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At least 127 records · Page 7Linked to original sources
PubMed1998

Dissociation of vascular and adrenal responsiveness to angiotensin II following calcium channel blockade.

Calcium channel blockers as a class reduce both vascular resistance and systemic blood pressure. However, it is not known if different classes of calcium channel blockers have similar effects on the renin-angiotensin-aldosterone system. We investigated vascular and adrenal responses to endogenous and exogenous angiotensin II in normotensive subjects before and after receiving isradipine or diltiazem. Subjects achieved low salt balance before study and underwent an angiotensin II infusion and upright posture study. After re-achieving salt balance the subjects received either isradipine (n=10), or diltiazem (n=7) for three days before repeating the study. Both agents lowered blood pressure and significantly shifted the dose response relationship of angiotensin II and mean blood pressure (P<0.01). In contrast, aldosterone secretion in response to upright posture and angiotensin II infusion was significantly reduced (P<0.01) by isradipine but not by diltiazem. The in vitro effects of both agents on aldosterone secretion from bovine adrenal glomerulosa cells paralleled the in vivo observations showing that angiotensin II-stimulated aldosterone secretion was markedly blunted by isradipine and minimally by diltiazem. These results suggest a tissue specificity for the effects of different classes of calcium channel blockers. Dihydropyridine calcium channel blockers may exert their antihypertensive effect by blocking both vascular and adrenal responses to angiotensin II.

Adrenal Glands↗
PubMed1986

N-methylaspartate-activated calcium channels in rat brain cortex slices. Effect of calcium channel blockers and of inhibitory and depressant substances.

N-Methyl-DL-aspartate, L-glutamate, kainate and DL-homocysteate were found to increase the initial rate and the maximal uptake of 45Ca into the non-inulin space of rat brain cortex slices incubated in vitro. The N-methylaspartate-stimulated calcium uptake was blocked by cadmium and cobalt ions, but not by the organic calcium channel blocker nifedipine or by tetrodotoxin, both of which stimulated the N-methylaspartate-independent calcium influx. gamma-Aminobutyrate increased the spontaneous calcium influx, and also reduced that stimulated by N-methylaspartate to the same level, as found with gamma-aminobutyrate alone. Adenosine (1-100 microM), ethanol (0.1 M), pentobarbital (10-100 microM) and morphine (0.2 mM), were unable to inhibit the N-methylaspartate-activated calcium influx. Ethanol (0.1 M), had no effect on the glutamate- or kainate-activated calcium influx. These findings suggest that the excitatory amino acids, because of their neuronal depolarizing action in brain cortex, lead to the opening of voltage-sensitive calcium channels, which may be blocked by cadmium, but not by the organic calcium channel antagonist, nifedipine. The activation of calcium channels by the excitatory amino acid N-methylaspartate, was entirely unaffected by the depressants ethanol, pentobarbital or morphine, or by the endogenous inhibitory substance, adenosine, thus suggesting that their inhibitory or depressant effects occur through interference with a neuronal mechanism unrelated to the one studied here. gamma-Aminobutyrate, on the other hand, considerably inhibited N-methylaspartate-induced calcium uptake, an effect interpreted as due to a gamma-aminobutyrate-induced increase in chloride conductance, that "clamps" the membrane potential and does not allow further depolarization by N-methylaspartate.

Animals↗
PubMed1999

Parathyroid hormone-related protein protects against kainic acid excitotoxicity in rat cerebellar granule cells by regulating L-type channel calcium flux.

The parathyroid hormone-related peptide (PTHrP) and PTH/PTHrP receptor genes are widely expressed in the CNS and both are highly expressed in the cerebellar granule cell. We have shown previously that PTHrP gene expression in granule cells is depolarization-dependent in vitro and is regulated specifically by Ca2+ influx via L-type voltage-sensitive calcium channels (L-VSCCs). Kainic acid induces long-latency excitotoxicity in granule cells via L-VSCC-mediated Ca2+ influx. Here, we show that PTHrP is just as effective as the L-VSCC blocker, nitrendipine (NTR), in preventing kainate excitotoxicity. A competitive inhibitor of PTHrP binding abrogates its neuroprotective effect. Both NTR and PTHrP decrease 45Ca2+ influx to the same degree. These findings suggest that PTHrP functions in an autocrine/paracrine neuroprotective feedback loop that can combat L-VSCC-mediated excitotoxcity.

Animals↗
PubMed1988

Cardiac calcium channels in planar lipid bilayers. L-type channels and calcium-permeable channels open at negative membrane potentials.

