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PubMed1988

Activation of dihydropyridine-sensitive calcium channels and biphasic cytosolic calcium responses by angiotensin II in rat adrenal glomerulosa cells.

The steroidogenic actions of angiotensin II (AII) and increased extracellular K+ concentrations [( K+]) in rat adrenal glomerulosa cells are selectively enhanced by the voltage-sensitive calcium channel agonist Bay K 8644 (BK 8644). The relationship between these effects of the dihydropyridine agonist and cytosolic calcium concentration [( Ca2+]i) was investigated in rat and bovine glomerulosa cells. In the rat glomerulosa cells, AII and increased [K+] elicited rapid elevations of [Ca2+]i with distinctive temporal characteristics. Whereas the [Ca2+]i response to [K+] declined to basal over 2-3 min, addition of 10 nM AII caused a biphasic increase in [Ca2+]i, with a rapid transient rise followed by a lower plateau phase that remained above basal for several minutes. BK 8644 alone did not affect [Ca2+]i, but at low concentrations (30 nM) increased the magnitude and duration of the [Ca2+]i response elicited by progressive elevation of extracellular [K+] to 12 mM. In AII-stimulated glomerulosa cells, 30 nM BK 8644 enhanced both phases of the cytosolic calcium response, with a more marked effect on the sustained plateau phase. In contrast to its prominent actions in rat glomerulosa cells, BK 8644 had no effect on AII-stimulated rises in [Ca2+]i in bovine glomerulosa cells, and only slightly enhanced their minor [Ca2+]i responses to potassium. These studies provide evidence that AII activates dihydropyridine-sensitive voltage-sensitive calcium channels in rat, but not bovine, adrenal glomerulosa cells. They also suggest that enhancement by BK 8644 of agonist-stimulated [Ca2+]i changes is responsible for its synergistic effects on aldosterone responses to potassium and AII in rat glomerulosa cells and emphasize the importance of the sustained phase of the cytosolic calcium signal in the steroidogenic action of AII.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1997

Mibefradil: A New Selective T-Channel Calcium Antagonist for Hypertension and Angina Pectoris.

Calcium antagonists are an established therapy for patients with hypertension and angina pectoris, but their current usage is often limited by their pharmacologic profilers and side effects. Mibefradil is a recently developed calcium antagonist with a unique chemical structure, site of action, and set of pharmacologic effects. Unlike currently available calcium channels as well as L-type channels. It is further distinguished from the other calcium antagonists in that it is the first member of a new class of calcium antagonists, the tetralol derivatives. With chronic oral dosing, mibefradil attains steady-state plasma concentrations within 3-4 days, has a bioavailability of approximately 90%, and a plasma half-life of 17-25 hours. It has a gradual onset of action and can be administered once daily without regard to food intake. It increases coronary blood flow and lowers peripheral vascular resistance. The vasodilatory effects of mibefradil are associated with a lack of inotropic effect on myocardium, lack of neurohormonal activation, and a reduction in heart rate. In clinical trials it has been demonstrated to be an effective agent in the treatment of patients with hypertension and angina pectoris, with a good safety and tolerability profile regardless of age, gender, or race.

Journal Article↗

PubMed1991

Sites, mechanisms of action, and differentiation of calcium channel antagonists.

The calcium channel antagonists are a chemically heterogeneous group of agents that includes verapamil, nifedipine, and diltiazem as first-generation agents. They owe their effectiveness to interactions at specific sites associated with a major protein of the L class of voltage-gated channel. The calcium channel may be viewed as a pharmacologic receptor, with specific sites for activator and antagonist ligands that are linked to the functional machinery of the channel. These sites are subject to homologous and heterologous regulation and a number of disease states--both experimental and clinical--alter their expression. The selective actions of these agents are reviewed from several perspectives, particularly that of voltage-dependent interactions that distinguish between cells according to membrane potential and other factors.

Animals↗

PubMed1992

[Evaluation of anti-atheromatous properties of calcium channel inhibitors].

