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PubMed1989

[Electrophysiologic effects of calcium channel blockers on supraventricular tachycardia in children].

Calcium channel blockers (diltiazem or verapamil) were administered in 17 pediatric patients with supraventricular tachycardia to evaluate their drug effects on electrophysiologic properties and the tachycardia zone. Using electrophysiologic technique, 10 patients were diagnosed as having orthodromic reciprocating tachycardia (ORT), including three patients with concealed atrioventricular bypass tracts. Four patients were diagnosed as having atrioventricular nodal re-entrant tachycardia (AVNRT) of the slow-fast type and three patients were diagnosed as having intra-atrial re-entrant tachycardia (IART). Diltiazem was given to 10 patients; verapamil, to eight patients at doses of 0.15-0.2 mg/kg intravenously. Electrophysiologic properties and the tachycardia zone were then evaluated before and after the administration of calcium channel blockers. Diltiazem and verapamil produced no significant changes in the sinus node and atrial functions including basic sinus cycle length, sinoatrial conduction time, maximum sinus node recovery time and the effective atrial refractory period. Although sinus cycle length was shortened after verapamil in half the cases, it was due to increased sympathetic tone secondary to hypotension rather than to direct action of verapamil. Calcium channel blockers, however, prolonged the PR interval and significantly increased the effective refractory period of the atrioventricular node. Properties of the atrioventricular bypass tracts were not affected by calcium channel blockers. Diltiazem and verapamil were markedly effective in ORT and AVNRT. Their re-entrant circuits, including the atrioventricular node and the tachycardia zones, were shortened or resolved. However, IART showed no significant change in the tachycardia zone after the administration of calcium channel blockers, because the re-entrant circuit was not present within the atrioventricular node.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1998

Involvement of dihydropyridine-sensitive calcium channels in human dendritic cell function. Competition by HIV-1 Tat.

The entry of extracellular calcium in leukocytes mediates several cellular processes; however, unlike in excitable tissues, the underlying molecular mechanisms are poorly defined. In this paper we provide phenotypical and biochemical evidence that peripheral blood-derived human dendritic cells express dihydropyridine-sensitive calcium channels. Exposure to the dihydropyridine drug nifedipine, which binds L-type calcium channels blocking calcium influx, prevents two dendritic cell functions that are dependent on extracellular calcium entry: apoptotic body engulfment and interleukin-12 production induced by cross-linking of the surface lectin NKRP1A. It is known that exogenous human immunodeficiency virus, type 1 Tat affects several Ca2+-dependent immune cell responses. Here we demonstrate that Tat inhibits apoptotic body engulfment and interleukin-12 production by blocking extracellular calcium influx. This inhibition is prevented by the calcium channel agonist dihydropyridine derivative Bay K 8644, suggesting the involvement of L-type calcium channels. This hypothesis is further supported by the observation that Tat and dihydropyridine drugs compete for binding to dendritic cells. Taken together, these findings indicate that exogenous Tat exerts its inhibitory effects on dendritic cells by blocking dihydropyridine-sensitive L-type calcium channels.

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

PubMed1992

Stable and functional expression of the calcium channel alpha 1 subunit from smooth muscle in somatic cell lines.

Voltage-activated calcium channels are membrane spanning proteins that allow the controlled entry of Ca2+ into the cytoplasm of cells. The principal channel forming subunit of an L-type calcium channel is the alpha 1 subunit. Transfection of Chinese hamster ovary (CHO) cells with complementary DNA encoding the calcium channel alpha 1 subunit from smooth muscle led to the expression of functional calcium channels which bind calcium channel blockers and show the voltage-dependent activation and slow inactivation and unitary current conductance characteristic of calcium channels in smooth muscle. The currents mediated by these channels are sensitive towards dihydropyridine-type blockers and agonists indicating that the calcium channel blocker receptor sites were present in functional form. The smooth muscle alpha 1 subunit cDNA alone is sufficient for stable expression of functional calcium channels with the expected kinetic and pharmacological properties in mammalian somatic cells.

Animals↗

PubMed2002

Functional interaction between mouse spermatogenic LVA and thapsigargin-modulated calcium channels.

