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PubMed1999

Calcium channel activation and self-biting in mice.

The L type calcium channel agonist (+/-)Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice. Self-biting is provoked by injecting small quantities of (+/-)Bay K 8644 directly into the lateral ventricle of the brain, suggesting a central effect of the drug. Similar behaviors can be provoked by administration of another L type calcium channel agonist, FPL 64176. The self-biting provoked by (+/-)Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine. However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil. The known actions of (+/-)Bay K 8644 as an L type calcium channel agonist, the reproduction of similar behavior with another L type calcium channel agonist, and the protection afforded by certain L type calcium channel antagonists implicate calcium channels in the mediation of the self-biting behavior. This phenomenon provides a model for studying the neurobiology of this unusual behavior.

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

PubMedDate not supplied

Calcium-channel blocking agents and chest pain.

Calcium-channel blocking agents can relieve anginal and chest pain associated with hypermotility of the esophagus. Although calcium-channel antagonists differ in their effects on the esophageal body and the lower esophageal sphincter, reduction of lower esophageal sphincter pressure theoretically could result in gastroesophageal reflux and pain. This pain may be difficult to differentiate from chest pain of cardiac origin. An association between calcium-channel blocking agents and chest pain is speculative at this time. However, the possibility of such an effect should be considered by clinicians in the total management of patients. Future clinical studies are warranted to address the issue of the incidence of such an effect and to define more precisely the potential interrelationship among the calcium-channel antagonists, their efficacy in relieving cardiac pain, and their potential liability in inducing chest pain of noncardiac origin.

Calcium Channel Blockers↗

PubMed1991

High voltage activated calcium channels: molecular composition and function.

Voltage-activated calcium channels comprise a group of similar yet distinct proteins or protein complexes that differ in electrophysiological properties, modulation by phosphorylation and GTP-binding proteins and in their relative sensitivity to organic calcium channel blockers. Cloning of the cDNA of L-type calcium channels from skeletal muscle, heart and smooth muscle opens the way to understanding the molecular basis of channel function and regulation and provides means of studying calcium channels in other tissues.

Animals↗

PubMed2005

Has the controversy over the use of calcium channel blockers in coronary artery disease been resolved?

Calcium channel blockers are used in the treatment of hypertension and angina. The negative findings on cardiovascular outcomes with some short-acting formulations of calcium channel blockers, described in the 1990s, have led to a much reduced use of calcium channel blockers in general. A Coronary disease Trial Investigating Outcome with Nifedipine (ACTION) investigated the effects of the long-acting gastrointestinal therapeutic system (GITS) formulation of nifedipine in patients with stable symptomatic coronary artery disease. There was less new overt heart failure in the nifedipine GITS group (117 of 3825 patients) than in the placebo group (158 of 3840), and coronary angiography and coronary bypass surgery were also lower in the nifedipine GITS than placebo group. Peripheral revascularisation was slightly higher in the nifedipine GITS (187/3825) than the placebo group (144/3840). The Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial compared a calcium channel blocker (amlodipine) and angiotensin-converting enzyme inhibitor (enalapril) in normotensive patients with coronary artery disease. The primary outcome of cardiovascular events occurred in 151 (23.1%), 110 (16.6%) and 136 (20.2%) of placebo, amlodipine and enalapril patients, respectively, with the only significant difference being a reduction with amlodipine compared with placebo. This reduction mainly represented a reduction in coronary revascularisation and hospitalisation for angina with amlodipine compared with placebo. These results suggest that calcium channel blockers are safe and beneficial in the treatment of coronary artery disease.

Calcium Channel Blockers↗

PubMed1984

Tissue heterogeneity of calcium channel antagonist binding sites labeled by [3H]nitrendipine.

Calcium channel antagonist binding sites have been labeled in cerebral cortex, heart, ileum, and skeletal muscle with [3H]nitrendipine. While the dissociation constants of the site from cortex, heart, and ileum are similar, KD approximately equal to 0.1-0.2 nM, the value in skeletal muscle is 2 nM. This difference is affinity is also reflected in the Ki values of dihydropyridine calcium channel antagonists, nifedipine, nimodipine, PY108068, SKF24260, and nisoldipine, and the calcium channel agonist CGP 28392, all of which show lower affinity for the skeletal muscle binding site. The diphenylalkylamine calcium channel antagonists, lidoflazine, cinnarizine, flunarizine, and prenylamine, however, show a 3- to 10-fold increase in affinity in skeletal muscle relative to the other three tissues. EDTA treatment of membranes decreases binding in cortex, heart, and ileum but increases binding in skeletal muscle. These changes are reversible upon addition of CaCl2, SrCl2, or BaCl2. The different properties of [3H]nitrendipine binding in various tissues may relate to the varying tissue sensitivity to organic calcium channel antagonists.

