydaline ( 10, 100 μmol · L-1 ) could inhibit L-type calcium channel current peak and the inhibitory rates were ( 9 ±7. 5 )%( n =5 )and ( 28. 6 ±8. 5 )%( n =5 )individually. Conclusions Perforated patch clamp method has more stability and accuracy than ordinary whole-cell patch clamp technique in recording L-type calcium channel current; dehydrocorydaline can suppress L-type calcium channel in a concentration-dependent manner.%目的 比较全细胞膜片钳和穿孔膜片钳方法记录大鼠心室肌细胞L型钙通道电流随时间经过的变化差异,并观察脱氢紫堇碱对L型钙通道的影响.方法 采用全细胞膜片钳和穿孔膜片钳方法记录急性分离的大鼠心室肌细胞L型钙通道电流.结果 采用全细胞膜片钳法记录到的L型钙通道电流峰值在15 min内衰减了(34±23)%(n=10),采用穿孔膜片钳方法记录到的L型钙通道电流峰值15 min内仅衰减了(2.7±3.4)%(n=9);采用穿孔膜片钳方法能够记录到人参皂苷Re(100 μmol·L-1)的抑制效应,而采用全细胞膜片钳方法产

  11. 钙离子通道阻滞剂自乳化给药系统的形成机理%Insight into the Formation Mechanisms Behind Self-emulsifying Drug Delivery Systems of Calcium Channel Blockers†

    Institute of Scientific and Technical Information of China (English)

    何芮; 王晓娜; 王歆悦; 邱娅; 杨胜勇; 尹宗宁

    2015-01-01

    Several self­emulsifying drug delivery systems( SEDDS) were constructed, using a series of poorly water­soluble dihydropyridines of calcium channel blockers( DHPs­CCBs) as the model drugs, and characte­ rized them with regards to self­emulsification area and solubility of the payloads. By establishing multiple linear regression( MLR) models between the molecular descriptors of building components and characteristics of the emulsions formed eventually, we then tried to reveal the formation mechanisms under self­emulsification process. It was found that emulsification process was primarily initialized by the intermolecular forces but simultaneously affected by the proportion of components, lipophilicity and molecular size. Larger molecular size of the mixed surfactants and better lipophilicity of drug contributed to higher drug solubility. Also, the stability of SEDDS after dilution correlated positively with the mass ratio of surfactants and co­surfactants and the molecular size of mixed surfactants. It is supposed that this work could generally be used as guidelines to screen the formulas of SEDDS.%以一系列难溶性的二氢吡啶类钙离子通道阻滞剂作为模型药物,以自乳化面积和药物在自乳化给药系统( SEDDS)中的溶解度作为自乳化评价指标,建立各组分的分子描述参数与自乳化性质之间的定量函数关系,通过模型讨论分子结构对自乳化形成机理的影响。结果表明,自乳化的发生是各组分含量、分子间作用力、亲脂性和分子大小等多方面因素综合作用的结果。当混合表面活性剂分子较大且药物脂溶性较好时, SEDDS对难溶性药物的增溶能力较强;表面活性剂与助表面活性剂的质量比较大,混合表面活性剂的分子较大时, SEDDS的稀释稳定性较好。

  12. Fibronectin-induced VEGF receptor and calcium channel transactivation stimulate GLUT-1 synthesis and trafficking through PPARγ and TC10 in mouse embryonic stem cells.

    Science.gov (United States)

    Suh, Han Na; Han, Ho Jae

    2013-05-01

    Extracellular matrix (ECM) mediates interactions between integrin and growth factor receptor (GFR) or ion channel. Although this crosstalk promotes integration of the downstream signal pathways and then regulates cellular function, the effect of ECM on glucose transporter (GLUT) in stem cells has not been elucidated. Therefore, we examined the effect of fibronectin on GLUT-1 expression, trafficking, and its related signal pathways in mouse embryonic stem cells (mESCs). Fibronectin increased 2-deoxyglucose (DG) uptake and GLUT-1 protein expression that were blocked by transcription or translation inhibitors. Integrin α5β1-bound fibronectin increased 2-DG uptake through cluster formation with vascular endothelial growth factor receptor (VEGFR) 2, and then activated Ras and PI3K/Akt. In another pathway, integrin α5β1 displayed structural and functional interactions with calcium channels, and stimulated 2-DG uptake through calcium influx and PKC activation. Akt and PKC-induced PPARγ phosphorylation enhanced the decreased expression of PPARγ protein, and subsequently increased GLUT-1 protein synthesis and 2-DG uptake. Fibronectin stimulated TC10 activity and cytoskeleton (F-actin) rearrangement, followed by GLUT-1 trafficking. In conclusion, integrin-bound fibronectin stimulates GLUT-1 synthesis through VEGFR2/Ras/PI3K/Akt and calcium channel/Ca(2+)/PKC, which are merged at PPARγ and GLUT-1 trafficking through TC10 and F-actin.

  13. Modulatory effects of the fruits of Tribulus terrestris L. on the function of atopic dermatitis-related calcium channels, Orai1 and TRPV3

    Institute of Scientific and Technical Information of China (English)

    Joo Hyun Nam; Hyo Won Jung; Young-Won Chin; Woo Kyung Kim; Hyo Sang Bae

    2016-01-01

    Objective: To examine the effects of Tribulus terrestris L. (T. terrestris) extract on the modulation of calcium channels to evaluate its use in topical agents for treatment of atopic dermatitis. Methods: The 70% methanol extract of T. terrestris was prepared. Human HEK293T cells with over-expressed calcium release-activated calcium channel protein 1 (Orai1), transient receptor potential vanilloid 1, or transient receptor potential vanilloid 3 (TRPV3) were treated with T. terrestris extract. Modulation of ion channels was measured using a conventional whole-cell patch-clamp technique. Results: T. terrestris extract (100 mg/mL) significantly inhibited Orai1 activity in Orai1-stromal interaction molecule 1 co-overexpressed HEK293T cells. In addition, T. terrestris extract significantly increased the TRPV3 activity compared with 2-Aminoethyl diphe-nylborinate (100 mmol/L), which induces the full activation of TRPV3. Conclusions: Our results suggest that T. terrestris extract may have a therapeutic po-tential for recovery of abnormal skin barrier pathologies in atopic dermatitis through modulating the activities of calcium ion channels, Orai1 and TRPV3. This is the first study to report the modulatory effect of a medicinal plant on the function of ion channels in skin barrier.

  14. Modulatory effects of the fruits of Tribulus terrestris L. on the function of atopic dermatitis-related calcium channels,Orai1 and TRPV3

    Institute of Scientific and Technical Information of China (English)

    Joo Hyun Nam; Hyo Won Jung; Young-Won Chin; Woo Kyung Kim; Hyo Sang Bae

    2016-01-01

    Objective: To examine the effects of Tribulus terrestris L.(T. terrestris) extract on the modulation of calcium channels to evaluate its use in topical agents for treatment of atopic dermatitis.Methods: The 70% methanol extract of T. terrestris was prepared. Human HEK293 T cells with over-expressed calcium release-activated calcium channel protein 1(Orai1),transient receptor potential vanilloid 1, or transient receptor potential vanilloid 3(TRPV3)were treated with T. terrestris extract. Modulation of ion channels was measured using a conventional whole-cell patch-clamp technique.Results: T. terrestris extract(100 mg/m L) significantly inhibited Orai1 activity in Orai1-stromal interaction molecule 1 co-overexpressed HEK293 T cells. In addition, T. terrestris extract significantly increased the TRPV3 activity compared with 2-Aminoethyl diphenylborinate(100 mmol/L), which induces the full activation of TRPV3.Conclusions: Our results suggest that T. terrestris extract may have a therapeutic potential for recovery of abnormal skin barrier pathologies in atopic dermatitis through modulating the activities of calcium ion channels, Orai1 and TRPV3. This is the first study to report the modulatory effect of a medicinal plant on the function of ion channels in skin barrier.

  15. Effects of Arecoline on Calcium Channel Currents and Caffeine-induced Calcium Release in Isolated Single Ventricular Myocyte of Guinea Pig

    Institute of Scientific and Technical Information of China (English)

    林先明; 李真; 胡本容; 夏国瑾; 姚伟星; 向继洲

    2002-01-01

    Summary: The effects of Arecoline (Are) on calcium mobilization were investigated. In isolatedsingle ventricular myocyte of guinea pig, patch clamp whole cell recording techniques were used torecord the current of L-type calcium channel and cytosolic Ca2+ level ([Ca2+]i) labeled with fluo-rescence probe Fluo-3/AM was measured under a laser scanning confocal microscope. Results re-vealed that Are (3-100 μmol/L) could inhibit L-type calcium current in a concentration-depen-dent manner and the value of IC50 was 33. 73μmol/L (n= 5). In the absence of extracellular calci-um, the resting levels of [Ca2+]i was not affected by Are (n=6, P>0. 05), but pretreatmentwith Are (30 μmol/L) could significantly inhibit the [Ca2+]i elevation induced by caffeine (10mmol/L, n = 6, P < 0. 01). It was concluded that Are could inhibit not only calcium influxthrough L-type calcium channel but also calcium release from sarcoplasmic reticulum.

  16. Dense spermatozoa in stallion ejaculates contain lower concentrations of mRNAs encoding the sperm specific calcium channel 1, ornithine decarboxylase antizyme 3, aromatase, and estrogen receptor alpha than less dense spermatozoa.

    Science.gov (United States)

    Ing, N H; Forrest, D W; Love, C C; Varner, D D

    2014-07-15

    Stallions are unique among livestock in that, like men, they commonly receive medical treatment for subfertility. In both species, about 15% of individuals have normal semen parameters but are subfertile, indicating a need for novel analyses of spermatozoa function. One procedure for improving fertilizing capability of stallions and men is isolation of dense spermatozoa from an ejaculate for use in artificial insemination. In the current study, dense and less dense spermatozoa were purified by density gradient centrifugation from individual ejaculates from seven reproductively normal adult stallions. The RNA isolated from the spermatozoa seemed to be naturally fragmented to an average length of 250 bases, consistent with reports of spermatozoa RNA from other species. The DNAse treatment of RNA prepared from spermatozoa removed any genomic DNA contamination, as assessed by PCR with intron spanning primers for the protamine 1 (PRM1) gene. Concentrations of seven mRNAs in spermatozoa, correlated with the fertility of men and bulls, were quantified by reverse transcription polymerase chain reaction in dense and less dense spermatozoa. Concentrations of four mRNAs were two- to four-fold lower in dense spermatozoa compared with less dense spermatozoa: Encoding the spermatozoa-specific calcium channel (P 0.1). These results identify new differences in mRNA concentrations in populations of spermatozoa with dissimilar densities.

  17. 旋覆代赭汤对反流性食管炎家兔食管下括约肌L型钙通道的作用研究%Regulation of L-type Calcium Channels by Xuanfu Daizhe Soup in the Lower Esophageal Sphincter Smooth Muscle of Rabbit Reflux Esophagitis Model

    Institute of Scientific and Technical Information of China (English)

    张俊杰; 吴茂申

    2014-01-01

    Objective]To research the regulation of L-type calcium channels by Xuanfu Daizhe soup in the lower esophageal sphincter(LES) smooth muscle of rabbit reflux esophagitis model induced by mixed perfusion of hydrochloric acid and bile. [Methods]Established the rabbit model of mixed reflux esophagitis, nifedipine was used to block L-type calcium channel.The muscle tension of L-type calcium channel were compared among groups in the experiments. [Results]The calcium releasing and flowing phase of LES in the model group was higher than that in the normal group, the whole recipe group, sweet-scending group, the getting rid of bitter-reducing group and the getting rid of lifting and declining group( P0.05). There was no significant difference between the normal group and the whole recipe group in calcium releasing and flowing phase of LES( P>0.05). [Conclusion]The decreasing of reflux esophagitis model LES tension was relevant with the L-type calcium channel dysfunction;Xuanfu Daizhe soup could improve the LES tension by regulating L-type calcium channels. The sweet-ascending group had a remarkable effect among those dismantle prescription groups.%[目的]研究旋覆代赭汤对酸和胆汁混合致反流性食管炎家兔食管下括约肌(LES)L型钙通道的调控机制。[方法]制备家兔反流性食管炎模型,用硝苯地平(nifedipine)阻断L型钙通道,比较各组LES环行肌L型钙通道阻断前后张力幅度的差异。[结果]L型钙通道阻断前后各组LES环行肌张力比较:正常组、全方组、甘升组、去苦降组、去升降相因组LES环行肌钙释放相、内流相张力均高于模型组(P<0.01),而苦降组、升降相因组、去甘升组LES环行肌钙释放相与模型组相比无显著性差异(P>0.05),正常组与全方组LES环行肌钙释放相、内流相张力相比无显著性差异(P>0.05)。[结论]酸和胆汁混合致反流性食管炎模型家兔LES环行肌张力下降,与L型钙通道功能障碍

  18. Myokardinfarkt und Beta-Blocker

    Directory of Open Access Journals (Sweden)

    Stühlinger H-G

    2003-01-01

    Full Text Available Im Rahmen eines akuten koronaren Syndroms (akuter Herzinfarkt, Angina pectoris kommt es, aufgrund eines Ungleichgewichtes zwischen Angebot und Bedarf, zu einem akuten Mangel an Sauerstoff im Herzmuskel. Ursache ist eine reduzierte Sauerstoffzufuhr durch verengte bzw. verschlossene Gefäße. Bis zur Behebung der Ursache vergehen oft mehrere Stunden. In dieser Phase muß - durch Verminderung des Sauerstoffbedarfs im Herzmuskel - eine Verlangsamung der Nekroseentwicklung erreicht werden. Das Ausmaß der Nekrose wird reduziert, somit die für die Langzeitprognose wichtige Linksventrikelfunktion verbessert. Eine Verminderung des Sauerstoffbedarfs erreicht man durch kontrollierte Frequenzsenkung mittels intravenöser Beta-Blockade. In optimaler Weise wird diese Methode durch die Anwendung eines kardioselektiven Beta-Blockers mit kurzer Halbwertszeit durchgeführt. Beta-Blocker haben nicht nur auf die Nekroseentwicklung, sondern auch auf die Inzidenz von Rhythmusstörungen - besonders in der Akutphase - Auswirkungen. Vor allem die mit dieser therapeutischen Maßnahme verbundene Reduktion von Kammerflimmern ist von großer Bedeutung.

  19. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.

    Science.gov (United States)

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  20. L型钙通道对软骨细胞分化的作用%The L-type calcium channels and chondrocyte' s differentiation

    Institute of Scientific and Technical Information of China (English)

    蔡俊; 颜连启; 王静成; 胡翰生; 冯新民; 杨建东

    2012-01-01

    Objective To investigate the effect of the L-type calcium channels on The type Ⅱ collagen synthesis of chondrocytes with patch-clamp.Methods The chondrocytes of rabbits,isolated and cultured in vitro,were divided into 2 groups:control group and insulin-like growth factor (IGF) group.Then,the L-type calcium channels was detected by patch-clamp,the calcium concentration by the laser confocal microscopy,and the type Ⅱ collagen was quantitatively assessed by immunohistochemistrical stain and Western blotting.Results The L-type calcium channel current density was (5.447 ± 0.208 ) pA/pF in IGF group,significantly higher than (4.925 ±0.316) pA/pF in control group (P<0.05).The fluorescence intensity of calcium in IGF group was significandy enhanced,and the type Ⅱ collagen staining of immunohistochemical was significantly deeper than the control group.The semi-quantitative analysis of the type Ⅱ collagen of the Western blot in IGF group was 22.96 ±4.92,and 16.19 ±5.54 in the control group (P < 0.05).Conclusion The L-type calcium channel is an important way of IGF to promote type Ⅱ collagen synthesis.%目的 利用膜片钳研究L型钙通道对软骨细胞合成Ⅱ型胶原的作用.方法 分离培养兔关节软骨细胞,随机分为对照组和胰岛素样生长因子(IGF)组.采用膜片钳记录L型钙通道的变化;激光共聚焦显微镜观察1周时细胞内钙离子浓度变化;免疫组织化学和Western blot法检测Ⅱ型胶原合成的变化.结果 IGF组L-型钙通道最大电流密度为(5.447±0.208) pA/pF,显著高于对照组(4.925 ±0.316) pA/pF(P <0.05).激光共聚焦显微镜观察到IGF组钙离子荧光强度明显增强.免疫组织化学观察到IGF组Ⅱ型胶原染色明显比对照组更深.Western blot法行Ⅱ型胶原半定量分析,实验组22.96±4.92,显著高于对照组16.19±5.54(P<0.05).结论 L型钙通道是IGF促进Ⅱ型胶原合成的一个重要途径.

  1. β-Adrenoceptor activation enhances L-type calcium channel currents in anterior piriform cortex pyramidal cells of neonatal mice: implication for odor learning.

    Science.gov (United States)

    Ghosh, Abhinaba; Mukherjee, Bandhan; Chen, Xihua; Yuan, Qi

    2017-03-01

    Early odor preference learning occurs in one-week-old rodents when a novel odor is paired with a tactile stimulation mimicking maternal care. β-Adrenoceptors and L-type calcium channels (LTCCs) in the anterior piriform cortex (aPC) are critically involved in this learning. However, whether β-adrenoceptors interact directly with LTCCs in aPC pyramidal cells is unknown. Here we show that pyramidal cells expressed significant LTCC currents that declined with age. β-Adrenoceptor activation via isoproterenol age-dependently enhanced LTCC currents. Nifedipine-sensitive, isoproterenol enhancement of calcium currents was only observed in post-natal day 7-10 mice. APC β-adrenoceptor activation induced early odor preference learning was blocked by nifedipine coinfusion.

  2. Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala

    DEFF Research Database (Denmark)

    Maigaard, Katrine; Pedersen, Ida Hageman; Jørgensen, Anders;

    2012-01-01

    Although affective disorders have high prevalence, morbidity and mortality, we do not fully understand disease etiopathology, nor have we determined the exact mechanisms by which treatment works. Recent research indicates that intracellular calcium ion dysfunction might be involved. Here we use...... the chronic restraint stress model of affective disorder (6 h restraint per day for 21 days) in combination with electroconvulsive stimulations to examine the effects of stress and an effective antidepressive treatment modality on L-type voltage gated calcium channel subunit mRNA expression patterns......, while stress only upregulated Ca(v)1.3 channel expression significantly in the dentate gyrus. ECS effects on Ca(v)1.2 channel expression were generally specific to stressed animals. Our findings are consistent with and extent previous studies on the involvement of intracellular calcium ion dysfunction...