The acrosome reaction in mouse is triggered by a long-lasting calcium signaling produced by a chain of openings of several calcium channels, a low-voltage-activated (LVA) calcium channel, an inositol trisphosphate receptor (IP(3)R), and the store-operated calcium channel TRP2. Since mature sperm cells are refractory to patch clamp experiments, we study the functional interactions among those sperm calcium channels in spermatogenic cells. We have studied the role of cytosolic calcium in voltage-dependent facilitation of low voltage-activated calcium channels. Calcium concentration was modified through the inclusion of the calcium buffers, EGTA and BAPTA, in the recording pipette solution, and by addition of calcium modulators like thapsigargin and the calcium ionophore A23187. We demonstrate that lowering calcium concentration below resting level allows to evidence a voltage-dependent facilitation. We also show that LVA calcium channels present strong voltage-dependent inhibition by thapsigargin. This effect is independent of cytosolic calcium elevation secondary to calcium store depletion and to the activation of TRP channels. Our data evidence an interesting functional relationship, in this cell type, between LVA channels and proteins whose activity is related to calcium filling state of the endoplasmic reticulum (presumably TRP channels and inositol triphosphate receptor). These relationships may contribute to the regulation of calcium signaling during acrosome reaction of mature sperm cell.

Animals↗

PubMed2006

Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker.

Benidipine is a dihydropyridine-derived calcium channel blocker developed in Japan, with several unique mechanisms of action, that is, triple calcium channels (L, N, and T) blocking action with a membrane approach. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate anti-hypertensive effects are not achieved by ARBs alone, indicating that benidipine is an useful calcium channel blocker in combination therapy for hypertension. Benidipine was launched on the Japanese market 14 years ago, but few severe side effects have been reported, suggesting that this is a drug with established safety and long-acting pharmacological effects.

Angina Pectoris↗

PubMed2000

Neuronal distribution and functional characterization of the calcium channel alpha2delta-2 subunit.

The auxiliary calcium channel alpha2delta subunit comprises a family of three genes, alpha2delta-1 to 3, which are expressed in a tissue-specific manner. alpha2delta-2 mRNA is found in the heart, skeletal muscle, brain, kidney, liver and pancreas. We report here for the first time the identification and functional characterization of alpha2delta-2 splice variants and their mRNA distribution in the mouse brain. The splice variants differ in the alpha2 and delta protein by eight and three amino acid residues, respectively, and are differentially expressed in cardiac tissue and human medullary thyroid carcinoma (hMTC) cells. In situ hybridization of mouse brain sections revealed the highest expression of alpha2delta-2 mRNA in the Purkinje cell layer of the cerebellum, habenulae and septal nuclei, and a lower expression in the cerebral cortex, olfactory bulb, thalamic and hypothalamic nuclei, as well as the inferior and superior colliculus. As the in situ data did not suggest a specific colocalization with any alpha1 subunit, coexpression studies of alpha2delta-2 were carried out either with the high-voltage-gated calcium channels, alpha1C, alpha1E or alpha1A, or with the low-voltage-gated calcium channel, alpha1G. Coexpression of alpha2delta-2 increased the current density, shifted the voltage dependence of channel activation and inactivation of alpha1C, alpha1E and alpha1A subunits in a hyperpolarizing direction, and accelerated the decay and shifted the steady-state inactivation of the alpha1G current.

Alternative Splicing↗

PubMed1985

Adverse effects of atrial fibrillation and syncope induced by calcium-channel blockers in hypertrophic cardiomyopathy.

Calcium-channel blockers are useful for the treatment of hypertrophic cardiomyopathy (HCM), but, their adverse effects, especially, those of diltiazem, have not been of much concern. Forty patients with HCM were treated with calcium-channel blockers such as nifedipine, diltiazem, and verapamil. Atrial fibrillation was induced by diltiazem in two patients and verapamil induced syncope in one patient. The clinical and hemodynamic characteristics of the patients were as follows. All of them had the obstructive type of HCM (HOCM). One of them had a high pressure gradient of the left ventricular outflow tract and the others had earlier onset. In these patients, the left atrial overload seemed to be severe. The vasodilating action of calcium-channel blockers decreases the systemic pressure and in turn, may increase the pressure gradient and the left ventricular end-diastolic pressure. The elevated left ventricular end-diastolic pressure causes the left atrial overload which could be at risk of atrial fibrillation in patients with HCM. Therefore, calcium-channel blockers should be used carefully in peculiar cases of HOCM.

Adult↗

PubMed1989

Activation of purified calcium channels by stoichiometric protein phosphorylation.