Calcium is involved in several biochemical atherogenesis processes and its activity is antagonised in cell and animal experimental models by all classes of slow channel calcium inhibitors. However, the doses required in animals to slow the development of atherosclerotic lesions are above therapeutically acceptable doses in man. The clinical relevance of their anti-atherosclerotic activity in the few clinical studies undertaken is difficult to assess because of the variable criteria of judgment used.

Animals↗

PubMed1993

Verapamil and diltiazem inhibit receptor-operated calcium channels and intracellular calcium oscillations in rat hepatocytes.

Fura-2 loaded rat hepatocytes were used to determine whether the L-type channel blockers, verapamil and diltiazem, affect receptor-operated calcium channels (ROCCs). The flux through ROCCs was followed by quenching of fura-2 fluorescence due to the influx of extracellular Mn2+ induced by vasopressin. Verapamil as well as diltiazem inhibited vasopressin-stimulated Mn2+ influx in a dose-dependent manner up to 60% at concentrations of 200-400 microM. Furthermore, both inhibitors decreased significantly the frequency of phenylephrine-induced oscillation of [Ca2+]i. The experimental findings indicate that L-type channel blockers inhibit ROCCs in rat hepatocytes.

Animals↗

PubMedDate not supplied

Immunosuppressive properties of calcium channel blockers.

Calcium channel blockers are extensively used for their beneficial effects on the cardiovascular system. Solid organ transplant recipients commonly have cardiovascular disease and are often treated with these agents. Research demonstrates that calcium antagonists may have beneficial effects in this population that are independent of their effects on the cardiovascular system. Indeed, both in vitro and in vivo studies suggested that they may possess immunosuppressive properties. Their actions at the cellular level in both the afferent and efferent arms of the immune system indicate that alone, as well as in combination with cyclosporine, these agents possess immunosuppressive properties that may potentially benefit the transplant population.

Animals↗

PubMed2005

Antihypertensive effects of the putative T-type calcium channel antagonist mibefradil are mediated by the L-type calcium channel Cav1.2.

The role of T-type Ca2+ channels for cardiovascular physiology, in particular blood pressure regulation, is controversial. Selective blockade of T-type Ca2+ channels in resistance arteries has been proposed to explain the effect of the antihypertensive drug mibefradil. In the present study, we used a third generation, time- and tissue-specific conditional knockout model of the L-type Ca2+ channel Cav1.2 (Cav1.2SMAKO mice) to genetically dissect the effects of mibefradil on T- and L-type Ca2+ channels. Myogenic tone and phenylephrine-induced contraction in hindlimb perfusion experiments were sensitive to mibefradil in control mice, whereas the drug showed no effect in Cav1.2-deficient animals. Mean arterial blood pressure in awake, freely moving control mice was reduced by 38+/-2.5 mm Hg at a dose of 1.25 mg/kg bodyweight mibefradil, but not changed in Cav1.2SMAKO mice. These results demonstrate that the effect of the putative T-type Ca2+ channel-selective blocker mibefradil on blood pressure and small vessel myogenic tone is mediated by the Cav1.2 L-type Ca2+ channel.

Animals↗

PubMed2002

Effect of calcium channel antagonist diltiazem and calcium ionophore A23187 on cyclosporine A-induced apoptosis of renal tubular cells.

