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At least 163 records · Page 9Linked to original sources
PubMed1994

Effect of calcium channel blockers on intracellular calcium accumulation.

Protection against acute renal failure by calcium channel blockers include radiocontrast agent, cyclosporin, aminoglycosides, amphotericin B, cisplatin nephrotoxicity, and ischaemia-induced toxicity. Calcium overload occurs in ischaemic cells. The type of calcium channel blocker influences the potential effect on protection against nephrotoxicity. A number of growth factors and hormones induce cellular activation by increasing calcium concentrations. Calcium channel blockers interfere with activation of different cell types, e.g. decrease platelet aggregation, macrophage activation, platelet-activating factor release and also proliferative response of vascular smooth muscle and mesangial cells. Uraemia is also a state of calcium accumulation. Increase of intracellular calcium [Ca2+]i in PMNLs is associated with deactivation. Treatment with calcium channel blockers normalizes elevated PMNL [Ca2+]i and improves functional parameters of PMNLs. Normalization of enhanced [Ca2+]i of PMNLs can also be achieved with effective 1,25(OH)2 vitamin D3 therapy by lowering PTH. Uraemia is also a state of insulin resistance. Elevated levels of [Ca2+]i in insulin target cells diminish sensitivity to insulin at the postbinding site. Therapeutic manoeuvres preventing the increase of cytosolic calcium may improve insulin resistance.

Acute Kidney Injury↗
PubMed1982

Calcium channel blocking drugs for chronic, stable angina.

The slow channel calcium blocking drugs have been shown to be efficacious in patients with chronic stable angina. They provide effective first alternative therapy to beta-blockers in preventing recurrent episodes of myocardial ischemia in patients who do not tolerate treatment with beta-blocking drugs because of, for example, pulmonary bronchospasm or hypoglycemia. The calcium blocking drugs often provide an additive effect in reducing anginal episodes when combined with beta-blocking agents and sometimes provide effective relief of chronic stable angina when beta-blocking drugs are unsuccessful. Diltiazem, nifedipine and verapamil are important additions to our therapeutic armentarium for the treatment of exercise-induced angina pectoris.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Three types of neuronal calcium channel with different calcium agonist sensitivity.

How many types of calcium channels exist in neurones? This question is fundamental to understanding how calcium entry contributes to diverse neuronal functions such as transmitter release, neurite extension, spike initiation and rhythmic firing. There is considerable evidence for the presence of more than one type of Ca conductance in neurones and other cells. However, little is known about single-channel properties of diverse neuronal Ca channels, or their responsiveness to dihydropyridines, compounds widely used as labels in Ca channel purification. Here we report evidence for the coexistence of three types of Ca channel in sensory neurones of the chick dorsal root ganglion. In addition to a large conductance channel that contributes long-lasting current at strong depolarizations (L), and a relatively tiny conductance that underlies a transient current activated at weak depolarizations (T), we find a third type of unitary activity (N) that is neither T nor L. N-type Ca channels require strongly negative potentials for complete removal of inactivation (unlike L) and strong depolarizations for activation (unlike T). The dihydropyridine Ca agonist Bay K 8644 strongly increases the opening probability of L-, but not T- or N-type channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Calcium channel subtypes and intracellular calcium stores modulate electric field-stimulated and -oriented nerve growth.

In culture, embryonic spinal neurites from Xenopus laevis show striking growth responses to steady dc electric fields, at a time when endogenous electric fields of similar size impinge on the developing nervous system. A high proportion of cultured neurites reorient, with both turning and branching directed cathodally. Neurite growth rates are increased and growth is differential (faster cathodally than anodally). Voltage-dependent calcium channels and calcium release from intracellular stores are shown to control these events. However, the pharmacological sensitivities of these phenomena differ, indicating different control mechanisms.

Animals↗
PubMed1992

Interventions that beneficially influence the evolution of coronary atherosclerosis. The case for calcium channel blockers.

