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PubMed1988

Pressor responses induced by Bay K 8644 involve both release of adrenal catecholamines and calcium channel activation.

1. The dihydropyridine calcium channel activator, Bay K 8644, is believed to increase mean arterial blood pressure in several animal models, as a result of direct activation of vascular smooth muscle cells by increasing calcium influx through the voltage-dependent calcium channels. The purpose of the current study was to elucidate further the mechanism of action of Bay K 8644, by examining the possibility that the pressor response to Bay K 8644 may also be the result of indirect activation of the vascular smooth muscle cells by release of adrenal catecholamines. 2. Intravenous administration of Bay K 8644 increased mean arterial pressure in a dose-dependent manner in conscious, normotensive rats. This pressor response was blocked by calcium channel blockers (nifedipine, verapamil, and diltiazem) at doses lower than were necessary to decrease resting mean arterial pressure. 3. alpha-Adrenoceptor antagonists (phentolamine, yohimbine, and prazosin) completely blocked the Bay K 8644-induced pressor responses and converted them to depressor responses. Adrenalectomy did not alter the inhibitory effect of phentolamine on the pressor response to Bay K 8644. However, adrenalectomy or adrenal demedullectomy prevented the phentolamine-induced reversal of the Bay K 8644 pressor response to a depressor response. In addition, adrenalectomy did not affect the ability of phentolamine to reverse the pressor response to exogenous adrenaline administration to a depressor response. 4. These data suggest that the pressor response to Bay K 8644 may involve both direct activation of vascular smooth muscle cells and indirect activation of the muscle cells by release of adrenal catecholamines.

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

PubMed1989

Calcium channel blockers in myocardial infarction.

Calcium channel blockers are currently approved for use in patients with arrhythmias, stable and unstable angina pectoris, and systemic hypertension. The hemodynamic and electrophysiologic properties of these agents suggest that their use would be appropriate in both the immediate and the long-term management of patients who suffered a myocardial infarction. Some experimental evidence accumulated from animal models supports the ability of these drugs to reduce both myocardial infarct size and the incidence of ventricular arrhythmias. The clinical trials with these drugs, however, have yielded disappointing results. Some data suggest a role of diltiazem therapy in reducing the incidence of transmural wall infarction and angina in those patients sustaining non-Q-wave myocardial infarctions. In the setting of Q-wave infarction, calcium channel blockers seem to be less effective than beta-blockade both for acute and long-term management. Finally, calcium channel blockers appear to be contraindicated in patients who have suffered a myocardial infarction and who have concomitant left ventricular dysfunction.

Calcium Channel Blockers↗

PubMedDate not supplied

Evolving role of calcium channel blockers in heart failure.

Calcium channel blockers are theoretically effective in the treatment of chronic systolic heart failure because of their actions as arteriolar dilators, antiischemic agents, and relaxants of diastolic left ventricular function, and because they may prevent progression of myocardial dysfunction. The first-generation calcium channel blockers nifedipine, verapamil, and diltiazem cause hemodynamic and clinical deterioration and may increase the frequency of cardiac events in postmyocardial infarction patients with heart failure. These drugs depress left ventricular contractility in the short term, and can activate neurohormonal systems due to their hypotensive effects. The second-generation calcium channel blocker felodipine does not activate the sympathetic nervous and renin-angiotensin systems, but has no effect on exercise capacity or mortality. Amlodipine increases exercise time and reduces symptoms and plasma norepinephrine concentration in heart failure. It also reduces morbidity and mortality in New York Heart Association class i.v. patients with nonischemic dilated cardiomyopathy, and appears to be effective as primary therapy for patients with dilated cardiomyopathy.

Calcium Channel Blockers↗

PubMed2006

Temperature dependence of T-type calcium channel gating.