  3. 豚鼠Ⅱ型前庭毛细胞乙酰胆碱敏感性大电导钙依赖性钾通道与L型钙通道共存%Co-location of Ach-sensitive BK channels and L-type calcium channels in type Ⅱ vestibular hair cells of guinea pig

    Institute of Scientific and Technical Information of China (English)

    郭长凯; 李冠乔; 孔维佳; 张松; 吴婷婷; 李家荔; 李擎天

    2008-01-01

    Objective To explore the mechanisms of the influx of calcium ions during the activation of Ach-sensitive BK channel(big conductance,calcium-dependent potassium channel)in type Ⅱ vestibular hair cells of guinea pigs. Methods Type Ⅱ vestibular hair cells were isolated by collagenase type IA.Under the whole-cell patch mode,the sensitivity of Ach-sensitive BK current to the calcium channels blockers was investigated,the pharmacological property of L-type calcium channel activator-sensitive current and Ach-sensitive BK current was compared. Results Following application of Ach, type Ⅱ vestibular hair cells displayed a sustained outward potassium current,with a reversal potential of(-70.5±10.6)mV(-x±s,n=10). At the holding potential of -50 mV, the current amplitude of Ach-sensitive potassium current activated by 100 μmol/L Ach was(267±106) pA(n=11). Ach-sensitive potassium current was potently sensitive to the BK current blocker, IBTX(iberiotoxin, 200 nmol/L). Apamin,the well-known small conductance, calcium-dependent potassium current blocker, failed to inhibit the amplitude of Ach-sensitive potassium current at a dose of 1 μmol/L. Ach-sensitive BK current was sensitive to NiCl2 and potently inhibited by CdCl2. NiCl2 and CdCl2 showed a dose-dependent blocking effect with a half inhibitionmaximal response of(135.5±18.5)μmol/L(n=7) and (23.4±2.6) μmol/L(n=7). The L-type calcium channel activator,(-)-Bay-K 8644(10 μmol/L),mimicked the role of Ach and activated the IBTX-sensitive outward current. Conclusion Ach-sensitive BK and L-type calcium channels are co-located in type Ⅱ vestibular hair cells of guinea pigs.%目的 研究豚鼠Ⅱ型前庭毛细胞乙酰胆碱(acetylcholine,ACh)敏感性大电导钙依赖性钾通道(big conductance,calcium-dependent potassium channel,BK)激活过程中的钙离子内流机制.方法 健康杂色豚鼠52只,断头后取出前庭终器,经胶原酶IA消化后获取Ⅱ型前庭毛细胞.采用全细胞膜片钳技术

  4. Real role of β-blockers in regression of left ventricular mass in hypertension patients

    Science.gov (United States)

    Xing, FuWei; Chen, Jialin; Zhao, BinLiang; Jiang, Jingzhou; Tang, Anli; Chen, Yili

    2017-01-01

    Abstract Background: Left ventricular hypertrophy (LVH) is commonly present in patients with hypertension (HT). According to the expert consensus document from American, angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARBs) were recommended as 1st-line therapeutic drugs. However, none noticed the different efficacy between fat-soluble and selective β1-receptor blockers (FS-β-B) and other β-blockers on regression of LVH before. The aim of this analysis was to compare the efficacy of FS-β-B with the other 4 different classes of antihypertensive drugs (ACEI, ARBs, calcium channel blockers [CCBs], and diuretics) on regression of LVH. Methods: Relative trials were identified in the PubMed, Web of Science, OVID EBM Reviews and Cochrane databases, and the relevant papers were examined. We performed both traditional and Bayesian meta-analysis of randomized controlled trials (RCTs) about the regression of LVH. Sensitivity analysis and regression analysis were performed to explore possible sources of heterogeneity. Inconsistency analysis was performed to check whether the analysis of the trials in the network was indeed consistent. Results: A total of 41 RCTs involving 2566 patients with HT and LVH were included in this analysis. Bayesian network meta-analysis indicated no statistically significant differences between these groups: FS-β-B and ACEI (MD, −7.09; 95% CI, −14.99, 1.27); FS-β-B and ARB (MD, −2.66; 95% Cl, −12.02, 6.31). Although FS-β-B showed greater efficacy when compared with diuretic (MD, 13.04; 95% CI, 3.38, 22.59) or CCB (MD, 10.90; 95% CI, 1.98, 19.49). The probabilities of being among the most efficacious treatments were: FS-β-B (72%), ARB (27%), ACEI (0.01%), CCB (0.00%), and diuretic (0.00%). Conclusion: Evidence from our analysis reveals that FS-β-B have potential to become 1st-line therapeutic drugs in HT and LVH patients. However, the real efficacy of FS-β-B on regression of LVH should be confirmed by

  5. Poor tolerance of beta-blockers by elderly patients with heart failure

    Directory of Open Access Journals (Sweden)

    Satoshi Yanagisawa

    2010-11-01

    Full Text Available Satoshi Yanagisawa, Noriyuki Suzuki, Toshikazu TanakaDepartment of Cardiology, Okazaki City Hospital, Aichi, JapanAbstract: Despite the well-understood importance of beta-blocker therapy in heart failure, it is sometimes not possible to use beta-blockers in elderly patients due to poor tolerance. In this report, we describe the case of an 83-year-old patient with severe systolic heart failure complicated by aortic valve stenosis and atrial fibrillation. A simple therapeutic approach involving discontinuation of beta-blockers remarkably alleviated the symptoms such as left ventricular ejection fraction, and improved the chest radiography and laboratory findings; further, atrial fibrillation converted to sinus rhythm. It is important to carefully administer beta-blocker therapy to elderly patients with heart failure, especially after considering cardiac output.Keywords: elderly, octogenarians, beta-blockers, heart failure

  6. Blockade of L-type calcium channel in myocardium and calcium-induced contractions of vascular smooth muscle by by CPU 86017

    Institute of Scientific and Technical Information of China (English)

    De-zai DAI; Hui-juan HU; Jing ZHAO; Xue-mei HAO; Dong-mei YANG; Pei-ai ZHOU; Cai-hong WU

    2004-01-01

    AIM: To assess the blockade by CPU 86017 on the L-type calcium channels in the myocardium and on the Ca2+related contractions of vascular smooth muscle. METHODS: The whole-cell patch-clamp was applied to investigate the blocking effect of CPU 86017 on the L-type calcium current in isolated guinea pig myocytes and contractions by KC1 or phenylephrine (Phe) of the isolated rat tail arteries were measured. RESULTS: Suppression of the L-type current of the isolated myocytes by CPU 86017 was moderate, in time- and concentration-dependent manner and with no influence on the activation and inactivation curves. The IC50 was 11.5 μmol/L. Suppressive effect of CPU 86017 on vaso-contractions induced by KC1 100 mmol/L, phenylephrine I μmol/Lin KH solution (phase 1),Ca2+ free KH solution ( phase 2), and by addition of CaCI2 into Ca2+-free KH solution (phase 3) were observed. The IC50 to suppress vaso-contractions by calcium entry via the receptor operated channel (ROC) and Voltage-dependent channel (VDC) was 0.324 μmol/L and 16.3 μmol/L, respectively. The relative potency of CPU 86017 to suppress vascular tone by Ca2+ entry through ROC and VDC is 1/187 of prazosin and 1/37 of verapamil, respectively.CONCLUSION: The blocking effects of CPU 86017 on the L-type calcium channel of myocardium and vessel are moderate and non-selective. CPU 86017 is approximately 50 times more potent in inhibiting ROC than VDC.

  7. Gentamicin Blocks the ACh-Induced BK Current in Guinea Pig Type II Vestibular Hair Cells by Competing with Ca2+ at the l-Type Calcium Channel

    Directory of Open Access Journals (Sweden)

    Hong Yu

    2014-04-01

    Full Text Available Type II vestibular hair cells (VHCs II contain big-conductance Ca2+-dependent K+ channels (BK and L-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh evoked the BK current by triggering the influx of Ca2+ ions through l-type Ca2+ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs. Aminoglycoside antibiotics, such as gentamicin (GM, are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC50 value of 36.3 ± 7.8 µM. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca2+ concentration ([Ca2+]o could antagonize it. Moreover, 50 µM GM potently blocked Ca2+ currents activated by (--Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca2+ at the l-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II.

  8. Cav2-type calcium channels encoded by cac regulate AP-independent neurotransmitter release at cholinergic synapses in adult Drosophila brain.

    Science.gov (United States)

    Gu, Huaiyu; Jiang, Shaojuan Amy; Campusano, Jorge M; Iniguez, Jorge; Su, Hailing; Hoang, Andy An; Lavian, Monica; Sun, Xicui; O'Dowd, Diane K

    2009-01-01

    Voltage-gated calcium channels containing alpha1 subunits encoded by Ca(v)2 family genes are critical in regulating release of neurotransmitter at chemical synapses. In Drosophila, cac is the only Ca(v)2-type gene. Cacophony (CAC) channels are localized in motor neuron terminals where they have been shown to mediate evoked, but not AP-independent, release of glutamate at the larval neuromuscular junction (NMJ). Cultured embryonic neurons also express CAC channels, but there is no information about the properties of CAC-mediated currents in adult brain nor how these channels regulate transmission in central neural circuits where fast excitatory synaptic transmission is predominantly cholinergic. Here we report that wild-type neurons cultured from late stage pupal brains and antennal lobe projection neurons (PNs) examined in adult brains, express calcium currents with two components: a slow-inactivating current sensitive to the spider toxin Plectreurys toxin II (PLTXII) and a fast-inactivating PLTXII-resistant component. CAC channels are the major contributors to the slow-inactivating PLTXII-sensitive current based on selective reduction of this component in hypomorphic cac mutants (NT27 and TS3). Another characteristic of cac mutant neurons both in culture and in whole brain recordings is a reduced cholinergic miniature excitatory postsynaptic current frequency that is mimicked in wild-type neurons by acute application of PLTXII. These data demonstrate that cac encoded Ca(v)2-type calcium channels regulate action potential (AP)-independent release of neurotransmitter at excitatory cholinergic synapses in the adult brain, a function not predicted from studies at the larval NMJ.

  9. Formaldehyde increases intracellular calcium concentration in primary cultured hippocampal neurons partly through NMDA receptors and T-type calcium channels

    Institute of Scientific and Technical Information of China (English)

    Ye-Nan Chi; Xu Zhang; Jie Cai; Feng-Yu Liu; Guo-Gang Xing; You Wan

    2012-01-01

    Objective Formaldehyde at high concentrations is a contributor to air pollution.It is also an endogenous metabolic product in cells,and when beyond physiological concentrations,has pathological effects on neurons.Formaldehyde induces mis-folding and aggregation of neuronal tau protein,hippocampal neuronal apoptosis,cognitive impairment and loss of memory functions,as well as excitation of peripheral nociceptive neurons in cancer pain models.Intracellular calcium ([Ca2+]i) is an important intracellular messenger,and plays a key role in many pathological processes.The present study aimed to investigate the effect of formaldehyde on [Ca2+]i and the possible involvement of N-methyl-D-aspartate receptors (NMDARs) and T-type Ca2+ channels on the cell membrane.Methods Using primary cultured hippocampal neurons as a model,changes of [Ca2+]i in the presence of formaldehyde at a low concentration were detected by confocal laser scanning microscopy.Results Formaldehyde at 1 mmol/L approximately doubled [Ca2+]i.(2R)-amino-5-phosphonopentanoate (AP5,25 μtmol/L,an NMDAR antagonist) and mibefradil (MIB,1 μtmol/L,a T-type Ca2+ channel blocker),given 5 min after formaldehyde perfusion,each partly inhibited the formaldehyde-induced increase of [Ca2+]i,and this inhibitory effect was reinforced by combined application of AP5 and MIB.When applied 3 min before formaldehyde perfusion,AP5 (even at 50 μmol/L) did not inhibit the formaldehyde-induced increase of [Ca2+]i,but MIB (1 μmol/L) significantly inhibited this increase by 70%.Conclusion These results suggest that formaldehyde at a low concentration increases [Ca2+]i in cultured hippocampal neurons; NMDARs and T-type Ca2+ channels may be involved in this process.

  10. The opening of maitotoxin-sensitive calcium channels induces the acrosome reaction in human spermatozoa: differences from the zona pellucida

    Institute of Scientific and Technical Information of China (English)

    Julio C Chávez; Claudia L Trevi(n)o; Gerardo A de Blas; José L de la Vega-Beltrán; Takuya Nishigaki; Mayel Chirinos; María Elena González-González; Fernando Larrea; Alejandra Solís; Alberto Darszon

    2011-01-01

    The acrosome reaction(AR),an absolute requirement for spermatozoa and egg fusion,requires the influx of Ca2+into the spermatozoa through voltage-dependent Ca2+channels and store-operated channels.Maitotoxin(MTx),a Ca2+-mobilizing agent,has been shown to be a potent inducer of the mouse sperm AR,with a pharmacology similar to that of the zona pellucida(ZP),possibly suggesting a common pathway for both inducers.Using recombinant human ZP3(rhZP3),mouse ZP and two MTx channel blockers(U73122 and U73343),we investigated and compared the MTx-and ZP-induced ARs in human and mouse spermatozoa.Herein,we report that MTx induced AR and elevated intracellular Ca2+([Ca2+]1)in human spermatozoa,both of which were blocked by U73122 and U73343.These two compounds also inhibited the MTx-induced AR in mouse spermatozoa.In disagreement with our previous proposal,the AR triggered by rhZP3 or mouse ZP was not blocked by U73343,indicating that in human and mouse spermatozoa,the AR induction by the physiologicalligands or by MTx occurred through distinct pathways.U73122,but not U73343(inactive analogue),can block phospholipase C(PLC).Another PLC inhibitor,edelfosine,also blocked the rhZP3-and ZP-induced ARs.These findings confirmed the participation of a PLC-dependent signalling pathway in human and mouse zona protein-induced AR.Notably,edelfosine also inhibited the MTx-induced mouse sperm AR but not that of the human,suggesting that toxin-induced AR is PLC-dependent in mice and PLC-independent in humans.

  11. Atrial Fibrillation and Stroke

    Science.gov (United States)

    ... Other treatments for AF include medications such as beta blockers or calcium channel blockers to slow the heartbeat, ... Other treatments for AF include medications such as beta blockers or calcium channel blockers to slow the heartbeat, ...

  12. 中枢N-型钙离子通道对应激性高血压大鼠去甲肾上腺素释放的影响%Effects of central N-type calcium channels on noradrenaline release from locus coeruleus projecting to hypothalamus in stress induced hypertension rats

    Institute of Scientific and Technical Information of China (English)

    吴军同; 巩万坤; 夏兆俊; 王峰; 黄宏平; 汪萌芽

    2016-01-01

    channels blocker,i.c.v.10 μg) led to inhibited NE release in the hypothalamus in SIH rats and lowered blood pressure (P<0.05),whereas weak effect of ralfinamide mesylate was seen in the control rats.Conclusion:Combined noise and foot-shock stresses may increase secretion of NE in the hypothalamus followed by electrical stimulation in locus coeruleus in rats .Central N-type calcium channel contributes to NE release in hypothalamus and blood pressure modulation in SIH rats.

  13. Upregulation of Voltage-Gated Calcium Channel Cav1.3 in Bovine Somatotropes Treated with Ghrelin

    Directory of Open Access Journals (Sweden)

    V. M. Salinas Zarate

    2013-01-01

    Full Text Available Activation of the growth hormone (GH secretagogue receptor (GHS-R by synthetic GH releasing peptides (GHRP or its endogenous ligand (Ghrelin stimulates GH release. Though much is known about the signal transduction underlying short-term regulation, there is far less information on the mechanisms that produce long-term effects. In the current report, using an enzyme-linked immunosorbent assay for GH detection and whole-cell patch-clamp recordings, we assessed the long-term actions of such regulatory factors on voltage-activated Ca2+ currents in bovine somatotropes (BS separated on a Percoll gradient and detected by immunohistochemistry. After 24 h of treatment with Ghrelin (10 nM or GHRP-6 (100 nM enhanced BS secretory activity; GH secretion stimulated by GHS through the activation of GHS-R because treatment with the antagonist of GHS-R (D-Lys3-GHRP-6, 10 μM blocked the GH secretion, and the effect was dose and time dependent (24, 48, and 72 h. GH secretion stimulated by GHRP-6 was abolished by nifedipine (0.5 μM, a blocker of L-type HVA Ca2+ channels, and KN-62 (10 μM, an inhibitor of Ca2+/CaM-KII. After 72 h in culture, all recorded BS exhibited two main Ca2+ currents: a low voltage-activated (LVA; T-type and a high voltage-activated (HVA; mostly dihydropyridine-sensitive L-type current. Interestingly, HVA and LVA channels were differentially upregulated by Ghrelin. Chronic treatment with the GHS induced a significant selective increase on the Ba2+ current through HVA Ca2+ channels, and caused only a small increase of currents through LVA channels. The stimulatory effect on HVA current density was accompanied by an augment in maximal conductance with no apparent changes in the kinetics and the voltage dependence of the Ca2+ currents, suggesting an increase in the number of functional channels in the cell membrane. Lastly, in consistency with the functional data, quantitative real-time RT-PCR revealed transcripts encoding for

  14. Fetal calcium regulates branching morphogenesis in the developing human and mouse lung: involvement of voltage-gated calcium channels.