Calcium channel blockers have been shown to retard the development of atherosclerosis in rabbits fed cholesterol-rich diets. The mechanism accounting for this effect is controversial but may be by stimulation of cholesteryl ester hydrolase activity in smooth muscle cells, by amelioration of hypercholesterolemia-induced endothelial dysfunction, or by inhibition of smooth muscle cell proliferation and migration. The effect of calcium channel blockers on the evolution of coronary atherosclerosis in humans has been assessed in two clinical trials. In the Montreal Heart Institute trial, nicardipine did not influence the overall rate of progression and regression; however, nicardipine-treated patients experienced significantly less progression of minimal lesions, defined as stenoses of < or = 20% severity. In the International Nifedipine Trial on Antiatherosclerotic Therapy, nifedipine had no effect on overall progression and regression but reduced the rate of appearance of new coronary lesions. These studies constitute a potentially important new approach to the management of coronary atherosclerosis.

Animals↗
PubMed1990

A comparison of the effect of calcium channel ligands and GABAB agonists and antagonists on transmitter release and somatic calcium channel currents in cultured neurons.

Glutamate release has been examined from cultured cerebellar granule neurons in the rat using the technique of prelabelling the releasable pool of glutamate with [3H]glutamine. Glutamate release was stimulated in control neurons by 2-min incubation with 50 mM K+, or in neurons continuously depolarized in Ca2(+)-free 50 mM K+ medium, by 2-min incubation with medium containing 5 mM Ca2+. The ability of the Ca2(+)-channel agonist (+)-202-791 to increase the stimulated release of [3H]glutamate was approximately doubled in the depolarized condition. The antagonist enantiomer (-)-202-791 produced a small inhibition of K(+)-stimulated release, whereas (-)-202-791 completely inhibited Ca2(+)-stimulated release from depolarized neurons at concentrations greater than 10 nM. (-)-Baclofen (100 microM) inhibited transmitter release similarly (25-30%) under the two conditions. Calcium-channel currents were recorded from cultured dorsal root ganglion neurons under control conditions at a holding potential of -80 mV, or in neurons depolarized to -30 mV. (-)-202-791 produced a greater effect at -30 than at -80 mV although even at -30 mV the inhibition was slow in onset and incomplete. (-)-Baclofen (100 microM) inhibited the amplitude of the calcium-channel current at both holding potentials by 30-50%, although it did not clearly slow activation of the current at the depolarized holding potential. The GABAB receptors associated with inhibition of glutamate release and of calcium-channel currents were both markedly blocked by phaclofen but not by 2-OH-saclofen. These findings suggest that the GABAB receptor associated with inhibitory modulation of transmitter release, and that associated with inhibition of calcium-channel currents show pharmacological similarities, and are able to exert their action even at levels of steady depolarization at which most N-type channels should be inactivated.

Animals↗
PubMed1998

The action of calcium channel blockers on recombinant L-type calcium channel alpha1-subunits.

1. CHO cells expressing the alpha(1C-a) subunit (cardiac isoform) and the alpha(1C-b) subunit (vascular isoform) of the voltage-dependent L-type Ca2+ channel were used to investigate whether tissue selectivity of Ca2+ channel blockers could be related to different affinities for alpha1C isoforms. 2. Inward current evoked by the transfected alpha1 subunit was recorded by the patch-clamp technique in the whole-cell configuration. 3. Neutral dihydropyridines (nifedipine, nisoldipine, (+)-PN200-110) were more potent inhibitors of alpha(1C-)b-subunit than of alpha(1C-a)-subunit. This difference was more marked at a holding potential of -100 mV than at -50 mV. SDZ 207-180 (an ionized dihydropyridine) exhibited the same potency on the two isoforms. 4. Pinaverium (ionized non-dihydropyridine derivative) was 2 and 4 fold more potent on alpha(1C-a) than on alpha(1C-b) subunit at Vh of -100 mV and -50 mV, respectively. Effects of verapamil were identical on the two isoforms at both voltages. 5. [3H]-(+)-PN 200-110 binding experiments showed that neutral dihydropyridines had a higher affinity for the alpha(1C-b) than for the alpha(1C-a) subunit. SDZ 207-180 had the same affinity for the two isoforms and pinaverium had a higher affinity for the alpha(1C-a) subunit than for the alpha(1C-b) subunit. 6. These results indicate marked differences among Ca2+ channel blockers in their selectivity for the alpha(1C-a) and alpha(1C-b) subunits of the Ca2+ channel.

