Presynaptic regulation of hippocampal acetylcholine release is unaffected by calcium channel blockers and intracellular calcium chelation.
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Acetylcholine↗
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Effect of calcium-channel blockers on calcium-phosphate metabolism in patients with end-stage renal disease.
BACKGROUND: After EDTA-induced hypocalcaemia, healthy volunteers treated with diltiazem display more severe hyperparathyroidism than subjects on felodipine studied under identical conditions. Therefore patients with end-stage renal disease (ESRD) and severe secondary hyperparathyroidism might be particularly sensitive to this side-effect. METHODS: To test this hypothesis, seven patients with ESRD on chronic haemodialysis (3 women and 4 men) with serum levels of intact PTH ranging from 204 to 675 pg/ml were studied both before and during the first 180 min of haemodialysis against a dialysate with low calcium concentration (0.75 mmol/l, n = 6 and 1 mmol/l, n = 1) under the following three experimental conditions: control, felodipine (10 mg/day) and diltiazem (120 mg b.i.d.). RESULTS: At onset of dialysis, plasma phosphorus level was higher on diltiazem (2.03 +/- 0.08 mM) than on felodipine (1.64 +/- 0.10, P < 0.02), and on the latter it was lower than in control condition (1.88 +/- 0.16, P < 0.02). As a probable consequence, blood ionized calcium concentration was lower on diltiazem (1.14 mM +/- 0.02, mean +/- SEM) than on felodipine (1.2 +/- 0.03, P < 0.05) or in control condition (1.17 +/- 0.01, NS). There was a trend for intact PTH to be higher on diltiazem (324 +/- 47 pg/ml) than on felodipine (246 +/- 55) or in control condition (305 +/- 49) and 1,25-dihydroxyvitamin D was higher indeed on diltiazem (6.70 +/- 0.92 pg/ml) than on felodipine (4.75 +/- 0.91, P < 0.02) or control (3.87 +/- 0.62, P < 0.05). Area under the curve PTH over the first 60 min of dialysis was higher by 16 +/- 7% on diltiazem than on felodipine (P < 0.05). CONCLUSIONS: While on diltiazem rather than on felodipine, patients with ESRD display higher plasma phosphorus levels, and slightly aggravate the degree of severity of hyperparathyroidism recorded during haemodialysis against low-calcium dialysate. The long-term effect of this new observation remains to be evaluated.
Aged↗
Ethanol effects on two types of voltage-activated calcium channels.
Ethanol has been shown to suppress calcium uptake into depolarized synaptosomes, to reduce the durations of calcium spikes in cultured cells and to reduce calcium conductances in invertebrate neurons. Voltage-activated calcium channels therefore appear to be an important target of ethanol action. However, the interactions of ethanol with specific types of calcium channels have yet to be defined. This study examined the effects of ethanol on two different populations of calcium channels in N1E-115 neuroblastoma and in NG108-15 neuroblastoma x glioma hybrid cells. Transient (type I) and long-lasting (type II) calcium channel currents were recorded with the whole-cell voltage clamp technique. At concentrations above 30 mM, ethanol reversibly suppressed both types of calcium channel currents, without changing the voltage dependence of activation. Concentration-response curves were essentially the same for type I and type II channels. Ethanol at concentrations of 100 and 300 mM blocked currents by approximately 15 and 40%, respectively. The voltage dependence of type I channel inactivation was not altered by ethanol concentrations as high as 300 mM, nor was there evidence of a use-dependent blocking action. The effects of ethanol on calcium channels were similar in NG108-15 cells; both channel types were blocked by ethanol at about the same concentrations as were effective in N1E-115 cells. Because ethanol interacts with opiate receptors in some systems, and leucine-enkephalin is known to block type II currents in NG108-15 cells, we examined whether the ethanol block of type II currents could be altered by naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)
Action Potentials↗
Contribution of two types of calcium channels to membrane conductance of single myocytes from guinea-pig coronary artery.