    Science.gov (United States)

    Brennan, Sarah C; Finney, Brenda A; Lazarou, Maria; Rosser, Anne E; Scherf, Caroline; Adriaensen, Dirk; Kemp, Paul J; Riccardi, Daniela

    2013-01-01

    Airway branching morphogenesis in utero is essential for optimal postnatal lung function. In the fetus, branching morphogenesis occurs during the pseudoglandular stage (weeks 9-17 of human gestation, embryonic days (E)11.5-16.5 in mouse) in a hypercalcaemic environment (~1.7 in the fetus vs. ~1.1-1.3 mM for an adult). Previously we have shown that fetal hypercalcemia exerts an inhibitory brake on branching morphogenesis via the calcium-sensing receptor. In addition, earlier studies have shown that nifedipine, a selective blocker of L-type voltage-gated Ca(2+) channels (VGCC), inhibits fetal lung growth, suggesting a role for VGCC in lung development. The aim of this work was to investigate the expression of VGCC in the pseudoglandular human and mouse lung, and their role in branching morphogenesis. Expression of L-type (CaV1.2 and CaV1.3), P/Q type (CaV2.1), N-type (CaV2.2), R-type (CaV2.3), and T-type (CaV3.2 and CaV3.3) VGCC was investigated in paraffin sections from week 9 human fetal lungs and E12.5 mouse embryos. Here we show, for the first time, that Cav1.2 and Cav1.3 are expressed in both the smooth muscle and epithelium of the developing human and mouse lung. Additionally, Cav2.3 was expressed in the lung epithelium of both species. Incubating E12.5 mouse lung rudiments in the presence of nifedipine doubled the amount of branching, an effect which was partly mimicked by the Cav2.3 inhibitor, SNX-482. Direct measurements of changes in epithelial cell membrane potential, using the voltage-sensitive fluorescent dye DiSBAC2(3), demonstrated that cyclic depolarisations occur within the developing epithelium and coincide with rhythmic occlusions of the lumen, driven by the naturally occurring airway peristalsis. We conclude that VGCC are expressed and functional in the fetal human and mouse lung, where they play a role in branching morphogenesis. Furthermore, rhythmic epithelial depolarisations evoked by airway peristalsis would allow for branching to match

  15. Separation of Five Dihydropyridine Calcium Channel Blockers by Micellar Electrokinetic Chromatography%胶束电动色谱分离5种二氢吡啶类钙拮抗剂

    Institute of Scientific and Technical Information of China (English)

    王杰; 陈海峰; 赵岚峰

    1999-01-01

    应用胶束电动毛细管色谱,以40mmol/L硼砂(pH8.0)-40mmol/L十二烷基硫酸钠(SDS)为运行缓冲溶液,柱温60℃,在13 min内分离了5种二氢吡啶类钙拮抗剂药物.讨论了SDS浓度、硼砂浓度、缓冲溶液pH、柱温对迁移时间和分离的影响.

  16. On the top of ARB N/L type Ca channel blocker leads to less elevation of aldosterone

    Science.gov (United States)

    Konoshita, Tadashi; Kaeriyama, Saori; Urabe, Machi; Nakaya, Takahiro; Yamada, Mika; Ichikawa, Mai; Yamamoto, Katsushi; Sato, Satsuki; Imagawa, Michiko; Fujii, Miki; Makino, Yasukazu; Zenimaru, Yasuo; Wakahara, Shigeyuki; Suzuki, Jinya; Ishizuka, Tamotsu; Nakamura, Hiroyuki

    2016-01-01

    The activation of the renin–angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan+amlodipine compared with valsartan+cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132±10/76±10 compared with 131±10/77±9, P=0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41±2.67 compared with 2.00±1.50 P=0.20, PAC (pg/ml): 77.3±31.0 compared with 67.4±24.8, P<0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9±216.1 compared with 73.9±122.2, P<0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine. PMID:27515419

  17. Effects of SO2 Derivatives on Calcium Channels in DRG Neurons%二氧化硫衍生物对背根神经元钙通道的影响

    Institute of Scientific and Technical Information of China (English)

    杜正清; 王丽娟

    2012-01-01

    The effects of SO2 derivatives on L-type and N-type calcium currents in freshly isolated rat dorsal root ganglion neurons were investigated using the whole-cell configuration of the path-clamp technique. The results showed: first,it was found that 1 μmol/L SO2 derivatives could increase the amplitudes of calcium currents in a voltage-dependent manner. The average increase of high-voltage-activated calcium currents was 63.4% ±5.7% at - 10 mV. Second,the sensitivity of SO2 derivatives on channel subtypes was quantitatively estimated based on the different ratios of L-,N-,r-( non-L- and non-N-types) types expressed in total high-voltage-activated calcium channels when the corresponding selective channel blockers were applied and the calcium currents were recorded. The data showed that 1 μmol/i SO2 derivatives increased L-type current by 82.2% ,increased N-type by 95.3% ,and increased residual r type Ca2+ currents by 9.4% ,which indicated that both N- and L-type Ca2+ channels were sensitive to SO,derivatives. It was suggested that SO2 derivatives could enhance both types of Ca2+ currents in dorsal root ganglion neurons and then lead to neuropathic pain.%应用全细胞膜片钳技术研究了SO2衍生物对大鼠DRG(背根神经节)神经元不同亚型钙通道的影响.结果表明,1μmol/LSO2衍生物对不同电压下的钙电流均有增大作用,在- 10 mV时可使钙电流增幅达到63.4%±5.7%.在细胞外液中加入不同亚型钙通道的阻滞剂并经过修正计算发现,1μmol/L SO2衍生物使L型钙电流增长了82.2%,N型钙电流增长了95.3%,r型(非L型、非N型)钙电流增长了9.4%,说明高阈值激活的N型和L型钙电流对SO2衍生物特别敏感,推测SO2衍生物诱发神经性疼痛,引起神经毒性,可能主要通过增大DRG神经元上N型和L型钙通道发生电流介导.

  18. Two distinct voltage-sensing domains control voltage sensitivity and kinetics of current activation in CaV1.1 calcium channels.

    Science.gov (United States)

    Tuluc, Petronel; Benedetti, Bruno; Coste de Bagneaux, Pierre; Grabner, Manfred; Flucher, Bernhard E

    2016-06-01

    Alternative splicing of the skeletal muscle CaV1.1 voltage-gated calcium channel gives rise to two channel variants with very different gating properties. The currents of both channels activate slowly; however, insertion of exon 29 in the adult splice variant CaV1.1a causes an ∼30-mV right shift in the voltage dependence of activation. Existing evidence suggests that the S3-S4 linker in repeat IV (containing exon 29) regulates voltage sensitivity in this voltage-sensing domain (VSD) by modulating interactions between the adjacent transmembrane segments IVS3 and IVS4. However, activation kinetics are thought to be determined by corresponding structures in repeat I. Here, we use patch-clamp analysis of dysgenic (CaV1.1 null) myotubes reconstituted with CaV1.1 mutants and chimeras to identify the specific roles of these regions in regulating channel gating properties. Using site-directed mutagenesis, we demonstrate that the structure and/or hydrophobicity of the IVS3-S4 linker is critical for regulating voltage sensitivity in the IV VSD, but by itself cannot modulate voltage sensitivity in the I VSD. Swapping sequence domains between the I and the IV VSDs reveals that IVS4 plus the IVS3-S4 linker is sufficient to confer CaV1.1a-like voltage dependence to the I VSD and that the IS3-S4 linker plus IS4 is sufficient to transfer CaV1.1e-like voltage dependence to the IV VSD. Any mismatch of transmembrane helices S3 and S4 from the I and IV VSDs causes a right shift of voltage sensitivity, indicating that regulation of voltage sensitivity by the IVS3-S4 linker requires specific interaction of IVS4 with its corresponding IVS3 segment. In contrast, slow current kinetics are perturbed by any heterologous sequences inserted into the I VSD and cannot be transferred by moving VSD I sequences to VSD IV. Thus, CaV1.1 calcium channels are organized in a modular manner, and control of voltage sensitivity and activation kinetics is accomplished by specific molecular mechanisms

  19. 环孢素A对心房颤动犬心房L型钙离子通道蛋白αlc亚单位的影响%Influence of cyclosporine A on atrial L-type calcium channel αlc subunit in a canine model of atrial fibrillation

    Institute of Scientific and Technical Information of China (English)

    黄亚; 卢才义; 颜伟; 高磊; 陈琪; 张亚晶

    2009-01-01

    Objective To investigate the impact of cyclosporine A (CsA) on atrial expression change of L-type calcium channel αlc subunit in a canine model of atrial fibrillation (AF). Methods AF was induced by rapid atrial pacing (400 baets/min) for 8 weeks in adult male dogs and placebo (n=6) or CsA (5 mg·kg-1·d-1, n=6) were orally administered to these animals. Sham operated animals served as normal controls (n=6). The atrial electrophysiological parameters including P wave duration, atrial effective refractory period (AERP) were recorded and analyzed at baseline and 8 weeks later. Animals were scarified at 8 weeks post final electrophysiological examinations and atrial expressions of L-type calcium channel αlc subunit were determined by Western blot. Results Compared to sham group, the P wave duration was significantly prolonged while AERP was significantly decreased in AF and CsA groups (all P <0. 05). AERP was significantly longer in CsA group than that in AF group (P < 0. 05 ). L-type calcium channel αlc subunit expression was significantly downregulated in AF group compared to sham group (P <0. 05) and CsA significantly attenuated this downregulation (P < 0. 01 vs. AF group). Conclusion CsA could attenuate the downreguahion of the L-type calcium channel αlc subunit expression and improve the atrial electrophysiological remodeling in this canine model of AF.%目的 研究环孢素A(CsA)作用下心房颤动(房颤)犬心房电生理特性及心房L型钙离子通道蛋白αlc亚单位(Lαle)表达变化.方法 实验犬分为CsA组、房颤组及假手术组(Sham组),快速起搏心房建立犬房颤模型,记录标测并对比各组起搏前后P波时程、心房有效不应期(AERP)的差异,应用Western blot免疫印迹技术比较各组问Lαlc表达的差异.结果 房颤组、CsA组较Sham组P波时程延长(P<0.05),AERP缩短P<0.05).CsA组较房颤组AERP延长(P<0.05).房颤组较Sham组Lαlc表达明显降低(P<0.01).CsA组较房颤组Lede升高(P<0

  20. Pharmacogenetics of ophthalmic topical β-blockers

    OpenAIRE

    Sidjanin, Duska J.; McCarty, Catherine A.; Patchett, Richard; Smith, Edward; Wilke, Russell A.

    2008-01-01

    Glaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical β-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical β-blockers. This review summarizes clinically significant polymorphisms that have been identified in the β-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications ...

  1. Age-dependent impact of CaV3.2 T-type calcium channel deletion on myogenic tone and flow-mediated vasodilatation in small arteries

    DEFF Research Database (Denmark)

    Mikkelsen, Miriam F.; Björling, Karl; Jensen, Lars Jørn

    2016-01-01

    .2-dependent and -independent effects. No changes in mRNA expression of several important K(+) and Ca(2+) channel genes were induced by CaV3.2 knock-out. However, the expression of the other T-type channel isoform (CaV3.1) was reduced at the mRNA and protein level in mature adult compared to young WT arteries......The myogenic response and flow-mediated vasodilatation are important regulators of local blood perfusion and total peripheral resistance, and are known to entail a calcium influx into vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), respectively. CaV3.2 T-type calcium channels...... are expressed in both VSMCs and ECs of small arteries. The T-type channels are important drug targets but due to the lack of specific antagonists our understanding of the role of CaV3.2 channels in vasomotor tone at various ages is scarce. We evaluated the myogenic response, flow-mediated vasodilatation...

  2. RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2.

    Science.gov (United States)

    Salvi, Julie; Bertaso, Federica; Mausset-Bonnefont, Anne-Laure; Metz, Alexandra; Lemmers, Céline; Ango, Fabrice; Fagni, Laurent; Lory, Philippe; Mezghrani, Alexandre

    2014-08-01

    Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while β-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress-induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease.

  3. Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A.

    Science.gov (United States)

    García Segarra, Nuria; Gautschi, Ivan; Mittaz-Crettol, Laureane; Kallay Zetchi, Christine; Al-Qusairi, Lama; Van Bemmelen, Miguel Xavier; Maeder, Philippe; Bonafé, Luisa; Schild, Laurent; Roulet-Perez, Eliane

    2014-07-15

    Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel Ca(V)2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3 bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant Ca(V)2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.

  4. Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca[superscript 2+]·calmodulins

    Energy Technology Data Exchange (ETDEWEB)

    Fallon, Jennifer L.; Baker, Mariah R.; Xiong, Liangwen; Loy, Ryan E.; Yang, Guojun; Dirksen, Robert T.; Hamilton, Susan L.; Quiocho, Florante A.; (Baylor); (Rochester-Med)

    2009-11-10

    Voltage-dependent calcium channels (Ca(V)) open in response to changes in membrane potential, but their activity is modulated by Ca(2+) binding to calmodulin (CaM). Structural studies of this family of channels have focused on CaM bound to the IQ motif; however, the minimal differences between structures cannot adequately describe CaM's role in the regulation of these channels. We report a unique crystal structure of a 77-residue fragment of the Ca(V)1.2 alpha(1) subunit carboxyl terminus, which includes a tandem of the pre-IQ and IQ domains, in complex with Ca(2+).CaM in 2 distinct binding modes. The structure of the Ca(V)1.2 fragment is an unusual dimer of 2 coiled-coiled pre-IQ regions bridged by 2 Ca(2+).CaMs interacting with the pre-IQ regions and a canonical Ca(V)1-IQ-Ca(2+).CaM complex. Native Ca(V)1.2 channels are shown to be a mixture of monomers/dimers and a point mutation in the pre-IQ region predicted to abolish the coiled-coil structure significantly reduces Ca(2+)-dependent inactivation of heterologously expressed Ca(V)1.2 channels.

  5. NMDA receptors in mouse anterior piriform cortex initialize early odor preference learning and L-type calcium channels engage for long-term memory.

    Science.gov (United States)

    Mukherjee, Bandhan; Yuan, Qi

    2016-10-14

    The interactions of L-type calcium channels (LTCCs) and NMDA receptors (NMDARs) in memories are poorly understood. Here we investigated the specific roles of anterior piriform cortex (aPC) LTCCs and NMDARs in early odor preference memory in mice. Using calcium imaging in aPC slices, LTCC activation was shown to be dependent on NMDAR activation. Either D-APV (NMDAR antagonist) or nifedipine (LTCC antagonist) reduced somatic calcium transients in pyramidal cells evoked by lateral olfactory tract stimulation. However, nifedipine did not further reduce calcium in the presence of D-APV. In mice that underwent early odor preference training, blocking NMDARs in the aPC prevented short-term (3 hr) and long-term (24 hr) odor preference memory, and both memories were rescued when BayK-8644 (LTCC agonist) was co-infused. However, activating LTCCs in the absence of NMDARs resulted in loss of discrimination between the conditioned odor and a similar odor mixture at 3 hr. Elevated synaptic AMPAR expression at 3 hr was prevented by D-APV infusion but restored when LTCCs were directly activated, mirroring the behavioral outcomes. Blocking LTCCs prevented 24 hr memory and spared 3 hr memory. These results suggest that NMDARs mediate stimulus-specific encoding of odor memory while LTCCs mediate intracellular signaling leading to long-term memory.

  6. Dopamine midbrain neurons in health and Parkinson's disease: emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels.

    Science.gov (United States)

    Dragicevic, E; Schiemann, J; Liss, B

    2015-01-22

    Dopamine (DA) releasing midbrain neurons are essential for multiple brain functions, such as voluntary movement, working memory, emotion and cognition. DA midbrain neurons within the substantia nigra (SN) and the ventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are differentially affected in diseases like schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease (PD). Apart from having diverse functions in health and disease states, DA midbrain neurons display distinct electrical activity patterns, crucial for DA release. These activity patterns are generated and modulated by specific sets of ion channels. Recently, two ion channels have been identified, not only contributing to these activity patterns and to functional properties of DA midbrain neurons, but also seem to render SN DA neurons particularly vulnerable to degeneration in PD and its animal models: L-type calcium channels (LTCCs) and ATP-sensitive potassium channels (K-ATPs). In this review, we focus on the emerging physiological and pathophysiological roles of these two ion channels (and their complex interplay with other ion channels), particularly in highly vulnerable SN DA neurons, as selective degeneration of these neurons causes the major motor symptoms of PD.

  7. Preparation and preliminary biological evaluation of radiogallium-labeled DTPA-amlodipine complex for possible L-type calcium channel imaging

    Energy Technology Data Exchange (ETDEWEB)

    Firuzyar, Tahereh; Shafiee-Ardestani, Mehdi; Khalaj, Ali [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Faculty of Pharmacy; Jalilian, Amir R.; Fazaeli, Yousef; Aboudzadeh, Mohammad Reza [Nuclear Science and Technology Research Institute (NSTRI), Tehran (Iran, Islamic Republic of). Radiopharmacy Research Group

    2014-07-01

    A DTPA-conjugated amlodipine analog (DTPA-AMLO) 3, was prepared for possible voltage gated calcium channel imaging after radiolabeling with Ga-67. [{sup 67}Ga]-DTPA-AMLO complex was prepared starting [{sup 67}Ga]gallium chloride and DTPA-AMLO in 60-90 min at 50-60 C in phosphate buffer. The partition co-efficient and stability of the tracer was determined in final solution (25 C) and presence of human serum (37 C) up to 24 h. The biodistribution of the labeled compound in wild-type rats were determined up to 72 h using organ counting and SPECT. The radiolabled complex was prepared in high radiochemical purity (>96%, RTLC and >98% HPLC) and significant specific activity (7-10 GBq/mmol). The log P for the complex was calculated as -0.594, consistent with a water soluble complex. The tracer is mostly washed out through kidneys which were in full compliance with the amlodipine metabolism and imaging studies demonstrated the same behavior. The tracer uptake in organs with smooth muscles was observed in stomach, colon as well as intestine.

  8. Effect of salvia miltiorrhiza compound liquid on L-type calcium channels in rats with cardiac hypertrophy%丹参复方液对大鼠肥大心肌L型钙电流的影响

    Institute of Scientific and Technical Information of China (English)

    王佐好; 韩晨光; 赵娟; 李海英; 佟长青

    2009-01-01

    [目的]探讨丹参复方液对高血压性肥大心肌L型钙电流的影响.[方法]利用腹主动脉缩窄法建立高血压性心肌肥大模型,利用灌胃法给予丹参复方液,采用离体大鼠心脏Langendorff灌注法急性分离心肌细胞,利用膜片钳全细胞技术记录L型钙电流,比较正常对照组、高血压未治疗组和丹参复方液组之间的区别.[结果]高血压未治疗组的L型钙电流密度显著高于正常对照组(P0.05).[结论]丹参复方液具有逆转高血压性肥大心肌L型钙电流的药理作用.%[Objective] To observe the effect of Salvia miltiorrhiza SM compound liquid on cardiocyte L-type calcium channel of cardiac hypertrophy induced by hypertension. [Methods] Cardiac hypertrophy models were made by partial hgation abdominal aortic. SM compound liquid was given by intragastric administration. Langendorff system was used to dissociate single ventricular cell. The current of L-type calcium channels was recorded by whole-cell patch clamp recording technique and compared with control group, hypertension without therapy group and SM compound liquid group. [Re-sults] The current density of L-type calcium channels of hypertension without therapy group was higher than that of con-trol group significantly(P0.05) . [Conclusions] SM compound liquid can reverse cardiocyte L type calcium channel of cardiac hypertrophy induced by hypertension.