T-type calcium channel isoforms are expressed in a multitude of tissues and have a key role in a variety of physiological processes. To fully appreciate the physiological role of distinct channel isoforms it is essential to determine their kinetic properties under physiologically relevant conditions. We therefore characterized the gating behavior of expressed rat voltage-dependent calcium channels (Ca(v)) 3.1, Ca(v)3.2, and Ca(v)3.3, as well as human Ca(v)3.3 at 21 degrees C and 37 degrees C in saline that approximates physiological conditions. Exposure to 37 degrees C caused significant increases in the rates of activation, inactivation, and recovery from inactivation, increased the current amplitudes, and induced a hyperpolarizing shift of half-activation for Ca(v)3.1 and Ca(v)3.2. At 37 degrees C the half-inactivation showed a hyperpolarizing shift for Ca(v)3.1 and Ca(v)3.2 and human Ca(v)3.3, but not rat Ca(v)3.3. The observed changes in the kinetics were significant but not identical for the three isoforms, showing that the ability of T-type channels to conduct calcium varies with both channel isoform and temperature.

Animals↗

PubMed1986

Inhibition of electrically induced seizures by a dihydropyridine calcium channel blocker.

Nimodipine, a calcium channel blocker with high affinity for central dihydropyridine Ca2+ channels, produced a dose-dependent suppression of electrically induced seizures in the rabbit. Verapamil, a diphenylalkylamine which acts at peripheral Ca2+ channels, was ineffective. Phenytoin was less effective than nimodipine. These results suggest that calcium flux into neurons may be a biochemical precipitant for seizure genesis. Centrally acting calcium channel blockers may prove to be a new class of anticonvulsants.

Animals↗

PubMed2002

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

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.

Animals↗

PubMed2000

Motor and electrographic response of refractory experimental status epilepticus in rats and effect of calcium channel blockers.

Effects of various calcium channel inhibitors have been studied in lithium-pilocarpine model of status epilepticus. Status epilepticus was induced by administration of lithium chloride (3 meq/kg) followed 21 hr later by pilocarpine (30 mg/kg). Diltiazem (5 and 10 mg/kg) was not effective in delaying onset of convulsions. Verapamil (20 mg/kg) showed protection against lithium-pilocarpine-induced convulsions. The dihydropyridine nifidepine (2.5 and 5 mg/kg) did not show any protection in this model. Amlodipine (5 and 10 mg/kg) as partially protective. Flunarizine (10 and 20 mg/kg) delayed the onset of forelimb clonus and rearing and only 60% of the rats underwent status in the 20 mg/kg group. Pre-treatment of MK-801 led to a potentiation of the antiseizure activity of calcium channel inhibitors. The percent increase in amplitude at various time points with amlodipine pretreatment was significant only at the 30th min recording, and at the rest of the time frames was practically similar as the controls. It can be concluded that the anticonvulsant action of MK-801 can be enhanced by centrally acting calcium channel inhibitors.

Animals↗

PubMedDate not supplied

Calcium-channel blocking agents.

The role of calcium in the cardiovascular system, and the pharmacology, pharmacokinetics, and studies evaluating the clinical use of three calcium-channel blocking agents--verapamil hydrochloride, nifedipine, and diltiazem hydrochloride--are reviewed. Inhibition of calcium conductance and alteration of calcium availability cause profound changes in: slow inward current of the cardiac action potential, myocardial contractility and metabolism, blood pressure regulation, and smooth-muscle activity. Calcium-channel blocking agents affect the movement of calcium through these channels in smooth and cardiac muscle; the specific agents in this class differ markedly in their inhibitory effects. Verapamil hydrochloride is useful intravenously for treating supraventricular rhythm disturbances. It is absorbed well when taken orally, but there is an extensive first-pass effect, so that about 20% enters the systemic circulation. The incidence of side effects in patients receiving verapamil is 9-10%; about 1% require discontinuation of therapy. Verapamil is contraindicated in patients with sinus-node disease, unstable atrioventricular block, and shock. Nifedipine has proven useful for hypertension, coronary-artery spasm, and exertional angina; it has little negative inotropic effect. Approximately 90% of an oral dose is absorbed, and 65-70% reaches the systemic circulation after first-pass metabolism. Protein binding of nifedipine ranges from 92 to 98%. Side effects of nifedipine, usually associated with the peripheral vasodilatory action, occur in approximately 15% of patients, requiring discontinuance in 2-5%. Diltiazem hydrochloride has been shown effective in the treatment of coronary-artery spasm; limited studies indicate it may be useful in treating exertional angina, hypertension, and possibly arrhythmias. Diltiazem's oral bioavailability is good (90% reaches systemic circulation), but there is significant interindividual variability between administered dose and resulting plasma concentration. Geriatric patients have delayed absorption and reduced clearance of diltiazem given in sustained-release tablets. Studies of diltiazem are limited at this time. The exact role of calcium-channel blocking agents has not yet been elucidated. However, their ability to influence the calcium channel greatly expands the therapeutic armamentarium for cardiovascular disease and other disorders.