Animals↗

PubMed1996

Evidence for a specific site for modulation of calcium channel activation by external calcium ions.

We have investigated the effect of permeant ion species on activation of transiently expressed neuronal alpha1A Ca channels. Equimolar replacement of Ba with Ca resulted in a consistent depolarizing shift of the half-activation potential whose magnitude (&sim;10 mV) was constant over a range of 2 to 100 mM permeant ion, suggesting that the effects of Ca ions were fully developed at concentrations below 2 mM and indicating that Ba and Ca screened surface charges equally. In mixtures of Ba and Ca at constant divalent cation concentration the voltage-shift, as a function of Ca mole fraction, was well described by a model in which Ba and Ca compete for a single site but only Ca ions produce a gating effect. Overall, our data are consistent with Ca ions exerting their effects on activation via a specific regulatory site.

Animals↗

PubMed1988

Calcium channel agonists and antagonists: effects of chronic treatment on pituitary prolactin synthesis and intracellular calcium.

PRL synthesis by GH cells in culture has previously been shown to increase when calcium is added to cultures grown in calcium-depleted medium or when cultures are treated for 18 h or longer with the dihydropyridine calcium channel agonist BAY K8644, whereas the antagonist nimodipine inhibits PRL. The experiments described here were designed to test whether differences in PRL synthesis caused by the dihydropyridines are due to changes in PRL mRNA levels, whether structurally different classes of calcium channel blockers alter PRL production, and whether long term treatment with calcium channel agonists and antagonists alters intracellular free calcium, [Ca2+]i. PRL synthesis and PRL mRNA levels were increased similarly by BAY K8644 and decreased in parallel by the dihydropyridine antagonist nimodipine, while overall protein and RNA synthesis were not changed by either the agonist or antagonist. Two calcium channel blockers which act at different sites on L-type channels than the dihydropyridines also inhibited PRL synthesis without affecting GH; 5 microM verapamil reduced PRL by 64% and 15 microM diltiazem by 89%. Partial depolarization with 5-25 mM KCl increased PRL synthesis up to 2-fold. The intracellular free calcium ion concentration was estimated by Quin 2 and averaged 142 nM for control cultures in normal medium, and 128 and 168 nM for cultures treated 72 h with nimodipine or BAY K8644, respectively. Nimodipine totally prevented the calcium rise obtained upon depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2003

Effect of hypoxia on calcium channels depends on extracellular calcium in CA1 hippocampal neurons.

Our previous studies have shown that short lasting hypoxia induces an increase of Ca(2+) influx into the cell through high voltage-activated Ca(2+) channels in hippocampal neurons. This effect was abolished by removing of free Ca(2+) from intracellular solution. The aim of this study was to compare hypoxic responses at different extracellular Ca(2+) concentrations ([Ca(2+)](e)) in hippocampal neurons to ascertain whether the hypoxic sensitivity is restricted to Ca(2+) ions. Whole-cell patch-clamp recordings were made from acutely dissociated CA1 hippocampal neurons of rats. Polarographic method for measurements of O(2) partial pressure was used. Here we found that at 2 mM [Ca(2+)](e) the hypoxic effect was significant (up to approximately 94%), whereas [Ca(2+)](e) elevations to 5 and 15 mM resulted in gradual decreasing of the effect. We found, that total Ca(2+) charge carried into the cell under the hypoxia was similar at all [Ca(2+)](e), whereas Ca(2+) charge carried at normoxia was different for different [Ca(2+)](e), being larger at higher [Ca(2+)](e). These data indicated a saturation of the hypoxic effect due to limitation in the channel conductance. Therefore, we suggested that the hypoxic effect can be connected with increase of channel conductance, and the level of channel conductance at normoxia can determine the amplitude of hypoxic effect.

Animals↗

PubMed2001

Calcium channel beta subunits differentially regulate the inhibition of N-type channels by individual Gbeta isoforms.

The direct inhibition of N- and P/Q-type calcium channels by G protein betagamma subunits is considered a key mechanism for regulating presynaptic calcium levels. We have recently reported that a number of features associated with this G protein inhibition are dependent on the G protein beta subunit isoform (Arnot, M. I., Stotz, S. C., Jarvis, S. E., Zamponi, G. W. (2000) J. Physiol. (Lond.) 527, 203-212; Cooper, C. B., Arnot, M. I., Feng, Z.-P., Jarvis, S. E., Hamid, J., Zamponi, G. W. (2000) J. Biol. Chem. 275, 40777-40781). Here, we have examined the abilities of different types of ancillary calcium channel beta subunits to modulate the inhibition of alpha(1B) N-type calcium channels by the five known different Gbeta subunit subtypes. Our data reveal that the degree of inhibition by a particular Gbeta subunit is strongly dependent on the specific calcium channel beta subunit, with N-type channels containing the beta(4) subunit being less susceptible to Gbetagamma-induced inhibition. The calcium channel beta(2a) subunit uniquely slows the kinetics of recovery from G protein inhibition, in addition to mediating a dramatic enhancement of the G protein-induced kinetic slowing. For Gbeta(3)-mediated inhibition, the latter effect is reduced following site-directed mutagenesis of two palmitoylation sites in the beta(2a) N-terminal region, suggesting that the unique membrane tethering of this subunit serves to modulate G protein inhibition of N-type calcium channels. Taken together, our data suggest that the nature of the calcium channel beta subunit present is an important determinant of G protein inhibition of N-type channels, thereby providing a possible mechanism by which the cellular/subcellular expression pattern of the four calcium channel beta subunits may regulate the G protein sensitivity of N-type channels expressed at different loci throughout the brain and possibly within a neuron.

