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At least 505 records · Page 28Linked to original sources
PubMed1996

Calcium channel blockers for anxiety disorders?

The role of calcium in the etiology of anxiety has been proposed for several decades. Calcium channel blockers profoundly influence calcium metabolism and the transport of calcium. Even though the evidence for the role of calcium remains weak, drugs affecting calcium might be useful in the treatment of anxiety disorders. One of these compounds, verapamil, has been used to treat mood disorders. Calcium channel blockers have also been tried in other indications such as premenstrual syndrome, irritable bowel syndrome, schizophrenia, tardive dyskinesia, and Tourette's syndrome. However, the number of articles on the use of calcium channel blockers in the treatment of anxiety disorders is low. Three reports (two open, one double-blind) described some success in the treatment of panic disorder with verapamil, diltiazem, or nimodipine and one open-label study described unsuccessful treatment of anxiety and phobia with nifedipine in patients with various anxiety disorders. Further double-blind placebo-controlled studies of calcium channel blockers in the treatment of anxiety disorders are warranted to determine a possible role of these compounds in the armamentarium of antianxiety drugs.

Anxiety Disorders↗
PubMed2004

Auxiliary subunit regulation of high-voltage activated calcium channels expressed in mammalian cells.

The effects of auxiliary calcium channel subunits on the expression and functional properties of high-voltage activated (HVA) calcium channels have been studied extensively in the Xenopus oocyte expression system, but are less completely characterized in a mammalian cellular environment. Here, we provide the first systematic analysis of the effects of calcium channel beta and alpha(2)-delta subunits on expression levels and biophysical properties of three different types (Ca(v)1.2, Ca(v)2.1 and Ca(v)2.3) of HVA calcium channels expressed in tsA-201 cells. Our data show that Ca(v)1.2 and Ca(v)2.3 channels yield significant barium current in the absence of any auxiliary subunits. Although calcium channel beta subunits were in principle capable of increasing whole cell conductance, this effect was dependent on the type of calcium channel alpha(1) subunit, and beta(3) subunits altogether failed to enhance current amplitude irrespective of channel subtype. Moreover, the alpha(2)-delta subunit alone is capable of increasing current amplitude of each channel type examined, and at least for members of the Ca(v)2 channel family, appears to act synergistically with beta subunits. In general agreement with previous studies, channel activation and inactivation gating was regulated both by beta and by alpha(2)-delta subunits. However, whereas pronounced regulation of inactivation characteristics was seen with the majority of the auxiliary subunits, effects on voltage dependence of activation were only small (< 5 mV). Overall, through a systematic approach, we have elucidated a previously underestimated role of the alpha(2)-delta(1) subunit with regard to current enhancement and kinetics. Moreover, the effects of each auxiliary subunit on whole cell conductance and channel gating appear to be specifically tailored to subsets of calcium channel subtypes.

Animals↗
PubMed2005

International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels.

The family of voltage-gated calcium channels serves as the key transducers of cell surface membrane potential changes into local intracellular calcium transients that initiate many different physiological events. There are 10 members of the voltage-gated calcium channel family that have been characterized in mammals, and they serve distinct roles in cellular signal transduction. This article presents the molecular relationships and physiological functions of these calcium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

Animals↗
PubMed1996

Depolarization-stimulated cholecystokinin secretion is mediated by L-type calcium channels in STC-1 cells.

