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PubMedDate not supplied

Prenatal toxicity studies in rats and rabbits with the calcium channel blocker diproteverine.

In prenatal toxicity studies, diproteverine, a calcium channel blocker with demonstrated antianginal properties, produced an unusual pattern of digital, heart, tail, and vertebral defects in rat fetuses from mothers treated during the major period of organogenesis, but only a very low incidence of heart abnormalities was seen in the rabbit. Heart changes were rarely seen in association with digital defects. The findings were consistent with those seen with other calcium channel blockers and add weight to the suggestion of Danielsson and colleagues (5) that digital malformations are a class effect for this type of compound, the effects being related to reduced uteroplacental blood flow. In addition, it is proposed that cardiovascular malformations are also a class response with calcium channel blockers. The distribution of fetal death and hemorrhages and the varying association between cardiovascular, digital, and tail abnormalities seen in the rat with increasing doses of diproteverine fits the pattern of changes reported following hypoxia in the chick embryo. Reduced uteroplacental blood flow with resultant embryonic hypoxia secondary to pharmacologic action is considered a probable mechanism of action for the induction of abnormalities produced by calcium channel blockers.

Abnormalities, Multiple↗

PubMed1987

Heterogeneity of calcium channels from a purified dihydropyridine receptor preparation.

Dihydropyridine receptors were purified from rabbit skeletal muscle transverse tubule membranes and incorporated into planar lipid bilayers. Calcium channels from both the purified dihydropyridine receptor preparation and the intact transverse tubule membranes exhibited two sizes of unitary currents, corresponding to conductances of 7 +/- 1 pS and 16 +/- 3 pS in 80 mM BaCl2. Both conductance levels were selective for divalent cations over monovalent cations and anions. Cadmium, an inorganic calcium channel blocker, reduced the single channel conductance of calcium channels from the purified preparation. The organic calcium channel antagonist nifedipine reduced the probability of a single channel being open with little effect on the single channel conductance. The presence of two conductance levels in both the intact transverse tubule membranes and the purified dihydropyridine receptor preparation suggests that the calcium channel may have multiple conductance levels or that multiple types of calcium channels with closely related structures are present in transverse tubule membranes.

Animals↗

PubMed2000

Calcium channels controlling acetylcholine release from preganglionic nerve terminals in rat autonomic ganglia.

Little is known about the nature of the calcium channels controlling neurotransmitter release from preganglionic parasympathetic nerve fibres. In the present study, the effects of selective calcium channel antagonists and amiloride were investigated on ganglionic neurotransmission. Conventional intracellular recording and focal extracellular recording techniques were used in rat submandibular and pelvic ganglia, respectively. Excitatory postsynaptic potentials and excitatory postsynaptic currents preceded by nerve terminal impulses were recorded as a measure of acetylcholine release from parasympathetic and sympathetic preganglionic fibres following nerve stimulation. The calcium channel antagonists omega-conotoxin GVIA (N type), nifedipine and nimodipine (L type), omega-conotoxin MVIIC and omega-agatoxin IVA (P/Q type), and Ni2+ (R type) had no functional inhibitory effects on synaptic transmission in both submandibular and pelvic ganglia. The potassium-sparing diuretic, amiloride, and its analogue, dimethyl amiloride, produced a reversible and concentration-dependent inhibition of excitatory postsynaptic potential amplitude in the rat submandibular ganglion. The amplitude and frequency of spontaneous excitatory postsynaptic potentials and the sensitivity of the postsynaptic membrane to acetylcholine were unaffected by amiloride. In the rat pelvic ganglion, amiloride produced a concentration-dependent inhibition of excitatory postsynaptic currents without causing any detectable effects on the amplitude or configuration of the nerve terminal impulse. These results indicate that neurotransmitter release from preganglionic parasympathetic and sympathetic nerve terminals is resistant to inhibition by specific calcium channel antagonists of N-, L-, P/Q- and R-type calcium channels. Amiloride acts presynaptically to inhibit evoked transmitter release, but does not prevent action potential propagation in the nerve terminals, suggesting that amiloride may block the pharmacologically distinct calcium channel type(s) on rat preganglionic nerve terminals.

Acetylcholine↗

PubMed1990

The dihydropyridine-sensitive calcium channel of the skeletal muscle: biochemistry and structure.