1. Whole-cell and single-channel current recordings were used to study calcium channels in single smooth muscle cells isolated from guinea-pig coronary artery. Potassium currents were blocked by intracellular Cs+ ions. 2. Whole-cell currents were recorded with 10 mM-barium in the bath. Step pulses of 200 ms from a holding potential of -90 mV activated calcium channel current when the depolarization reached -55 to -50 mV. All cells showed a current component which inactivated slowly and incompletely. About half of the cells showed an additional current component with a rapid inactivation time course. Both components were abolished by Cd2+ ions (1 mM) and were reduced by changing the holding membrane potential to -40 mV or by addition of 0.1 mM-Ni2+. 3. Single calcium channel currents were measured in cell-attached patches with 110 or 10 mM-Ba2+ as a current carrier. Two different types of single calcium channel activity were observed. 4. A high-conductance calcium channel was activated near -30 mV with 110 mM-Ba2+ and this threshold was changed to about -60 mV with 10 mM-Ba2+ in the patch pipette. The conductance was 28.0 +/- 1.5 pS (mean +/- S.D.) in 110 mM-Ba2+ and 16.0 +/- 1.0 pS in 10 mM-Ba2+. Dependence of the conductance on the concentration of Ba2+ in the patch pipette followed a Langmuir curve: the apparent dissociation constant of Ba2+ was 8 mM. It was concluded that this channel type corresponds to L-type calcium channels. 5. Another calcium channel was found in these experiments. It had a low conductance and was activated at around -50 mV with 110 mM-Ba2+, and this threshold was shifted to about -70 mV when 10 mM-Ba2+ was the charge carrier. The conductance of this calcium channel was 7.5 +/- 0.6 pS in 110 mM-Ba2+ and 5.5 +/- 1.0 pS in 10 mM-Ba2+. With 10 mM-Ba2+, inactivation of the mean current was slow at potentials -70 to -50 mV, but fast and complete (within 100 ms) at more positive potentials. It was concluded that this type of calcium channel corresponds to T-type calcium channels. 6. With the membrane potential continuously held at -50 to -40 mV (with 10 mM-Ba2+ in the patch pipette), i.e. close to the usual resting potential of these cells, T-type calcium channels were completely inactivated whereas rare openings of L-type calcium channels could be detected.(ABSTRACT TRUNCATED AT 400 WORDS)
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Potentiation of pancuronium induced neuromuscular blockade by calcium channel blockers in vitro.
The calcium channel blockers verapamil, methoxyverapamil, diltiazem, and nisoldipine have been tested for interactions with the nondepolarizing muscle relaxant pancuronium bromide by using the indirectly stimulated in vitro preparation of the rat hemidiaphragm. Dose response curves of each calcium channel blocker, pancuronium bromide, and combinations of both were determined. Each of the four calcium channel blocking drugs showed agonistic interaction in potentiating pancuronium induced neuromuscular blockade.
Animals↗
Fundamentals of calcium channel blockers.
The important role calcium ions play in cellular function and specifically in muscular contraction has been well established. The details of the calcium migration into the cell and its specific mechanism of action however have only recently been elucidated. Still, our current understanding of these issues represents only a tip of the iceberg. The introduction of the calcium channel blockers have heralded to some extent a new revolution in the management of many cellular disfunctions (disease states) which are, in part, related to and are dependent on the migration of calcium ions across the cell membrane. In this article, an overview of the current understanding of the role of calcium ions in cellular function with special attention to the cardiovascular system is presented. In addition, the mechanism of action of the calcium channel blockers is discussed. Finally, the usefulness of these agents in clinical medicine is mentioned, and a review of several major studies demonstrating beneficial effects of calcium channel blockers in various disorders is presented.
Angina Pectoris↗
Effects of tetrandrine on calcium channel currents of bovine chromaffin cells.
Calcium channel currents of bovine chromaffin cells are blocked by the bis-benzyl-isoquinoline alkaloid tetrandrine, which is isolated from the roots of the chinese medical herb Stephania tetrandra. The half-maximal inhibition (IC50) occurred at a concentration of about 10 microM. Bovine chromaffin cells possess no low-voltage-activated, but different types of high-voltage activated calcium channel currents. Tetrandrine blocks omega-conotoxin-sensitive N-type, dihydropyridine-sensitive L-type and omega-conotoxin- and dihydropyridine-insensitive calcium channel currents of chromaffin cells. The I/V relationship in not shifted by tetrandrine, indicating that the block is not voltage-dependent. After tetrandrine application the currents become transient in a depolarization- and a concentration-dependent manner. Tetrandrine blocks open calcium channels and the block is use-dependent. When the holding potential returns to resting levels, the channels are unblocked in about 1 sec.
Alkaloids↗
Use of calcium channel antagonists for cardiovascular disease.