  9. 钙离子通道与老龄心房颤动心房电重构的研究进展%Advances in Research of Calcium Channel Current and Atrial Electrical Remodeling of Atrial Fibrillation

    Institute of Scientific and Technical Information of China (English)

    李耀东; 汤宝鹏

    2011-01-01

    随着心房颤动电生理机制研究的广泛深人,已经认识到离子通道重构在心房颤动的发生和维持过程中起重要作用.L-型钙通道及其基因表达的改变可能是老年人容易发生心房颤动电生理重建的离子和分子基础.现就心脏钙离子通道及年龄与心房颤动的研究进展予以综述.%It is important to recognize that atrial fibrillation (AF) modifies the calcium channel of the atrium promotes its occurrence and maintenance. Changes of L-type calcium channels and their gene expression in the elderly may explain ion electrophysiology and molecular reconstruction in AF. This review analyzes the relationship between the heart calcium channel current and AF in the aged.

  10. Detrimental effects of beta-blockers in COPD - A concern for nonselective beta-blockers

    NARCIS (Netherlands)

    van der Woude, HJ; Zaagsma, J; Postma, DS; Winter, TH; van Hulst, M; Aalbers, R

    2005-01-01

    Introduction: beta-Blockers are known to worsen FEV1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. Design: A double-blind, placebo-controlled, randomized,

  11. Physiology and evolution of voltage-gated calcium channels in early diverging animal phyla: Cnidaria, Placozoa, Porifera and Ctenophora

    Directory of Open Access Journals (Sweden)

    Adriano Senatore

    2016-11-01

    Full Text Available Voltage-gated calcium (Cav channels serve dual roles in the cell, where they can both depolarize the membrane potential for electrical excitability, and activate transient cytoplasmic Ca2+ signals. In animals, Cav channels play crucial roles including driving muscle contraction (excitation-contraction coupling, gene expression (excitation-transcription coupling, pre-synaptic and neuroendocrine exocytosis (excitation-secretion coupling, regulation of flagellar/ciliary beating, and regulation of cellular excitability, either directly or through modulation of other Ca2+-sensitive ion channels. In recent years, genome sequencing has provided significant insights into the molecular evolution of Cav channels. Furthermore, expanded gene datasets have permitted improved inference of the species phylogeny at the base of Metazoa, providing clearer insights into the evolution of complex animal traits which involve Cav channels, including the nervous system. For the various types of metazoan Cav channels, key properties that determine their cellular contribution include: ion selectivity, pore gating, and, importantly, cytoplasmic protein-protein interactions that direct sub-cellular localization and functional complexing. It is unclear when many of these defining features, many of which are essential for nervous system function, evolved. In this review, we highlight some experimental observations that implicate Cav channels in the physiology and behavior of the most early-diverging animals from the phyla Cnidaria, Placozoa, Porifera and Ctenophora. Given our limited understanding of the molecular biology of Cav channels in these basal animal lineages, we infer insights from better-studied vertebrate and invertebrate animals. We also highlight some apparently conserved cellular functions of Cav channels, which might have emerged very early on during metazoan evolution, or perhaps predated it.

  12. Physiology and Evolution of Voltage-Gated Calcium Channels in Early Diverging Animal Phyla: Cnidaria, Placozoa, Porifera and Ctenophora

    Science.gov (United States)

    Senatore, Adriano; Raiss, Hamad; Le, Phuong

    2016-01-01

    Voltage-gated calcium (Cav) channels serve dual roles in the cell, where they can both depolarize the membrane potential for electrical excitability, and activate transient cytoplasmic Ca2+ signals. In animals, Cav channels play crucial roles including driving muscle contraction (excitation-contraction coupling), gene expression (excitation-transcription coupling), pre-synaptic and neuroendocrine exocytosis (excitation-secretion coupling), regulation of flagellar/ciliary beating, and regulation of cellular excitability, either directly or through modulation of other Ca2+-sensitive ion channels. In recent years, genome sequencing has provided significant insights into the molecular evolution of Cav channels. Furthermore, expanded gene datasets have permitted improved inference of the species phylogeny at the base of Metazoa, providing clearer insights into the evolution of complex animal traits which involve Cav channels, including the nervous system. For the various types of metazoan Cav channels, key properties that determine their cellular contribution include: Ion selectivity, pore gating, and, importantly, cytoplasmic protein-protein interactions that direct sub-cellular localization and functional complexing. It is unclear when these defining features, many of which are essential for nervous system function, evolved. In this review, we highlight some experimental observations that implicate Cav channels in the physiology and behavior of the most early-diverging animals from the phyla Cnidaria, Placozoa, Porifera, and Ctenophora. Given our limited understanding of the molecular biology of Cav channels in these basal animal lineages, we infer insights from better-studied vertebrate and invertebrate animals. We also highlight some apparently conserved cellular functions of Cav channels, which might have emerged very early on during metazoan evolution, or perhaps predated it. PMID:27867359

  13. IgG anti-GalNAc-GD1a antibody inhibits the voltage-dependent calcium channel currents in PC12 pheochromocytoma cells.

    Science.gov (United States)

    Nakatani, Yoshihiko; Nagaoka, Takumi; Hotta, Sayako; Utsunomiya, Iku; Yoshino, Hiide; Miyatake, Tadashi; Hoshi, Keiko; Taguchi, Kyoji

    2007-03-01

    We investigated the effects of IgG anti-GalNAc-GD1a antibodies, produced by immunizing rabbits with GalNAc-GD1a, on the voltage-dependent calcium channel (VDCCs) currents in nerve growth factor (NGF)-differentiated PC12 pheochromocytoma cells. VDCCs currents in NGF-differentiated PC12 cells were recorded using the whole-cell patch-clamp technique. Immunized rabbit serum that had a high titer of anti-GalNAc-GD1a antibodies inhibited the VDCCs currents in the NGF-differentiated PC12 cells (36.0+/-9.6% reduction). The inhibitory effect of this serum was reversed to some degree within 3-4 min by washing with bath solution. Similarly, application of purified IgG from rabbit serum immunized with GalNAc-GD1a significantly inhibited the VDCCs currents in PC12 cells (30.6+/-2.5% reduction), and this inhibition was recovered by washing with bath solution. Furthermore, the inhibitory effect was also observed in the GalNAc-GD1a affinity column binding fraction (reduction of 31.1+/-9.85%), while the GalNAc-GD1a affinity column pass-through fraction attenuated the inhibitory effect on VDCCs currents. Normal rabbit serum and normal rabbit IgG did not affect the VDCCs currents in the PC12 cells. In an immunocytochemical study using fluorescence staining, the PC12 cells were stained using GalNAc-GD1a binding fraction. These results indicate that anti-GalNAc-GD1a antibodies inhibit the VDCCs currents in NGF-differentiated PC12 cells.

  14. Inhibition of T-Type Voltage Sensitive Calcium Channel Reduces Load-Induced OA in Mice and Suppresses the Catabolic Effect of Bone Mechanical Stress on Chondrocytes.

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    Padma P Srinivasan

    Full Text Available Voltage-sensitive calcium channels (VSCC regulate cellular calcium influx, one of the earliest responses to mechanical stimulation in osteoblasts. Here, we postulate that T-type VSCCs play an essential role in bone mechanical response to load and participate in events leading to the pathology of load-induced OA. Repetitive mechanical insult was used to induce OA in Cav3.2 T-VSCC null and wild-type control mouse knees. Osteoblasts (MC3T3-E1 and chondrocytes were treated with a selective T-VSCC inhibitor and subjected to fluid shear stress to determine how blocking of T-VSCCs alters the expression profile of each cell type upon mechanical stimulation. Conditioned-media (CM obtained from static and sheared MC3T3-E1 was used to assess the effect of osteoblast-derived factors on the chondrocyte phenotype. T-VSCC null knees exhibited significantly lower focal articular cartilage damage than age-matched controls. In vitro inhibition of T-VSCC significantly reduced the expression of both early and late mechanoresponsive genes in osteoblasts but had no effect on gene expression in chondrocytes. Furthermore, treatment of chondrocytes with CM obtained from sheared osteoblasts induced expression of markers of hypertrophy in chondrocytes and this was nearly abolished when osteoblasts were pre-treated with the T-VSCC-specific inhibitor. These results indicate that T-VSCC plays a role in signaling events associated with induction of OA and is essential to the release of osteoblast-derived factors that promote an early OA phenotype in chondrocytes. Further, these findings suggest that local inhibition of T-VSCC may serve as a therapy for blocking load-induced bone formation that results in cartilage degeneration.

  15. S-nitrosothiols dilate the mesenteric artery more potently than the femoral artery by a cGMP and L-type calcium channel-dependent mechanism.

    Science.gov (United States)

    Liu, Taiming; Schroeder, Hobe J; Zhang, Meijuan; Wilson, Sean M; Terry, Michael H; Longo, Lawrence D; Power, Gordon G; Blood, Arlin B

    2016-08-31

    S-nitrosothiols (SNOs) are metabolites of NO with potent vasodilatory activity. Our previous studies in sheep indicated that intra-arterially infused SNOs dilate the mesenteric vasculature more than the femoral vasculature. We hypothesized that the mesenteric artery is more responsive to SNO-mediated vasodilation, and investigated various steps along the NO/cGMP pathway to determine the mechanism for this difference. In anesthetized adult sheep, we monitored the conductance of mesenteric and femoral arteries during infusion of S-nitroso-l-cysteine (L-cysNO), and found mesenteric vascular conductance increased (137 ± 3%) significantly more than femoral conductance (26 ± 25%). Similar results were found in wire myography studies of isolated sheep mesenteric and femoral arteries. Vasodilation by SNOs was attenuated in both vessel types by the presence of ODQ (sGC inhibitor), and both YC-1 (sGC agonist) and 8-Br-cGMP (cGMP analog) mediated more potent relaxation in mesenteric arteries than femoral arteries. The vasodilatory difference between mesenteric and femoral arteries was eliminated by antagonists of either protein kinase G or L-type Ca(2+) channels. Western immunoblots showed a larger L-type Ca(2+)/sGC abundance ratio in mesenteric arteries than in femoral arteries. Fetal sheep mesenteric arteries were more responsive to SNOs than adult mesenteric arteries, and had a greater L-Ca(2+)/sGC ratio (p = 0.047 and r = -0.906 for correlation between Emax and L-Ca(2+)/sGC). These results suggest that mesenteric arteries, especially those in fetus, are more responsive to SNO-mediated vasodilation than femoral arteries due to a greater role of the L-type calcium channel in the NO/cGMP pathway.

  16. Syntaxin-3 Binds and Regulates Both R- and L-Type Calcium Channels in Insulin-Secreting INS-1 832/13 Cells.

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    Li Xie

    Full Text Available Syntaxin (Syn-1A mediates exocytosis of predocked insulin-containing secretory granules (SGs during first-phase glucose-stimulated insulin secretion (GSIS in part via its interaction with plasma membrane (PM-bound L-type voltage-gated calcium channels (Cav. In contrast, Syn-3 mediates exocytosis of newcomer SGs that accounts for second-phase GSIS. We now hypothesize that the newcomer SG Syn-3 preferentially binds and modulates R-type Cav opening, which was postulated to mediate second-phase GSIS. Indeed, glucose-stimulation of pancreatic islet β-cell line INS-1 induced a predominant increase in interaction between Syn-3 and Cavα1 pore-forming subunits of R-type Cav2.3 and to lesser extent L-type Cavs, while confirming the preferential interactions between Syn-1A with L-type (Cav1.2, Cav1.3 Cavs. Consistently, direct binding studies employing heterologous HEK cells confirmed that Syn-3 preferentially binds Cav2.3, whereas Syn-1A prefers L-type Cavs. We then used siRNA knockdown (KD of Syn-3 in INS-1 to study the endogenous modulatory actions of Syn-3 on Cav channels. Syn-3 KD enhanced Ca2+ currents by 46% attributed mostly to R- and L-type Cavs. Interestingly, while the transmembrane domain of Syn-1A is the putative functional domain modulating Cav activity, it is the cytoplasmic domain of Syn-3 that appears to modulate Cav activity. We conclude that Syn-3 may mimic Syn-1A in the ability to bind and modulate Cavs, but preferring Cav2.3 to perhaps participate in triggering fusion of newcomer insulin SGs during second-phase GSIS.

  17. Effects of octreotide on expression of L-type voltage-operated calcium channels and on intracellular Ca2+ in activated hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    丁惠国; 王宝恩; 贾继东; 夏华向; 王振宇; 赵春惠; 徐燕琳

    2004-01-01

    Background The contractility of hepatic stellate cells (HSCs) may play an important role in the pathogenesis of cirrhosis with portal hypertension. The aim of this study was to research the effects of octreotide, an analogue of somatostatin, on intracellular Ca2+ and on the expression of L-type voltage-operated calcium channels (L-VOCCs) in activated HSCs, and to try to survey the use of octreotide in treatment and prevention of cirrhosis with portal hypertension complications. Methods HSC-T6, an activated HSCs line, was plated on small glass coverslips in 35-mm culture dishes at a density of 1×105/ml, and incubated in DMEM media for 24 hours. After the cells were loaded with Fluo-3/AM, intracellular Ca2+ was measured by Laser Scanning Confocal Microscopy (LSCM). The dynamic changes in activated HSCs of intracellular Ca2+, stimulated by octreotide, endothelin-1, and KCl, respectively, were also determined by LSCM. Each experiment was repeated six times. L-VOCC expression in HSCs was estimated by immunocytochemistry. Results After octreotide stimulation, a signifcant decrease in the intracellular Ca2+ of activated HSCs was observed. However, octreotide did not inhibit the increases in intracellular Ca2+ after stimulation by KCl and endothelin-1. Moreover, octreotide did not significantly affect L-VOCC expression. These results suggest that neither L-VOCC nor endothelin-1 receptors in activated HSCs are inhibited by octreotide. Conclusions Octreotide may decrease portal hypertension and intrahepatic vascular tension by inhibiting activated HSCs contractility through decreases in intracellular Ca2+. The somatostatin receptors in activated HSCs may be inhibited by octreotide.

  18. L-type calcium channels play a critical role in maintaining lens transparency by regulating phosphorylation of aquaporin-0 and myosin light chain and expression of connexins.

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    Rupalatha Maddala

    Full Text Available Homeostasis of intracellular calcium is crucial for lens cytoarchitecture and transparency, however, the identity of specific channel proteins regulating calcium influx within the lens is not completely understood. Here we examined the expression and distribution profiles of L-type calcium channels (LTCCs and explored their role in morphological integrity and transparency of the mouse lens, using cDNA microarray, RT-PCR, immunoblot, pharmacological inhibitors and immunofluorescence analyses. The results revealed that Ca (V 1.2 and 1.3 channels are expressed and distributed in both the epithelium and cortical fiber cells in mouse lens. Inhibition of LTCCs with felodipine or nifedipine induces progressive cortical cataract formation with time, in association with decreased lens weight in ex-vivo mouse lenses. Histological analyses of felodipine treated lenses revealed extensive disorganization and swelling of cortical fiber cells resembling the phenotype reported for altered aquaporin-0 activity without detectable cytotoxic effects. Analysis of both soluble and membrane rich fractions from felodipine treated lenses by SDS-PAGE in conjunction with mass spectrometry and immunoblot analyses revealed decreases in β-B1-crystallin, Hsp-90, spectrin and filensin. Significantly, loss of transparency in the felodipine treated lenses was preceded by an increase in aquaporin-0 serine-235 phosphorylation and levels of connexin-50, together with decreases in myosin light chain phosphorylation and the levels of 14-3-3ε, a phosphoprotein-binding regulatory protein. Felodipine treatment led to a significant increase in gene expression of connexin-50 and 46 in the mouse lens. Additionally, felodipine inhibition of LTCCs in primary cultures of mouse lens epithelial cells resulted in decreased intracellular calcium, and decreased actin stress fibers and myosin light chain phosphorylation, without detectable cytotoxic response. Taken together, these observations

  19. "Slow" Voltage-Dependent Inactivation of CaV2.2 Calcium Channels Is Modulated by the PKC Activator Phorbol 12-Myristate 13-Acetate (PMA.

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    Lei Zhu

    Full Text Available CaV2.2 (N-type voltage-gated calcium channels (Ca2+ channels play key roles in neurons and neuroendocrine cells including the control of cellular excitability, neurotransmitter / hormone secretion, and gene expression. Calcium entry is precisely controlled by channel gating properties including multiple forms of inactivation. "Fast" voltage-dependent inactivation is relatively well-characterized and occurs over the tens-to- hundreds of milliseconds timeframe. Superimposed on this is the molecularly distinct, but poorly understood process of "slow" voltage-dependent inactivation, which develops / recovers over seconds-to-minutes. Protein kinases can modulate "slow" inactivation of sodium channels, but little is known about if/how second messengers control "slow" inactivation of Ca2+ channels. We investigated this using recombinant CaV2.2 channels expressed in HEK293 cells and native CaV2 channels endogenously expressed in adrenal chromaffin cells. The PKC activator phorbol 12-myristate 13-acetate (PMA dramatically prolonged recovery from "slow" inactivation, but an inactive control (4α-PMA had no effect. This effect of PMA was prevented by calphostin C, which targets the C1-domain on PKC, but only partially reduced by inhibitors that target the catalytic domain of PKC. The subtype of the channel β-subunit altered the kinetics of inactivation but not the magnitude of slowing produced by PMA. Intracellular GDP-β-S reduced the effect of PMA suggesting a role for G proteins in modulating "slow" inactivation. We postulate that the kinetics of recovery from "slow" inactivation could provide a molecular memory of recent cellular activity and help control CaV2 channel availability, electrical excitability, and neurotransmission in the seconds-to-minutes timeframe.

  20. Inhibition of Voltage-Gated Calcium Channels After Subchronic and Repeated Exposure of PC12 Cells to Different Classes of Insecticides.