The dihydropyridine-sensitive calcium channel of the rabbit skeletal muscle is the first voltage-gated calcium channel which has been purified and biochemically characterized. The alpha 1-subunit, a 165 kDa protein, of the purified dihydropyridine receptor contains all regulatory sites of a L-type calcium channel and the calcium conducting unit. The purpose of this review is to summarize and discuss recent findings on the structure and possible function of the skeletal muscle calcium channel subunits.

Animals↗

PubMed1985

Agonists Bay-K8644 and CGP-28392 open calcium channels reconstituted from skeletal muscle transverse tubules.

The recently described calcium channel agonists Bay-K8644 and CGP-28392 have been used to induce long-term opening of calcium channels from purified rat muscle transverse tubules (t-tubules) incorporated into planar phospholipid bilayers. Agonist-open channels are selective for divalent cations (except Mg++), display voltage-dependent kinetics, and are blocked by the calcium channel antagonist, nitrendipine. The sensitivity to dihydropyridine agonists and antagonists indicate that a pool of t-tubule calcium channels remain functional after membrane fractionation and purification.

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

PubMedDate not supplied

Blockade of mammalian and invertebrate calcium channels by lead.

We have compared the effects of Pb2+ on voltage-dependent calcium channels of the marine mollusc Aplysia, studied with a two electrode voltage clamp, with those on calcium channels in cultured rat dorsal root ganglion (DRG) neurons studied with whole cell patch clamp. In both preparations Pb2+ was a potent blocker of calcium channel currents at concentrations that did not significantly affect potassium and sodium currents. The blockade was concentration dependent and the percentage of blockade was reduced when the concentration of the charge carrier was elevated. In Aplysia the threshold Pb2+ concentration was about 1 microM, and the Hill coefficient near 1.0 under all conditions. Pb2+ did not significantly change inactivation but shifted the voltage dependence of activation to hyperpolarized voltages in a dose-dependent manner. The blockade of calcium currents by Pb2+ was highly voltage dependent and increased with depolarization. Rat dorsal root ganglion cells exhibit three different types of voltage-dependent calcium channels (N, L and T) which can be distinguished by the potential at which the channel activates or inactivates and by their sensitivity to pharmacologic antagonists. The IC50 for blockade of the L current was 1.03 microM with a Hill slope of 1.15. Currents elicited by voltage steps which activate N plus L currents had an IC50 of 0.64 microM and a Hill slope of 1.16. T currents were less sensitive, having an IC50 of 6 microM. Sodium and potassium currents were relatively unaffected in both preparations at concentrations at which the calcium channel was blocked more than 60% (1 microM or 200 microM respectively). The blockade in DRG neurons was less voltage-dependent and reversible than that in the invertebrate model system. These observations indicate that Pb2+ is a potent, reversible and selective blocker of voltage-dependent calcium channels at low concentrations.

Animals↗

PubMed1988

Amiloride selectively blocks the low threshold (T) calcium channel.

More than one type of voltage-gated calcium channel has been identified in muscle cells and neurons. Many specific organic and inorganic blockers of the conventional, slowly inactivating high threshold (L) calcium channel have been reported. No specific blockers of the low threshold (T) channel have been as yet identified. Amiloride, a potassium sparing diuretic, has now been shown to selectively block the low threshold calcium channel in mouse neuroblastoma and chick dorsal root ganglion neurons. The selective blockade of the T-type calcium channel will allow identification of this channel in different tissues and characterization of its specific physiological role.

Amiloride↗

PubMed2003

Voltage-operated calcium channel heterogeneity in pancreatic beta cells: physiopathological implications.

Voltage-operated calcium channels play crucial roles in stimulus-secretion coupling in pancreatic beta cells. A growing body of evidence indicates that these channels in beta cells are heterogeneous. In particular, not all the high-threshold calcium channels expressed belong to the best known L-type. In rat insulinoma cells, for example, L, N, and P/Q-type channels are present, while in human beta cells L-type and P/Q-type dominate. Where present, N-type and P/Q-type channels participate, alongside with the dominant L-type, in the control of sugar- or depolarization-induced hormone release. Distinct biophysical properties and selective modulation of the channel subtypes are likely to play important physiological roles. T-type channels are involved in beta cell apoptosis, while calcium channel autoantibodies recognizing high-threshold channels in beta cells, have been described both in neurological and diabetic patients. Subtype-selective calcium channel drugs have the potential for being beneficial in beta cell pathological states.