To examine the role of calcium channels in depolarization-activated cholecystokinin (CCK) release, studies were performed in an intestinal CCK-secreting cell line, STC-1. Blockade of potassium channels with barium chloride (5 mM) increased the release of CCK by 374.6 +/- 46.6% of control levels. Barium-induced secretion was inhibited by the L-type calcium-channel blocker, nicardipine. Nicardipine (10(-9)-10(-5) M) produced a dose-dependent inhibition in barium-stimulated secretion with a half-maximal inhibition (IC50) value of 0.1 microM. A second L-type calcium-channel blocker, diltiazem (10(-9)-10(-4) M), also inhibited barium-induced CCK secretion with an IC50 value of 5.1 microM. By contrast, the T-type calcium-channel blocker, nickel chloride (10(-7)-10(-8) M), failed to significantly inhibit barium-induced CCK secretion. To further evaluate a role for L-type calcium channels in the secretion of CCK, the effects of the L-type calcium channel opener, BAY K 8644, were examined. BAY K 8644 (10(-8)-10(-4) M) produced a dose-dependent stimulation in CCK release with a mean effective concentration value of 0.2 microM. Recordings of single-channel currents from inside-out membrane patches showed activation of calcium channels by BAY K 8644 (1 microM), with a primary channel conductance of 26.0 +/- 1.2 pS. It is concluded that inhibition of potassium channel activity depolarizes the plasma membrane, thereby activating L-type, but not T-type, calcium channels. The corresponding influx of calcium serves to trigger secretion of CCK.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

Targeting chronic and neuropathic pain: the N-type calcium channel comes of age.

The rapid entry of calcium into cells through activation of voltage-gated calcium channels directly affects membrane potential and contributes to electrical excitability, repetitive firing patterns, excitation-contraction coupling, and gene expression. At presynaptic nerve terminals, calcium entry is the initial trigger mediating the release of neurotransmitters via the calcium-dependent fusion of synaptic vesicles and involves interactions with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex of synaptic release proteins. Physiological factors or drugs that affect either presynaptic calcium channel activity or the efficacy of calcium-dependent vesicle fusion have dramatic consequences on synaptic transmission, including that mediating pain signaling. The N-type calcium channel exhibits a number of characteristics that make it an attractive target for therapeutic intervention concerning chronic and neuropathic pain conditions. Within the past year, both U.S. and European regulatory agencies have approved the use of the cationic peptide Prialt for the treatment of intractable pain. Prialt is the first N-type calcium channel blocker approved for clinical use and represents the first new proven mechanism of action for chronic pain intervention in many years. The present review discusses the rationale behind targeting the N-type calcium channel, some of the limitations confronting the widespread clinical application of Prialt, and outlines possible strategies to improve upon Prialt's relatively narrow therapeutic window.

Animals↗
PubMed1998

HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers.

We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/IsK K+ channels. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in transfected COS cells, HERG is blocked in a concentration-dependent manner by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM), and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1/IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K+ channels HERG and KvLQT1/IsK, which represent together the cardiac delayed rectifier K+ current, are sensitive targets to calcium channel blockers. This work may help in understanding the mechanisms of action of verapamil in certain ventricular tachycardia, as well as some of the deleterious adverse cardiac events associated with bepridil.

Animals↗
PubMed1987

Aggression and defeat-induced opioid analgesia displayed by mice are modified by calcium channel antagonists and agonists.

The effects of the calcium channel antagonists diltiazem, nifedipine and verapamil and the calcium channel agonist, BAY K 8644, on offensive and defensive aggression and defeat-induced opioid analgesia were examined in male mice in resident-intruder interactions. The calcium channel antagonists decreased and the agonist increased the aggressive behaviors displayed by the mice. In addition, the calcium channel antagonists augmented, while the agonist attenuated defeat-induced analgesia displayed by the intruder mice. These results suggest that calcium channel antagonists have inhibitory influences on aggressive behavior and may facilitate endogenous opioid activity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1997

Bradykinin inhibition of N- and L-type calcium channel currents in NG108-15 cells.

The bradykinin regulation of calcium channel currents in NG108-15 neuroblastoma x glioma hybrid cells was examined, in order to determine: (1) which type of bradykinin receptors mediates the inhibition of N-type calcium channels in these cells; and (2) whether bradykinin can modulate other types of calcium channels in these cells. Bradykinin inhibited both N- and L-type calcium channels in NG108-15 cells, with EC50S of 10 +/- 2 nM and 29 +/- 7 nM, respectively. The inhibition of both L- and N-type calcium channels by bradykinin (100 nM) could be completely inhibited by the bradykinin B2 receptor antagonist Hoe 140 (10 nM). Bradykinin appeared to inhibit that portion of the L-type calcium channel current that was also reversibly inhibited by omega-conotoxin GVIA. The bradykinin inhibition of the L-type calcium channel current was partly reduced by pretreatment of the cells with pertussis toxin, whereas the inhibition of the N-type current was pertussis toxin-insensitive. In some cultures it was observed that the bradykinin B1 receptor agonist desArg9bradykinin inhibited the L-type calcium channel current.

