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At least 109 records · Page 6Linked to original sources
PubMed1987

Inhibition of platelet-activating factor binding to human platelets by calcium channel blockers.

Calcium channel blockers may impair cell activation either by inhibiting calcium influx or by inhibiting agonist binding. Because of this dual action of calcium channel blockers and because of the close relationship between calcium influx and platelet-activating factor (PAF) binding to platelets the current studies examined the effect of calcium channel blockers on PAF binding to washed human platelets. Diltiazem and verapamil inhibited aggregation by PAF in a dose-dependent manner with 50% inhibition at 2.8 +/- 1.4 X 10(-5) M diltiazem (mean +/- SD, n = 5) and 4.2 +/- 2.0 X 10(-5) M verapamil. Both channel blockers also inhibited PAF binding in a dose-dependent manner with 50% inhibition at 4.7 +/- 2.5 X 10(-5) M diltiazem and 6.3 +/- 1.2 X 10(-5) M verapamil. Analysis of the mechanisms of inhibition of binding indicate both competitive and non-competitive effects of the channel blockers. Scatchard analysis of PAF binding in the presence of different fixed concentrations of either diltiazem or verapamil revealed that these agents both increased PAF receptor number and decreased the receptor binding affinity. Lineweaver-Burke analysis of the same data revealed a family of lines which intersect to the right of the ordinate. The channel blockers also dissociated previously-bound PAF from platelets. The current studies indicate that calcium channel blockers inhibit platelet activation by PAF by more than one mechanism and suggest that the PAF receptor may be closely associated with calcium channels.

Adult↗
PubMed1992

Effects of potassium channel openers and calcium channel blockers on the force responses of the electrically driven rat right ventricle strip.

1. The effects of potassium channel openers (cromakalim and pinacidil) and of calcium channel blockers (verapamil, diltiazem and flunarizine) on the contractile responses of the rat right ventricle have been determined. 2. On the electrically driven rat right ventricle cromakalim at 3 x 10(-7), 10(-6), 3 x 10(-6) M and 10(-5) M, and pinacidil at 10(-6), 10(-5) and 3 x 10(-5) M had no effect on the force responses to cardiac stimulation or to isoprenaline. 3. Pinacidil at 10(-4) M in a vehicle of 0.7% ethanol reduced the force responses to cardiac stimulation. This inhibitory effect was solely due to the ethanol. Pinacidil in 5 x 10(-4) M HCl (which had no effect alone) potentiated some of the responses to isoprenaline. 4. Verapamil, greater than or equal to 10(-6) M, diltiazem, greater than or equal to 10(-5) M, and flunarizine, greater than or equal to 10(-6) M, reduced the force responses to cardiac stimulation and to isoprenaline. 5. The present study has shown that calcium channel blockers, but not potassium channel openers, have inhibitory effects on the rat right ventricle.

Animals↗
PubMed1998

[Tissue selectivity of calcium channel blockers].

Calcium channel blockers are also termed calcium antagonists or calcium entry blockers. The use of calcium antagonists for the management of hypertension is well established. Their control of vascular tone is related to their interaction with the alpha 1 subunit of L-type calcium channels. This interaction is not simple since prolonged depolarisation promotes the inactivated state of the channels resulting in a change of affinity which is different for various molecules so far considered. The isoforms of alpha 1 subunits and the duration of the stimulus required to activate heart or vessels are important parameters to be considered with the nature of the molecule. Those parameters influence the vascular selectivity which is quantified as the ratio of the concentrations required to reduce by 50% the contraction of heart and of vessels. This selectivity is an important component in the therapeutic action. Another component of this action is the prevention of structural changes noted in heart and arteries. As well as lowering blood pressure, calcium channel blockers have also been found to exert blood pressure independent effects. For instance, they reduce cardiac and vascular hypertrophy and avoid renal damage. In the stroke-prone rat, such protective effects are accompanied by reduction of the salt-dependent overexpression of the gene of endothelin-1 and of fetal genes associated with cardiac hypertrophy. This paper summarizes available information about those components and discuss their significance.

Animals↗
PubMed1985

Mechanism of calcium channel inhibition by phenytoin: comparison with classical calcium channel antagonists.