    Science.gov (United States)

    Meijer, Marieke; Brandsema, Joske A R; Nieuwenhuis, Desirée; Wijnolts, Fiona M J; Dingemans, Milou M L; Westerink, Remco H S

    2015-10-01

    We previously demonstrated that acute inhibition of voltage-gated calcium channels (VGCCs) is a common mode of action for (sub)micromolar concentrations of chemicals, including insecticides. However, because human exposure to chemicals is usually chronic and repeated, we investigated if selected insecticides from different chemical classes (organochlorines, organophosphates, pyrethroids, carbamates, and neonicotinoids) also disturb calcium homeostasis after subchronic (24 h) exposure and after a subsequent (repeated) acute exposure. Effects on calcium homeostasis were investigated with single-cell fluorescence (Fura-2) imaging of PC12 cells. Cells were depolarized with high-K(+) saline to study effects of subchronic or repeated exposure on VGCC-mediated Ca(2+) influx. The results demonstrate that except for carbaryl and imidacloprid, all selected insecticides inhibited depolarization (K(+))-evoked Ca(2+) influx after subchronic exposure (IC50's: approximately 1-10 µM) in PC12 cells. These inhibitory effects were not or only slowly reversible. Moreover, repeated exposure augmented the inhibition of the K(+)-evoked increase in intracellular calcium concentration induced by subchronic exposure to cypermethrin, chlorpyrifos, chlorpyrifos-oxon, and endosulfan (IC50's: approximately 0.1-4 µM). In rat primary cortical cultures, acute and repeated chlorpyrifos exposure also augmented inhibition of VGCCs compared with subchronic exposure. In conclusion, compared with subchronic exposure, repeated exposure increases the potency of insecticides to inhibit VGCCs. However, the potency of insecticides to inhibit VGCCs upon repeated exposure was comparable with the inhibition previously observed following acute exposure, with the exception of chlorpyrifos. The data suggest that an acute exposure paradigm is sufficient for screening chemicals for effects on VGCCs and that PC12 cells are a sensitive model for detection of effects on VGCCs.

  1. Alterations of voltage-dependent calcium channel currents in basilar artery smooth muscle cells at early stage of subarachnoid hemorrhage in a rabbit model.

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    Xianqing Shi

    Full Text Available OBJECTIVE: To investigate the changes in the currents of voltage-dependent calcium channels (VDCCs in smooth muscle cells of basilar artery in a rabbit model of subarachnoid hemorrhage (SAH. METHODS: New Zealand white rabbits were randomly divided into five groups: sham (C, normal (N, 24 hours (S1, 48 hours (S2 and 72 hours (S3 after SAH. Non-heparinized autologous arterial blood (1 ml/kg was injected into the cisterna magna to create SAH after intravenous anesthesia, and 1 ml/kg of saline was injected into cisterna magna in the sham group. Rabbits in group N received no injections. Basilar artery in S1, S2, S3 group were isolated at 24, 48, 72 hours after SAH. Basilar artery in group C was isolated at 72 hours after physiological saline injection. Basilar artery smooth muscle cells were isolated for all groups. Whole-cell patch-clamp technique was utilized to record cell membrane capacitance and VDCCs currents. The VDCCs antagonist nifedipine was added to the bath solution to block the Ca(++ channels currents. RESULTS: There were no significant differences in the number of cells isolated, the cell size and membrane capacitance among all the five groups. VDCC currents in the S1-S3 groups had higher amplitudes than those in control and sham groups. The significant change of current amplitude was observed at 72 hours after SAH, which was higher than those of 24 and 48 hours. The VDCCs were shown to expression in human artery smooth muscle cells. CONCLUSIONS: The changes of activation characteristics and voltage-current relationship at 72 hours after SAH might be an important event which leads to a series of molecular events in the microenvironment of the basilar artery smooth muscle cells. This may be the key time point for potential therapeutic intervention against subarachnoid hemorrhage.

  2. Role of glycine residues highly conserved in the S2-S3 linkers of domains I and II of voltage-gated calcium channel alpha(1) subunits.

    Science.gov (United States)

    Teng, Jinfeng; Iida, Kazuko; Ito, Masanori; Izumi-Nakaseko, Hiroko; Kojima, Itaru; Adachi-Akahane, Satomi; Iida, Hidetoshi

    2010-05-01

    The pore-forming component of voltage-gated calcium channels, alpha(1) subunit, contains four structurally conserved domains (I-IV), each of which contains six transmembrane segments (S1-S6). We have shown previously that a Gly residue in the S2-S3 linker of domain III is completely conserved from yeasts to humans and important for channel activity. The Gly residues in the S2-S3 linkers of domains I and II, which correspond positionally to the Gly in the S2-S3 linker of domain III, are also highly conserved. Here, we investigated the role of the Gly residues in the S2-S3 linkers of domains I and II of Ca(v)1.2. Each of the Gly residues was replaced with Glu or Gln to produce mutant Ca(v)1.2s; G182E, G182Q, G579E, G579Q, and the resulting mutants were transfected into BHK6 cells. Whole-cell patch-clamp recordings showed that current-voltage relationships of the four mutants were the same as those of wild-type Ca(v)1.2. However, G182E and G182Q showed significantly smaller current densities because of mislocalization of the mutant proteins, suggesting that Gly(182) in domain I is involved in the membrane trafficking or surface expression of alpha(1) subunit. On the other hand, G579E showed a slower voltage-dependent current inactivation (VDI) compared to Ca(v)1.2, although G579Q showed a normal VDI, implying that Gly(579) in domain II is involved in the regulation of VDI and that the incorporation of a negative charge alters the VDI kinetics. Our findings indicate that the two conserved Gly residues are important for alpha(1) subunit to become functional.

  3. Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.

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    Casillas-Espinosa, Pablo Miguel; Hicks, Ashleigh; Jeffreys, Amy; Snutch, Terrance P; O'Brien, Terence J; Powell, Kim L

    2015-01-01

    Temporal lobe epilepsy (TLE) is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg) was assessed in fully kindled rats (5 class V seizures) as compared to vehicle, ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg). Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg), ETX (100mg/kg) or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (pkindled state (pkindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.

  4. Effect of morphine on L-calcium channel of SK-N-SH human neuroblastoma cells%吗啡对人神经母细胞瘤SK-N-SH细胞L-Ca2+ 通道的作用

    Institute of Scientific and Technical Information of China (English)

    雷洪伊; 徐世元; 张庆国; 叶小平

    2008-01-01

    Objective To study the effect of morphine on L-calcium channels of SK-N-SH human neuroblastoma cells.Metllods SK-N-SH human neuroblastoma cells were cultured in vitro. Electrical current and conductance of calcium channels of SK-N-SH cells were measured using cell-attached patch clamp technique in the presence of morphine with different concentrations(0.10-8 mol/L,10-7 mol/L,10-6 mol/L and 10-5 mol/L)preteated with or without naloxone(10-5 mol/L).Results Electrical current of L-calcium channels of SK-N-SH human neuroblastoma cells was concentration-dependently depressed by morphine(P <0.01 at concentrations of 10-7,10-6 and 10-5 mol/L).Pretreatment with naloxone eliminated the morphine-induced depression on electrical current of calcium channels. Electric conductance of calcium channels did not change in the presence or absence of morohine. Conclusions Morphine inhibits electric current of L-type calcium channels of SK-N-SH human neuroblastoma cells in a manner of concentration dependence,probably via blockade of μ-opioid receptor;but does not influence electric conductence ot L-type calcium channels.%目的 观察吗啡对人神经母细胞瘤SK-N-SH细胞L-Ca2+通道的影响.方法 培养人神经母细胞瘤SK-N-SH细胞,应用细胞贴附式膜片钳技术记录在不同浓度吗啡(0、10-8 mol/L、10-7 mol/L、10-6 mol/L、10-5 mol/L)作用下SK-N-SH细胞L-Ca2+通道电流和电导变化.预先加入10-5 mol/L纳洛酮后,再依次加入上述不同浓度吗啡,记录此通道电流和电导.结果 10-7 mol/L、10-6 mol/L、10-5 mol/L吗啡可抑制SK-N-SH细胞L-型Ca2+通道电流,吗啡浓度为10-6mol/L、10-5 mol/L时抑制作用更明显(P<0.01),具有浓度依赖性;各浓度吗啡对L-Ca2+通道电导无影响;预先加入纳络酮,可阻断吗啡对该通道的抑制作用.结论 吗啡可抑制SK-N-SH细胞上L-Ca2+通道电流,对该通道电导无作用.纳络酮可翻转吗啡的作用,其抑制作用可能通过μ阿片受体产生.

  5. Comparative effects of three beta blockers (atenolol, metoprolol, and propranolol) on survival after acute myocardial infarction.

    Science.gov (United States)

    Gottlieb, S S; McCarter, R J

    2001-04-01

    The beneficial impact of beta blockade after an acute myocardial infarction (AMI) is clear, but beta-adrenergic blockers differ in multiple characteristics, including lipophilicity and selectivity. The impact of these factors on the effects of beta blockade is unknown. We therefore compared the effects of different beta blockers on mortality after AMI. Charts of 201,752 patients with AMI were abstracted by the Cooperative Cardiovascular Project, a quality assurance program sponsored by the Health Care Financing Administration. Of the 69,338 patients prescribed beta blockers, we compared mortality of patients receiving different beta-adrenergic blockers using the Cox proportional-hazards model accounting for multiple factors that might influence survival. The mortality rates of the 2 selective agents, metoprolol and atenolol, were virtually identical (13.5% and 13.4% 2-year mortality, respectively). Compared with metoprolol, patients discharged on propranolol had a slightly increased mortality (15.9% 2-year mortality), which may be related to undetected differences at baseline. Survival with all of the drugs was superior to the 23.9% 2-year mortality seen in patients not receiving beta blockers. Beta blockade overall was associated with a 40% improvement in survival. Although the use of beta blockade after AMI has major prognostic importance, the present study suggests that the specific beta blocker chosen will have little influence on mortality.

  6. Effect of beta-blocker therapy on functional status in patients with heart failure--a meta-analysis

    DEFF Research Database (Denmark)

    Abdulla, Jawdat; Køber, Lars; Christensen, Erik

    2005-01-01

    BACKGROUND: The results of randomised control trials (RCTs) evaluating the effect of beta-blockers on functional status in patients with chronic heart failure are conflicting. AIM: To perform a systematic review and meta-analysis of RCTs evaluating the effect of beta-blockers on New York Heart...... Association (NYHA) classification and exercise tolerance in chronic heart failure. METHODS AND RESULTS: We selected 28 RCTs evaluating beta-blocker versus placebo in addition to ACE inhibitor therapy. Combined results of 23 RCTs showed that beta-blockers improved NYHA class by at least one class with odds...... ratio (OR) 1.80 (1.33-2.43) pbeta-blockers had no significant effect...

  7. Topical beta-Blockers and Mortality

    NARCIS (Netherlands)

    Muskens, Rogier P. H. M.; Wolfs, Roger C. W.; Wittenian, Jacqueline C. M.; Hofman, Albert; de Jong, Paulus T. V. M.; Stricker, Bruno H. C.; Jansonius, Nomdo M.

    2008-01-01

    Purpose: To study the associations between long-term and short-term use of topical beta-blockers and mortality. Design: Prospective population-based cohort study. Participants: To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484

  8. Scientific evidence contradicts findings and assumptions of Canadian Safety Panel 6: microwaves act through voltage-gated calcium channel activation to induce biological impacts at non-thermal levels, supporting a paradigm shift for microwave/lower frequency electromagnetic field action.

    Science.gov (United States)

    Pall, Martin L

    2015-01-01

    This review considers a paradigm shift on microwave electromagnetic field (EMF) action from only thermal effects to action via voltage-gated calcium channel (VGCC) activation. Microwave/lower frequency EMFs were shown in two dozen studies to act via VGCC activation because all effects studied were blocked by calcium channel blockers. This mode of action was further supported by hundreds of studies showing microwave changes in calcium fluxes and intracellular calcium [Ca2+]i signaling. The biophysical properties of VGCCs/similar channels make them particularly sensitive to low intensity, non-thermal EMF exposures. Non-thermal studies have shown that in most cases pulsed fields are more active than are non-pulsed fields and that exposures within certain intensity windows have much large biological effects than do either lower or higher intensity exposures; these are both consistent with a VGCC role but inconsistent with only a heating/thermal role. Downstream effects of VGCC activation include calcium signaling, elevated nitric oxide (NO), NO signaling, peroxynitrite, free radical formation, and oxidative stress. Downstream effects explain repeatedly reported biological responses to non-thermal exposures: oxidative stress; single and double strand breaks in cellular DNA; cancer; male and female infertility; lowered melatonin/sleep disruption; cardiac changes including tachycardia, arrhythmia, and sudden cardiac death; diverse neuropsychiatric effects including depression; and therapeutic effects. Non-VGCC non-thermal mechanisms may occur, but none have been shown to have effects in mammals. Biologically relevant safety standards can be developed through studies of cell lines/cell cultures with high levels of different VGCCs, measuring their responses to different EMF exposures. The 2014 Canadian Report by a panel of experts only recognizes thermal effects regarding safety standards for non-ionizing radiation exposures. Its position is therefore contradicted by each

  9. 2012 consensus document of the Italian Society of Hypertension (SIIA): strategies to improve blood pressure control in Italy: from global cardiovascular risk stratification to combination therapy.

    Science.gov (United States)

    Volpe, Massimo; Rosei, Enrico Agabiti; Ambrosioni, Ettore; Cottone, Santina; Cuspidi, Cesare; Borghi, Claudio; De Luca, Nicola; Fallo, Francesco; Ferri, Claudio; Morganti, Alberto; Muiesan, Maria Lorenza; Sarzani, Riccardo; Sechi, Leonardo; Virdis, Agostino; Tocci, Giuliano; Trimarco, Bruno; Filippi, Alessandro; Mancia, Giuseppe

    2013-03-01

    Observational clinical studies have demonstrated that only 30-40% of patients with arterial hypertension achieve the recommended blood pressure goals (below 140/90 mmHg). In contrast, interventional trials consistently showed that it is possible to achieve effective blood pressure targets in about 70% of treated hypertensive patients with different cardiovascular risk profiles, especially through the use of rational, effective and well tolerated combination therapies. In order to bridge the gap between current and desired blood pressure control and to achieve more effective prevention of cardiovascular diseases, the Italian Society of Hypertension (SIIA) has developed an interventional strategy aimed at reaching nearly 70% of treated controlled hypertensive patients by 2015. This ambitious goal can be realistically achieved by a more rational use of modern tools and supports, and also through the use of combination therapy in hypertension in daily clinical practice, especially if this approach can be simplified into a single pill (fixed combination therapy), which is a therapeutic option now also available in Italy. Since about 70-80% of treated hypertensive patients require a combination therapy based on at least two classes of drugs in order to achieve the recommended blood pressure goals, it is of key importance to implement this strategy in routine clinical practice. Amongst the various combination therapies currently available for hypertension treatment and control, the use of those strategies based on drugs that antagonize the renin-angiotensin system, such as angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) and ACE inhibitors, in combination with diuretics and/or calcium channel blockers, has been shown to significantly reduce the risk of major cardiovascular events and to improve patient compliance to treatment, resulting in a greater antihypertensive efficacy and better tolerability compared with monotherapy. The present document

  10. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

    Directory of Open Access Journals (Sweden)

    Miroslav Radenkovic

    2016-01-01

    Full Text Available The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.

  11. Role of tumor necrosis factor-αin the regulation of T-type calcium channel current in HL-1 cells

    Institute of Scientific and Technical Information of China (English)

    RAO Fang; SHAN Zhi-xin; ZHU Jie-ning; XIE Zhi; WU Shu-lin; DENG Chun-yu; XUE Yu-mei; YU Xi-yong; WEI Wei; LIU Fang-zhou; YANG Hui; KUANG Su-juan; CHEN Shao-xian; XIAO Ding-zhang

    2016-01-01

    AIM:Increasing evidence indicates that inflammation contributes to the initiation and perpetuation of atrial fibrillation ( AF) .Al-though tumor necrosis factor ( TNF)-αlevels are increased in patients with AF , the role of TNF-αin the pathogenesis of AF remains unclear.Recent research has revealed that T-type Ca2+currents ( ICa,T ) play an important role in the pathogenesis of AF .METH-ODS:In this study , we used the whole-cell voltage-clamp technique and biochemical assays to explore the role of TNF-αin the regula-tion of ICa,T in atrial myocytes.RESULTS:We found that compared with sinus rhythm (SR) controls, T-type calcium channel (TCC) subunit mRNA levels were decreased , while TNF-αexpression levels were increased , in human atrial tissue from patients with AF .In murine atrial myocyte HL-1 cells, after cultured for 24 h, 12.5, 25 and 50 μg/L TNF-αsignificantly reduced the protein expression levels of the TCC α1G subunit in a concentration-dependent manner .The peak current was reduced by the application of 12.5 or 25μg/L TNF-αin a concentration-dependent manner [from ( -15.08 ±1.11) pA/pF in controls to ( -11.89 ±0.83) pA/pF and (-8.54 ±1.55) pA/pF in 12.5 and 25 μg/L TNF-αgroups, respectively].TNF-αapplication also inhibited voltage-dependent inactivation of ICa,T shifted the inactivation curve to the left .CONCLUSION:These results suggest that TNF-αis involved in the path-ogenesis of AF, probably via decreasing ICa,T function in atrium-derived myocytes through impaired channel function and down -regula-tion of channel protein expression .This pathway thus represents a potential pathogenic mechanism in AF .

  12. Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms.

    Directory of Open Access Journals (Sweden)

    Matthew Prideaux

    Full Text Available Parathyroid Hormone (PTH can exert both anabolic and catabolic effects on the skeleton, potentially through expression of the PTH type1 receptor (PTH1R, which is highly expressed in osteocytes. To determine the cellular and molecular mechanisms responsible, we examined the effects of PTH on osteoblast to osteocyte differentiation using primary osteocytes and the IDG-SW3 murine cell line, which differentiate from osteoblast to osteocyte-like cells in vitro and express GFP under control of the dentin matrix 1 (Dmp1 promoter. PTH treatment resulted in an increase in some osteoblast and early osteocyte markers and a decrease in mature osteocyte marker expression. The gene expression profile of PTH-treated Day 28 IDG-SW3 cells was similar to PTH treated primary osteocytes. PTH treatment induced striking changes in the morphology of the Dmp1-GFP positive cells in IDG-SW3 cultures and primary cells from Dmp1-GFP transgenic mice. The cells changed from a more dendritic to an elongated morphology and showed increased cell motility. E11/gp38 has been shown to be important for cell migration, however, deletion of the E11/gp38/podoplanin gene had no effect on PTH-induced motility. The effects of PTH on motility were reproduced using cAMP, but not with protein kinase A (PKA, exchange proteins activated by cAMP (Epac, protein kinase C (PKC or phosphatidylinositol-4,5-bisphosphonate 3-kinase (Pi3K agonists nor were they blocked by their antagonists. However, the effects of PTH were mediated through calcium signaling, specifically through L-type channels normally expressed in osteoblasts but decreased in osteocytes. PTH was shown to increase expression of this channel, but decrease the T-type channel that is normally more highly expressed in osteocytes. Inhibition of L-type calcium channel activity attenuated the effects of PTH on cell morphology and motility but did not prevent the downregulation of mature osteocyte marker expression. Taken together, these

  13. Inflammatory cytokine signaling in insulin producing beta-cells enhances the colocalization correlation coefficient between L-type voltage-dependent calcium channel and calcium-sensing receptor.