Animals↗

PubMed2001

Differentiation of NG108-15 cells induced by the combined presence of dbcAMP and dexamethasone brings about the expression of N and P/Q types of calcium channels and the inhibitory influence of muscarinic receptors on calcium influx.

Differentiation of cholinergic cell line NG108-15 induced by a combination of dibutyryl cyclic AMP (dbcAMP) and dexamethasone enhances the cholinergic phenotype of the cells more than that induced by either agent alone. We investigated the effect of treatment with dbcAMP and dexamethasone on potassium depolarization-evoked influx of calcium and its regulation by the muscarinic agonist carbachol. Depolarization of control cells and of cells differentiated in the presence of dbcAMP or dexamethasone alone, or in the combined presence of dbcAMP and dexamethasone induced, respectively, 2.2-, 4.3-, 2.7- and 10.7-fold increases of the resting [Ca(2+)](i). Dexamethasone alone and the combination of dbcAMP and dexamethasone augmented the number of muscarinic receptors by 25 and 40%, respectively. Inhibitors of N (omega-conotoxin GVIA) or P/Q (omega-agatoxin TK) calcium channels had no effect on Ca(2+) influx in control cells, whereas in cells differentiated in the combined presence of dbcAMP and dexamethasone they significantly diminished the influx of Ca(2+) by 20 and 5%, respectively. Carbachol attenuated calcium influx in differentiated cells in an atropine-insensitive manner if it was present during stimulation. This effect of carbachol was probably due to an open-channel block of L type channels. In the presence of nifedipine, carbachol attenuated the influx of Ca(2+) into cells differentiated with dbcAMP and dexamethasone by 20% in an atropine-sensitive way. Data show that differentiation of NG108-15 cells by dbcAMP and dexamethasone promotes the expression of functional nifedipine-insensitive N and P/Q types of Ca(2+) channels and that the nifedipine-insensitive calcium influx becomes subject to inhibitory regulation by muscarinic receptors.

Animals↗

PubMed2002

Interaction between brain L-type calcium channels and alpha2-adrenoceptors in the inhibition of sodium appetite.

Calcium channels mediate the actions of many drugs. The present work investigated whether diltiazem, an L-type calcium channel blocker, alters the inhibition of sodium appetite induced by noradrenaline and the alpha2-adrenoceptor agonist clonidine. Adult male Holtzman rats (N=4-8) with cannula implanted into the third cerebral ventricle were submitted to sodium depletion (furosemide sc+24-h removal of ambiente sodium). Sodium depleted control animals that received 0.9% NaCl as vehicle injected intracerebroventricularly (i.c.v.) ingested 13.0+/-1.5 ml/120 min of 1.8% NaCl. Intracerebroventricular injection of either noradrenaline (80 nmol) or clonidine (20 nmol) inhibited 1.8% NaCl intake from 70 to 90%. Prior i.c.v. injection of diltiazem (6-48 nmol) inhibited from 50 to 100% the effect of noradrenaline and clonidine in a dose-response manner. Diltiazem alone at 100 nmol inhibited, but at 50 nmol had no effect on, sodium appetite. The results suggest: (1) common ionic mechanisms involving calcium channels for the inhibition that noradrenaline and clonidine exert on sodium appetite and (2) a dual role for the benzothiazepine site of L-type calcium channels in the control of sodium appetite.

Adrenergic alpha-Agonists↗

PubMed2005

Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering.

Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the alpha(1)2.1 subunit of Ca(v)2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K(v) voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K(v) channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K(v) channels, reduced the frequency of restraint- and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K(v) channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K(v) channels. That both stress- and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.

4-Aminopyridine↗

PubMedDate not supplied

Calcium channel modulation by neurotransmitters, enzymes and drugs.

Calcium channels in excitable membranes are of great importance for many cellular functions. Modulation of these channels by neurotransmitters and drugs regulates calcium influx into the cell and thereby alters the functional state of the cell. Recently it has become possible to measure properties of single calcium channels directly and to obtain evidence on mechanisms of their modulation.