Until recently, only three calcium channel antagonists--verapamil, diltiazem and nifedipine--were available for managing cardiovascular disorders such as hypertension and ischemic heart disease. In the past few years, however, several dihydropyridine calcium channel antagonists, including nicardipine, isradipine, felodipine, nimodipine, and amlodipine, have been marketed. Others are currently awaiting FDA approval. In addition, bepridil, which belongs to a new class of calcium channel antagonists, has recently been marketed for refractory angina pectoris. Clinical uses of calcium channel antagonists have been expanded since the 1970s to include management of cardiovascular disorders such as supraventricular arrhythmias, CHF secondary to diastolic dysfunction, and myocardial reinfarction in selected patients. Calcium channel antagonists are also being investigated for prevention of atherosclerosis. Calcium channel antagonists are a heterogeneous group of pharmacologic agents. Differences in tissue selectivity are largely responsible for the variations in hemodynamic and electrophysiologic properties of these agents. Thus, their clinical uses and side effect profiles differ. These differences must be taken into consideration in the selection of the most appropriate agent for a specific indication. Potential advantages of some of the newer dihydropyridine calcium channel antagonists include less frequent dosing (amlodipine and isradipine) and little or no negative inotropic effect (nicardipine, felodipine, amlodipine, isradipine) compared with the prototype calcium channel antagonists. Additional clinical experience with these newer agents is required, however, before their role in the management of cardiovascular disorders can be fully delineated. The availability of sustained-release formulations of verapamil, diltiazem, nifedipine, felodipine, and nicardipine, as well as the recent marketing of calcium channel antagonists with relatively long half-lives (amlodipine and isradipine), makes once- or twice-daily dosing possible with most calcium channel blockers. However, selection of a particular agent will depend on several factors, including clinical efficacy, side effect profile, cost, and patient characteristics such as concomitant disease states and baseline hemodynamic status.
Angina Pectoris↗
Altered cocaine effects in mice lacking Ca(v)2.3 (alpha(1E)) calcium channel.
Much evidence indicates that calcium channel plays a role in cocaine-induced behavioral responses. We assessed the contributions of Ca(v)2.3 (alpha(1E)) calcium channel to cocaine effects using Ca(v)2.3 knockout mice (Ca(v)2.3-/-). Acute administration of cocaine enhanced the locomotor activity in wild-type mice (Ca(v)2.3+/+), but failed to produce any response in Ca(v)2.3-/- mice. Repeated exposure to cocaine induced the behavioral sensitization and conditioned place preference in both genotypes. Pretreatment with a D1-receptor antagonist, SCH23390, blocked the cocaine-induced place preference in Ca(v)2.3+/+ mice; however, it had no significant effect in Ca(v)2.3-/- mice. Microdialysis and RT-PCR analysis revealed that the levels of extracellular dopamine and dopamine D1 and D2 receptor mRNAs were not altered in Ca(v)2.3-/- mice. These data indicate that Ca(v)2.3 channel contributes to the locomotor-stimulating effect of cocaine, and the deletion of Ca(v)2.3 channel reveals the presence of a novel pathway leading to cocaine rewarding which is insensitive to D1 receptor antagonist.
Animals↗
Hyperinsulinemic-euglycemic therapy for intoxication with calcium channel blockers.
Conventional therapy for intoxication with calcium channel blockers consists of crystalloid solutions, calcium gluconate, glucagon and vasopressor agents. These therapies often fail to improve hemodynamic function in intoxicated patients. The pathophysologic mechanism proposed for intoxication with these agents, suggest hypoinsulinemia as the determinant factor. We will describe the case of a 77 years old man treated for an overdose of nifedipine and atenolol who arrived at our institution with hypotension and bradycardia. After conventional therapy failed to improve the patient's hemodynamic status, hyperinsulinemia and euglycemia contributed to the improvement of the patient's neurologic and hemodynamic condition. Thus, hyperinsulinemic-euglycemic therapy was of benefit in this patient with hemodynamic compromise secondary to intoxication with calcium channel blocker not responding to conventional therapy. We will review the mechanism of action of calcium channel blocker drugs as well as the clinical presentation and treatment options for calcium channel blocker intoxication.
Aged↗
Blockade of voltage-operated calcium channels, increase in spontaneous catecholamine release and elevation of intracellular calcium levels in bovine chromaffin cells by the plant alkaloid tetrandrine.