    Science.gov (United States)

    Parkash, Jai

    2008-08-01

    The immunological processes in type 1 diabetes and metabolic/inflammatory disorder in type 2 diabetes converge on common signaling pathway(s) leading to beta-cell death in these two diseases. The cytokine-mediated beta-cell death seems to be dependent on voltage-dependent calcium channel (VDCC)-mediated Ca2+ entry. The Ca2+ handling molecular networks control the homeostasis of [Ca2+]i in the beta-cell. The activity and membrane density of VDCC are regulated by several mechanisms including G protein-coupled receptors (GPCRs). CaR is a 123-kDa seven transmembrane extracellular Ca2+ sensing protein that belongs to GPCR family C. Tumor necrosis factor-alpha (TNF-alpha), is a cytokine widely known to activate nuclear factor-kappaB (NF-kappaB) transcription in beta-cells. To obtain a better understanding of TNF-alpha-induced molecular interactions between CaR and VDCC, confocal fluorescence measurements were performed on insulin-producing beta-cells exposed to varying concentrations of TNF-alpha and the results are discussed in the light of increased colocalization correlation coefficient. The insulin producing beta-cells were exposed to 5, 10, 20, 30, and 50 ng/ml TNF-alpha for 24 h at 37 degrees . The cells were then immunolabelled with antibodies directed against CaR, VDCC, and NF-kappaB. The confocal fluorescence imaging data showed enhancement in the colocalization correlation coefficient between CaR and VDCC in beta-cells exposed to TNF-alpha thereby indicating increased membrane delimited spatial interactions between these two membrane proteins. TNF-alpha-induced colocalization of VDCC with CaR was inhibited by nimodipine, an inhibitor of L-type VDCC thereby suggesting that VDCC activity is required for spatial interactions with CaR. The 3-D confocal fluorescence imaging data also demonstrated that addition of TNF-alpha to RIN cells led to the translocation of NF-kappaB from the cytoplasm to the nucleus. Such molecular interactions between CaR and VDCC in tissues

  14. Troponin T3 regulates nuclear localization of the calcium channel Ca{sub v}β{sub 1a} subunit in skeletal muscle

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Tan; Taylor, Jackson; Jiang, Yang [Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Pereyra, Andrea S. [Department of Histology, National University of La Plata, 1900 La Plata (Argentina); Messi, Maria Laura; Wang, Zhong-Min [Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Hereñú, Claudia [Department of Histology, National University of La Plata, 1900 La Plata (Argentina); Delbono, Osvaldo, E-mail: odelbono@wakehealth.edu [Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States); Neuroscience Program, Wake Forest School of Medicine, Winston-Salem, NC 27157 (United States)

    2015-08-15

    The voltage-gated calcium channel (Ca{sub v}) β{sub 1a} subunit (Ca{sub v}β{sub 1a}) plays an important role in excitation–contraction coupling (ECC), a process in the myoplasm that leads to muscle-force generation. Recently, we discovered that the Ca{sub v}β{sub 1a} subunit travels to the nucleus of skeletal muscle cells where it helps to regulate gene transcription. To determine how it travels to the nucleus, we performed a yeast two-hybrid screening of the mouse fast skeletal muscle cDNA library and identified an interaction with troponin T3 (TnT3), which we subsequently confirmed by co-immunoprecipitation and co-localization assays in mouse skeletal muscle in vivo and in cultured C2C12 muscle cells. Interacting domains were mapped to the leucine zipper domain in TnT3 COOH-terminus (160–244 aa) and Ca{sub v}β{sub 1a} NH{sub 2}-terminus (1–99 aa), respectively. The double fluorescence assay in C2C12 cells co-expressing TnT3/DsRed and Ca{sub v}β{sub 1a}/YFP shows that TnT3 facilitates Ca{sub v}β{sub 1a} nuclear recruitment, suggesting that the two proteins play a heretofore unknown role during early muscle differentiation in addition to their classical role in ECC regulation. - Highlights: • Previously, we demonstrated that Ca{sub v}β{sub 1a} is a gene transcription regulator. • Here, we show that TnT3 interacts with Ca{sub v}β{sub 1a}. • We mapped TnT3 and Ca{sub v}β{sub 1a} interaction domain. • TnT3 facilitates Ca{sub v}β{sub 1a} nuclear enrichment. • The two proteins play a heretofore unknown role during early muscle differentiation.

  15. Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model.

    Directory of Open Access Journals (Sweden)

    Pablo Miguel Casillas-Espinosa

    Full Text Available Temporal lobe epilepsy (TLE is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg was assessed in fully kindled rats (5 class V seizures as compared to vehicle, ethosuximide (ETX, 100mg/kg and carbamazepine (30mg/kg. Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg, ETX (100mg/kg or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (p<0.05, IV (p<0.01 or V (p<0.0001 seizure, and to reach a fully kindled state (p<0.01, than animals receiving vehicle. There was no significant difference in the mRNA expression of the T-type Ca2+ channels in the hippocampus or amygdala. Our results show that selectively targeting T-type Ca2+ channels with Z944 inhibits the progression of amygdala kindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.

  16. 心房肌细胞钙通道和钾通道免疫电镜定位研究%The study of distribution of calcium channel and potassium channel in atrial myocytes by immunoelectromicroscopy

    Institute of Scientific and Technical Information of China (English)

    袁平; 张建成; 何爱华; 颜永碧

    2002-01-01

    @@ 离子通道是一种跨膜蛋白,迄今为止,尚未见关于离子通道的细胞内分布情况的报道.心脏L-型电压依赖钙通道(L-type voltage dependent calcium channel, LVDCC)和电压依赖KV4.3钾通道(voltage dependent potassium channel,VDKV4.3)对心肌细胞动作电位有重要作用.

  17. L-型钙离子通道抑制剂药效团模型的构建%Pharmacophore model construction of L-type calcium channel antagonists

    Institute of Scientific and Technical Information of China (English)

    梁英喜; 贺煜甦; 崔帅; 李斌; 张燕玲; 张小华

    2015-01-01

    Objective This study was amid to construct a pharmacophore model of L‐type calcium channel antagonists in the applica‐tion of a approach for discovering novel L‐type calcium channel antagonists from leading compounds by screening traditional Chi‐nese medicine (TCM) database .Methods Qualitative hypotheses were generated by HipHop separately on the basis of 12 com‐pounds with antagonistic action on L‐type calcium channel expressed in rabbit cardiac muscle .Database searching method was used to evaluate the hypotheses .Results The results showed that optimal qualitative hypothesis is with certain features ,i .e .two hydrogen‐bond acceptors ,four hydrophobic groups ,and the CAI value of 2 .78 .Conclusion It was concluded that the pharma‐cophores are reliable and can be used to screen database for novel L‐type calcium channel antagonists .%目的:构建L‐型钙离子通道抑制剂的药效团模型,为从中药化学成分中发现具有钙离子通道抑制作用的成分提供了新的方法,同时为先导物改造成为活性较好的钙离子通道抑制剂提供思路。方法以来源于NCBI数据库中对新西兰兔心脏L‐型钙离子通道具有抑制作用的12个化合物为研究对象,利用HipHop定性药效团模型构建方法,建立L‐型钙离子通道拮抗剂的药效团模型,利用数据库搜索方法对药效团模型进行优劣评价。结果获得最优药效团模型具有以下几个特征:2个氢键受体和4个疏水基团,其综合评价指数CAI为2.78。结论构建的定性药效团具有一定的可靠性,可用于开展活性化合物筛选和指导先导化合物的结构改造,有助于指导发现中药中的L‐型钙离子通道阻滞剂。

  18. Synthesis and evaluation of 6-pyrazoylamido-3N-substituted azabicyclo[3,1,0]hexane derivatives as T-type calcium channel inhibitors for treatment of neuropathic pain.

    Science.gov (United States)

    Kim, Jung Hyun; Nam, Ghilsoo

    2016-11-01

    A new series of aryls, including benzo[d]imidazole/isoxazole/pyrazole, conjugated to 3N-substituted-azabicyclo[3.1.0]hexane derivatives were designed and synthesized as inhibitors of T-type calcium channels. Among the synthesized compounds, 3N-R-substituted azabicyclo[3.1.0]hexane carboxamide derivatives containing 5-isobutyl-1-phenyl-pyrazole ring exhibited potent and selective T-channel inhibition and good metabolic stability without CYP450 inhibition. Compounds 10d and 10e contained hydrophobic substituents at the 3N-position and exhibited potent in vitro efficacy, as well as neuropathic pain alleviation in rats.

  19. Role of β-blocker therapy in pediatric heart failure.

    Science.gov (United States)

    Patel, Akash R; Shaddy, Robert E

    2010-01-01

    Heart failure is becoming an increasingly common and significant problem in the field of pediatric cardiology. The numerous types of cardiomyopathies, and more recently, long-term survival of patients with congenital heart disease, have added to a growing patient population. Over the last several decades, our knowledge base regarding mechanisms of disease and therapeutic intervention in adult patients with heart failure has drastically changed. The most recent and important breakthrough in the pharmacologic treatment of heart failure has been the particular role of β-blocker therapy. This medication has led to significant improvements in survival and symptoms in adults, with less convincing findings in limited studies in pediatrics. The ability to study the benefits of this therapy in patients has been challenging owing to the heterogeneity of the patient population and lack of large sample sizes. However, as we investigate the mechanisms behind the disease process, the differences that exist between disease conditions and ages, and the significant alterations that may exist at the molecular and genetic level, our understanding of β-blocker therapy in pediatric heart failure will improve, and ultimately may lead to patient-specific therapy.

  20. Prescription of renin–angiotensin system blockers and risk of acute kidney injury: a population-based cohort study

    Science.gov (United States)

    Nitsch, Dorothea; Smeeth, Liam; Bhaskaran, Krishnan; Tomlinson, Laurie A

    2016-01-01

    Objective To investigate whether there is an association between use of ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) and risk of acute kidney injury (AKI). Study design We conducted a new-user cohort study of the rate of AKI among users of common antihypertensives. Setting UK primary care practices contributing to the Clinical Practice Research Datalink (CPRD) eligible for linkage to hospital records data from the Hospital Episode Statistics (HES) database between April 1997 and March 2014. Participants New users of antihypertensives: ACEI/ARB, β-blockers, calcium channel blockers and thiazide diuretics. Outcomes The outcome was first episode of AKI. We estimated incidence rate ratio (RR) for AKI during time exposed to ACEI/ARB compared to time unexposed, adjusting for age, sex, comorbidities, use of other antihypertensive drugs and calendar period using Poisson regression. Covariates were time updated. Results Among 570 445 participants, 303 761 were prescribed ACEI/ARB with a mean follow-up of 4.1 years. The adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 1.12 (95% CI 1.07 to 1.17). This relative risk varied depending on absolute risk of AKI, with lower or no increased relative risk from the drugs among those at greatest absolute risk. For example, among people with stage 4 chronic kidney disease (who had 6.69 (95% CI 5.57 to 8.03) times higher rate of AKI compared to those without chronic kidney disease), the adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 0.66 (95% CI 0.44 to 0.97) in contrast to 1.17 (95% CI 1.09 to 1.25) among people without chronic kidney disease. Conclusions Treatment with ACEI/ARB is associated with only a small increase in AKI risk while individual patient characteristics are much more strongly associated with the rate of AKI. The degree of increased risk varies between patient groups. PMID:28003286

  1. Histamine 2 blocker potentiates the effects of histamine 1 blocker in suppressing histamine-induced wheal

    Directory of Open Access Journals (Sweden)

    Dhanya N

    2008-01-01

    Full Text Available Background : Histamine is responsible for the wheal and flare reaction in various allergic conditions. Classical antihistamines are the drugs which block the H 1 receptors and are widely used in various allergic conditions, whereas H 2 blockers are mainly used for acid peptic disease. Although H 1 receptor-mediated actions of histamine are primarily responsible for vasodilatation, vasopermeability, and itching, it has been observed that combined blocking of both H 1 and H 2 receptors may provide better relief. Aim: To compare the efficacy of levocetirizine (H 1 blocker versus levocetirizine and ranitidine (H 2 blocker in suppressing histamine-induced wheal. Methods: Fifteen volunteers were given a single dose of levocetirizine 5 mg on day 1 and a single dose of levocetirizine 5 mg with ranitidine 150 mg twice a day on day 7. A pretest was performed by intradermal histamine prick test. After administration of the drugs, the prick test was repeated at 1 hour, 2, 3, 6, and 24 hours, and the size of the wheal measured and statistically analyzed. Results: At 1 hour, there was no statistically significant difference in the wheal size between levocetirizine alone and the combination of levocetirizine and ranitidine. Levocetirizine with ranitidine resulted in statistically significant reduction of wheal size at 2, 3, 6, and 24 hours when compared with levocetirizine alone. Conclusion: H2 blocker potentiates the effects of an H1 blocker in suppressing histamine-induced wheal.

  2. Alpha 1-blockers vs 5 alpha-reductase inhibitors in benign prostatic hyperplasia. A comparative review

    DEFF Research Database (Denmark)

    Andersen, J T

    1995-01-01

    During recent years, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become the primary treatment choice for an increasing number of patients. The 2 principal drug classes employed are alpha 1-blockers and 5 alpha-reductase inhibitors. Current information from...... of patients who will respond well to alpha 1-blockers have yet to be identified, and data concerning the long term effects of these drugs are not yet available. 5 alpha-Reductase inhibitors have a slow onset of effect, but treatment leads to improvement in symptoms, reduction of the size of the prostate gland...... or unwilling to undergo surgical resection of the prostate will benefit from such therapy....

  3. Gαi2- and Gαi3-specific regulation of voltage-dependent L-type calcium channels in cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Sara Dizayee

    Full Text Available BACKGROUND: Two pertussis toxin sensitive G(i proteins, G(i2 and G(i3, are expressed in cardiomyocytes and upregulated in heart failure. It has been proposed that the highly homologous G(i isoforms are functionally distinct. To test for isoform-specific functions of G(i proteins, we examined their role in the regulation of cardiac L-type voltage-dependent calcium channels (L-VDCC. METHODS: Ventricular tissues and isolated myocytes were obtained from mice with targeted deletion of either Gα(i2 (Gα(i2 (-/- or Gα(i3 (Gα(i3 (-/-. mRNA levels of Gα(i/o isoforms and L-VDCC subunits were quantified by real-time PCR. Gα(i and Ca(vα(1 protein levels as well as protein kinase B/Akt and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation levels were assessed by immunoblot analysis. L-VDCC function was assessed by whole-cell and single-channel current recordings. RESULTS: In cardiac tissue from Gα(i2 (-/- mice, Gα(i3 mRNA and protein expression was upregulated to 187 ± 21% and 567 ± 59%, respectively. In Gα(i3 (-/- mouse hearts, Gα(i2 mRNA (127 ± 5% and protein (131 ± 10% levels were slightly enhanced. Interestingly, L-VDCC current density in cardiomyocytes from Gα(i2 (-/- mice was lowered (-7.9 ± 0.6 pA/pF, n = 11, p<0.05 compared to wild-type cells (-10.7 ± 0.5 pA/pF, n = 22, whereas it was increased in myocytes from Gα(i3 (-/- mice (-14.3 ± 0.8 pA/pF, n = 14, p<0.05. Steady-state inactivation was shifted to negative potentials, and recovery kinetics slowed in the absence of Gα(i2 (but not of Gα(i3 and following treatment with pertussis toxin in Gα(i3 (-/-. The pore forming Ca(vα(1 protein level was unchanged in all mouse models analyzed, similar to mRNA levels of Ca(vα(1 and Ca(vβ(2 subunits. Interestingly, at the cellular signalling level, phosphorylation assays revealed abolished carbachol-triggered activation of ERK1/2 in mice lacking Gα(i2. CONCLUSION: Our data provide novel evidence for an isoform

  4. L-type calcium channels may regulate neurite initiation in cultured chick embryo brain neurons and N1E-115 neuroblastoma cells.

    Science.gov (United States)

    Audesirk, G; Audesirk, T; Ferguson, C; Lomme, M; Shugarts, D; Rosack, J; Caracciolo, P; Gisi, T; Nichols, P

    1990-08-01

    The intracellular free Ca2+ concentration, [Ca2+]i, plays an important role in regulating neurite growth in cultured neurons. Insofar as [Ca2+]i is partly a function of Ca2+ influx through voltage-sensitive calcium channels (VSCC), Ca2+ entry through VSCC should influence neurite growth. Vertebrate neurons may possess several types of VSCC. The most frequently described VSCC types are usually designated L, T and N. In most preparations, these VSCC types respond differently to certain pharmacological agents, including Cd2+, Ni2+, the dihydropyridines nifedipine and BAY K8644, and the aminoglycoside antibiotics. We used these agents to study the role of Ca2+ influx in regulating neurite initiation and length in cultures of chick embryo brain neurons and N1E-115 mouse neuroblastoma cells. In chick neurons, nifedipine and Cd2+ (less than 50 microM), which have been reported to inhibit L-type channels, reduced neurite initiation, but not mean neurite length. Ni2+ (less than 100 microM), reported to inhibit T-type channels, had no effect on either initiation or length. Low concentrations of most aminoglycosides (less than 300 microM), reported to inhibit N-type channels, had no effect on neurite initiation, but high concentrations of streptomycin (great than 300 microM), reported to inhibit both L- and N-type channels, reduced neurite initiation. BAY K8644, which enhances current flow through L-type channels, had no effect except at high concentration (50 microM), which inhibited initiation. N1E-115 neuroblastoma cells have been reported to contain L-type and T-type channels, but thus far no channel similar to the N-type has been described. In cultured N1E-115 cells, nifedipine (5 microM), Cd2+ (5 microM), and streptomycin (200 microM) reduced neurite initiation, while nickel (50 microM) and neomycin (100 microM) did not affect initiation. None of these agents altered neurite length. In N1E-115 cells, whole-cell voltage clamp recordings showed that nifedipine and Cd2

  5. Relationship between voltage-gated calcium channel and orofacial pain%电压门控性钙离子通道与口腔颌面部疼痛的关系

    Institute of Scientific and Technical Information of China (English)

    曹鹂俪; 胡荣城(综述); 朴正根(审校)

    2015-01-01

    Nerve injuries in oral and maxillofacial region can cause neuropathic pain which underlying mechanism is complicated, and there is still lack of effective treatment measures. In recent years, the important role of calcium chan-nels, especially voltage-gated calcium channels in the neuropathic pain has been recognized gradually. Now, this review presents the current understanding of the role of voltage-gated calcium channels in orofacial neuropathic pain, in order to provide ideas for orofacial pain study.%口腔颌面部神经损伤可引起神经病理性疼痛,其发病机制复杂,目前仍缺乏有效治疗措施。钙离子通道在疼痛的发生中起重要作用,近年来的许多研究发现电压门控性钙离子通道与神经病理性疼痛密切相关,本文就电压门控性钙离子通道与口腔颌面部疼痛的关系作一综述,为研究口腔颌面部疼痛的机制提供思路。

  6. Progress in modulation of T-type calcium channels by ;G protein-coupled receptors%G蛋白偶联受体对T型钙通道调节机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    黄沙; 黄东阳; 张海林

    2014-01-01

    T 型钙通道组织分布广泛,并且在生理和病理情况中都发挥着非常重要的作用,如神经放电、激素分泌、疼痛、癌症等。因此,阐明 T 型钙通道的调节机制有重要意义。大量研究表明 G 蛋白偶联受体及下游多种第二信使都对 T 型钙通道起到一定调节作用。该文重点总结了有关 G 蛋白偶联受体对 T 型钙通道的调节机制的研究进展。%T-type calcium channels are expressed in various tis-sues and play key roles in physiology and pathophysiology,inclu-ding neuronal firing,hormone secretion,pain,and cancer,etc. Hence,it is critical to understand the molecular mechanisms un-derlying the regulation of T-type channels.Substantial literature suggests many G protein-coupled receptors (GPCRs)and related second messengers can modulate T-type channel in some extent. Here,this review focuses on the modulation of T-type calcium channels by GPCRs and related second messengers.