Calcium channel antagonists have been reported to have a favorable impact on cyclosporin A (CsA)-treated kidney transplant recipients. However, it is not clear whether this is because of their direct effect on antagonizing the toxicity of CsA to renal tubular cells. In this study, we have used Madin-Darby canine kidney tubular cells as a model to examine the effect of diltiazem, a calcium channel antagonist, on CsA-induced apoptosis. Moreover, to investigate the possible regulation of CsA cytotoxicity by intracellular calcium level, the effect of the calcium ionophore A23187 on CsA-induced apoptosis was also examined. We found that treatment of CsA (20 microM) alone caused 20-30% cell death, which was apparently (30-40%) enhanced by diltiazem at 100 microg/ml, accompanied by more severe DNA fragmentation, activation of caspases, and a decreased level of Bcl-2. The caspase inhibitor ZVAD-fmk or Bcl-2 overexpression was capable of suppressing apoptosis induced by the synergistic effect of diltiazem and CsA. Moreover, the survival rate of cells treated with CsA (30 microM) alone remained only 30%, however, it was markedly (approximately 40%) elevated by co-treatment with A23187 (75 ng/ml). The rescue of cells from CsA-induced apoptosis by A23187 was correlated with AKT activation, BAD phosphorylation, and caspase-3 inactivation. Taken together, our results suggest that the reported favorable impact of diltiazem on kidney grafts is likely not because of its direct protection on renal tubular cells. Instead, it enhances the toxicity of CsA to renal tubular cells. In addition, our findings raise a possibility that the intracellular calcium level and the AKT pathway may participate in the regulation of CsA cytotoxicity.

Animals↗

PubMed1987

Parathyroid hormone-activated calcium channels in an osteoblast-like clonal osteosarcoma cell line. cAMP-dependent and cAMP-independent calcium channels.

Changes in free cytosolic calcium were measured in UMR-106 cells in response to parathyroid hormone (PTH) stimulation. Bovine PTH-(1-34) induced an increase in [Ca2+]i with the contour of the rise in [Ca2+]i occurring in three successive phases: a rapid increase in [Ca2+]i occurring within seconds, rapid decrement in [Ca2+]i to near-resting levels within 1 min, and slow increment in [Ca2+]i. Phase one and phase three increases in [Ca2+]i were dependent on medium calcium. The phase one rise in [Ca2+]i was inhibitable by the calcium channel blockers lanthanum and verapamil. Only the phase one rise in [Ca2+]i was blocked by preincubation of the cells with the phorbol ester, phorbol 12-myristate 13-acetate. This channel was also blocked when cellular cAMP levels were increased prior to PTH stimulation. The phase two decrement of [Ca2+]i was due to the rapid inactivation of the phase one calcium channel. The phase three rise in [Ca2+]i was mediated by cellular cAMP levels. This cAMP-dependent Ca2+ channel was insensitive to pretreatment of the cells with phorbol diesters and showed low sensitivity to Ca2+ channel blockers. It is concluded that UMR-106 cells respond to PTH stimulation by the activation of a cAMP-independent Ca2+ channel. This channel rapidly inactivates. The subsequent PTH-dependent increase in cellular cAMP is followed by activation of a cAMP-dependent Ca2+ channel resulting in a slow rise in [Ca2+]i.

Animals↗

PubMed2000

A suicide attempt with an oral calcium channel blocker.

Calcium channel blockers are widely used in all-aged populations. The drugs are generally safe in therapeutic dosage, but severe side effects with elevated intake are increasingly described, mainly in adult patients. We report an adolescent girl who intentionally ingested an overdose of nifedipine.

Adolescent↗

PubMed1997

Toxins affecting calcium channels in neurons.

Calcium enters the cytoplasm mainly via voltage-activated calcium channels (VACC), and this represents a key step in the regulation of a variety of cellular processes. Advances in the fields of molecular biology, pharmacology and electrophysiology have led to the identification of several types of VACC (referred to as T-, N-, L-, P/Q- and R-types). In addition to possessing distinctive structural and functional characteristics, many of these types of calcium channels exhibit differential sensitivities to pharmacological agents. In recent years a large number of toxins, mainly small peptides, have been purified from the venom of predatory marine cone snails and spiders. Many of these toxins have specific actions on ion channels and neurotransmitter receptors, and the toxins have been used as powerful tools in neuroscience research. Some of them (omega-conotoxins, omega-agatoxins) specifically recognize and block certain types of VACC. They have common structural backbones and some been synthesized with identical potency as the natural ones. Natural, synthetic and labeled calcium channel toxins have contributed to the understanding of the diversity of the neuronal calcium channels and their function. In particular, the toxins have been useful in the study of the role of different types of calcium channels on the process of neurotransmitter release. Neuronal calcium channel toxins may develop into powerful tools for diagnosis and treatment of neurological diseases.