Bradykinin↗
PubMed1992

Activation of dihydropyridine-sensitive parotid salivary gland calcium channels by epidermal growth factor.

The calcium channel complex of the parotid was isolated from solubilized acinar-cell membranes by affinity chromatography on wheatgerm agglutinin. The channel, after labelling the calcium antagonist-receptor site with [3H]-PN200-100, was reconstituted into phosphatidylcholine vesicles that exhibited active 45Ca2+ uptake. This uptake was independent of sodium and potassium gradients, indicating its electroneutrality. The channels responded in a dose-dependent manner to the dihydropyridine calcium antagonist, PN200-110, which at 0.4 microM exerted a maximal inhibitory effect of 75% on 45Ca2+ uptake; a 46% enhancement in 45Ca2+ uptake occurred with a specific calcium-channel activator, BAY K8644. On epidermal growth-factor (EGF) binding in the presence of ATP, there was an increase in tyrosine phosphorylation of 55 and 170 kDa calcium-channel proteins. Such phosphorylated channels, after reconstitution into vesicles, displayed a 61% greater 45Ca2+ uptake, indicating the involvement of tyrosine kinase in EGF-dependent activation of the calcium channel. The results point towards the importance of EGF in the regulation of calcium homeostasis in salivary gland.

Animals↗
PubMed2004

Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart.

Calcium channel blockers are among the most commonly used therapeutic drugs. Nevertheless, the utility of calcium channel blockers for heart disease is limited because of the potent vasodilatory effect that causes hypotension, and other side effects attributable to blockade of noncardiac channels. Therefore, focal calcium channel blockade by gene transfer is highly desirable. With a view to creating a focally applicable genetic calcium channel blocker, we overexpressed the ras-related small G-protein Gem in the heart by somatic gene transfer. Adenovirus-mediated delivery of Gem markedly decreased L-type calcium current density in ventricular myocytes, resulting in the abbreviation of action potential duration. Furthermore, transduction of Gem resulted in a significant shortening of the electrocardiographic QTc interval and reduction of left ventricular systolic function. Focal delivery of Gem to the atrioventricular (AV) node significantly slowed AV nodal conduction (prolongation of PR and AH intervals), which was effective in the reduction of heart rate during atrial fibrillation. Thus, these results indicate that gene transfer of Gem functions as a genetic calcium channel blocker, the local application of which can effectively modulate cardiac electrical and contractile function.

Action Potentials↗
PubMed1996

Immunoassays fail to detect antibodies against neuronal calcium channels in amyotrophic lateral sclerosis serum.

Recent studies suggested that autoantibodies that bind to voltage-dependent calcium channels and activate calcium entry may play a role in the progressive degeneration of motoneurons in sporadic amyotrophic lateral sclerosis. Immunoassays were performed to assess autoantibody titer in patients with amyotrophic lateral sclerosis or Lambert-Eaton myasthenic syndrome, a disease in which the presence of anti-calcium channel antibodies is well documented. Based on immunoprecipitation assays for antibodies against N-type calcium channels, only 8% (2/25) of amyotrophic lateral sclerosis patients had marginally positive titers, whereas 58% (18/31) of patients with Lambert-Eaton myasthenic syndrome had positive titers. Enzyme-linked immunosorbent assays with purified neuronal N-type calcium channels revealed immunoreactivity in 2 of 25 amyotrophic lateral sclerosis sera and 12 of 31 Lambert-Eaton myasthenic syndrome sera, which is not compatible with suggestions that enzyme-linked immunosorbent assay is a more sensitive technique for the detection of autoantibodies in amyotrophic lateral sclerosis. Furthermore, based on immunoprecipitation assays, amyotrophic lateral sclerosis sera were totally negative for antibodies against L-type calcium channels from skeletal muscle or brain. These data do not support the hypothesis that an autoimmune response against calcium channels plays a primary role in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Attenuation of ketamine effects by nimodipine pretreatment in recovering ethanol dependent men: psychopharmacologic implications of the interaction of NMDA and L-type calcium channel antagonists.