Animals↗
PubMed2002

Unexpected cross talk: small GTPase regulation of calcium channel trafficking.

Calcium ions can serve as both charge carriers and second messengers. Most cells have voltage-dependent calcium channels that control the membrane permeability to calcium. These channels at the membrane open in response to changes in membrane potential. Their activity is further modulated by phosphorylation by various kinases, such as protein kinase A and protein kinase C, and by changes in intracellular calcium concentration through the action of calcium calmodulin (Ca(2+)/CaM). Trimmer discusses a potential mechanism by which the expression of these channels can be regulated through an interaction with a small guanosine triphosphatase (GTPase), kir/Gem, that influences trafficking of the channels through effects on assembly with auxiliary subunits that occurs in the biosynthetic pathway.

Animals↗
PubMed1986

Effects of calcium channel blocking agents on calcium and centrilobular necrosis in the liver of rats treated with hepatotoxic agents.

Carbon tetrachloride, chloroform, dimethylnitrosamine, thioacetamide or acetaminophen was each administered to rats in a single hepatotoxic dose. Nifedipine, verapamil or chlorpromazine was administered in association with the hepatotoxic agents to determine if calcium channel blocking agents would prevent an increase in liver cell calcium associated with hepatotoxicity and to determine if these agents would protect against the development of centrilobular necrosis. Following a latent period different for each toxic agent, a 4- to 18-fold increase in liver cell calcium content had occurred by 24 hr. The calcium increase and the centrilobular necrosis (mean histologic score) were correlated. A relatively high calcium to necrosis ratio was obtained with dimethylnitrosamine, thioacetamide and acetaminophen. A lesser calcium to necrosis ratio was obtained with chloroform and carbon tetrachloride, the two toxic agents that destroyed the intracellular calcium sequestration activity of the liver endoplasmic reticulum. Nifedipine or chlorpromazine, administered prior to and 7 hr after the toxic agent, completely prevented the centrilobular necrosis caused by thioacetamide, carbon tetrachloride and acetaminophen; almost completely prevented necrosis with dimethylnitrosamine; and provided partial protection against chloroform toxicity. Two doses of verapamil provided partial protection against necrosis when carbon tetrachloride was the toxic agent and provided almost complete protection with dimethylnitrosamine. A reduction in liver cell calcium was associated with the protective action of the three calcium channel blocking agents. These findings are compared with earlier studies of the protective effects of calcium channel blocking agents in cardiac ischemia.

Acetaminophen↗
PubMed1994

Myocardial action potential prolongation by calcium channel activation under calcium-free EGTA condition in guinea pigs and rats.

1. Prolongation of action potentials upon the addition of isoproterenol or dbcAMP under Ca-free EGTA condition were observed in isolated myocardial preparations from both the guinea pig and the rat, whose action potential configuration greatly differ. The degree of prolongation was greater in the rat than in the guinea pig. 2. The prolongation of the action potential was rapidly reversed upon the addition of calcium ion and was dose-dependently suppressed by the addition of calcium antagonists. The sensitivity to nicardipine of this action potential was tenfold higher than of the so-called slow response action potentials. The duration of the prolonged action potential was dependent on the external sodium concentration, but was not affected by tetrodotoxin. 3. Thus, it was demonstrated in intact myocardia that sodium ion may persistently pass through the calcium channel to prolong the action potential when it is activated under the condition where the calcium-mediated inactivation of calcium channels is removed. 4. Contribution of calcium-mediated inactivation of calcium channels to the repolarization of normal myocardium may be larger in the rat than in the guinea pig.

Action Potentials↗
PubMed1995

Sensitization of InsP3-dependent calcium signalling through structural modification of voltage-dependent calcium channel: a physiological relevance of the calcium channel beta subunit.

The expression in Xenopus oocytes of the human voltage-dependent Ca2+ channel (VDCC) beta 2 subunit subtype (h beta 2) enhances the endogenous Ca2+ channel activity. By using the native Ca(2+)-dependent chloride conductance to monitor fast intracellular Ca2+ variations, we point out that the beta-enhanced Ca2+ entry (T1 component) is currently associated with a second delayed elevation of internal Ca2+ (T2 component). Further experiments show that this additional component absolutely requires Ca2+ entry through the beta-modulated channels although it directly derives from a Ca2+ release from intracellular inositol (1,4,5)-trisphosphate (InsP3)-sensitive stores. Finally, our study demonstrates that InsP3-evoked response in oocytes is dramatically modified since it gains a new shape of voltage dependency directly derived from the beta-modified Ca2+ influx. The main conclusion is that the spatiotemporal pattern of InsP3-dependent Ca2+ release may be closely influenced by the intrinsic characteristics of working VDCCs.