Planar lipid bilayer recordings were used to study Ca channels from bovine cardiac sarcolemmal membranes. Ca channel activity was recorded in the absence of nucleotides or soluble enzymes, over a range of membrane potentials and ionic conditions that cannot be achieved in intact cells. The dihydropyridine-sensitive L-type Ca channel, studied in the presence of Bay K 8644, was identified by a detailed comparison of its properties in artificial membranes and in intact cells. L-type Ca channels in bilayers showed voltage dependence of channel activation and inactivation, open and closed times, and single-channel conductances in Ba2+ and Ca2+ very similar to those found in cell-attached patch recordings. Open channels were blocked by micromolar concentrations of external Cd2+. In this cell-free system, channel activity tended to decrease during the course of an experiment, reminiscent of Ca2+ channel "rundown" in whole-cell and excised-patch recordings. A purely voltage-dependent component of inactivation was observed in the absence of Ca2+ stores or changes in intracellular Ca2+. Millimolar internal Ca2+ reduced unitary Ba2+ influx but did not greatly increase the rate or extent of inactivation or the rate of channel rundown. In symmetrical Ba2+ solutions, unitary conductance saturated as the Ba2+ concentration was increased up to 500 mM. The bilayer recordings also revealed activity of a novel Ca2+-permeable channel, termed "B-type" because it may contribute a steady background current at negative membrane potentials, which is distinct from L-type or T-type Ca channels previously reported. Unlike L-type channels, B-type channels have a small unitary Ba2+ conductance (7 pS), but do not discriminate between Ba2+ and Ca2+, show no obvious sensitivity to Bay K 8644, and do not run down. Unlike either L- or T-type channels, B-type channels did not require a depolarization for activation and displayed mean open times of greater than 100 ms.

Animals↗
PubMed1991

Calcium channels in the brain as targets for the calcium-channel modulators used in the treatment of neurological disorders.

Recent investigations of calcium channels in brain cells by voltage-clamp techniques have revealed that, in spite of electrophysiological similarities, the pharmacological properties of these channels differ considerably from channels in peripheral tissues, e.g., heart and smooth muscle. Therefore, instead of extrapolation from results obtained on cardiac or smooth muscle cells, a reclassification of calcium-channel modulators applied in disorders of the brain appears necessary. The present article reviews some pertinent observations from groups involved in neuronal calcium-channel characterization and draws the attention to major pharmacological differences on neurons in comparison to those in the heart and in smooth muscle. For certain therapeutic applications in neurology particularly, the low-voltage activated types of calcium channels deserve considerable attention.

Animals↗
PubMed1997

Cell-cycle arrest in G0/G1 phase of growth factor-induced endothelial cell proliferation by various calcium channel blockers.

Calcium channel blockers cause antiproliferative effects on various cells in culture. Since angioneogenesis is a crucial step in the development of tumor growth, we examined the influence of different calcium channel blockers on human umbilical arterial endothelial cell (HUAEC) growth. Cell growth was measured by cell count, by [3H]thymidine incorporation, and by a 5-bromo-2-deoxyuridine (BrdU-incorporation immunofluorescence assay. Cell-cycle analysis was performed by flow cytometric analysis. Nifedipine, isradipine, diltiazem, and verapamil dose-dependently inhibited the basic fibroblast growth factor (bFGF)-induced [3H]thymidine incorporation. Fifty micromolars of nifedipine, isradipine, diltiazem, and verapamil completely inhibited bFGF-induced proliferation of HUAEC. Ten micromolars of each calcium channel blocker abolished the bFGF-induced increase in cell count. Five micromolars of isradipine completely blocked the bFGF-induced BrdU incorporation. Stimulation of HUAEC with bFGF (50 ng/ml) for 24 h caused a 2-fold increase in cells that entered S and G2+M phase in comparison with control cells. Five micromolars of isradipine abolished this effect completely. We conclude that calcium channel blockers are able to inhibit cell proliferation by a cell-cycle arrest in G0/G1 phase.

Calcium Channel Blockers↗
PubMed1982

Absence of blocking effects on cardiac slow calcium channels by the intracellular calcium antagonist 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene.