  7. Research progress of calcium channels in the pathogenesis of pulmonary arterial hypertension%钙通道在肺动脉高压发病机制中的研究进展

    Institute of Scientific and Technical Information of China (English)

    黄子旭(综述); 沈捷(审校)

    2016-01-01

    肺动脉高压是一类严重的进展性疾病,最终导致患者右心衰竭,甚至死亡。肺血管收缩、肺血管重构、血栓形成和血管硬化等诸多原因导致肺动脉高压的发生。众多研究表明,Ca 2+信号在维持血管张力和调控血管平滑肌细胞增殖、凋亡等过程中发挥了重要作用,而这一信号转导机制主要由钙通道来调节操纵。文章综述钙通道在肺动脉高压发病机制中的研究进展。%Pulmonary arterial hypertension (PAH) is a group of severe and progressive diseases, and eventually leading to right heart failure even death. Pulmonary vasoconstriction, Pulmonary vascular remodeling , thrombosis, and vascular stiffness are the major causes for PAH. Numerous studies have shown that Ca2+ signal plays indispensable role in maintaining vascular tension and the regulation of vascular smooth muscle cell proliferation and apoptosis, and these processes are mainly mediated by calcium channels. This paper will focus on the advances of calcium channels in the pathogenesis of pulmonary arterial hypertension.

  8. TMEM16A is associated with voltage-gated calcium channels in mouse retina and its function is disrupted upon mutation of the auxiliary α2δ4 subunit

    Science.gov (United States)

    Caputo, Antonella; Piano, Ilaria; Demontis, Gian Carlo; Bacchi, Niccolò; Casarosa, Simona; Santina, Luca Della; Gargini, Claudia

    2015-01-01

    Photoreceptors rely upon highly specialized synapses to efficiently transmit signals to multiple postsynaptic targets. Calcium influx in the presynaptic terminal is mediated by voltage-gated calcium channels (VGCC). This event triggers neurotransmitter release, but also gates calcium-activated chloride channels (TMEM), which in turn regulate VGCC activity. In order to investigate the relationship between VGCC and TMEM channels, we analyzed the retina of wild type (WT) and Cacna2d4 mutant mice, in which the VGCC auxiliary α2δ4 subunit carries a nonsense mutation, disrupting the normal channel function. Synaptic terminals of mutant photoreceptors are disarranged and synaptic proteins as well as TMEM16A channels lose their characteristic localization. In parallel, calcium-activated chloride currents are impaired in rods, despite unaltered TMEM16A protein levels. Co-immunoprecipitation revealed the interaction between VGCC and TMEM16A channels in the retina. Heterologous expression of these channels in tsA-201 cells showed that TMEM16A associates with the CaV1.4 subunit, and the association persists upon expression of the mutant α2δ4 subunit. Collectively, our experiments show association between TMEM16A and the α1 subunit of VGCC. Close proximity of these channels allows optimal function of the photoreceptor synaptic terminal under physiological conditions, but also makes TMEM16A channels susceptible to changes occurring to calcium channels. PMID:26557056

  9. IgG from Amyotrophic Lateral Sclerosis Patients Increases Current Through P-Type Calcium Channels in Mammalian Cerebellar Purkinje Cells and in Isolated Channel Protein in Lipid Bilayer

    Science.gov (United States)

    Llinas, R.; Sugimori, M.; Cherksey, B. D.; Smith, R. Glenn; Delbono, O.; Stefani, E.; Appel, S.

    1993-12-01

    The effect of the IgG from amyotrophic lateral sclerosis (ALS) patients was tested on the voltage-dependent barium currents (IBa) in mammalian dissociated Purkinje cells and in isolated P-type calcium channels in lipid bilayers. Whole cell clamp of Purkinje cells demonstrates that ALS IgG increases the amplitude of IBa without modifying their voltage kinetics. This increased IBa could be blocked by a purified nonpeptide toxin from Agelenopsis aperta venom (purified funnel-web spider toxin) or by a synthetic polyamine analog (synthetic funnel-web spider toxin) and by a peptide toxin from the same spider venom, ω-Aga-IVA. Similar results were obtained on single-channel recordings from purified P channel protein. The addition of ALS IgG increased single-channel IBa open time without affecting slope conductance. The results described above were not seen with normal human IgG nor with boiled ALS IgG. It is concluded that ALS IgG enhances inward current through P-type calcium channels. Since P-type Ca2+ channels are present in motoneuron axon terminals, we propose that the enhanced calcium current triggered by ALS IgG may contribute to neuronal damage in ALS.

  10. SAFETY AND EFFICACY OF BETA-BLOCKERS IN THE TREATMENT OF STABLE ANGINA-PECTORIS

    NARCIS (Netherlands)

    DEMUINCK, ED; LIE, KI

    1990-01-01

    In stable exercise-induced angina pectoris, beta-blockers exert their beneficial effects mainly through a reduction in heart rate, blood pressure, and contractility. Additional beneficial effects are an improvement in myocardial oxygen supply through a redistribution of coronary flow, a lengthening

  11. Heart rate and use of beta-blockers in stable outpatients with coronary artery disease.

    Directory of Open Access Journals (Sweden)

    Ph Gabriel Steg

    Full Text Available BACKGROUND: Heart rate (HR is an emerging risk factor in coronary artery disease (CAD. However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR. METHODS AND FINDINGS: CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%. Mean (SD age was 64.2 (10.5 years, HR by pulse was 68.3 (10.6 bpm, and by electrocardiogram was 67.2 (11.4 bpm. Overall, 44.0% had HR ≥ 70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR ≥ 70 bpm. HR ≥ 70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents. CONCLUSIONS: Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR ≥ 70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.

  12. Systematic review of use of β-blockers in sepsis

    Directory of Open Access Journals (Sweden)

    Cyril Jacob Chacko

    2015-01-01

    Conclusion: There is insufficient evidence to justify the routine use of β-blockers in sepsis. A large adequately powered multi-centered randomized controlled clinical trial is required to address the question on the efficacy of β-blocker usage in sepsis. This trial should also consider a number of important questions including the choice of β-blocker used, optimal dosing, timing of intervention, duration of intervention and discontinuation of the drug. Until such time based on the available evidence, there is no place for the use of β-blockers in sepsis in current clinical practice.

  13. Responsiveness of voltage-gated calcium channels in SH-SY5Y human neuroblastoma cells on quasi-three-dimensional micropatterns formed with poly (l-lactic acid

    Directory of Open Access Journals (Sweden)

    Kisaalita WS

    2013-01-01

    Full Text Available Ze-Zhi Wu,1 Zheng-Wei Wang,1 Li-Guang Zhang,1 Zhi-Xing An,1 Dong-Huo Zhong,1 Qi-Ping Huang,1 Mei-Rong Luo,1 Yan-Jian Liao,1 Liang Jin,1 Chen-Zhong Li,2 William S Kisaalita31Key Laboratory of Biorheological Science and Technology of the State Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, People’s Republic of China; 2Nanobioengineering/Bioelectronics Laboratory, Department of Biomedical Engineering, Florida International University, Miami, Florida, 3Cellular Bioengineering Laboratory, College of Engineering, University of Georgia, Athens, Georgia, USAIntroduction: In this study, quasi-three-dimensional (3D microwell patterns were fabricated with poly (l-lactic acid for the development of cell-based assays, targeting voltage-gated calcium channels (VGCCs.Methods and materials: SH-SY5Y human neuroblastoma cells were interfaced with the microwell patterns and found to grow as two dimensional (2D, 3D, and near two dimensional (N2D, categorized on the basis of the cells’ location in the pattern. The capability of the microwell patterns to support 3D cell growth was evaluated in terms of the percentage of the cells in each growth category. Cell spreading was analyzed in terms of projection areas under light microscopy. SH-SY5Y cells’ VGCC responsiveness was evaluated with confocal microscopy and a calcium fluorescent indicator, Calcium GreenTM-1. The expression of L-type calcium channels was evaluated using immunofluorescence staining with DM-BODIPY.Results: It was found that cells within the microwells, either N2D or 3D, showed more rounded shapes and less projection areas than 2D cells on flat poly (l-lactic acid substrates. Also, cells in microwells showed a significantly lower VGCC responsiveness than cells on flat substrates, in terms of both response magnitudes and percentages of responsive cells, upon depolarization with 50 mM K+. This lower VGCC responsiveness could not be explained by the difference in

  14. Effect of Tanshinone Ⅱ -A on L-type calcium channel in rat ventricular myocytes%丹参Ⅱ-A对大鼠心肌细胞L-型钙通道的影响 

    Institute of Scientific and Technical Information of China (English)

    黄健; 裴娟慧; 滕思勇; 郝杰; 张银辉; 浦介麟; 惠汝太

    2012-01-01

    目的 研究丹参酮Ⅱ-A对大鼠心肌细胞L型钙通道的影响.方法 采用酶解法制备大鼠心肌细胞,应用全细胞膜片钳技术检测大鼠心肌细胞L-型钙通道的电流密度和动力学.结果 丹参酮Ⅱ-A对L-型钙通道有抑制作用.在0μmol/L、10 μmol/L、20μmol/L和40μmol/L丹参酮Ⅱ-A作下,L-型钙通道的峰值电流密度分别为-13.34±1.06 pA/pF、-10.46 ±0.75 pA/pF、-7.62±0.50 PA/pF和-4.69±0.18 PA/pF,其抑制率分别为28.40%、52.14%和73.50% (n=8,P<0.05).结论 丹参酮Ⅱ-A抑制大鼠心肌细胞L-型钙通道,降低L-型钙通道的电流密度,呈浓度依赖性.%Objective To investigate the effect of Tanshinone Ⅱ -A on L-type calcium channel in isolated rat ventricular myocytes. Methods rat ventricular myocytes were isolated by enzymatic method, whole cell patch clamp technique was used to record the current and gating. Result Tanshinone Ⅱ-A inhibit L-type calcium channel current density. Tanshinone Ⅱ -A at μmol/L, 10μmol/L, 20μmol/L and 40 μmol/L,peak L-type calcium channel current density(Ica-L) were -13.34± 1.06 pA/pF, -10.46±0.75 pA/pF, -7.62±0.50 pA/pF and -4.69 ±0.18 pA/pF respectively, the inhibition rates were 28.40%, 52.14% and 73.50% respectively (n=8,P<0.05). Conclusion Effect of Tanshinone Ⅱ-A on rat cardiac myocytes L-type calcium current was significantly inhibited.

  15. Regulation of voltage-gated calcium channels by proteolysis%蛋白质水解对电压门控Ca2+通道的调节

    Institute of Scientific and Technical Information of China (English)

    ABELE Kathryn; 杨建

    2012-01-01

    电压门控Ca2+通道是由多个亚基组成的膜蛋白,其分布广泛,生理功能极为重要,可被众多蛋白和信号传导通路调节.本综述重点介绍蛋白质水解对电压门控Ca2+通道的调节作用及其生理功能.Ca2+通道的主亚基Cavα1可被蛋白质水解,从而调控Ca2+通道的功能和降解,影响基因表达和细胞兴奋性.根据其组织分布,L类Ca2+通道有两种水解模式:在心脏和骨骼肌,Cavα1的羧基末端被水解后与剩余的羧基端结合,抑制Ca2+通道电流.这种自身抑制可被体内分泌的肾上腺素解除,引发心肌和骨骼肌Ca2+电流大量增加,在“打或逃”之类的应激反应中起重要作用,Cavα1羧基末端水解在大脑也存在,并可能是由calpain蛋白质水解酶催化;在某些大脑区域,Cavα1的整个羧基端可被水解并迁移至细胞核,起到转录因子的作用.P/Q类Ca2+通道Cavα1的羧基末端也可被水解,并迁移到细胞核.许多基因突变产生截断型P/Q Cavα1,而这些截断型Cavα1可严重影响正常Ca2+通道的功能,导致人类的疾病.截断型N类Ca2+通道Cavα1可通过诱变产生,影响正常通道的表达.新型Ca2+通道水解新模式可能是未来Ca2+通道研究中一个重要的探索方向.%Voltage gated calcium channels (VGCCs) are multi-subunit membrane proteins present in a variety of tissues and control many essential physiological processes.Due to their vital importance,VGCCs are regulated by a myriad of proteins and signaling pathways.Here we review the literature on the regulation of VGCCs by proteolysis of the pore-forming α1 subunit,Cavα1.This form of regulation modulates channel function and degradation and affects cellular gene expression and excitability.L-type Ca2+ channels are proteolyzed in two ways,depending on tissue localization.In the heart and skeletal muscle,the distal C-terminus of Cavα1 is cleaved and acts as an autoinhibitor when it reassociates with the proximal C

  16. Regulation of neuronal L-type voltage-gated calcium channels and brain ischemia%中枢神经系统L-型电压门控钙通道的功能调控与脑缺血

    Institute of Scientific and Technical Information of China (English)

    侯筱宇; 张光毅

    2004-01-01

    中枢神经系统L-型电压门控钙通道(L-type voltage-gated calcium channels, L-VGCCs)由α1C(D)亚基和辅助亚基组成.α1C亚基的C-端包含多个功能结构域,可分别与钙调素、钙调蛋白酶、cAMP依赖性蛋白激酶、Src家族酪氨酸蛋白激酶(Src family protein tyrosine kinases,SrcPTKs)等相互作用,从而参与L-VGCCs的功能调控.SrcPTKs介导的两种钙通道-- L-VGCCs和N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体的对话可能是缺血性脑损伤的重要机制.

  17. PFXYD motif plays a role in the modulation of L-type calcium channels by phospholemman%PFXYD序列参与phospholemman对L型钙通道的调节作用

    Institute of Scientific and Technical Information of China (English)

    郭凯; 黄从新; 王先明; 高国锋; Blaise Z.Peterson

    2009-01-01

    Objective To explore the role of the PFXYD motif in the modulation of L-type calcium channels by phospholemman (PLM), a newly defined phosphoprotein. Methods We used site-directed muta-genesis to replace amino acids comprising the PFXYD motif with alanine (A) to generate the PLM mutant, ALLS. Calcium phosphate precipitation was used to introduce cDNAs encoding L-type calcium channels with either empty vector (EV), or wild type PLM (WT), or mutant PLM (ALL5) into HEK 293 cells. Whole-cell patch clamp was used to measure the L-type calcium currents (Ica(L)) and analyzed the changes in gating ki-netics. Results At voltage steps of -20 mV and - 10 mV,ALL5 slowed activation of Ica(L) to a much greater degree than WT,and also slowed inactivation of Ica(L). In contrast to WT,ALL5 did not appreciably slow deac-tivation of Ica(L). Importantly,the changes in Ica(L) gating kinetics induced by ALL5 was not attributed to the current density. Conclusion The chemical and/or physical properties of the PFXYD motif can be altered to im-pact PLM-dependent modulation of L-type calcium channels, suggesting that the PFXYD motif plays an impor-tant role in the modulation of L-type calcium channels by PLM.%目的 探讨PFXYD序列在phospholemman(PLM)调节L型钙通道中的作用.方法用丙氨酸(Ala/A)替换组成PFXYD序列的5个氨基酸,得到突变型PLM-ALL5.用磷酸钙沉淀法将编码L型钙通道的cDNA分别与编码载体质粒(empty vector,EV)、野生型PLM(wild type,WT)、突变型PLM(ALL5)的cDNA转染到HEK 293细胞中,待其表达相应蛋白后,用全细胞膜片钳方法记录L型钙电流(ICa(L))并分析其动力学特性.结果 在除极化电位为-20 mV和-10 mV时,ALL5较WT更加明显地减慢了ICa(L)激活速度,而在相同电位下ALL5使ICa(L)失活速度也明显减慢;与WT相反,ALL5没有减慢ICa(L)灭活速度,反使其加快了;以上ALL5所致的ICa(L)改变与电流大小无关.结论 PFXYD序列理化性质的改变可以引起PLM对L型

  18. Effects of hydrogen sulfide on arrhythmias induced by ouabain and L-type calcium channel of myocardial cell%硫化氢对心室肌细胞触发活动及L型钙通道的影响

    Institute of Scientific and Technical Information of China (English)

    刘慧霞

    2015-01-01

    目的:研究硫化氢(H2 S)对哇巴因诱发的触发性心律失常及 L 型钙通道的作用,探讨硫化氢抗心律失常的机制。方法运用全细胞膜片钳技术,记录 L 型钙通道电流,观察硫化氢对单个心室肌细胞 L 型钙通道各参数的影响。结果 H2 S 抑制哇巴因诱发的迟后去极化(DAD)及触发活动(TA),50,100和200μmol/ L 硫氢化钠(H2 S 的供体)使 ICa - L的峰值降低,浓度依赖性的使 I - V 曲线上移,峰值由(-13.9±1.4)pA/ pF 分别至(-10.7±1.4)pA/ pF(n =6,P <0.05)、(-7.4±2.5)pA/ pF(P <0.01)和(-5.3±1.1)pA/ pF(P <0.01),H2 S 使稳态激活曲线右移,而不影响稳态失活曲线。结论 H2 S 通过对 L 型钙通道的抑制而发挥抗心律失常作用。%Objective:To investigate effects of hydrogen sulfide(H2 S)on arrhythmias induced by ouabain and L-type calcium channel of myocardial cell. Methods:The whole-cell patch clamp technique was applied to record the current of L-type calcium channel and observe the effects on arrhythmias induced by ouabain and L-type calcium channel of single ar-rhythmic ventricular cell. Results:H2 S showed protective function of inhibiting the delayed afterdepolarization(DAD)and triggerd activity(TA)induced by ouabain. The peak current of Ica - L was decreased from( - 13. 9 ± 1. 4)pA/ pF to( -10. 7 ± 1. 4)pA/ pF(n = 5,P < 0. 05),( - 7. 4 ± 2. 5)pA/ pF(P < 0. 01)and( - 5. 3 ± 1. 1)pA/ pF(P < 0. 01)by 50, 100,200μmol sodium hydrosulfide(H2 S donor)respectively,and I - V curve was shifted upward in a concentration-de-pendent manner. The steady state activation curve was shifted to the right by H2 S while no effect on inactivation curve was shown. Conclusion:H2 S shows anti-arrhythmic function through its effects on L-type calcium channel.