The mechanism of calcium channel antagonism by phenytoin was studied by comparing the effects of phenytoin and classical calcium channel antagonists on K+-stimulated 45Ca uptake and [3H]nitrendipine binding in the PC12 pheochromocytoma cell line. Inhibition of K+-stimulated 45Ca uptake occurred at clinically relevant concentrations of phenytoin (IC50 = 9.6 +/- 2.1 microM) and was not significantly modified by Na channel blockade with tetrodotoxin, K channel blockade with tetraethylammonium or depolarization with carbachol rather than K+. Phenytoin, verapamil and diltiazem inhibited 45Ca uptake with Hill coefficients of less than 0.7, whereas values for nimodipine and flunarizine were close to 1.0. Phenytoin inhibited binding of the dihydropyridine Ca channel antagonist [3H]nitrendipine to PC12 membranes (Ki = 31 +/- 3 microM) by decreasing binding affinity, with no change in the maximal number of binding sites. Phenytoin and nimodipine reduced [3H]nitrendipine binding without altering the first-order rate constant for dissociation; this rate was increased by verapamil and flunarizine and decreased by diltiazem. Diltiazem enhanced inhibition of [3H]nitrendipine binding by phenytoin, reversed inhibition by verapamil and flunarizine and had no effect on inhibition by nimodipine. These findings suggest that phenytoin and classical Ca channel antagonists inhibit voltage-gated Ca++ flux by distinct but functionally linked mechanisms.

Adrenal Gland Neoplasms↗
PubMed1996

Structural implications in the function of L-type voltage-dependent calcium channels.

The calcium channels play a key role in controlling many physiological processes in the body. Voltage dependent calcium channels have been extensively characterized in terms of their electrophysiological and pharmacological properties. The L-type voltage-dependent calcium channel is composed of several subunits, from which the alpha 1 subunit is the most important. Recent interest has been focused more on the functional implication of the subunit structures and/or their parts. Therefore, this review will concentrate on the structure-functional studies of the voltage-dependent calcium channel rather than on the progress in the study of their structure and tissue specificity.

Animals↗
PubMed1990

Effects of the 1,4-dihydropyridine-sensitive L-type calcium channel antagonist nimodipine and calcium channel activator Bay K 8644 on local cerebral glucose utilization in the rat.

The quantitative [14C]-2-deoxy-D-glucose autoradiographic method was used to compare the acute effects of the Ca2+ channel antagonist nimodipine (10 mg/kg) and the Ca2+ channel activator Bay K 8644 (1.25 mg/kg) on local cerebral glucose utilization of rat brain after single, intraperitoneal application. Nimodipine reduced glucose metabolism significantly in 23 of the 49 brain regions evaluated. Bay K 8644 decreased the local cerebral glucose utilization to an even greater extent in all regions studied. The anatomic localization of those regions with the largest decrease of glucose utilization was almost identical for both drugs (globus pallidus, hippocampus, geniculate body, substantia nigra, and entorhinal cortex). No increase in glucose metabolism was measured in any of the brain areas evaluated.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Bay K-8644 in different solvents acts as a transient calcium channel antagonist and a long-lasting calcium channel agonist.

This report describes the effect of Bay K-8644 dissolved in various solvents on two types of calcium channel currents in neuroblastoma cells. Transient calcium channel (T channel) currents were not affected by Bay K-8644 dissolved in ethanol (EtOH) or polyethylene glycol (PEG). However, at the same concentration of 0.6 microM, Bay K-8644 dissolved in dimethylsulfoxide (DMSO) (Bay K-8644/DMSO) decreased the T channel current by 50%. The concentration of all three solvents in the bath was fixed at 0.3% to reach different final concentrations of Bay K-8644. At this fixed solvent concentration, the inhibitory effect of Bay K-8644/DMSO on T channel currents was dose-dependent; the solvents alone did not have any effect on T channel currents; and DMSO pretreatment of cells did not render the T channel current sensitive to Bay K-8644 dissolved in EtOH or PEG. Bay K-8644/DMSO was dried using a flash evaporator and redissolved in EtOH or PEG. Dried Bay K-8644 that was redissolved in EtOH or PEG to achieve a final concentration of 0.6 microM inhibited T channel currents by 39 or 35%, respectively. Furthermore, Bay K-8644 (10 nM) increased L channel currents by 80% with DMSO, but only 30% with EtOH as the solvent. These results show that in neuroblastoma cells Bay K-8644/DMSO, within the concentration range examined, is a T channel antagonist and more effective L channel agonist than Bay K-8644 dissolved in the two other solvents.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Regulation of the renal basolateral transport system for organic anions by calcium channel blockers.