Extensive pharmacological evidence supports the contention that 2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene hydrochloride (pr-MDI) is a calcium antagonist with a predominantly intracellular site of action. On the other hand, electro-physiological evidence points to a possible membrane slow inward calcium channel blocking property of this agent. To gain further insight as to the site of action of pr-MDI, the interactions between the negative inotropic action of this agent and the positive inotropic actions of excess extracellular calcium (which directly penetrates the myocardial cells through the slow calcium channels), isoproterenol (which indirectly augments calcium influx through the slow calcium channels), and ouabain (which enhances calcium influx through membrane calcium entry routes distinct from the slow calcium channels) were investigated in the isolated, electrically drive guinea pig left atrium. Although excess extracellular calcium, isoproterenol, and ouabain reversed the negative inotropic effect of pr-MDI, an analysis of the concentration-response relationships to all three positive inotropic agents in the presence and the absence of pr-MDI demonstrated that this agent did not significantly inhibit the contractile effects of calcium, isoproterenol, or ouabain, at pr-MDI concentrations which exhibit intrinsic negative inotropic effects. It is concluded that pr-MDI does not block the membrane slow inward calcium channel nor other presumptive membrane routes of calcium entry into myocardial cells at concentrations of 10(-4) M or less. At very high concentrations (3 X 10(-4) M) some inhibition of slow channel calcium influx may occur.

Animals↗
PubMed1988

Positive inotropic effects of calcium channel antagonists are not necessarily caused by partial calcium channel agonism.

Recently it has been reported that some dihydropyridine calcium channel antagonists (nifedipine, nimodipine, nitrendipine) are able to produce positive inotropic effects in isolated perfused guinea pig hearts. We studied the effects of nifedipine in isolated perfused paced rat hearts under constant pressure and constant flow perfusion conditions. We found that nifedipine is able to produce a positive inotropic effect under constant pressure conditions but not under constant flow conditions. We conclude that nifedipine does not have partial calcium channel agonistic properties and that the positive inotropic effect seen under constant pressure conditions is a result of the vasodilating properties of the drug. Positive inotropic effects caused by vasodilatation can be explained by the "garden-hose-effect".

Animals↗
PubMed1985

Slow channel calcium activators, a new group of pharmacological agents.

Specific calcium channels in myocardium and vascular smooth muscle and pharmacologic agents which possess the ability to block them have been the subject of intense research over the past several years. Many studies have utilized dihydropyridine derivatives (e.g. nifedipine, nitrendipine, nisoldipine) which have been shown to be efficacious inhibitors of calcium influx through voltage sensitive slow channels. Administration of these agents results in vascular smooth muscle relaxation and negative inotropic effects. Recently, novel dihydropyridines such as Bay k 8644, CGP 28 392 and YC-170, with actions diametrically opposed to those of compounds typified by nifedipine have been synthesized. These agents demonstrate vaso-constrictor and positive inotropic effects - actions which might be expected of compounds capable of stimulating the transmembrane influx of calcium into vascular smooth muscle and myocardium. Actions of Bay k 8644 and CGP 28 392 studied in vitro and in vivo have also shown that pharmacological blockade of beta or alpha adrenergic receptors does not influence the direct effects of these agents. Future analogs, with similar but more selective actions on myocardial calcium channels, may prove useful in the management of pathologic states characterized by insufficient contractile function of the heart.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

A role for voltage gated T-type calcium channels in mediating "capacitative" calcium entry?

Calcium entry through plasma membrane calcium channels is one of the most important cell signaling mechanism involved in such diverse functions as secretion, contraction and cell growth by regulating gene expression, proliferation and apoptosis. The identity of plasma membrane calcium channels, the main regulators of calcium entry, involved in cell proliferation has been thus extensively sought. Among these, a calcium entry pathway called capacitative calcium entry (CCE), activated by calcium store depletion, is particularly important in non-excitable cells. Though this capacitative calcium entry is generally supposed to occur through TRP channels there is some evidence that voltage-dependent T-type calcium channels may contribute to calcium entry after store depletion. Here we show that though mibefradil, a T-type calcium channel blocker, is able to reduce capacitative calcium entry induced by either thapsigargin or ATP, this was not mimicked by any other T-type calcium channel inhibitors even in cells overexpressing alpha(1H) T-type calcium channels, leading us to conclude that T-type calcium channels are not responsible for the capacitative calcium entry observed in different cancer cell lines. On the contrary, we show that the action of mibefradil on capacitative calcium entry is due to an action on store-operated calcium channels.

Calcium↗
PubMed1992

Effect of calcium channel blockers on platelet GPIIb-IIIa as a calcium channel in liposomes: comparison with effects on the intact platelet.