Animals↗

PubMed2004

R-type calcium channels in myenteric neurons of guinea pig small intestine.

Currents carried by L-, N-, and P/Q-type calcium channels do not account for the total calcium current in myenteric neurons. This study identified all calcium channels expressed by guinea pig small intestinal myenteric neurons maintained in primary culture. Calcium currents were recorded using whole cell techniques. Depolarizations (holding potential = -70 mV) elicited inward currents that were blocked by CdCl(2) (100 microM). Combined application of nifedipine (blocks L-type channels), Omega-conotoxin GVIA (blocks N-type channels), and Omega-agatoxin IVA (blocks P/Q-type channels) inhibited calcium currents by 56%. Subsequent addition of the R-type calcium channel antagonists, NiCl(2) (50 microM) or SNX-482 (0.1 microM), abolished the residual calcium current. NiCl(2) or SNX-482 alone inhibited calcium currents by 46%. The activation threshold for R-type calcium currents was -30 mV, the half-activation voltage was -5.2 +/- 5 mV, and the voltage sensitivity was 17 +/- 3 mV. R-type currents activated fully in 10 ms at 10 mV. R-type calcium currents inactivated in 1 s at 10 mV, and they inactivated (voltage sensitivity of 16 +/- 1 mV) with a half-inactivation voltage of -76 +/- 5 mV. These studies have accounted for all of the calcium channels in myenteric neurons. The data indicate that R-type calcium channels make the largest contribution to the total calcium current in myenteric neurons. The relatively positive half-activation voltage and rapid activation kinetics suggest that R-type channels could contribute to calcium entry during somal action potentials or during action potential-induced neurotransmitter release.

Animals↗

PubMed1997

A toxin from the spider Phoneutria nigriventer that blocks calcium channels coupled to exocytosis.

1. The aim of the present experiments was to investigate the pharmacological action of a toxin from the spider Phoneutria nigriventer, Tx3-3, on the function of calcium channels that control exocytosis of synaptic vesicles. 2. Tx3-3, in confirmation of previous work, diminished the intracellular calcium increase induced by membrane depolarization with KCl (25 mM) in rat cerebrocortical synaptosomes. The toxin was very potent (IC50 0.9 nM) at inhibiting calcium channels that regulate calcium entry in synaptosomes. In addition, Tx3-3 blocked the exocytosis of synaptic vesicles, as measured with the fluorescent dye FM1-43. 3. Using omega-toxins that interact selectively with distinct neuronal calcium channels, we investigated whether the target of Tx3-3 overlaps with known channels that mediate exocytosis. The results indicate that the main population of voltage-sensitive calcium channels altered by Tx3-3 can also be inhibited by omega-agatoxin IVA, an antagonist of P/Q calcium channels. Omega-conotoxin GVIA, which inhibits N type calcium channels did not decrease significantly the entry of calcium or exocytosis of synaptic vesicles in depolarized synaptosomes. 4. It is concluded that Tx3-3 potently inhibits omega-agatoxin IVA-sensitive calcium channels, which are involved in controlling exocytosis in rat brain cortical synaptosomes.

Animals↗

PubMed1989

Role of voltage-dependent calcium channels in secretion of calcitonin from human medullary thyroid carcinoma cells.

Extracellular calcium concentration is an important regulator of calcitonin secretion. We used primary cell cultures of human medullary thyroid carcinoma to study the role of voltage dependent calcium channels for stimulus secretion coupling. Increasing extracellular calcium concentration (1.6-5.0 mM) in the medium caused a dose dependent release of calcitonin. The calcium channel activator BAY K 8644, a dihydropyridine, stimulated calcitonin secretion in a dose dependent manner (10(-7)-10(-5) M). This effect was completely inhibited by equimolar concentrations of the calcium channel blocker nifedipine and abolished in the absence of extracellular calcium. Similarly, nifedipine suppressed the stimulatory action of extracellular calcium. The effects of calcium and BAY K 8644 with and without nifedipine suggest that calcium influx via voltage dependent calcium channels plays an important role in calcitonin secretion. The primary cell culture of human medullary thyroid carcinoma is a good model for the study of stimulus secretion coupling.