Adolescent↗

PubMed1984

Nitrendipine and isoproterenol induce phosphorylation of a 42,000 dalton protein that co-migrates with the affinity labeled calcium channel regulatory subunit.

Slow inward calcium channels in canine cardiac membranes were affinity labeled with the calcium channel analogue, [3H]o-NCS [2,6 dimethyl-3,5-dicarbomethoxy-4-(2- isothiocyanatophenyl )-1, 4-dihydropyridine], in the presence and absence of cold o-NCS or nicardipine. A major specifically labeled peak was identified with Mr 42,000 on NaDodSO4 polyacrylamide gels. In parallel experiments the effects of the calcium channel antagonist, nitrendipine and a variety of other chemical mediators were tested for their ability to stimulate protein phosphorylation in cardiac membranes. These data demonstrate that both nitrendipine and isoproterenol induce the phosphorylation of a 42,000 dalton protein via a kinase endogenous to the cardiac membranes and that the effects of isoproterenol are attenuated by carbachol.

Affinity Labels↗

PubMed1996

Pharmacologic and therapeutic differences among calcium channel antagonists: profile of mibefradil, a new calcium antagonist.

Calcium antagonists are a heterogeneous group of drugs, each with a different chemical structure and cardiovascular profile. Distinguishing factors include pharmacokinetics, mode of calcium mobilization affected, class and subclass of calcium channel inhibited, state-dependent interactions, and effect of disease on the drug's activity. A new calcium antagonist, mibefradil, has a unique chemical structure and cardiovascular profile compared with those currently available, and it appears to represent a new class of calcium antagonists.

Animals↗

PubMed1995

Voltage-dependent inactivation in a cardiac-skeletal chimeric calcium channel.

The loci for inactivation in calcium channel proteins are unknown. Mechanisms for inactivation may be distributed across Ca2+ channel subunits and appear to be complex, multiple and interacting. We took advantage of the properties of chimeras, constructed between cardiac (H4) and skeletal muscle (Sk4) calcium channel alpha 1 subunits to study the molecular mechanism of inactivation in L-type calcium channels. Sk1H3, a chimeric construct of these two L-type calcium channels, was expressed in Xenopus oocytes in the absence of auxiliary subunits. Sk1H3 incorporated repeat I from skeletal muscle alpha 1 and repeats II, III, IV from heart alpha 1 subunit. Sk1H3 inactivated faster (tau = 300 ms) and more fully than the wild-type H4 with Ba2+ ions as the charge carrier. Thus, inactivation of Sk1H3 was 90% complete after a 5-s conditioning pulse at +20 mV while inactivation of H4 was only 37% complete. Sk1H3 inactivation also developed at more negative potentials with E0.5 = -15 mV as compared to E0.5 = -5 mV for H4. In the presence of external calcium ions, the extent of inactivation significantly increased from 37 to 83% for H4 while inactivation of Sk1H3 was only slightly increased. Inactivation with Ba2+ as the charge carrier was confirmed at the single- channel level where averaged single-channel ensembles showed a similar rate of inactivation. Collectively, these observations demonstrate that Sk1H3 inactivation appears to have a prominent voltage-dependent component. Whether Sk1H3 inactivation involves interactions within repeat I alone or interactions between repeat I and site(s) located in the three other repeats of the alpha 1 subunit has yet to be determined.