The platelet membrane glycoprotein IIb-IIIa complex is essential for platelet aggregation and functions as a fibrinogen receptor on the activated platelet. When incorporated into phospholipid vesicles, this glycoprotein complex can function as an apparent calcium channel which facilitates the transit of calcium across a phospholipid barrier. In order to further evaluate this calcium channel, the effect of calcium channel blockers of the dihydropyridine (nifedipine and nicardipine), arylalkylamine (verapamil) and benzothiazepine (diltiazem) classes were evaluated on GPIIb-IIIa liposomes with encapsulated fura-2 (a fluorescent calcium indicator). Nicardipine, verapamil, and nifedipine significantly inhibited calcium influx into GPIIb-IIIa liposomes; however, this required 190 microM, 400 microM, and 140 microM drug, respectively. These concentrations are 10-1,000 fold greater than those clinically obtainable. In contrast, diltiazem at concentrations greater than 220 microM and amiloride at concentrations greater than 800 microM showed no inhibitory effects. When aspirinized platelets were activated with 30 micrograms/ml bovine fibrillar collagen, both nicardipine and diltiazem produced a decrease in both the initial rise and maximum cytoplasmic calcium concentration. Parallel experiments were performed to assess the effects of verapamil, nicardipine, and diltiazem on platelet aggregation in platelet rich plasma. Nicardipine, 190-380 microM, induced a prolongation of the lag phase, but no effect on the final degree of platelet aggregation to collagen. Similar inhibition of platelet aggregation was seen with diltiazem and verapamil although the effect of diltiazem was less pronounced particularly at higher concentrations of collagen. No effect was seen on aggregation with 32 microM ADP which is release independent, or on the primary wave of low dose ADP induced platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport, Active↗
PubMed1992

Evidence that the antiproliferative effect of verapamil on afferent and efferent immune responses is independent of calcium channel inhibition.

Calcium channel blockers are capable of inhibiting the afferent and efferent limbs of the immune responses of human peripheral blood mononuclear cells in in vitro systems. This effect is thought to be related to the ability of the calcium channel blocker to limit the transmembrane flux of calcium. We report herein that two optical enantiomers of verapamil, one (S-) which is capable of blocking the slow calcium channel and mitogen-stimulated 45Ca++ uptake into human lymphocytes, while the other (R+) is incapable of either activity, share almost identical capabilities of depressing both the afferent and efferent limbs of immunity. These observations suggest that the inhibitory effects of verapamil on various afferent and efferent immune events are, in part at least, unrelated to the inhibition of transmembrane calcium flux.

Adult↗
PubMed2006

Remodeled cardiac calcium channels.

Cardiac calcium channels play a pivotal role in the proper functioning of cardiac cells. In response to various pathologic stimuli, they become remodeled, changing how they function, as they adapt to their new environment. Specific features of remodeled channels depend upon the particular disease state. This review will summarize what is known about remodeled cardiac calcium channels in three disease states: hypertrophy, heart failure and atrial fibrillation. In addition, it will review the recent advances made in our understanding of the function of the various molecular building blocks that contribute to the proper functioning of the cardiac calcium channel.

Animals↗
PubMed1988

Increased concentration of calcium channel and intracellular free calcium in the acute phase of deoxycorticosterone acetate salt hypertension.

Cardiac calcium channels and platelet Ca2+ concentrations were examined in deoxycorticosterone acetate (DOCA)-salt hypertension in rats to clarify the role of calcium channels in the regulation of intracellular Ca2+. Calcium channels were determined by the radioligand binding method and platelet Ca2+ concentrations were measured by a fluorescent Ca2+ indicator, Quin-2. The number of cardiac calcium channels was increased in DOCA-salt hypertension compared with controls 10 days after nephrectomy. Platelet Ca2+ concentrations were also increased in the acute phase of DOCA-salt hypertension. No significant changes were observed in the number of cardiac calcium channels and in platelet Ca2+ concentrations in the chronic phase of DOCA-salt hypertension. These results suggest that the increased platelet Ca2+ concentrations are induced by the increase in the number of calcium channels in the acute phase of hypertension.

5'-Nucleotidase↗
PubMed1998

Comparative pharmacological properties among calcium channel blockers: T-channel versus L-channel blockade.