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

PubMed1996

Spinal antinociceptive action of an N-Type voltage-dependent calcium channel blocker and the synergistic interaction with morphine.

BACKGROUND: Four different voltage-dependent calcium channels (L-, N-, T-, and P-types) are distinguished in the central nervous system. Both L- and N-type calcium channels have been implicated in the release of neurotransmitters from sensory neurons in the spinal cord. It has been demonstrated that intrathecal L-type calcium channel blockers, which alone do not exhibit any antinociceptive effects, potentiate the antinociceptive effect of intrathecal morphine. The current study was designed to investigate the antinociceptive effects of the intrathecally administered N-type calcium channel blocker, omega-conotoxin GVIA (omega-CgTx). The interaction between morphine and omega-CgTx at the level of the spinal cord also was examined. METHODS: In male Sprague-Dawley rats, lumbar intrathecal catheters were chronically implanted. Tail flick and mechanical paw pressure tests were used to assess thermal and mechanical nociceptive thresholds, respectively. Morphine, omega-CgTx, or a combination of morphine and omega-CgTx was administered intrathecally, and the nociceptive thresholds were determined. Isobolographic analyses were used to define the nature of the functional interactions between morphine and omega-CgTx. RESULTS: Intrathecal omega-CgTx produced antinociception in a dose- and time-dependent manner. Isobolographic analyses revealed that intrathecal omega-CgTx and morphine interacted synergistically in both nociceptive tests. CONCLUSIONS: This study indicates the importance of the N-type calcium channel in the spinal cord on nociception and suggests the functional interaction between the N-type calcium channel blocker and opioid at the level of the spinal cord.

Analgesics↗

PubMed1985

Therapeutic application of calcium-channel antagonists for pulmonary hypertension.

Calcium-channel antagonists may provide an effective approach to the treatment of pulmonary hypertensive disorders. Biochemical evidence suggests that pulmonary vasoconstriction results from the transmembrane flux of calcium into vascular smooth muscle; accordingly, the pulmonary pressor responses in experimental hypoxic pulmonary hypertension can be attenuated by verapamil and nifedipine. In patients with chronic obstructive lung disease, nifedipine decreases pulmonary artery pressures and pulmonary vascular resistance in proportion to the severity of hypoxemia before treatment. However, little pulmonary vasodilator effect is seen when hypoxemia is corrected by inhalation of oxygen, and systemic arterial oxygen desaturation can occur after nifedipine in patients breathing room air; most importantly, long-term studies in patients with chronic lung disease are lacking. In selected patients with primary pulmonary hypertension and other obliterative diseases of the pulmonary vasculature, nifedipine produces short- and long-term hemodynamic improvement at rest and during exercise, and these benefits are frequently paralleled by amelioration of dyspnea and fatigue. However, in patients in whom right ventricular function has been severely compromised by chronic pressure overload, both verapamil and nifedipine may exert notable depressant effects on right ventricular performance, despite the decrease in right ventricular afterload that would be expected to accompany a decrease in pulmonary vascular resistance. These negative inotropic actions may result in serious deleterious clinical reactions. Although calcium-channel antagonists represent a promising approach to the management of patients with pulmonary hypertension, the long-term efficacy and safety of these drugs in this disorder remain to be established.

Animals↗

PubMed1996

The IVS6 segment of the L-type calcium channel is critical for the action of dihydropyridines and phenylalkylamines.

The current through the L-type calcium channel is inhibited and stimulated by distinct dihydropyridines at very low concentrations. The molecular determinants for the high affinity block and stimulation were investigated using chimeras between the class C and E calcium channels. Mutation of three amino acids in the last putative transmembrane segment (IVS6) of the alpha1C subunit decreased the affinity for (+)isradipine 100-fold without significantly affecting the basic properties of the expressed channel. Mutation of two of these three amino acids completely abolished the stimulatory effect of the calcium channel agonist Bay K 8644. These mutations only slightly affected the blocking efficacy of mibefradil and the phenylalkylamine devapamil. Three distinct but adjacently located amino acids mediated the high affinity block by devapamil. These results suggest that the IVS6 segment of the alpha1C subunit is critical for the high affinity interaction between the L-type calcium channel and the calcium channel agonist Bay K 8644 and the two antagonists isradipine and devapamil.

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