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At least 829 records · Page 46Linked to original sources

PubMed2000

N-Type calcium channels control sympathetic neurotransmission in human heart atrium.

BACKGROUND: Because knowledge about the type of calcium channels involved in action potential-induced norepinephrine release from the human peripheral sympathetic nervous system is sparse, we investigated which types of calcium channels are functionally important in the sympathetic nerves of human cardiac tissue. METHODS AND RESULTS: In superfused segments of human right atrial appendages, the type of calcium channels that control [(3)H]norepinephrine release evoked by transmural electrical stimulation was determined. [(3)H]norepinephrine release was almost abolished by 0.2 micromol/L omega-conotoxin GVIA (a selective blocker of N-type channels) but was not modified by 0.1 micromol/L omega-agatoxin IVA (a selective blocker of P- and Q-type channels). Mibefradil (a T-type and N-type calcium channel blocker) at concentrations of 0.3 to 3 micromol/L reduced the evoked tritium overflow in a frequency- and calcium-dependent manner, whereas 0.1 to 10 micromol/L amlodipine, diltiazem, and verapamil (selective blockers of L-type channels) were ineffective. CONCLUSIONS: Norepinephrine release from cardiac sympathetic nerves is triggered by Ca(2+) influx via N-type but not L- and P/Q-type calcium channels. The inhibitory effect of mibefradil on norepinephrine release at clinically relevant concentrations is probably due to its blocking action on N-type Ca(2+) channels. This property of mibefradil is unique among the calcium channel blockers that have been or still are therapeutically applied and may considerably contribute to its slight negative chronotropic effect in vivo.

Adult↗

PubMed1999

Molecular and functional diversity of voltage-gated calcium channels.

The contributing roles of voltage-gated calcium channels (VGCC) to the generation of electrical signaling are well documented. VGCCs open in response to depolarization of the plasma membrane and mediate the flux of calcium into excitable cells, which further depolarizes the membrane. But a more relevant role of VGCCs is to serve as highly regulated mechanisms to deliver calcium ions into specific intracellular locales for a variety of calcium-dependent processes including neurotransmitter release, hormone secretion, neuronal survival, and muscle contraction. Recent biochemical and molecular biological studies have demonstrated that the calcium channel pore-forming subunit (alpha 1) is not an isolated entity, but in fact interacts physically with a variety of strategically localized proteins. The functional consequences of such interactions as well as other molecular aspects of VGCC will be discussed. Finally, although far from a final conclusion, what is currently known about the molecular composition of native calcium channels will be summarized.

Alternative Splicing↗

PubMed1994

Pharmacological profile of a novel neuronal calcium channel blocker includes reduced cerebral damage and neurological deficits in rat focal ischemia.

Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage following ischemia. Therefore, blocking voltage-operated calcium channels on nerve cells should provide significant neuroprotection in ischemia. We now report on a novel neuronal calcium channel blocker, NNC 09-0026, in terms of its selective effects on neuronal calcium current and its efficacy in reducing infarct size and neurological deficits in a rat model of focal stroke. In the present studies, the effects of NNC 09-0026 on neuronal calcium influx, calcium channel binding, and cardiovascular parameters were determined. Also, phencyclidine, NNC 09-0026, or vehicle were administered i.v. to rats subjected to permanent middle cerebral and common carotid artery occlusions. Infarct volumes and contralateral forepaw and hindlimb neurological deficits were assessed at 24 and 48 h after onset of stroke. NNC 09-0026 exhibited a pharmacological profile suggesting selectivity at neuronal calcium channels. It inhibited potassium-stimulated calcium uptake into rat synaptosomes with an IC50 of 13 microM. Voltage-operated calcium currents measured from cultured rat dorsal root ganglion cells using the patch clamp technique were blocked by 43% at 10 microM (p < 0.05). The compound showed only weak effects on smooth muscle from the guinea pig taenia coli and was relatively inactive at displacing nitrendipine and omega-conotoxin in receptor-binding studies. Single, bolus injections of NNC 09-0026 as high as 10 mg/kg i.v. produced only 12% reduction in heart rate and a 28% decrease in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Which calcium channel blocker for ischaemic heart disease?