Calcium antagonists are potent vasodilators and are widely used in the treatment of hypertension and angina pectoris. The currently available compounds belong to three classes: (1) dihydropyridines (e.g. nifedipine, amlodipine and felodipine), (2) phenylalkylamines (e.g. verapamil) and (3) benzothiazepines (e.g. diltiazem). The three classes differ in their pharmacological profile and safety. For example, verapamil and diltiazem lower heart rate, while dihydropyridines increase it or leave it unchanged. With most of the latter compounds, a marked activation of the sympathetic nervous system has been noted. Most compounds exhibit negative inotropic effects, particularly the first-generation molecules, which is disadvantageous in patients with impaired left-ventricular function. The most common side effects of these drugs are flushing, headache and edema. With verapamil, constipation may represent a problem in certain patients. Hence, in spite of a large number of calcium antagonists available, there remains a need for new compounds with enhanced efficacy and improved tolerability. A new compound should lack any negative inotropism, avoid any increase in sympathetic outflow or heart rate and exhibit a high degree of vascular selectivity. Furthermore, a low incidence of side effects, particularly ankle edema and optimal pharmacokinetics allowing once-daily dosing would be desirable. Mibefradil is a new calcium antagonist with promising pharmacological and clinical properties. The compound has a high bioavailability, lacks negative inotropic effects at therapeutic concentrations, does not exhibit reflex tachycardia during vasodilation and actually slightly decreases heart rate. It is a potent direct vasodilator efficacious in hypertension and chronic angina pectoris, elicits endothelium-dependent relaxations and facilitates the effects of nitric oxide in vascular smooth muscle. The drug is a particularly efficacious vasodilator in intramyocardial coronary arteries which may be important for its anti-ischemic effects and the lack of steal in the coronary circulation. Furthermore, mibefradil has antiproliferative properties in human vascular smooth muscle cells in culture. As a unique property, mibefradil blocks T-type calcium channels and hence represents a new class of calcium channel blockers. In patients with hypertension, mibefradil has a high efficacy in controlling blood pressure. The drug does not cause constipation and has a low incidence of ankle edema. A large trial is under way to further delineate the properties of this new calcium antagonist in patients with heart failure.

Animals↗
PubMed1991

Tetrandrine: a novel calcium channel antagonist inhibits type I calcium channels in neuroblastoma cells.

Tetrandrine, an alkaloid isolated from the Chinese herb, Radix stephaniae tetrandrae, has been used clinically as a hypotensive agent for a long time. Recently, several studies have demonstrated that tetrandrine behaves like a calcium entry blocker. In the present investigation, the whole cell version of the patch clamp technique was used to study the effect of tetrandrine on the type I (transient inward) calcium current in neuroblastoma cells. These results showed that tetrandrine inhibited the transient inward current, without affecting the channel kinetics. The effects of tetrandrine were dose-dependent and reversible but did not depend on the frequency of stimulation (use-dependence) or the membrane potential. These data clearly demonstrate that tetrandrine is a novel and potent antagonist of the transient inward current in neuroblastoma cells.

Alkaloids↗
PubMed1997

The intracellular loop between domains I and II of the B-type calcium channel confers aspects of G-protein sensitivity to the E-type calcium channel.

Neuronal voltage-dependent calcium channels undergo inhibitory modulation by G-protein activation, generally involving both kinetic slowing and steady-state inhibition. We have shown previously that the beta-subunit of neuronal calcium channels plays an important role in this process, because when it is absent, greater receptor-mediated inhibition is observed (). We therefore hypothesized that the calcium channel beta-subunits normally may occlude G-protein-mediated inhibition. Calcium channel beta-subunits bind to the cytoplasmic loop between transmembrane domains I and II of the alpha1-subunits (). We have examined the hypothesis that this loop is involved in G-protein-mediated inhibition by making chimeras containing the I-II loop of alpha1B or alpha1A inserted into alpha1E (alpha1EBE and alpha1EAE, respectively). This strategy was adopted because alpha1B (the molecular counterpart of N-type channels) and, to a lesser extent, alpha1A (P/Q-type) are G-protein-modulated, whereas this has not been observed to any great extent for alpha1E. Although alpha1B, coexpressed with alpha2-delta and beta1b transiently expressed in COS-7 cells, showed both kinetic slowing and steady-state inhibition when recorded with GTPgammaS in the patch pipette, both of which were reversed with a depolarizing prepulse, the chimera alpha1EBE (and, to a smaller extent, alpha1EAE) showed only kinetic slowing in the presence of GTPgammaS, and this also was reversed by a depolarizing prepulse. These results indicate that the I-II loop may be the molecular substrate of kinetic slowing but that the steady-state inhibition shown by alpha1B may involve a separate site on this calcium channel.

Animals↗