Calcium channel blockers have been reported to exert multiple effects on renal tubular function. Therefore, the effects of the calcium channel blockers nifedipine and verapamil on the cellular uptake of tritiated para -aminohippuric acid (PAH) into microdissected non-perfused rabbit kidney S2 proximal tubule segments were investigated to study a possible influence of calcium channel blockers on renal PAH transport. Since the tubules were entirely collapsed, the accumulated radioactivity overwhelmingly reflects the transport across the basolateral membrane. Tubular PAH accumulation was increased by 1 and 10 microm verapamil, and by 1 microm nifedipine, but it was unaffected by lower or higher concentrations of these calcium channel blockers. The increase in PAH accumulation caused by 1 microm nifedipine or 10 microm verapamil was independent from changes in intracellular Ca(2+) and inhibited by staurosporine (1 and 10 n m) a potent inhibitor of protein kinase C (PKC). Our results indicate that the calcium channel blockers nifedipine and verapamil increase the transport of organic anions across the basolateral membrane of proximal tubules, probably by an activation of PKC. Furthermore, the increased tubular PAH transport may disturb the estimation of the renal PAH-clearance.

Adenosine Triphosphate↗
PubMed2001

The influence of nifedipine (calcium channel blocker) and Bay-K-8644 (calcium channel agonist) on the development of experimental acute pancreatitis.

The aim of this paper was to evaluate the influence of nifedipine (calcium channel blocker) and Bay-K-8644 (calcium channel agonist) on cerulein acute pancreatitis (AP) in rats. AP was induced according to the Lampel and Kern method (1) by the continuous intravenous infusion of cerulein in the doses of 5 x 10(-6) g/kg/h for 12 hours. There was obtained a statistically significant decrease in serum amylase activity and pancreatic weight in the groups treated with higher doses of nifedipine before infusion of the cerulein compared with rats treated only with cerulein. However, in the group treated with Bay-K-8644 before infusion of cerulein statistically significant increase was obtained in serum amylase activity and pancreatic weight compared with the group treated only with cerulein. The investigations suggest a beneficial effect of higher doses of nifedipine on cerulein induced AP. The inflammatory changes in the pancreas in the groups treated with nifedipine observed under the light microscope were smaller than in the group treated only with cerulein.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Calcium channel blockers.

Calcium ions are essential for the chain of events that leads to myocardial contraction. Its role in the cardiac cycle has been studied extensively for years. Calcium is thought to be effective in the slow channels. Calcium channel blockers were first introduced in this country, more than 20 years ago. The pharmacological effects, usages, side effects, and dosages of some of the most commonly used calcium channel blockers are discussed. In addition, some anesthetic considerations and the latest controversy regarding calcium channel blockers are reviewed.

Anesthesia↗
PubMed1989

Esophageal blood flow in the rabbit: response to calcium channel blockers.

Calcium channel blockers have recently been added to the therapeutic regimen for patients who have chest pain of esophageal origin. Although relief of symptoms has been reported, this has not always been associated with changes in esophageal contraction pressures or luminal pH. Myoischemia has been proposed as one possible mechanism for esophageal chest pain. We have investigated the effect of the calcium channel blockers verapamil, nifedipine, and diltiazem on esophageal blood flow in the rabbit model. Esophageal blood flow was measured three times in each rabbit with use of the radiolabeled microsphere technique after a 30-minute continuous infusion of (1) saline solution (baseline), (2) a low dose, and (3) a high dose of each agent. Esophageal mucosal blood flow significantly decreased with nifedipine but was unchanged with verapamil and diltiazem. Esophageal muscle blood flow significantly increased--approximately 100% after administration of each of the calcium channel blockers. Thus esophageal muscle blood flow is enhanced after administration of calcium channel blockers, and this may be one therapeutic mechanism of the calcium channel blockers in the relief of esophageal chest pain in some esophageal diseases.