  19. Angiotensin receptor blockers in diabetic nephropathy

    DEFF Research Database (Denmark)

    Parving, Hans-Henrik; Andersen, Steen; Jacobsen, Peter

    2004-01-01

    The activity of the renin-angiotensin-aldosterone system (RAAS) is elevated both in the circulation and in the renal tissue of diabetic and nondiabetic nephropathies. The increased RAAS activity plays an important role in the hemodynamic and nonhemodynamic pathogenetic mechanisms involved in kidney...... with diabetic nephropathy have demonstrated that angiotensin II receptor blockers (ARB) induce favorable changes in systemic blood pressure, renal hemodynamics, and proteinuria similar to those induced by angiotensin-converting enzyme (ACE) inhibition. Studies have revealed the optimal renoprotective dose...... in diabetic nephropathy. In addition, dual RAAS blockade is safe and well tolerated. Impaired autoregulation of glomerular filtration rate (GFR); demonstrated with some blood pressure-lowering agents implies disturbances in the downstream transmission of the systemic blood pressure into the glomerulus...

  20. Perioperative beta blockers in patients having non-cardiac surgery

    DEFF Research Database (Denmark)

    Bangalore, Sripal; Wetterslev, Jørn; Pranesh, Shruthi

    2008-01-01

    American College of Cardiology and American Heart Association (ACC/AHA) guidelines on perioperative assessment recommend perioperative beta blockers for non-cardiac surgery, although results of some clinical trials seem not to support this recommendation. We aimed to critically review the evidence...... to assess the use of perioperative beta blockers in patients having non-cardiac surgery....

  1. Effects of N- and L-type calcium channel antagonists on the responses of nociceptive spinal cord neurons to mechanical stimulation of the normal and the inflamed knee joint.

    Science.gov (United States)

    Neugebauer, V; Vanegas, H; Nebe, J; Rümenapp, P; Schaible, H G

    1996-12-01

    1. The present study addresses the involvement of voltage-dependent calcium channels of the N and L type in the spinal processing of innocuous and noxious input from the knee joint, both under normal conditions and under inflammatory conditions in which spinal cord neurons become hyperexcitable. In 30 anesthetized rats, extracellular recordings were performed from single dorsal horn neurons in segments 1-4 of the lumbar spinal cord. All neurons had receptive fields in the ipsilateral knee joint. In 22 rats, an inflammation was induced in the ipsilateral knee joint by kaolin and carrageenan 4-16 h before the recordings. The antagonist at N-type calcium channels, omega-conotoxin GVIA (omega-CTx GVIA), was administered topically in solution to the dorsal surface of the spinal cord at the appropriate spinal segments in 6 rats with normal joints and in 12 rats with inflamed knee joints. The antagonist at L-type channels, nimodipine, was administered topically in 5 rats with normal joints and in 11 rats with inflamed knee joints. In another five rats with inflamed joints, antagonists at L-type calcium channels (diltiazem and nimodipine) and omega-CTx GVIA were administered ionophoretically with multibarrel electrodes close to the neurons recorded. 2. The topical administration of omega-CTx GVIA to the spinal cord reduced the responses to both innocuous and noxious pressure applied to the knee joint in a sample of 11 neurons with input from the normal joint and in a sample of 16 neurons with input from the inflamed joint (hyperexcitable neurons). The responses were decreased to approximately 65% of the predrug values within administration times of 30 min. A similar reduction of the responses to innocuous and noxious pressure was observed when omega-CTx GVIA was administered ionophoretically to nine hyperexcitable neurons. In neurons with input from the normal or the inflamed knee joint, the administration of omega-CTx GVIA led also to a reduction of the responses to

  2. An investigation into sustainable construction stimulators and blockers

    Directory of Open Access Journals (Sweden)

    M Osmani

    2014-10-01

    Full Text Available The UK Government has been using a combination of regulation, economic instruments and voluntary agreements to meet targets of ethical, social and environmental performancein driving the climate change agenda. The UK is the first country worldwide to set a legally binding 80% greenhouse-gas emissions reduction target by 2050. The built environment in the UK is responsible for about 40% of carbon emissions, 32% of solid waste generation,20% of water effluents, and 40% of all energy used. As such, the construction industry has been targeted to facilitate the transition to a low-carbon economy.Indeed, sustainabilitywithin the built environment has become the forefront of all sustainable development policies in the UK. However; various studies have outlined the difficulty of translating theUK’s 80% greenhouse-gas emissions reduction target to a micro level such as construction projects. This research engaged the top 100 UK contractorsto investigate stimulators that drivethe implementation of sustainability in their projects,and assess associated blockers.Findings reveal that sustainability requirements driven by financial and business were viewed by participating contractors as being the key motivators in construction projects. Corporate Social Responsibility (CSR was viewed as a vehicle to improve social and environmental dynamics of sustainability through local community support initiatives,which in turn has increased companies’ opportunities to secure new projects, particularly from public clients. On the other hand, respondents called for clearer and inclusivelegislation; increased awareness; enhanced communication and coordination among project stakeholders; and widespread sharing and dissemination of sustainableconstruction best practice data.Keywords: UK; contractors; sustainable construction; stimulators; blockers.

  3. A potent potassium channel blocker from Mesobuthus eupeus scorpion venom.

    Science.gov (United States)

    Gao, Bin; Peigneur, Steve; Tytgat, Jan; Zhu, Shunyi

    2010-12-01

    Scorpion venom-derived peptidyl toxins are valuable pharmacological tools for investigating the structure-function relationship of ion channels. Here, we report the purification, sequencing and functional characterization of a new K(+) channel blocker (MeuKTX) from the venom of the scorpion Mesobuthus eupeus. Effects of MeuKTX on ten cloned potassium channels in Xenopus oocytes were evaluated using two-electrode voltage-clamp recordings. MeuKTX is the orthologue of BmKTX (α-KTx3.6), a known Kv1.3 blocker from the scorpion Mesobuthus martensii, and classified as α-KTx3.13. MeuKTX potently blocks rKv1.1, rKv1.2 and hKv1.3 channels with 50% inhibitory concentration (IC(50)) of 203.15 ± 4.06 pM, 8.92 ± 2.3 nM and 171 ± 8.56 pM, respectively, but does not affect rKv1.4, rKv1.5, hKv3.1, rKv4.3, and hERG channels even at 2 μM concentration. At this high concentration, MeuKTX is also active on rKv1.6 and Shaker IR. Our results also demonstrate that MeuKTX and BmKTX have the same channel spectrum and similar pharmacological potency. Analysis of the structure-function relationships of α-KTx3 subfamily toxins allows us to recognize several key sites which may be useful for designing toxins with improved activity on hKv1.3, an attractive target for T-cell mediated autoimmune diseases.

  4. Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

    Science.gov (United States)

    Khodr, Christina E; Chen, Lihua; Dave, Sonya; Al-Harthi, Lena; Hu, Xiu-Ti

    2016-10-01

    Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K(+) influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca(2+) influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca(2+) potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca(2+) influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca(2+) dysregulation in the mPFC.

  5. N- and L-type voltage-gated calcium channels mediate fast calcium transients in axonal shafts of mouse peripheral nerve.

    Directory of Open Access Journals (Sweden)

    Ruxandra eBarzan

    2016-06-01

    Full Text Available In the peripheral nervous system a vast number of axons are accommodated within fiber bundles that constitute peripheral nerves. A major function of peripheral axons is to propagate action potentials along their length, and hence they are equipped with Na+ and K+ channels, which ensure successful generation, conduction and termination of each action potential. However little is known about Ca2+ ion channels expressed along peripheral axons and their possible functional significance. The goal of the present study was to test whether voltage-gated Ca2+ channels (VGCCs are present along peripheral nerve axons in situ and mediate rapid activity-dependent Ca2+ elevations under physiological circumstances. To address this question we used mouse sciatic nerve slices, Ca2+ indicator Oregon Green BAPTA-1, and 2-photon Ca2+ imaging in fast line scan mode (500 Hz. We report that transient increases in intra-axonal Ca2+ concentration take place along peripheral nerve axons in situ when axons are stimulated electrically with single pulses. Furthermore, we show for the first time that Ca2+ transients in peripheral nerves are fast, i.e. occur in a millisecond time-domain. Combining Ca2+ imaging and pharmacology with specific blockers of different VGCCs subtypes we demonstrate that Ca2+ transients in peripheral nerves are mediated mainly by N-type and L-type VGCCs. Discovery of fast Ca2+ entry into the axonal shafts through VGCCs in peripheral nerves suggests that Ca2+ may be involved in regulation of action potential propagation and/or properties in this system, or mediate neurotransmitter release along peripheral axons as it occurs in the optic nerve and white matter of the central nervous system.

  6. N- and L-Type Voltage-Gated Calcium Channels Mediate Fast Calcium Transients in Axonal Shafts of Mouse Peripheral Nerve.

    Science.gov (United States)

    Barzan, Ruxandra; Pfeiffer, Friederike; Kukley, Maria

    2016-01-01

    In the peripheral nervous system (PNS) a vast number of axons are accommodated within fiber bundles that constitute peripheral nerves. A major function of peripheral axons is to propagate action potentials along their length, and hence they are equipped with Na(+) and K(+) channels, which ensure successful generation, conduction and termination of each action potential. However little is known about Ca(2+) ion channels expressed along peripheral axons and their possible functional significance. The goal of the present study was to test whether voltage-gated Ca(2+) channels (VGCCs) are present along peripheral nerve axons in situ and mediate rapid activity-dependent Ca(2+) elevations under physiological circumstances. To address this question we used mouse sciatic nerve slices, Ca(2+) indicator Oregon Green BAPTA-1, and 2-photon Ca(2+) imaging in fast line scan mode (500 Hz). We report that transient increases in intra-axonal Ca(2+) concentration take place along peripheral nerve axons in situ when axons are stimulated electrically with single pulses. Furthermore, we show for the first time that Ca(2+) transients in peripheral nerves are fast, i.e., occur in a millisecond time-domain. Combining Ca(2+) imaging and pharmacology with specific blockers of different VGCCs subtypes we demonstrate that Ca(2+) transients in peripheral nerves are mediated mainly by N-type and L-type VGCCs. Discovery of fast Ca(2+) entry into the axonal shafts through VGCCs in peripheral nerves suggests that Ca(2+) may be involved in regulation of action potential propagation and/or properties in this system, or mediate neurotransmitter release along peripheral axons as it occurs in the optic nerve and white matter of the central nervous system (CNS).

  7. Use of beta blockers in various clinical states

    Directory of Open Access Journals (Sweden)

    Radović Vesna V.

    2011-01-01

    Full Text Available Introduction. According to the convincing evidence, a decline in mortality rate has been achieved with beta-blockers in patients with an acute myocardial infarction and in post-infarction follow-up. In fact, there has been a clear reduction of sudden coronary death. The necessary condition for the efficiency of beta-blockers is an early use. They are also a medication of choice for angina after an infarction. The objective of this work was to evaluate the use of beta-blockers after a myocardial infarction in various clinical states and to eliminate doubts concerning their prescription. Beta blockers Even in conditions considered contraindications for administration of beta blockers such as old age, diabetes, non-Q-wave myocardial infarction, peripheral vascular disease, arterial disease, heart insufficiency, ventricular arrhythmias, renal disease, chronic obstructive pulmonary disease, asthma and depression, patients benefit from beta blockers when they are given along with a right choice of the medication and a regular follow-up of the patient. Preference is given to cardioselective beta blockers in patients with diabetes or lung disease. Beta-blockers do not cause long-term lipid alterations. Therefore, the matter of clinically significant alterations of lipids or blood glucose levels should not need further consideration as a problem of the treatment of diabetics. Discussion and conclusion. Investigations have proved that the use of beta-blockers reduces the development of cerebrovascular accidents, heart insufficiency and hypertension. Despite strong arguments and numerous recommendations, beta-blockers have not been accepted to a sufficient extent as an integral part of treatment of acute coronary syndrome and related diseases, to the detriment of many lost lives and in spite of favourable pharmaco-economic aspect.

  8. DMPD: Lipopolysaccharide-binding molecules: transporters, blockers and sensors. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15241548 Lipopolysaccharide-binding molecules: transporters, blockers and sensors. ...binding molecules: transporters, blockers and sensors. PubmedID 15241548 Title Lipopolysaccharide-binding mo...lecules: transporters, blockers and sensors. Authors Chaby R. Publication Cell Mo

  9. β-blockers as endocrine disruptors: the potential effects of human β-blockers on aquatic organisms.

    Science.gov (United States)

    Massarsky, Andrey; Trudeau, Vance L; Moon, Thomas W

    2011-06-01

    β-Adrenergic blockers or β-blockers have been used therapeutically to treat human hypertension since the late 1960s. The global market value and prescription rates of β-blockers keep rising substantially each year, and over the past decade the number of prescriptions has doubled. The widespread use of β-blockers has resulted in their appearance in the aquatic environment originating primarily from sewage effluents. The objective of this review is to analyze the literature as a means to determine the endocrine-disrupting potential of β-blockers in aquatic organisms. The mammalian adrenergic system is compared with the adrenergic system of fish and the homologous octopaminergic system in aquatic invertebrates, in particular mollusks. The structure and functions of these systems are linked to the molecular similarities between adrenoceptors and the octopaminergic/tyraminergic receptors, the various catecholamine molecules (epinephrine, norepinephrine, octopamine, and tyramine), and the processes controlled. Knowledge of these similarities as well as the effects of β-blockers, mainly in humans, is then used to create a broad picture of the endocrine-disrupting potential of β-blockers, particularly during the stress response. The main conclusion is that β-blockers have endocrine-disrupting effects.

  10. External bioenergy-induced increases in intracellular free calcium concentrations are mediated by Na+/Ca2+ exchanger and L-type calcium channel.

    Science.gov (United States)

    Kiang, Juliann G; Ives, John A; Jonas, Wayne B

    2005-03-01

    External bioenergy (EBE, energy emitted from a human body) has been shown to increase intracellular calcium concentration ([Ca2+]i, an important factor in signal transduction) and regulate the cellular response to heat stress in cultured human lymphoid Jurkat T cells. In this study, we wanted to elucidate the underlying mechanisms. A bioenergy specialist emitted bioenergy sequentially toward tubes of cultured Jurkat T cells for one 15-minute period in buffers containing different ion compositions or different concentrations of inhibitors. [Ca2+], was measured spectrofluorometrically using the fluorescent probe fura-2. The resting [Ca2+]i in Jurkat T cells was 70 +/- 3 nM (n = 130) in the normal buffer. Removal of external calcium decreased the resting [Ca2+]i to 52 +/- 2 nM (n = 23), indicating that Ca2+ entry from the external source is important for maintaining the basal level of [Ca2+]i. Treatment of Jurkat T cells with EBE for 15 min increased [Ca2+]i by 30 +/- 5% (P EBE did not attenuate [Ca2+]i responsiveness to EBE. Removal of external Ca2+ or Na+, but not Mg2+, inhibited the EBE-induced increase in [Ca2+]i. Dichlorobenzamil, an inhibitor of Na+/Ca2+ exchangers, also inhibited the EBE-induced increase in [Ca2+]i in a concentration-dependent manner with an IC50 of 0.11 +/- 0.02 nM. When external [K+] was increased from 4.5 mM to 25 mM, EBE decreased [Ca2+]i. The EBE-induced increase was also blocked by verapamil, an L-type voltage-gated Ca2+ channel blocker. These results suggest that the EBE-induced [Ca2+]i increase may serve as an objective means for assessing and validating bioenergy effects and those specialists claiming bioenergy capability. The increase in [Ca2+]i is mediated by activation of Na+/Ca2+ exchangers and opening of L-type voltage-gated Ca2+ channels.

  11. L-type calcium channels play a crucial role in the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Wen, Li [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China); Wang, Yu [Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Wang, Huan [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China); Kong, Lingmin [Department of Fundamental Medicine, Cell Engineering Research Centre, Fourth Military Medical University, Xi' an 710032 (China); Zhang, Liang [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China); Chen, Xin [Department of General Dentistry, The 174th Hospital of Chinese PLA, Xiamen 361003 (China); Ding, Yin, E-mail: dingyin@fmmu.edu.cn [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer We detect the functional Ca{sup 2+} currents and mRNA expression of VDCC{sub L} in rMSCs. Black-Right-Pointing-Pointer Blockage of VDCC{sub L} exert antiproliferative and apoptosis-inducing effects on rMSCs. Black-Right-Pointing-Pointer Inhibiting VDCC{sub L} can suppress the ability of rMSCs to differentiate into osteoblasts. Black-Right-Pointing-Pointer {alpha}1C of VDCC{sub L} may be a primary functional subunit in VDCC{sub L}-regulating rMSCs. -- Abstract: L-type voltage-dependent Ca{sup 2+} channels (VDCC{sub L}) play an important role in the maintenance of intracellular calcium homeostasis, and influence multiple cellular processes. They have been confirmed to contribute to the functional a