Amino Acid Sequence↗

PubMed1993

Different types of calcium channels mediate central synaptic transmission.

Synaptic transmission is mediated by calcium entry through voltage-dependent calcium channels in presynaptic nerve terminals. Various types of calcium channel have been characterized in neuronal somata, but it is not clear which subtypes induce transmitter release at central synapses. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTx) suppresses the excitatory postsynaptic responses only partially, whereas potassium-induced release of glutamate from brain synaptosomes can be blocked by omega-Aga-VIA (ref. 9), a blocker of P-type calcium channels and possibly of other types of calcium channels. Here we test type-specific calcium-channel blockers on postsynaptic currents recorded from neurons in thin slices of rat central nervous system. Inhibitory postsynaptic currents in cerebellar and spinal neurons and excitatory postsynaptic currents in hippocampal neurons are markedly suppressed by omega-Aga-IVA and reduced to a lesser extent by omega-CgTx. The L-type calcium channel blocker nicardipine had no effect. Our results indicate that at least two types of calcium channel mediate synaptic transmission in the mammalian central nervous system.

Animals↗

PubMed1994

Involvement of N- and non-N-type calcium channels in synaptic transmission at corticostriatal synapses.

Calcium channels participate in the events linking axon terminal depolarization to neurotransmitter secretion. We wished to evaluate the role of N-type and non-N-type calcium channels in glutamatergic transmission at corticostriatal synapses, since this is a well defined excitatory synapse. In addition, these synapses are subject to a variety of forms of presynaptic modulation, some of which may involve alterations in calcium channel function. Application of the selective N-type channel blocker omega-conotoxin GVIA produced an irreversible depression of excitatory synaptic transmission in rat neostriatal slices shown by a decrease of approximately 50% in the amplitude of the synaptically driven population spike during field potential recording and a similar decrease in the amplitude of excitatory postsynaptic potentials during whole-cell recording. The component of transmission which was resistant to omega-conotoxin GVIA was blocked by omega-conotoxin MVIIC. omega-Agatoxin IVA had little effect on transmission. Activation of a presynaptic metabotropic glutamate receptor depressed transmission to a similar extent before and after omega-conotoxin GVIA treatment. Likewise, protein kinase C-activating phorbol esters potentiated transmission to the same extent before and after omega-conotoxin GVIA treatment. N-type calcium channels appear to be crucial for a component of excitation-secretion coupling at corticostriatal synapses. A component of transmission involves non-N-, non-L-type high-voltage-activated calcium channels. The effects of presynaptic metabotropic receptors and protein kinase C activation cannot be accounted for solely by alterations in the N-type channel function.

Animals↗

PubMed1984

Comparative effects of calcium channel blocking agents and varying extracellular calcium concentration on hypoxia/reoxygenation and ischemia/reperfusion-induced cardiac injury.

OUr study was designed to evaluate and compare the effects of three structurally different calcium channel blocking drugs, verapamil (10 and 100 ng/ml), diltiazem (1 and 10 micrograms/ml) and nifedipine (10 and 100 ng/ml), and altering calcium concentration on two models of heart damage, hypoxia/reoxygenation and ischemia/reperfusion (60 min/15 min) of isolated rat hearts. The increase in creatine phosphokinase release by hypoxia and reoxygenation was significantly decreased by treatment with all three drugs. Reoxygenation-induced enzyme efflux was enhanced by a 3-fold elevation in external CaCl2 and depressed by a two-thirds calcium reduction. In contrast, elevation of calcium concentration had no significant effect on postischemia reperfusion-induced creatine phosphokinase efflux whereas "low calcium" decreased release during reperfusion. Two drugs which effectively reduced reperfusion- (nifedipine) or reoxygenation- (diltiazem) induced enzyme release as well as reducing calcium concentration were evaluated to determine during which phase of perfusion these treatments exerted their beneficial effect. The reduction of creatine phosphokinase release during reoxygenation by diltiazem was dependent on the drug's presence during the hypoxia phase of perfusion whereas low calcium (either reoxygenation or reperfusion) or nifedipine treatment (reperfusion) was protective irrespective of whether the treatment was present during hypoxia/ischemia or reoxygenation/reperfusion. The reduction in enzyme release was associated with an enhanced mechanical recovery and a reduction in arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Comparative actions of dihydropyridine slow channel calcium blocking agents in conscious dogs: alterations in baroreflex sensitivity.