Experiments were performed in bovine chromaffin cells in short term primary culture. Tetrandrine is a plant alkaloid from the chinese medical herb Stefania tetrandra. The aim of the present study was to investigate the mechanisms by which tetrandrine interacts with calcium signalling and to provide a quantitative description of effects. Tetrandrine blocked voltage-operated calcium channel currents concentration-dependently as shown in whole cell patch-clamp recordings. The blockade of calcium channels reduced the potassium-stimulated catecholamine release. Besides, the drug increased the spontaneous (not stimulated) release of catecholamines in the presence of extracellular calcium. Measurements of intracellular calcium levels [Ca]i showed a calcium release from intracellular stores by tetrandrine. This tetrandrine-induced [Ca]i elevation was higher in calcium containing as compared to calcium free solution. Tetrandrine effects partially overlap with those of thapsigargin, but tetrandrine has additional targets, since it increased [Ca]i in cells pretreated with thapsigargin. We conclude that tetrandrine blocks voltage-operated calcium channels and increases [Ca]i by blocking endoplasmic and other calcium pumps.
Alkaloids↗
Slow inactivation of the Ca(V)3.1 isotype of T-type calcium channels.
T-type calcium channels (the Ca(V)3 channel family) are involved in defining the resting membrane potential and in neuronal activities such as oscillations and rebound depolarization. Their physiological roles depend upon the channel activation and inactivation kinetics. A fast inactivation that stops the ionic flux of calcium in tens of milliseconds has already been described in both native and heterologously expressed channels. Here, using HEK 293 cells expressing the rat Ca(V)3.1 channel and whole-cell voltage clamp, we investigate an additional inactivation process, which can be distinguished from the previously described fast inactivation by its slow time course of recovery from inactivation (tau= 1 s) and by its sensitivity to external calcium. Steady-state slow inactivation is voltage dependent around the resting membrane potential (the potential of half-inactivation (V(0.5)) =-70 mV, slope factor = 7.4 mV) and can reduce the calcium current by up to 50%. Near resting potential, the slow inactivation displays a half-time of induction of tens of seconds. The slow inactivation therefore modulates the availability of T-type calcium channels depending upon recent cell history, providing a mechanism to store information in a time scale of seconds.
Algorithms↗
Hemodynamic effects of calcium channel blockers in essential hypertension.
Calcium channel blockers decrease blood pressure in essential hypertension due to a marked reduction of systemic vascular resistance (arteriolar tone). They also dilate conducting arteries but have no venodilatory effect in antihypertensive doses. With the dihydropyridines (e.g. nifedipine) and diltiazem there is a transient increase in heart rate and cardiac output but this is not observed with verapamil. The vasodilatory responsiveness in the resistance vessels to calcium channel blockers is selectively enhanced in patients with established essential hypertension but not in the early borderline phase of hypertension. During treatment with chlorthalidone, atenolol, acebutolol or nitrendipine for four to six weeks the reduction of blood pressure is accompanied by a selective decrease in the vasodilatory responsiveness to calcium channel blockers.
Blood Pressure↗
[Calcium channel blockers and tissue remodeling in hypertension].
Calcium channel blockers and tissue remodeling in hypertension. Calcium channel blockers (calcium antagonists) are members of various chemical groups. They share the ability to inhibit calcium entry into depolarized smooth muscle cells. This results in reduction of vascular tone and vasodilatation. This action is the rationale for their use in the management of hypertension. The purpose of this paper is to summarize recent experiments aiming to test the hypothesis that the long term effects of calcium channel blockers are not related to reduction of hemodynamic overload.
Blood Pressure↗
Ion migration and inactivation in the calcium channel.
1. Calcium conduction has been studied under voltage clamp in isolated nerve cell bodies of Helix aspersa. A suction pipette method was used to produce internal perfusion and low access resistance to the cell's interior. 2. Ca current does not obey the independence principle and saturates with increasing extracellular Ca concentration. The effect is voltage-dependent. 3. The unit conductance for the Ca channel is between 10(-12) and 10(-13) S, values consistent with impeded conduction. 4. Inactivation is partly dependent upon an increase of intracellular Ca activity due to Ca current. However, a component remains after the increase in [Ca]i has been prevented with EGTA. 5. The Ca channel may have two open states or there may be two sets of Ca channels.
Animals↗
Localization and pharmacological characterization of voltage dependent calcium channels in cultured neocortical neurons.