Animals↗

PubMed1997

Differential effects of lipid-soluble toxins on sodium channels and L-type calcium channels in frog ventricular cells.

The effect of grayanotoxin I (GTX I), veratridine and aconitine with either an external or internal concentration of 100 microM on L-type calcium (Ca) channels was studied using the whole cell patch clamp and internal dialysis methods. The experimental conditions for the modification of sodium (Na) channels induced by the internal application of these toxins was determined by showing sustained inward currents with depolarizing repetitive pulses. These toxins failed to generate any change in Ca channels under the same experimental protocol as for Na channels. However, external application of these toxins caused a moderate block of the Ca channels without changing the kinetics.

Aconitine↗

PubMed1990

Gingival hyperplasia in rats induced by oxodipine--a calcium channel blocker.

Oxodipine, a new calcium channel blocker, induced gingival hyperplasia in rats. This is the first time that a calcium channel blocker has been documented as resulting in gingival hyperplasia in rats. In contrast to diphenylhydantoin, the hyperplastic changes induced by oxodipine were not precipitated by any prior irritation. The histology consisted of purely fibroblastic proliferation without infiltrate of inflammatory cells.

Animals↗

PubMed2006

Novel T-type calcium channel blockers: dioxoquinazoline carboxamide derivatives.

T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pains. Since the withdrawal of mibefradil, a T-type calcium channel blocker, there have been a lot of efforts to develop T-type calcium channel blockers. A small molecule library of dioxoquinazoline carboxamide derivatives containing 155 compounds was designed, synthesized, and biologically evaluated for T-type calcium channel blocking activity. Among those compounds synthesized, the compound 1n shows the most potent T-type calcium current blocking activity with an IC(50) value of 1.52 microM, which is comparable to that of mibefradil.

Amides↗

PubMed2000

Comparative study on calcium channel antagonists in the human radial artery: clinical implications.

OBJECTIVES: The radial artery is spastic, and calcium channel antagonists have been used clinically in the radial artery for their antispastic effects. To choose a proper calcium channel antagonist for such a purpose, we compared the in vitro antispastic effects of 4 clinically used calcium channel antagonists (nicardipine, nifedipine, verapamil, and diltiazem) in the human radial artery. METHODS: Radial artery segments taken from patients undergoing coronary bypass operations were studied in the organ bath. The relaxation by the calcium channel antagonists was compared in the potassium-precontracted (25 mmol/L) radial artery. The inhibitory effect of the calcium channel antagonists at the clinically relevant plasma concentration and a higher concentration was also studied for the calcium channel antagonists. RESULTS: All calcium channel antagonists induced a full relaxation (97.8%-100%, n = 5-7 for each), with higher sensitivity (P =.005, analysis of variance [ANOVA] among the calcium channel antagonists for the effective concentration of the constrictor [or dilator] agent that caused 50% of maximal contraction [or relaxation]) to nifedipine (-7.37 +/- 0. 20 log(10) M) than nicardipine (-6.43 +/- 0.39 log(10) M, P =.1), verapamil (-6.08 +/- 0.13 log(10) M, P =.03), and diltiazem (-5.87 +/- 0.07 log(10) M, P =.01). Pretreatment with the plasma concentration of the calcium channel antagonists (60 nmol/L for diltiazem and 20 nmol/L for the others) inhibited the potassium-induced contraction (n = 6 for each) by nicardipine (from 138.6% +/- 5.8% to 101.4% +/- 7.6%, P =.001) and nifedipine (to 87. 7% +/- 6.8%, P =.0003) but not by verapamil (to 140.3% +/- 15.2%, P =.9) or diltiazem (to 132.8% +/- 7.3%, P =.8), although at higher contractions (-4.5 log(10) M) all 4 calcium channel antagonists abolished the contraction. CONCLUSIONS: Although all calcium channel antagonists have antispastic effects in the radial artery, the vessel has different sensitivities to them. Dihydropyridine derivatives may be the most potent calcium channel antiagonists and therefore are recommended for the clinical use for this purpose.