Purified dihydropyridine-sensitive calcium channels from rabbit skeletal muscle were reconstituted into phosphatidylcholine vesicles to evaluate the effect of phosphorylation by cyclic AMP-dependent protein kinase (PK-A) on their function. Both the rate and extent of 45Ca2+ uptake into vesicles containing reconstituted calcium channels were increased severalfold after incubation with ATP and PK-A. The degree of stimulation of 45Ca2+ uptake was linearly proportional to the extent of phosphorylation of the alpha 1 and beta subunits of the calcium channel up to a stoichiometry of approximately 1 mol of phosphate incorporated into each subunit. The calcium channels activated by phosphorylation were determined to be incorporated into the reconstituted vesicles in the inside-out orientation and were completely inhibited by low concentrations of dihydropyridines, phenylalkylamines, Cd2+, Ni2+, and Mg2+. The results demonstrate a direct relationship between PK-A-catalyzed phosphorylation of the alpha 1 and beta subunits of the purified calcium channel and activation of the ion conductance activity of the dihydropyridine-sensitive calcium channels.

Adenosine Triphosphate↗

PubMed2002

Immunohistochemical localization of voltage-activated calcium channels in the rat oesophagus.

Voltage-activated calcium channels play an important role in the physiology of the enteric nervous system. To determine which types of voltage-activated calcium channels are present in the rat oesophagus, an immunohistochemical study was performed using specific antibodies for the alpha1 subunits of Cav2.1 (P/Q-type), Cav2.2 (N-type), Cav1.2 and Cav1.3 (L-type) calcium channels. All myenteric cell bodies showed Cav2.2 immunoreactivity, whereas labelling for this N-type channel was absent in nerve fibres. Cav1.2 immunoreactivity was found on nerve fibres in the myenteric plexus and on fibres innervating the striated muscle of the rat oesophagus, whereas no labelling was detected on neuronal somata. Immunoreactivity against Cav1.3 was not detected in the myenteric plexus or at the level of the striated muscle. Labelling for Cav2.1 was absent at the level of the myenteric plexus, but present in the striated muscle layer at the level of the motor endplates. Comparison with recent literature data from rat small intestine reveals region-specific distribution patterns of the various subtypes of voltage-activated calcium channels within the enteric nervous system. In addition, the present immunohistochemical data corroborate our physiological data (see accompanying paper), which indicate that the Cav2.2 (N-type) channel is the predominant channel involved in the generation of the calcium-dependent action potential evoked by intrasomatic depolarizing current pulses in all rat oesophageal myenteric neurones.

Animals↗

PubMed2005

[Calcium channel blockers and bone metabolism].

The effects of calcium channel blockers have been studied on calcitropic hormones and cells involved in bone turnover, osteoblasts and osteoclasts. The secretion of parathyroid hormone is affected by calcium channel blockers, but the modes of action seem to depend upon the species of calcium channel blockers. Generally, overall effects of calcium channel blockers on bone metabolisms and bone mineral density should be trivial and the adverse side effects in this field must be negate. Recent development of a new analogue which may act on the calcium channel of osteoblasts and enhance the differentiation of these cells is intriguing.

Animals↗

PubMed1987

Toxins that affect voltage-dependent calcium channels.

At this time, there are five potential candidates for calcium channel specific toxins. All five of these toxins appear to affect the function of voltage-dependent calcium channels. Atrotoxin, beta-leptinotarsin-h and maitotoxin activate channels, whereas both taicatoxin and omega-conotoxin are inhibitors. Neither maitotoxin nor omega-conotoxin alters the binding of dihydropyridines to membranes derived from the cells upon which the toxins exert their effects. In contrast, both atrotoxin and taicatoxin inhibit the binding of dihydropyridines to ventricular membranes. It is not currently known whether beta-leptinotarsin-h affects the binding. The effects of maitotoxin and atrotoxin are blocked by dihydropyridines and verapamil. Direct binding studies with radiolabeled toxins have been performed only with omega-conotoxin, and the binding site density for this toxin appears to be at least one order of magnitude greater than the density of dihydropyridine binding sites in synaptosomes. Studies to examine the third and fourth criteria which we have listed (i.e. that the effects are not via a second messenger, or an enzyme activity) have not been reported for either beta-leptinotarsin-h or omega-conotoxin. Atrotoxin and taicatoxin, added outside a patch pipette, have no effects on calcium channels within the patch and are, therefore, probably not affecting calcium channels via a second messenger. Maitotoxin, however, affects the formation of inositol phosphates and, hence, could be affecting the channel indirectly. The fractions containing the toxic components atrotoxin and taicatoxin have no phospholipase or protease activity, and this is presumably true also for omega-conotoxin since it has been purified to homogeneity. Although all of the toxins have the potential to be important tools with which to study calcium channel structure and function, a number of experiments remain to be done in order to establish conclusively that these five toxins bind specifically to the voltage-dependent calcium channel. In conclusion, we would like to briefly mention why so much effort is being devoted to the search for these calcium channel specific toxins. Such a toxin would provide a very valuable tool in the study of calcium channels for a number of reasons. First, the toxin would be another ligand for the channel and, as such, would provide an alternative to organic ligands such as the dihydropyridines which are lipophilic and, in many tissues, have more than one binding site.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding Sites↗