Animals↗
PubMed1992

Effects of calcium channel blockers on calcium uptake in rat aortic valve allografts.

BACKGROUND: The life span of human aortic valve allografts is finite, and many fail because of cusp rupture or calcification. Subcellular changes occurring in aortic valves in response to transplantation include the uptake of calcium. This study uses a heterotropic rat aortic valve transplant model to determine whether the calcium channel blockers diltiazem and verapamil might attenuate leaflet calcification. METHODS AND RESULTS: The 60 rats studied were divided into the following groups: 1) control: valves from normal, unoperated F1 generation of Lewis and Brown Norway cross (LBNF1) rats; 2) control: valves from syngeneic transplant combinations (Lewis/Lewis); 3) control: valves from allogeneic transplant combinations (LBNF1/Lewis, donor/recipient); 4) experimental: valves from allogeneic strain combinations treated with 30 mg/kg per day diltiazem; 5) experimental: valves from allogeneic strain combinations treated with 30 mg/kg per day verapamil. Drugs or saline (controls) were administered with osmotic pumps placed subcutaneously 2 days before transplantation. Animals were killed 3 weeks later, and the valves were harvested and prepared for calcium analysis. Energy-dispersive x-ray microanalysis was used to measure the calcium in a section of one leaflet from each valve studied. Paired t tests showed that allograft valves treated with diltiazem or verapamil contained significantly less calcium than allograft controls treated with saline (p < 0.001). When all five groups were subjected to one-way ANOVA, the valves in the allograft control group contained significantly more calcium than all other groups. All other groups were not different from each other. CONCLUSIONS: The calcium channel blockers verapamil and diltiazem were effective in preventing early calcification that occurs in aortic valves after transplantation. Thus, these agents might play a role in prolonging the life of human aortic valve allografts.

Analysis of Variance↗
PubMed2005

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

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

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1982

[3H]nitrendipine-labeled calcium channels discriminate inorganic calcium agonists and antagonists.

[3H]Nitrendipine binds with high affinity to brain membranes with a drug specificity indicating association with sites mediating the pharmacologic actions of dihydropyridine slow-calcium-channel antagonist drugs. In brain membranes, [3H]nitrendipine binding is absolutely dependent on the presence of calcium ions. Interactions of cation with [3H]nitrendipine binding sites correlate with their physiologic actions at voltage-dependent calcium channels. Ions such as strontium and barium, which mimic calcium physiologically, share the action of calcium in enhancing [3H]nitrendipine binding. Ions such as lanthanum an cobalt, which block the effects of calcium, can inhibit [3H]nitrendipine binding and block the stimulating actions of calcium. The ability to monitor the influence of ions on an agonist-antagonist continuum at [3H]nitrendipine binding sites provides a molecular probe to explore the regulation of cellular function by calcium and other cations.

Animals↗
PubMed1992

Molecular basis of calcium channel blockade.

Calcium plays a central role in cellular regulation, where its major function is activation. In the sinoatrial node, the entry of positively charged calcium ions through calcium channels in the plasma membrane generates an inward (depolarizing) current that contributes to pacemaker activity, whereas calcium entry in the atrioventricular (AV) node provides the major depolarizing current during AV conduction. In the working myocardial cells of the atria and ventricles, calcium entry through plasma membrane channels triggers calcium release from intracellular stores in the sarcoplasmic reticulum, and so plays a central role in excitation-contraction coupling. Calcium also serves as an intracellular messenger that binds to members of a family of intracellular calcium-binding proteins that include troponin and calmodulin. In the heart, calcium binding to troponin initiates systole, and formation of the calcium-calmodulin complex in vascular smooth muscle initiates a cascade of reactions that leads to vasoconstriction. Calcium channel blockers, by inhibiting the opening of calcium channels, attenuate all of these reactions; in the heart, they slow the sinus pacemaker and AV conduction and depress myocardial contractility. In smooth muscle, these drugs are vasodilators. Different members of the diverse group of chemical structures that block calcium channels have different specificities for different channels, and so differ in their effects on the cardiovascular system.

Animals↗