Calcium channel blockers have been available since the early 1960s. Extensive research has been undertaken to evaluate their usefulness in the treatment of patients with ischaemic heart disease. We have reviewed the pharmacology of these drugs and the major clinical trials. In particular, we have examined the effect of calcium channel blockers on the progression of atheroma, and their role in the following clinical settings: following myocardial infarction, following non-Q-wave myocardial infarction, and in unstable angina.

Angina, Unstable↗

PubMed1989

Modulation of calcium channels in cardiac and neuronal cells by an endogenous peptide.

Calcium channels mediate the generation of action potentials, pacemaking, excitation-contraction coupling, and secretion and signal integration in muscle, secretory, and neuronal cells. The physiological regulation of the L-type calcium channel is thought to be mediated primarily by guanine nucleotide-binding proteins (G proteins). A low molecular weight endogenous peptide has been isolated and purified from rat brain. This peptide regulates up and down the cardiac and neuronal calcium channels, respectively. In cardiac myocytes, the peptide-induced enhancement of the L-type calcium current had a slow onset (half-time approximately 75 seconds), occurred via a G protein-independent mechanism, and could not be inhibited by alpha 1-adrenergic, beta-adrenergic, or angiotensin II blockers. In neuronal cells, on the other hand, the negative effect had a rapid onset (half-time less than 500 milliseconds) and was observed on both T-type and L-type calcium channels.

Angiotensin II↗

PubMed2001

Abnormality of calcium channel inhibitor released from fetal membranes in preterm labor.

OBJECTIVE: This study was undertaken to test the hypothesis that an inhibitor of uterine contractions acting at the level of the dihydropyridine receptor of the uterine L -type uterine calcium channel is released in greater amounts from fetal membranes before term than at term. STUDY DESIGN: Endogenous calcium channel inhibitor activity was generated with standardized 25-cm2 surface area fetal membrane samples from the following 4 categories of women: preterm in labor, preterm not in labor, term in labor, and term not in labor. The amount of inhibitor in each membrane category was quantified by means of a competitive binding assay. Inhibition of uterine contractions induced by Bay K 8644 (an L -type calcium channel agonist) was used as another test of endogenous calcium channel inhibitor activity released from fetal membranes of all 4 groups of patients. RESULTS: Endogenous calcium channel inhibitor activity was most variable but present in the greatest amount in fetal membranes of women who were preterm not in labor followed by those in women at term not in labor and at term in labor. Fetal membranes from women in preterm labor had the least amount of measured endogenous calcium channel inhibitor activity. Consistent with the competitive binding assay, endogenous calcium channel inhibitor activity from fetal membranes from women who were preterm not in labor, at term not in labor, and at term in labor inhibited Bay K 8644-induced uterine contractions. Fetal membranes from women in preterm labor did not inhibit Bay K 8644-induced contractions. Endogenous calcium channel inhibitor activity was present in the chorion, the decidua, and the placenta, with little activity in the amnion. CONCLUSION: The down-regulation of endogenous calcium channel inhibitor activity with advancing gestation is consistent with a potential role for this inhibitor in maintaining uterine quiescence and in regulating the transition into labor. One possible cause of idiopathic preterm labor may be an abnormally low amount of endogenous calcium channel inhibitor activity in fetal membranes.

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

PubMed1998

A calcium agonist, Bay k 8644, suppresses the embryotoxic effects induced by dihydropyridines calcium channel blockers in cultured rat embryos.

Day 9 rat embryos were exposed to 1,4-dihydropyridine calcium channel blockers; nifedipine (NIF), nicardipine (NIC) or nitrendipine (NIT), for 48 hr in the whole embryo culture system. There were dose-dependent growth retardation and abnormalities, predominantly in cardiovascular system. The three compounds exhibited very similar pattern of dysmorphogenic effects, but the potency of these compounds were quantitatively different. The incidences of embryos with the abnormalities were 100%, 100% and 85% following either exposure of NIF, NIC or NIT at concentration of 300, 8 and 15 microM, respectively. This study was to investigate whether these blocker-induced embryotoxicity was due to calcium channel blocking properties themselves in the embryos. Day 9 rat embryos were co-exposed to 1,4-dihydropyridine calcium channel agonist, Bay k 8644 (BAY) and each calcium channel blocker under the same culture condition. The retarded embryonic growth induced by 200 or 300 microM of NIF, 8 microM of NIC and 15 microM of NIT nearly of completely ameliorated when embryos were co-exposed with BAY at one-third or half concentration of each calcium channel blocker. Supplementation of BAY reduced the incidence of abnormalities by NIF-, NIC- and NIT-alone. These results suggested that one of mechanisms for embryotoxicity induced by calcium channel blocker was directly related to channel blocking property of the chemicals.