The effects of five dihydropyridine slow channel calcium blocking agents, nifedipine, nitrendipine, FR 34235, niludipine and nisoldipine were compared to those of the peripheral vasodilator hydralazine on the reflex bradycardia and tachycardia after abrupt increases and decreases in arterial pressure in conscious dogs. On alternate days, the baroreflex was elicited during control conditions (drug vehicle) and/or after low (2.5 micrograms/kg/min) or high (5.0 micrograms/kg/min) equihypotensive doses of calcium antagonists or hydralazine (0.05 and 0.1 mg/kg/min). Baroreflexes were elicited by means of bolus injection of nitroprusside and phenylephrine. Certain of the dihydropyridine calcium channel blocking agents were found to interfere significantly with the reflex bradycardia after a rise in pressure, a phenomenon usually attributed to an increase in parasympathetic tone. Nisoldipine, niludipine and FR 34235 decreased baroreceptor sensitivity (defined as delta cardiac interval/delta systolic arterial pressure; milliseconds per millimeter of mercury) in a dose-related manner. On the other hand, nifedipine, nitrendipine and hydralazine had no significant effect. The dihydropyridines and hydralazine had little effect on baroreceptor-induced withdrawal of vagal tone or increases in sympathetic tone in response to sudden decreases in blood pressure. Calcium antagonists with isopropyl substitution as part of the ester function on the dihydropyridine nucleus, nisoldipine, niludipine and FR 34235, interfered to a greater extent with the vagally mediated reduction in cardiac rate. Changes in baroreflex gain may provide a basis for differential actions of dihydropyridine calcium channel blockers on the magnitude of change in heart rate in response to an abrupt increase in arterial pressure.

Animals↗

PubMed1997

Calcium channel subtypes in lamprey sensory and motor neurons.

Pharmacologically distinct calcium channels have been characterized in dissociated cutaneous sensory neurons and motoneurons of the larval lamprey spinal cord. To enable cell identification, sensory dorsal cells and motoneurons were selectively labeled with fluorescein-coupled dextran amine in the intact spinal cord in vitro before dissociation. Calcium channels present in sensory dorsal cells, motoneurons, and other spinal cord neurons were characterized with the use of whole cell voltage-clamp recordings and specific calcium channel agonist and antagonists. The results show that a transient low-voltage-activated (LVA) calcium current was present in a proportion of sensory dorsal cells but not in motoneurons, whereas high-voltage-activated (HVA) calcium currents were seen in all neurons recorded. The different components of HVA current were dissected pharmacologically and similar results were obtained for both dorsal cells and motoneurons. The N-type calcium channel antagonist omega-conotoxin-GVIA (omega-CgTx) blocked >70% of the HVA current. A large part of the omega-CgTx block was reversed after washout of the toxin. The L-type calcium channel antagonist nimodipine blocked approximately 15% of the total HVA current. The dihydropyridine agonist (+/-)-BayK 8644 markedly increased the amplitude of the calcium channel current. The BayK-potentiated current was not affected by omega-CgTx, indicating that the reversibility of the omega-CgTx effect is not due to a blockade of L-type channels. Simultaneous application of omega-CgTx and nimodipine left approximately 15% of the HVA calcium channel current, a small part of which was blocked by the P/Q-type channel antagonist omega-agatoxin-IVA. In the presence of the three antagonists, the persistent residual current (approximately 10%) was completely blocked by cadmium. Our results provide evidence for the existence of HVA calcium channels of the N, L, and P/Q types and other HVA calcium channels in lamprey sensory neurons and motoneurons. In addition, certain types of neurons express LVA calcium channels.