PubMed1995

Role of calcium channels in parathyroid hormone secretion.

Experimental evidence exists for the presence of parathyroid cell membrane calcium channels that respond to plasma calcium. In previous reports, the effects of various calcium channel agents on PTH secretion have revealed conflicting results. To resolve some of these inconsistencies, we have compared the pure calcium channel agonist, (+)202-791, and its antagonistic enantiomer (-)202-791 with other calcium channel agents--verapamil, nifedipine, and (+)Bay-K-8644. The agonist (+)202-791 enhanced 45Ca+2 uptake and decreased PTH secretion, while the antagonist (-)202-791 decreased 45Ca+2 uptake and increased PTH secretion. The calcium channel appears coupled to a G-protein as indicated by pertussis toxin treatment of the cells. The enantiomers (+/-)202-791 had little effect on intracellular cAMP production suggesting that the calcium channel may not be responsible for the previously observed calcium-mediated changes in cAMP. The antagonist (-)202-791 increased the phosphorylation of a 60-kd protein. The enantiomers (+/-)202-791 did not alter the effect of depolarizing concentrations of potassium on PTH secretion. Our results suggest that calcium channels provide a pathway for the movement of calcium across the plasma membrane and that this pool of calcium regulates, at least in part, PTH secretion.

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

PubMed1990

Potent blocking action of chlorpromazine on two types of calcium channels in cultured neuroblastoma cells.

The effects of chlorpromazine on calcium channel currents were studied in cultured mouse neuroblastoma cells (N1E-115) using the whole-cell variation of the patch-clamp technique. Two types of calcium channel currents (type I and type II) as carried by barium ions were recorded separately on the basis of their different voltage- and time-dependent kinetics. Chlorpromazine reversibly reduced the amplitude of both types of calcium channel currents. The concentration dependence of the calcium channel block indicated a one-to-one binding stoichiometry for both type I and type II currents, with an apparent dissociation constant of 15 microM in both cases. The block of calcium channels was dependent on the holding potential for both type I and type II currents, being enhanced by depolarization. This voltage dependence of the block was due to a higher affinity of chlorpromazine for the inactivated state of the calcium channels than the resting state, as demonstrated by a hyperpolarizing shift of the steady-state inactivation curve. The activation kinetics were not affected by chlorpromazine in either type I or type II current. The time course of inactivation of the type I current was not changed by chlorpromazine, whereas that of the type II current was accelerated, suggesting an involvement of an open channel block. Chlorpromazine block of type I current was independent of the level of test depolarizing pulse, whereas that of type II current was augmented with an increase in depolarization. It was concluded that chlorpromazine binds preferentially to the inactivated form of both type I and type II calcium channels, without affecting the gating kinetics of channel activation.

Animals↗

PubMed2006

Direct G protein modulation of Cav2 calcium channels.

The regulation of presynaptic, voltage-gated calcium channels by activation of heptahelical G protein-coupled receptors exerts a crucial influence on presynaptic calcium entry and hence on neurotransmitter release. Receptor activation subjects presynaptic N- and P/Q-type calcium channels to a rapid, membrane-delimited inhibition-mediated by direct, voltage-dependent interactions between G protein betagamma subunits and the channels-and to a slower, voltage-independent modulation involving soluble second messenger molecules. In turn, the direct inhibition of the channels is regulated as a function of many factors, including channel subtype, ancillary calcium channel subunits, and the types of G proteins and G protein regulatory factors involved. Twenty-five years after this mode of physiological regulation was first described, we review the investigations that have led to our current understanding of its molecular mechanisms.

Animals↗

PubMed1999

L-type calcium channels contribute to the tottering mouse dystonic episodes.