Ketamine blocks the calcium channel associated with N-methyl-D-aspartate (NMDA) glutamate receptors. It has transient behavioral effects in healthy humans that resemble aspects of schizophrenia, dissociative disorders, and ethanol intoxication. Ethanol is an antagonist of both NMDA receptors and L-type voltage-sensitive calcium channels (VSCC) and it has minimal psychotogenic activity in humans. A double-blind placebo-controlled study was conducted that evaluated whether pretreatment with the L-type VSCC antagonist, nimodipine, 90 mg D, modulated ketamine response (bolus 0.26 mg/kg, infusion of 0.65 mg/kg/hr) in 26 ethanol-dependent inpatients who were sober for at least one month prior to testing. This study found that nimodipine reduced the capacity of ketamine to induce psychosis, negative symptoms, altered perception, dysphoria, verbal fluency impairment, and learning deficits. Nimodipine improved memory function, but had no other intrinsic behavioral activity in this patient group. Nimodipine pretreatment attenuated the perceived similarity of ketamine effects to ethanol as well as ketamine-induced euphoria and sedation. However, nimodipine did not reduce the stimulant effects of ketamine. These data suggest that antagonism of L-type VSCCs attenuates the behavioral effects of NMDA antagonists in humans. They support the continued evaluation of nimodipine in the treatment of neuropsychiatric disorders. They also suggest that drugs, such as ethanol, that combine NMDA and L-type VSCC antagonism may have enhanced tolerability without attenuation of their stimulant effects.

Adult↗
PubMed1992

Divalent-selective voltage-independent calcium channels in Lymnaea neurons: permeation properties and inhibition by intracellular magnesium.

Calcium channels are tightly regulated. Voltage-gated calcium channels open only in response to depolarization, while voltage-independent calcium channels usually open only in response to specific intracellular or extracellular ligands. Voltage-independent calcium channels have been described in several invertebrate neurons. One difficulty in understanding the function of the neuronal channels is that their regulators are unknown. They open rarely in intact cells but are activated by formation of a cell-free patch, suggesting that some intracellular inhibitor usually keeps them closed. This article provides evidence that intracellular Mg2+ is one important regulator of the voltage-independent calcium channel (HP channel) in neurons of the pond snail Lymnaea stagnalis. Mg2+ (1 mM) rapidly and reversibly inhibited activity of this calcium channel when applied to the intracellular side of cell-free membrane patches. The primary effect of the Mg2+ was to promote long closings of the channel. The mechanism of the intracellular Mg2+ inhibition is distinct from open channel block, a phenomenon seen in a variety of cation channels. Open channel block can also be seen in the HP channels, but only at very positive membrane potentials. Some of the permeability and selectivity characteristics of these channels were also examined. The channels are permeable to Mg2+ and Ca2+ as well as Ba2+. Outward currents carried by monovalent cations can be observed only at very positive membrane potentials, indicating high selectivity for divalent over monovalent cations. The single channel current-voltage relationship is markedly nonlinear, becoming quite shallow near the reversal potential, and hence is qualitatively similar to that seen in many voltage-activated calcium channels.

Animals↗
PubMed1997

Calcium channel blockers: an evidence-based review.