The physiological significance and subcellular distribution of voltage dependent calcium channels was defined using calcium channel blockers to inhibit potassium induced rises in cytosolic calcium concentration in cultured mouse neocortical neurons. The cytosolic calcium concentration was measured using the fluorescent calcium chelator fura-2. The types of calcium channels present at the synaptic terminal were determined by the inhibitory action of calcium channel blockers on potassium-induced [3H]GABA release in the same cell preparation. L-, N-, P-, Q- and R-/T-type voltage dependent calcium channels were differentially distributed in somata, neurites and nerve terminals. omega-conotoxin MVIIC (omega-CgTx MVIIC) inhibited approximately 40% of the Ca(2+)-rise in both somata and neurites and 60% of the potassium induced [3H]GABA release, indicating that the Q-type channel is the quantitatively most important voltage dependent calcium channel in all parts of the neuron. After treatment with thapsigargin the increase in cytosolic calcium was halved, indicating that calcium release from thapsigargin sensitive intracellular calcium stores is an important component of the potassium induced rise in cytosolic calcium concentration. The results of this investigation demonstrate that pharmacologically distinct types of voltage dependent calcium channels are differentially localized in cell bodies, neurites and nerve terminals of mouse cortical neurons but that the Q-type calcium channel appears to predominate in all compartments.
Action Potentials↗
Direct effect of calcium channel antagonists on osteoclast function: alterations in bone resorption and intracellular calcium concentrations.
Osteoclasts attach to mineralized surfaces and resorb bone matrix, releasing calcium into the area surrounding the osteoclast. The production of high levels of extracellular calcium increases intracellular calcium concentrations ([Ca2+]i), and bone resorption is decreased. To study this mechanism, the dihydropyridine-sensitive L-type calcium channel antagonists PN 200-110, (-)202-791, and nifedipine were studied for their effects on bone resorption using the disaggregated osteoclast pit assay. Changes in [Ca2+]i after treatment with these compounds were determined with the fluoroprobe fura2. In osteoclast-enriched cultures, significant decreases in bone resorption were noted in the presence of PN 200-110 and (-)202-791. The decrease in bone resorption correlated with an increase in [Ca2+]i. To determine whether the effects of these compounds on osteoclasts were mediated via osteoblasts, proliferation and differentiation of rat osteoblast-like cells (ROS 17/2.8) were examined after the addition of these agents. There were no changes in osteoblast proliferation or differentiation, as determined by [3H]thymidine incorporation and specific activity of alkaline phosphatase, after treatment with these compounds at concentrations that inhibited bone resorption in the disaggregated pit assay. This lack of effect of calcium channel antagonists on osteoblast growth and differentiation at concentrations used to inhibit osteoclast function suggests that the effects of PN 200-110 and (-)202-791 on the osteoclast are not mediated via the osteoblast. In addition, conditioned medium recovered from ROS 17/2.8 cultures treated with PN 200-110 or (-)202-791 had no effect on pit formation compared to the conditioned medium from cell-free cultures. This lack of effect of calcium channel conditioned medium on bone resorption provides additional evidence that PN 200-110 and (-)202-791 are decreasing bone resorption directly by altering osteoclast function, not through osteoblast-osteoclast interactions. The addition of (-)202-791 or PN 200-110 to osteoclasts resulted in a dose-dependent rise in [Ca2+]i. These data suggest that calcium channel antagonists may bind to the calcium channel of the osteoclast and lock it in an open state, leading to increased [Ca2+]i and decreased bone resorption.
Animals↗
P-type calcium channels blocked by the spider toxin omega-Aga-IVA.
Voltage-dependent calcium channels mediate calcium entry into neurons, which is crucial for many processes in the brain including synaptic transmission, dendritic spiking, gene expression and cell death. Many types of calcium channels exist in mammalian brains, but high-affinity blockers are available for only two types, L-type channels (targeted by nimodipine and other dihydropyridine channel blockers) and N-type channels (targeted by omega-conotoxin). In a search for new channel blockers, we have identified a peptide toxin from funnel web spider venom, omega-Aga-IVA, which is a potent inhibitor of both calcium entry into rat brain synaptosomes and of 'P-type' calcium channels in rat Purkinje neurons. omega-Aga-IVA will facilitate characterization of brain calcium channels resistant to existing channel blockers and may assist in the design of neuroprotective drugs.
Amino Acid Sequence↗