Animals↗

PubMed1989

Barium ions enter chromaffin cells via voltage-dependent calcium channels and induce secretion by a mechanism independent of calcium.

Barium ions enter chromaffin cells via voltage-sensitive calcium channels, although the intracellular site of barium action is distinct from that of calcium. The entry of barium primarily through voltage-sensitive channels was indicated by experiments showing inhibition of 133Ba2+ uptake by blockers of voltage-dependent calcium channels. In addition, 133Ba2+ uptake was stimulated by 50 mM KCl but not by nicotine. Furthermore, 133Ba2+ uptake was inhibited by hyperosmolarity, which specifically blocks the voltage-sensitive calcium channel but not the receptor-associated calcium channel. These conclusions from studies on barium uptake were also borne out by experiments measuring catecholamine secretion. Thus, blockers of voltage-dependent calcium channels which inhibited barium uptake also inhibited barium-induced catecholamine secretion. In other experiments, simultaneous stimulation with nicotine and barium in the presence of calcium evoked coincident and additive catecholamine secretion. By contrast, when 50 mM KCl was substituted for nicotine in the same experimental design, barium ions inhibited potassium-induced catecholamine secretion at low calcium concentrations. Only at high calcium concentrations were barium-induced and potassium-induced secretion additive. These data also indicate that barium and calcium compete at the voltage-sensitive pathway. Furthermore, these additivity data suggest that once inside the cell, barium and calcium have two distinct mechanisms of action. As predicted by this hypothesis, in digitonin-permeabilized chromaffin cells either calcium or barium stimulated catecholamine release, and in the presence of both cations catecholamine secretion was equivalent to the sum of secretion with either cation alone. Additional support of this concept comes from experiments showing that while calcium-mediated catecholamine secretion is sensitive to trifluoperazine and imipramine, barium-mediated secretion is not. Taken together, all these data indicate that there are two distinct intracellular sites of action for barium and calcium. In contrast to catecholamine secretion, non-exocytotic ascorbic acid secretion was induced by nicotine and potassium in the presence of calcium, but not by barium alone. These data provide additional evidence that barium acts by a different mechanism than calcium, in still another secretory system in chromaffin cells.

Animals↗

PubMed1990

Binding of [125I]iodipine to parathyroid cell membranes: evidence of a dihydropyridine-sensitive calcium channel.

The parathyroid cell is unusual, in that an increase in extracellular calcium concentrations inhibits PTH release. Calcium channels are glycoproteins that span cell membranes and allow entry of extracellular calcium into cells. We have demonstrated that the calcium channel agonist (+)202-791, which opens calcium channels, inhibits PTH release and that the antagonist (-)202-791, which closes calcium channels, stimulates PTH release. To identify the calcium channels responsible for these effects, we used a radioligand that specifically binds to calcium channels. Bovine parathyroid cell membranes were prepared and incubated under reduced lighting with [125I] iodipine (SA, 2000 Ci/mmol), which recognizes 1,4-dihydropyridine-sensitive calcium channels. Bound ligand was separated from free ligand by rapid filtration through Whatman GF/B filters. Nonspecific binding was measured by the inclusion of nifedipine at 10 microM. Specific binding represented approximately 40% of the total binding. The optimal temperature for [125I] iodipine binding was 4 C, and binding reached equilibrium by 30 min. The equilibrium dissociation constant (Kd) was approximately 550 pM, and the maximum number of binding sites was 780 fmol/mg protein. Both the calcium channel agonist (+)202-791 and antagonist (-)202-791 competitively inhibited [125I] iodipine binding, with 50% inhibition concentrations of 20 and 300 nM, respectively. These data indicate the presence of dihydropyridine-sensitive calcium channels on parathyroid cell membranes.

Animals↗