Amino Acid Sequence↗

PubMed1995

Mechanisms of the potent and long-lasting antihypertensive action of the new calcium channel blocker pranidipine. Evidence for strong affinity to the calcium channels or membranes.

To elucidate the mechanisms of the potent and long-lasting antihypertensive action of pranidipine (CAS 99522-79-9, OPC-13340), a wash-out experiment in isolated rat aorta preparations and a displacement binding experiment of (+)[3H]PN200-110 (isradipine) with pranidipine and other dihydropyridines to porcine skeletal T-tubules was conducted. It was revealed that the inhibition of KCl-induced contraction by pranidipine remained complete even after washing out the drug 9 times. Also, pranidipine had the lowest Ki value for (+)[3H]PN200-110 binding in skeletal T-tubules. The lipophilicity of pranidipine measured by octanol-buffer partition coefficient was the highest among the tested compounds, and the order of lipophilicity coincided with the order of potency in the displacement binding experiments. These results suggest that pranidipine has a very high affinity to Ca channels or to T-tubule membranes, and strongly support the "membrane-bilayer pathway hypothesis" which assumes the partitioning of the drug into the lipid bilayer before drug binding to Ca channels as an explanation of the potent and long-lasting action of pranidipine compared with other dihydropyridines.

Animals↗

PubMed2005

[Clinically significant drug-drug and drug-food interactions associated with calcium channel blockers].

Calcium channel blockers have been widely used for treatment of hypertension, angina pectoris, arrhythmia, and other heart diseases. Nowadays, combination therapy is widely common for these diseases. However, combination therapy is associated with increasing risks of pharmacokinetic or pharmacodynamic drug-drug interaction, and therefore clinicians should pay attention to prevent it. Furthermore, in addition to drug-drug interactions, we need to be cautions for drug interaction with food and drink including health-food and supplement.

Calcium Channel Blockers↗

PubMed2000

Rat dorsal root ganglia express distinctive forms of the alpha2 calcium channel subunit.

Calcium channel alpha2 delta subunit is a glycosylated structural subunit consistent of the alpha2 subunit and the delta peptide. Previous studies have indicated distinctive alpha2 subunit expression in rat spinal cord and dorsal root ganglia (DRG). This study examined whether differential glycosylation underlies the molecular basis of distinct alpha2 delta subunits. The migration patterns of deglycosylated alpha2 subunits from rat spinal cord, DRG, brain and skeletal muscle were compared in Western blots. The data reported indicate that there are two forms of the alpha2 subunit in DRG that are different from the alpha2 subunit in other tissues examined, at least at the glycosylation level. Thus, post-translational modification may be important in tissue specific and functional expression of the alpha2 delta subunit.

Animals↗

PubMedDate not supplied

The ascidian dihydropyridine-resistant calcium channel as the prototype of chordate L-type calcium channel.

This review describes recent findings on voltage-gated Ca channel (Cav channel) cloned from ascidians, the most primitive chordates. Ascidian L-type like Cav channel has several unusual features: (1). it is closely related to the prototype of chordate L-type Cav channels by sequence alignment; (2). it is resistant to dihydropyridine due to single amino acid change in the pore region, and (3). maternally provided RNA putatively encodes a truncated protein which has remarkable suppressive effect on Cav channel expression during development. Ascidian Cav channel will provide a useful molecular clue in the future to understand Ca(2+)-regulated cell differentiation and physiology with the background of recently defined ascidian genome and molecular biological tools.

Amino Acid Sequence↗

PubMed1996

Blood pressure and cationic transport systems during combined calcium channel blocker and calcium administration in males.