Calcium channel blockers are widely used in the treatment of cardiovascular disease, but their proper therapeutic role is controversial. Nevertheless, drugs from this class have been evaluated in many controlled clinical trials of adequate size and duration in different patient populations. Although many important questions remain unanswered, these trials have clarified when and how these drugs should be used. In general, the benefits of calcium channel blockers in controlling angina and hypertension are much more clearly documented than are their long term effects on harder end-points such as mortality. Such long term data are sorely needed, particularly for hypertension. An increased risk with dihydropyridine calcium channel blockers has been clearly seen across several studies of patients with coronary disease. In coronary patients with heart failure, the deleterious effects of nifedipine, diltiazem and verapamil outweigh any possible benefit. Long acting formulations and newer calcium channel blockers may not share all of the adverse effects of the older drugs of this class; however, their long term safety has not yet been documented. An understanding of the limitations of calcium channel blockers, based upon clinical trial evidence, often leads the practitioner to choose a drug from another class, where efficacy has been clearly proven.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Calcium channel blockers in systemic hypertension.

Calcium channel blockers selectively inhibit transmembrane flux of calcium in excitable tissue. Their ability to block calcium-mediated electromechanical coupling in contractile tissue produces peripheral vasodilation and has led to their clinical use in patients with systemic hypertension. The drugs appear to be well tolerated and have excellent safety profiles. Sustained-release preparations allow the drugs to be used once or twice daily. The calcium channel blockers will play an important role in the management of patients with mild, moderate, and severe hypertension when used as monotherapy or when combined with other antihypertensive medications. They can also be used in patients with concomitant diseases, such as angina pectoris and arrhythmia.

Angina Pectoris↗
PubMed1998

Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery.

N- and P/Q-type calcium channels are localized in high density in presynaptic nerve terminals and are crucial elements in neuronal excitation-secretion coupling. In addition to mediating Ca2+ entry to initiate transmitter release, they are thought to interact directly with proteins of the synaptic vesicle docking/fusion machinery. As outlined in the preceding article, these calcium channels can be purified from brain as a complex with SNARE proteins which are involved in exocytosis. In addition, N-type and P/Q-type calcium channels are co-localized with syntaxin in high-density clusters in nerve terminals. Here we review the role of the synaptic protein interaction (synprint) sites in the intracellular loop II-III (L(II-III)) of both alpha1B and alpha1A subunits of N-type and P/Q-type calcium channels, which bind to syntaxin, SNAP-25, and synaptotagmin. Calcium has a biphasic effect on the interactions of N-type calcium channels with SNARE complexes, stimulating optimal binding in the range of 10-20 microM. PKC or CaM KII phosphorylation of the N-type synprint peptide inhibits interactions with native brain SNARE complexes containing syntaxin and SNAP-25. Introduction of the synprint peptides into presynaptic superior cervical ganglion neurons reversibly inhibits EPSPs from synchronous transmitter release by 42%. At physiological Ca2+ concentrations, synprint peptides cause an approximate 25% reduction in transmitter release of injected frog neuromuscular junction in cultures, consistent with detachment of 70% of the docked vesicles from calcium channels based on a theoretical model. Together, these studies suggest that presynaptic calcium channels not only provide the calcium signal required by the exocytotic machinery, but also contain structural elements that are integral to vesicle docking, priming, and fusion processes.

Action Potentials↗
PubMed1997

Analysis of the risks associated with calcium channel blockade: implications for the obstetrician-gynecologist.

Calcium channel antagonists are widely prescribed in obstetrics and gynecology for blood pressure control and tocolysis. Concerns have recently arisen regarding the safety of these agents. Several studies found that short-acting forms of calcium channel blockers were associated with increased cardiovascular mortality, malignancy, and gastrointestinal bleeding. A recent meta-analysis found a significant increase in the risk of mortality in patients treated with a short-acting form of nifedipine. Another subgroup analysis of an observational study of older hypertensive patients found a significantly increased risk of cancer and gastrointestinal hemorrhage in patients prescribed calcium channel blockers. Both in vitro and small human in vitro series have reported a potential for cardiac toxicity in pregnant women treated concomitantly with calcium channel blockers and magnesium sulfate. Until additional data are available, we suggest that when calcium channel blockers are used in obstetrics and gynecology, the long-acting variety be prescribed. Concurrent use of calcium channel blockers and magnesium sulfate should be undertaken cautiously because of the potential for synergistic depression of cardiac function.

Calcium Channel Blockers↗