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

PubMed1995

Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes.

BACKGROUND: Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert-Eaton syndrome. The calcium-channel subtype that is responsible is not known. METHODS: We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex. RESULTS: P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti-P/Q-type calcium-channel antibodies were found in serum from all 32 patients with Lambert-Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with Lambert-Eaton syndrome without cancer. Anti-N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert-Eaton Syndrome. Lower titers of anti-P/Q-type and anti-N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma. CONCLUSIONS: The high frequency of P/Q-type calcium-channel antibodies found in patients with Lambert-Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.

Autoantibodies↗

PubMed1996

The use of calcium-channel blockers in pregnancy.

Over the past 10 yrs, calcium-channel blockers have been used in obstetrics and gynecology for the treatment of patients with both gestational hypertension and preterm labor. Several randomized trials have been performed which demonstrated that calcium-channel blockers are at least as efficacious as other, better-known antihypertensive agents. Despite animal studies which have shown unfavorable outcomes with the use of some of these agents, the use of calcium-channel blockers in pregnancy has been increasing. As we gain further information on the correlation between calcium homeostasis and several additional disease states, the role of calcium-channel blockers will become further elucidated.

Animals↗

PubMed1996

Dopamine modulates unitary conductance of single PL-type calcium channels in Roccus chrysops retinal horizontal cells.

1. Dopamine modulation of the PL-type calcium channel of white bass retinal horizontal cells was studied in isolated, cultured neurons. Single-channel recordings were made of calcium channels in outside-out patches, under conditions which favoured the expression of calcium channel activity. 2. Analysis of single-channel properties revealed that dopamine potentiated the activity of the sustained calcium channel in three ways. First, it increased unitary conductance through individual channels. Under the influence of dopamine, single-channel conductance doubled. 3. Dopamine also increased the probability of channel opening and increased channel mean open time. The probability of opening increased 4-fold while mean open time doubled. 4. The mean closed time was also affected. The time between individual openings was not affected but the closed time between bursts of openings was shortened by over 50%. 5. The effects of dopamine were mediated via the activation of a D1-type receptor and the resulting activation of a cAMP-mediated second messenger system. 6. The combination of the effects of dopamine significantly increased the net calcium influx into the cell.

Animals↗

PubMed1996

Anti-ischaemic therapy during the follow-up phase of acute coronary syndromes. Is there a role for calcium channel blockers?

Various pharmacological strategies are currently being sought to enhance the efficacy of thrombolysis after an acute myocardial infarction (AMI). Apart from the use of new thrombolytic agents, novel anticoagulants and antiplatelet drugs, attention has recently been focused on agents such as the calcium channel blockers (calcium antagonists) traditionally used (prior to the thrombolytic era) for secondary prevention after an AMI. In this context, although calcium channel blockers have not been definitively proven to have any benefit with regard to all-cause mortality or subsequent infarctions, diltiazem has been shown to reduce cardiac mortality, recurrent nonfatal infarction and myocardial ischaemia after non-Q-wave AMI. These benefits have been linked to the drug's effect of lowering heart rate. Since both non-Q-wave AMI and the AMI treated with thrombolytic therapy result in early reperfusion and clinical manifestations of 'incomplete infarction', and are characterised by a similar high incidence of ischaemic complications, it is plausible to hypothesise that prophylactic calcium channel blocker administration to AMI patients post-thrombolysis might decrease the cumulative occurrence of reinfarction and refractory ischaemia during long term follow-up. With this in mind, the Incomplete INfarction Trial of European Research Collaborators Evaluating Prognosis Post-Thrombolysis with Tildiem was initiated in September 1994. This represents the first prospective study to investigate the efficacy of a calcium channel blocker (long-acting diltiazem 300 mg/day) administered as adjunctive therapy with aspirin 160 mg/day in up to 920 patients with an uncomplicated first AMI receiving early thrombolytic therapy. The primary trial objective is to assess the efficacy of blinded therapy on the 6-month cumulative occurrence of a combined clinical end-point (cardiac death, recurrent non-fatal infarction, medically refractory ischaemia)-an end-point identical to that utilised in the assessment of diltiazem in non-Q-wave AMI.