A double-blind, placebo-controlled parallel study was conducted on the effects of a high daily oral supplementation of 1 g elemental calcium, given twice daily for 16 weeks, followed by additional administration of 2 mg b.i.d. lacidipine or placebo for 8 weeks, on blood pressure, intracellular cationic concentrations and transport systems, plasma total calcium, ionized calcium and calciotropic hormones in normal male subjects. No significant difference in the effect of lacidipine vs. placebo on standing or recumbent systolic or diastolic blood pressure or heart rate was found between calcium- and placebo-treated subjects. The difference in lacidipine effect on erythrocyte Mg2+ concentration and platelet membrane cholesterol content between the placebo and calcium groups was statistically significant. There was no additional effect between groups of lacidipine on erythrocyte and platelet intracellular Ca2+, Na+ and K+ concentrations or transport systems and on plasma Ca2+ levels and calciotropic hormones. Combined calcium and lacidipine administrations in normal male subjects did not induce antihypertensive effects different from those induced by either agent alone.

Administration, Oral↗

PubMed1991

Improved outcome of cadaveric renal transplantation due to calcium channel blockers.

Calcium channel blockers (CCB) administered to recipients of cadaveric renal transplants have been shown to improve graft function, decrease the incidence of delayed function, prevent acute cyclosporine toxicity, and lessen the number of rejection episodes in the first several weeks posttransplant. In order to determine whether CCB provide a similar long-term benefit, a retrospective analysis of 83 first cadaveric renal transplants performed in 1987 and 1988 was performed. The clinical course of 17 patients who were discharged and maintained on CCB therapy for 1 year was compared with that of 24 patients who never received CCB during the same 1-year period. The remaining 42 patients were excluded for failing to meet these inclusion criteria. The two groups were similar with respect to age, sex, cold ischemia time, degree of sensitization, HLA matching, DR matching, and DR mismatching. The no CCB group did receive a significantly greater number of pretransplant transfusions. In the 1 year of follow-up, graft loss in the CCB group was less than in the no CCB group (1/17, 5.9% vs. 6/24, 25%). There was a striking decrease in the percentage of first rejection episodes in the CCB group as compared with no CCB therapy (35% vs. 83%, P less than 0.005). In addition, a similar decrease in second rejection episodes was found in the CCB group (18% vs. 33%, P less than 0.05). The two groups also were compared with respect to graft function. Despite similar serum creatinine levels at 1 month (CCB 1.8 mg% vs. no CCB 2.2 mg%, P = 0.37) and 1 year (CCB 1.7 mg% vs. no CCB 2.4 mg%, P = 0.19), the CCB group had a significantly higher glomerular filtration rate at 1 month (53.9 vs. 38.7, P less than 0.05) and 1 year (57.0 vs. 35.0, P less than 0.001) as measured by clearance of radiolabeled iothalamate. These results suggest that the short-term improvements noted in both graft function and rejection episodes with CCB are maintained for the first year posttransplant. More importantly, CCB use results in improved 1-year graft survival.

Adult↗

PubMed1998

Single-channel properties of L-type calcium channels from failing human ventricle.

OBJECTIVE: The aim of our study was to analyse the single-channel properties of L-type calcium channels from failing human heart and to compare them to the respective animal data. Furthermore, we intended to evaluate the feasibility of future single-channel studies on the role of calcium channels in the pathophysiology of heart failure. METHODS: Single L-type calcium channels were recorded in ventricular myocytes from explanted failing human heart, using the cell-attached configuration of the patch-clamp technique. RESULTS: One or more successful registrations of calcium channels could be obtained in 11 of 19 cell isolations. Determination of single-channel conductance yielded a mean value of 16.6 +/- 1.2 pS (70 mM Ba2+ as the charge carrier) under control conditions and 23.7 +/- 2.8 pS in presence of the calcium-channel agonist FPL 64176. The rapid gating process could be described by a C<-->C<-->O gating scheme. Slow gating analysis revealed a highly significant clustering of active and non-active sweeps. CONCLUSION: Single-channel measurements of L-type calcium channels in human failing ventricle are feasible and reproducible despite the varying patient characteristics. Their channel properties are qualitatively comparable to those found in other mammals. Whether there are quantitative differences due to the underlying heart failure can be elucidated in further studies.

Adult↗