Tottering mice inherit a recessive mutation of the calcium channel alpha1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the tottering mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block L-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced tottering mouse motor episodes. Conversely, the L-type calcium channel agonist Bay K8644 induced stereotypic tottering mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated that L-type calcium channel alpha1C subunit mRNA expression was up-regulated in the Purkinje cells of tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of L-type calcium channels in tottering mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in tottering mice, L-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of L-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.

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

PubMed1988

Effect of calcium channel modulators on isolated endothelial cells.

Indirect evidence, using organic calcium channel modulators suggests that calcium channels exist in endothelial cells. Using freshly prepared and cultured bovine aortic endothelial cells, we have studied the effect of calcium channel modulators on Fura-2 fluorescence and have examined the binding of the dihydropyridine, (+)[3H]PN200-110. In both isolated primary and cultured cells, external calcium (0.5-2 mM) and bradykinin (10(-8) M) increased the intracellular calcium concentration. In cultured cells, the increase in calcium was not significantly attenuated by preincubation with nitrendipine (10(-8) M) or d-cis-diltiazem (10(-6) M). The calcium agonists (-)Bay k8644 and (+)202-791 had no effect on intracellular calcium concentration, but other agonists including ATP (10(-4) M) and thrombin (1.5 micrograms/ml) significantly increased the calcium concentration. Competition binding studies with (+)[3H]PN200-110 indicated specific binding of this ligand with a KD of 57 nM and a Bmax of 2.1 pmol/10(6) cells. While these data do not provide convincing evidence for the existence of calcium channels in cultured or fresh bovine aortic endothelial cells, explanations may yet reconcile our observations with the presence of calcium channels in these cells.

Adenosine Triphosphate↗

PubMed1998

[The role of peptidic toxins in the pharmacological approach of the diversity of calcium channels].

Peptidic toxins extracted from spider, marine snails or snakes venoms, have considerably helped the pharmacological characterization of calcium channels. They have successfully been used for calcium channels mapping. However, the actual situation remains unclear. Genetic investigations demonstrated the existence of a great number of types or sub-types of calcium channels. In recent year a large number of toxins have been purified. Many of these toxins have specific actions on calcium channels and have been used as powerful tools in pharmacological approaches of calcium channels. However the pharmacology of the calcium channels remains very limited, many of them are waiting for the discovery of pharmacological tools allowing their molecular approach in order to determinate their biological implications. In this paper we describe the different families of calcium channels and toxins that interact with these channels. We also recapitulate the "non defined" calcium channels i.e. calcium channel which does not correspond to a N, L, P/Q, R or T type channel and for which no effector are available. We report the discovery and characterization of mapacalcine, a toxin extracted for a marine sponge, as an example of an approach of an undefined calcium channels first characterized by electrophysiological techniques and for which a specific toxin has been purified allowing its pharmacological approach. We also state the possible role of calcium channel toxins in the domain of therapeutic applications.

Calcium Channels↗

PubMed1992

Contractile agonists activate voltage-dependent calcium channels in airway smooth muscle cells.

To determine whether agents that cause contraction of airway smooth muscle affect sarcolemmal calcium channel activity, unitary calcium channel currents (using Ba2+ as the charge carrier) were recorded in on-cell configuration from acutely dissociated (dog, pig, and ferret) and cultured (human) airway smooth muscle cells. Addition of the contractile agonists methacholine or bradykinin increased the open-state probability of the large-conductance calcium channel 37.2- and 45-fold, respectively. The increase in open-state probability was not due to cellular depolarization because increases occurred in the absence of depolarization. Channel activation by the agonist was determined to result in the favoring of a long (16.5 +/- 5.0 ms) open lifetime for the channel, which was not observed under control conditions, in the absence of BAY K 8644. We also report the unitary calcium channel currents from a second, smaller conductance calcium channel. This channel was present in all cell types and had a mean conductance of 9.5 +/- 0.8 pS (80 mM Ba2+). Exposure of cells to agonist also resulted in an increase in the open-channel probability of the small-conductance calcium channel (10.4-fold), which did not result from cellular depolarization. These experiments demonstrate that the molecular pathways exist between contractile agonist receptors and sarcolemmal calcium channels in airway smooth muscle cells. Because membrane patches were not directly exposed to agonist, receptor-channel linkage probably occurs via a second messenger-coupling pathway.

Bradykinin↗