Adrenergic beta-Antagonists↗

PubMed1996

Use of calcium channel antagonists in myocardial revascularization procedures.

Calcium channel antagonists possess a number of properties that may be beneficial after revascularization procedures. Therefore, we present an overview of the use of these drugs after percutaneous intervention in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT), and compare the results in CAVEAT with those in published randomized trials. Also reviewed are the use of calcium channel antagonists to control perioperative hypertension, reduce myocardial necrosis, and prevent arrhythmias during cardiopulmonary bypass.

Angioplasty, Balloon, Coronary↗

PubMed2006

L-type calcium channels mediate water intake induced by angiotensin injection into median preoptic nucleus.

Calcium ions are widely accepted as critically important in responses of neurons to a stimulus. We have show previously the central involvement of angiotensin II (ANGII) in water intake. This study determined whether voltage-dependent calcium channels are involved in ANGII-induced behavioral drinking implicating nitrergic mechanism. The antidipsogenic actions of L-type calcium channel antagonists nifedipine, on ANGII-induced drinking behavior were studied when it is injected into the median preoptic nucleus (MnPO). The influence of nitric oxide (NO) on nifedipine antidipsogenic action was also studied by utilizing the N(W)-nitro-L-arginine methyl ester (L-NAME) a constitutive nitric oxide synthase inhibitor constitutive (cNOSI) and 7-nitroindazol (7-NIT) a specific neuronal nitric oxide synthase inhibitor (nNOSI) and L-arginine a NO donor. Rats 200-250 g, with cannulae implanted into MnPO, pre-treated into MnPO with either nifedipine, followed by ANGII, drank significantly less water than controls during the first 15 min after injection. However, L-NAME potentiated the dipsogenic effect of ANGII that is blocked by prior injection of nifedipine and L-arginine. 7-NIT injected prior to ANGII into MnPO also potentiated the dipsogenic effect of ANGII but with a less intensity than L-NAME that it is also blocked by prior injection of nifedipine. The results described in this paper provide evidence that calcium channels play important roles in the ANGII-induced behavioral water intake. The structures containing NO in the brain such as MnPO include both endothelial cells and neurons might be responsible for the influence of nifedipine on dipsogenic effect of ANGII. These data shows the correlation between L-type calcium channel and a free radical gas NO produced endogenously from amino acids L-arginine by endothelial and neuronal NO synthase in the control of ANGII-dipsogenic effect. This suggests that an L-type calcium channel participates in both short- and longer-term neuronal actions of ANGII by nitrergic way.

Angiotensin II↗

PubMed1997

Alteration of loosely bound calcium in the guinea pig organ of Corti after treatment with diltiazem as calcium channel blocker.

After oral administration of the organic calcium channel blocker diltiazem to guinea pigs for 7 days, calcium ions were precipitated with potassium antimonate in the cochleae. The spatial distribution of the precipitates was studied by energy-filtering transmission electron microscopy and the amount of the ultrastructural reaction products formed was determined semiquantitatively by an image processing system. Compared with untreated control ears, the number of the formed precipitates was reduced drastically in the inner hair cells after diltiazem treatment. In addition, electron microscopic analysis revealed that the number of calcium precipitates attached at the basolateral membrane of the outer hair cells was clearly reduced when compared with untreated control specimens. A large number of histochemical reaction products could be identified in the basilar membrane and were also observed in the untreated control specimens. The spatial distribution of the calcium precipitates in the lamina reticularis was not affected by diltiazem treatment and calcium precipitates could be identified within different cell membranes. The techniques used was considered to be helpful for identifying calcium channels ultrastructurally in intact undissected tissues and to support light microscopic analyses and patch-clamp electrophysiological measurements.

Administration, Oral↗

PubMed1991

Primary structure and functional expression from complementary DNA of a brain calcium channel.