Analysis of Variance↗

PubMed2006

High-throughput screening for N-type calcium channel blockers using a scintillation proximity assay.

N-type calcium channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Accordingly, N-type calcium channel blockers may have clinical utility as analgesic drugs. A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. To develop a small-molecule N-type calcium channel blocker, the authors developed a 96-well plate high-throughput screening scintillation proximity assay (SPA) for N-type calcium channel blockers using [125I]-labeled omega-conotoxin GVIA as a channel-specific ligand. Assay reagents were handled using Caliper's Allegro automation system, and bound ligands were detected using a PerkinElmer TopCount. Using this assay, more than 150,000 compounds were screened at 10 microM and approximately 340 compounds were identified as hits, exhibiting at least 40% inhibition of [125I]GVIA binding. This is the 1st demonstration of the use of [125I]-labeled peptides with SPA beads to provide a binding assay for the evaluation of ligand binding to calcium channels. This assay could be a useful tool for drug discovery.

Animals↗

PubMed2000

Differential modulation of N-type 1B and P/Q-type 1A calcium channels by different G protein subunit isoforms.

Using transient calcium phosphate transfection into the human embryonic kidney tsa-201 cell line and subsequent whole-cell patch-clamp protocols, we examined the tonic modulation of cloned N- and P/Q-type calcium channels by five different G protein beta subunits via strong depolarizing voltage prepulses. For N- and P/Q-type channels, the magnitude of inhibition was dependent on the Gbeta subtype co-expressed. Both the absolute and relative magnitudes of Gbeta subunit-induced inhibition of P/Q-type channels differed from those observed with the N-type channel. For each calcium channel subtype, kinetics of both the prepulse-mediated recovery from inhibition and the re-inhibition following the prepulse were examined for each of the Gbeta subunits by varying either the duration between the pre- and the test pulse or the length of the prepulse. For each channel subtype, we observed a differential Gbeta subunit rank order with regard to the rates of re-inhibition and recovery from inhibition. On average, P/Q-type channels exhibited more rapid rates of recovery from inhibition than those observed with N-type channels. Different Gbeta subtypes mediated different degrees of slowing of activation kinetics. The differential modulation of P/Q- and N-type channels by various Gbeta subtypes may provide a mechanism for fine tuning the amount of calcium entering the presynaptic nerve termini.

Animals↗

PubMedDate not supplied

Incidence of pedal edema formation with dihydropyridine calcium channel blockers: issues and practical significance.

Dihydropyridine calcium channel blockers comprise a class of powerful, well-tolerated, and safe antihypertensive agents that are widely used either alone or as a key component of combination therapy for hypertension. Peripheral edema, particularly of the lower limbs, is one of the most common adverse effects of dihydropyridine calcium channel blockers and may result in the need for dose reduction or drug withdrawal, both of which can adversely affect antihypertensive efficacy. Optimal use of these important drugs will involve careful dosing and sensitivity to strategies to diminish the likelihood of edema. Diuretics, either loop or thiazide, are usually not effective in alleviating pedal edema. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in combination with a dihydropyridine calcium channel blocker may be helpful in this regard. Some calcium channel blockers may be less likely to cause pedal edema compared with others. This paper will review existing explanations of why there may be differences. A favorable tolerability profile is of particular importance for an antihypertensive medication, since hypertension is a chronic disorder necessitating long-term treatment and patient compliance.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2005

RETRACTED: Requirement of voltage-gated calcium channel beta4 subunit for T lymphocyte functions.

Calcium is known to play vital roles in diverse physiological processes, and it is known that voltage-gated calcium channels (Cav) mediate calcium influx in excitable cells. However, no consensus exists on the molecular identity of the calcium channels present in nonexcitable cells such as T lymphocytes. Here, we demonstrate that T lymphocytes express both regulatory beta4 and poreforming Cav1 alpha1 subunits of Cav channels. Cav beta4-mutant T lymphocytes fail to acquire normal functions and display impairment in the calcium response, activation of the transcription factor NFAT, and cytokine production. Although Cav1 channels of lymphocytes retain their voltage dependency, T cell receptor stimulation dramatically increases channel opening, providing a new mechanism for calcium entry in lymphocytes.

Animals↗

PubMed2003

[Advance in calcium channel blockers relaxing corpus cavernosum smooth muscle].

Calcium channels exist extensively in the membrane of cardiac, skeletal, smooth muscle cell and neuron. Calcium channel blockers (CCB) were widely used for the treatment of cardiovascular diseases because they could relax vascular smooth muscle. Experimental researches on calcium channel blockers relaxing corpus cavernosum smooth muscle have been reported recently. Whether the blockers can be used for the clinical diagnosis and treatment of erectile dysfunction still need to be further investigated.

Animals↗