Animals↗
PubMed1996

Inhibition of membrane L-type calcium channel activity and intracellular calcium concentration by 24R, 25-dihydroxyvitamin D3 in vascular smooth muscle.

Pharmacological doses of 24R,25-dihydroxyvitamin D3 (24,25D3) inhibited both phasic and tonic contraction of Sprague-Dawley (SD) rat tail artery helical strips induced by KCl, norepinephrine (NE), and arginine vasopressin (AVP) in organ-bath studies. 24,25D3 also decreased the tension dependent on external calcium influx induced by KCl, AVP, and NE and the tension dependent on internal calcium release from intracellular calcium stores induced by NE. In vascular smooth muscle cells isolated from SD rat tail artery, 24,25D3 reduced membrane L-type calcium channel current and the increment of intracellular calcium concentration induced by KCl. It is suggested that 24,25D3 directly relaxed precontracted SD rat-tail artery by its inhibitory effect on plasma membrane and intracellular organelle calcium channels.

24,25-Dihydroxyvitamin D 3↗
PubMed1986

Ultrastructural evidence in rabbit ear arteries that barium enters smooth muscle cells through calcium channels.

The calcium channel blocker methoxyverapamil, at 10(-5) mol/l, abolished contractile responses of isolated perfused rabbit ear arteries to barium. Entry of barium into smooth muscle cells was detected by the presence of mitochondrial granules specific for barium. Methoxyverapamil (10(-5) mol/l) prevented the appearance of barium granules. In a further series of experiments, eight out of twelve arteries incubated with barium, 2.5 mmol/l, showed granules; when the incubate contained 2.5 mmol/l of both barium and calcium, granules were found in only one of twelve specimens; thus calcium appears to compete with barium for entry. These results are consistent with the hypothesis that contractile responses to barium depend on entry of barium into the cells through calcium channels.

Animals↗
PubMed1993

Interaction of calcium channel antagonists with calcium: structural studies on verapamil and its Ca2+ complex.

The conformation of the calcium channel antagonist verapamil has been determined in acetonitrile, in the absence and presence of Ca2+, using two-dimensional 1H-NMR and molecular modeling techniques. Interproton connectivities in the drug molecule were identified from the observed NOESY cross peaks and interproton distances were estimated from the magnitudes of the volume integrals of the cross peaks. The molecular modeling program utilized the Monte Carlo simulation to generate a random ensemble of conformers complying with the NOESY-derived distance constraints. The energies of these conformers were subsequently computed. The minimum-energy structure of the free drug obtained in this manner exhibited some significant differences from the structure of verapamil determined by X-ray crystallography. In particular, the torsional angles in the middle region of the molecule containing the aliphatic "backbone" were such that the two aromatic rings at either end of the drug molecules were moved farther apart from each other in solution than in the crystal structure. The nearly perpendicular orientation of the aromatic rings seen in the crystal was, however, maintained in the solution structure as well. The addition of Ca2+ to a solution of verapamil in acetonitrile caused marked changes in the difference absorbance of the drug in the 200-300-nm region and in many of its 1H-NMR resonances. The changes were most significant up to a mole ratio of about 0.5 Ca2+:drug. Analysis of the binding data at 25 degrees C showed the presence of both 2:1 and 1:1 drug:Ca2+ complexes in equilibrium, the former "sandwich" complex being dominant at the lower cation concentrations with an estimated dissociation constant of about 300 microM. All of the NOESY cross peaks of the free drug remained on addition of 0.5 mol ratio of Ca2+ to verapamil in deuterated acetonitrile and only two new connectivities were observed. Using the interproton distances calculated from these NOESY data, molecular modeling of the 2:1 drug:Ca2+ complex was carried out to yield the minimum-energy conformer. In this conformer, Ca2+ was coordinated to two methoxy oxygens from each of the two drug molecules. The implications of the verapamil-Ca2+ interaction are discussed in terms of available experimental data on the binding of verapamil to the dihydropyridine-sensitive channel and in terms of a hypothesis on the formation of a drug-Ca(2+)-receptor complex in the lipid bilayer environment.