The primary structure of a voltage-dependent calcium channel from rabbit brain has been deduced by cloning and sequencing the complementary DNA. Calcium channel activity expressed from the cDNA is dramatically increased by coexpression of the alpha 2 and beta subunits, known to be associated with the dihydropyridine receptor. This channel is a high voltage-activated calcium channel that is insensitive both to nifedipine and to omega-conotoxin. We suggest that it is expressed predominantly in cerebellar Purkinje cells and granule cells.

Amino Acid Sequence↗

PubMed1987

Effects of in vitro and in vivo lead exposure on voltage-dependent calcium channels in central neurons of Lymnaea stagnalis.

Currents through calcium channels of members of an identified cluster of neurons (B cells) in the pond snail Lymnaea stagnalis were studied under voltage clamp. The normal physiological saline was modified to maximize the visibility of voltage-dependent calcium currents and minimize contamination by other currents. Barium was used as the charge carrier for the calcium channels. Depolarizing voltage steps induce an inward current, the magnitude of which varies with the barium concentration. In brains taken from animals not exposed in vivo to lead, in vitro addition of lead acetate to the recording medium (0.25 to 14 microM) inhibits the barium current by 59 +/- 14% (mean +/- s.d.), in a manner that is independent of the lead concentration. The magnitude of the residual current still varies with the barium concentration. The voltage dependence of the current appears to be unaffected by lead. In contrast to some other calcium-channel blockers, such as cobalt, the inhibition of barium currents by in vitro lead exposure is irreversible, at least in short-term experiments. Contrary to expectations based on these in vitro results, barium currents in B cells of animals exposed to 5 microM lead for 6 to 12 weeks in vivo were approximately twice as large as barium currents in B cells from unexposed controls, when both were recorded in lead-free saline. It is possible that chronic in vivo lead exposure causes an increase in the number of calcium channels in these neurons.

Animals↗

PubMed1995

Selective blockade of P-type calcium channels by lead in cultured hippocampal neurons.

The effects of lead ions (Pb2+) on neuronal calcium channels were examined in cultured hippocampal neurons. Pb2+ blocked calcium channels in a concentration-dependent manner. The current-voltage relationship of the inhibition suggested a selective blockade of high-threshold calcium channels by Pb2+ up to a concentration of 3 microM. Pb2+ (3 microM) preferentially suppressed the omega-agatoxin IVA-sensitive components of the calcium channels. These findings suggest that Pb2+ mainly affects the P-type calcium channels at low concentrations.

Animals↗

PubMed1996

Inhibition of Na+,K+-ATPase by ouabain opens calcium channels coupled to acetylcholine release in guinea pig myenteric plexus.

Ouabain, an Na+K+ATPase inhibitor, increases the release of acetylcholine (ACh) from various preparations in a Ca2+ -independent way. However, in other preparations the release of ACh evoked by ouabain is dependent on the presence of extracellular calcium. In the present study, we have labeled the ACh of myenteric plexus longitudinal muscles of guinea pig ileum and compared the effect of calcium channel blockers on ouabain-evoked release of [3H]ACh. Release of [3H]ACh evoked by ouabain is dose dependent and decreased markedly in the absence of calcium or in the presence of cadmium, a nonspecific calcium channel blocker. N-type calcium channel blockage by the omega-conotoxins GVIA (selective N-type calcium channel blocker) and MVIC (a nonselective calcium channel blocker) inhibited by 45 and 55%, respectively, the release of [3H]ACh. L-type calcium channel suppression by low concentrations of verapamil, nifedipine, and diltiazem had no effect on the release of [3H]ACh. The release of transmitter was also not affected significantly by nickel, a T-type calcium channel blocker. In addition, omega-agatoxin-IVA, at concentrations that block P- and Q-type calcium channels, did not affect significantly the release of [3H]ACh. Thus, extracellular Ca2+ is essential for the release of ACh induced by ouabain from guinea pig ileum myenteric plexus. In this preparation, the N-type calcium channel plays a dominant role in transmitter release evoked by inhibition of Na+K+-ATPase, but other routes of calcium entry in addition to these channels can also support the release of neurotransmitter induced by ouabain.

Acetylcholine↗