Binding Sites↗
PubMed1993

Neuropharmacological characterization of voltage-sensitive calcium channels: possible existence of neomycin-sensitive, omega-conotoxin GVIA- and dihydropyridines-resistant calcium channels in the rat brain.

We attempted to characterize the functional roles of subtypes of voltage-sensitive calcium channels in the brain. The maximal number of [125I]omega-conotoxin GVIA (omega-CTX) binding sites in rat brain associated with N-type calcium channels (N-channels) was approximately 10 times more than that of [3H]-PN200-110 associated with L-type calcium channels (L-channels). [125I]omega-CTX binding was inhibited by aminoglycoside antibiotics, neomycin and dynorphin A(1-13), but not by various classes of L-channel antagonists. A 6-hydroxydopamine-induced lesion of the striatum resulted in a marked reduction of both [125I]-omega-CTX and [3H]PN200-110 binding. Kainic acid-induced lesion of the striatum reduced [3H]PN200-110 binding by 57%, but did not reduce [125I]omega-CTX binding. Omega-CTX produced a small (18%) but significant reduction of potassium-stimulated Ca2+ influx into rat brain synaptosomes, although it produced a concentration-dependent inhibition in chick brain synaptosomes. Neomycin inhibited Ca2+ influx in both preparations in a concentration-dependent manner. Both omega-CTX and neomycin inhibited potassium-stimulated [3H]dopamine (DA) release from rat striatal slices. The L-channel antagonists had no effect on either Ca2+ influx or [3H]DA release. These results suggest that DA release in the striatum is regulated by Ca2+ influx through N-channels located in presynaptic nerve terminals, and that the most of the Ca2+ influx in rat brain appears to be governed by neomycin-sensitive, omega-CTX- and DHP-resistant calcium channels.

Animals↗
PubMed1998

Effects of intrathecally administered aminoglycoside antibiotics, calcium-channel blockers, nickel and calcium on acetic acid-induced writhing test in mice.

1. Antinociceptive effects of intrathecally administered aminoglycoside antibiotics, calcium-channel blockers, nickel and calcium ions on the acetic acid-induced writhing test in mice were examined. 2. Neomycin (0.5-20.0 micrograms/mouse) gentamicin (5-40 micrograms/mouse), nicardipine, diltiazem and verapamil (0.5-80.0 micrograms/mouse) and calcium ions (0.02-1.0 mumol/mouse) exerted a dose-dependent antinociceptive activity on the acetic acid-induced writhing test. Nickel ions (2.5, 5.0 and 10.0 mumol/mouse) were found ineffective in this test. 3. These results suggest that N- and L-type, but not T-type, voltage-dependent calcium channels are implicated in the spinal processing of nociceptive information.

Acetic Acid↗
PubMed1997

P/Q-type calcium channels activate neighboring calcium-dependent potassium channels in mouse motor nerve terminals.

The identity of the voltage-dependent calcium channels (VDCC), which trigger the Ca2+-gated K+ currents (IK(Ca)) in mammalian motor nerve terminals, was investigated by means of perineurial recordings. The effects of Ca2+ chelators with different binding kinetics on the activation of IK(Ca) were also examined. The calcium channel blockers of the P/Q family, omega-agatoxin IVA (omega-Aga-IVA) and funnel-web spider toxin (FTX), have been shown to exert a strong blocking effect on IK(Ca). In contrast, nitrendipine and omega-conotoxin GVIA (omega-CgTx) did not affect the Ca2+-activated K+ currents. The intracellular action of the fast Ca2+ buffers BAPTA and DM-BAPTA prevented the activation of the IK(Ca), while the slow Ca2+ buffer EGTA was ineffective at blocking it. These data indicate that P/Q-type VDCC mediate the Ca2+ influx which activates IK(Ca). The spatial association between Ca2+ and Ca2+-gated K+ channels is discussed, on the basis of the differential effects of the fast and slow Ca2+ chelators.

Animals↗