SEARCH · PubMed Health

Results for “Calcium Channels”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources

PubMed1985

Reversible dihydropyridine isothiocyanate binding to brain calcium channels.

Voltage-dependent calcium channels from ileal smooth muscle can be affinity-labeled with a [3H]dihydropyridine isothiocyanate radioligand. We examined the binding of this agent to brain membranes, to compare the properties of calcium channel drug binding sites in brain with those previously described in ileum. In brain, the [3H]dihydropyridine isothiocyanate labels sites that correspond in number and pharmacologic characteristics to binding sites for the classic calcium entry blocker, [3H]nitrendipine. However, in contrast to the covalent nature of dihydropyridine isothiocyanate binding in ileum, brain calcium channels are labeled reversibly. This difference in binding properties may reflect structural variations in voltage-dependent calcium channels in different tissues.

Animals↗

PubMed2003

Background potassium concentrations and epileptiform discharges. II. Involvement of calcium channels.

Potassium- and calcium conductances regulate neuronal excitability and epileptiform activity. In this study, the effects of different extracellular potassium concentrations ([K(+)](o)) were investigated on the modulatory effect of the L-type transmembranous calcium currents on epileptiform discharges. The in vitro brain slice technique was used to examine the effects of calcium channel blockers, verapamil and nifedipine, on the repetition rate, amplitude, and duration of epileptiform field potentials (EFP) in the presence of low, physiological, and high background [K(+)](o) in guinea pig hippocampal slices. Epileptiform activity was induced by omission of Mg(2+) from artificial cerebrospinal fluid contained 2, 4, and 8 mM [K(+)](o). Both verapamil and nifedipine suppressed EFP after a transient increase in repetition rate. The extent of EFP frequency rate acceleration significantly increased with reduction of [K(+)](o). The increase in EFP frequency rate induced by application of verapamil and nifedipine was accompanied by a reduction in the EFP amplitude and a reversible increase in the burst discharge duration. The extent of burst discharge prolongation was also significantly higher with decreasing [K(+)](o). Further application of verapamil and nifedipine suppressed the epileptiform burst activity in the presence of different [K(+)](o). The latency of EFP depression was significantly diminished both with increased and decreased background potassium concentrations. The data indicate the importance of the effect of the L-type transmembranous calcium currents on the regulatory effect of background [K(+)](o) on epileptiform burst discharge frequency and duration.

Animals↗

PubMed1994

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

Conformational features of nicardipine in acetonitrile, in the absence and presence of Ca2+, were investigated by one-dimensional NMR and difference absorption spectroscopy techniques. The data show that in acetonitrile solution the antiperiplanar form of nicardipine is dominant. The addition of Ca2+ to the drug solution caused marked changes in the difference absorbance spectra in the 200-400 nm region and in many of its 1H and 13C NMR resonances. The changes were most significant up to a ratio of 0.5 Ca2+:drug. Analysis of the binding data showed the predominant species to be a 2:1 drug:Ca2+ "sandwich" complex with an estimated dissociation constant of 100 microM at 25 degrees C. One-dimensional nuclear Overhauser effect (NOE) experiments revealed through-space connectivities in the drug before and after Ca2+ binding. These changes in conjunction with the changes in 1H and 13C chemical shifts suggest a structure in which the 4-aryl ring substitute of the pyridine moiety moves closer to the C3-side chain in the presence of Ca2+. This attraction is achieved via the chelation of the Ca2+ ion by the oxygen atoms in the m-NO2 of the aryl group and the COOCH2 group in the side chain of the dihydropyridine ring, and gives rise to a stable synperiplanar conformation. A preference for this conformation was also observed in the Ca2+ complex of nifedipine in acetonitrile as inferred from the rather limited NOE data obtained. Our study provides a detailed solution structure for nicardipine and also leads to a suggestion of a role for Ca2+ in the action of this and possibly other dihydropyridines.

Acetonitriles↗

PubMed1993

Interaction of calcium channel antagonists with calcium: spectroscopic and modeling studies on diltiazem and its Ca2+ complex.

Using spectral techniques, the solution conformation of diltiazem was studied in acetonitrile with special reference to the effect of Ca2+ on the drug structure. Complete assignment of the proton resonances in the 1H-NMR spectrum of the drug was made using one-and two-dimensional spectral analyses. A two-dimensional 1H-NOESY spectrum (in the phase-sensitive mode) was obtained to identify the interproton connectivities in the drug molecule. A molecular modeling program involving Monte Carlo simulation and energy minimization was employed to arrive at the structure of the drug. The program was run with and without the input of the interproton distances derived from the NOESY cross peaks. Both the protocols led to a structure of the drug which was generally similar to that reported from X-ray diffraction data on crystalline diltiazem hydrochloride (Kojic-Prodic, et al. Helv. Chim. Acta 1984, 67, 916-926). However, significant differences between the two structures were seen in the orientations of the substituent groups attached to the benzothiazepine ring. Substantial changes in the circular dichroic (CD) and 1H-NMR spectra of diltiazem were observed on addition of Ca2+ up to a mole ratio of 0.5 Ca2+ per drug. Relatively large changes were seen in 1H resonances of the N-methyl protons and the methylene protons attached to the heterocyclic nitrogen. Analysis of the binding isotherms from CD data at 22 +/- 1 degrees C indicated a 2:1 drug:Ca2+ "sandwich" complex with an estimated dissociation constant of 140 microM. One-dimensional difference NOE and two-dimensional NOESY spectra revealed interproton connectivities between two drug molecules that were compatible with the sandwich complex formation. The interproton distances derived from the volume integrals of the NOESY cross peaks were used as geometrical constraints in modeling the Ca(2+)-bound conformation of diltiazem. The minimum-energy conformation corresponded to the sandwich complex where Ca2+ was coordinated to three oxygens in each of the two drug molecules. Combined with our earlier data on the ability of diltiazem to translocate Ca2+ across the lipid bilayer in synthetic liposomes (Ananthanarayanan, V.S.; Taylor, L.; Pirritano, S.Biochem. Cell Biol. 1992, 70, 608-612), the structural data presented here point to a role for Ca2+ in the interaction of diltiazem with its membrane-bound receptor.

Calcium↗

PubMed1989

Bone remodeling signaled by a dihydropyridine- and phenylalkylamine-sensitive calcium channel.

An osteoblast calcium channel demonstrated by single channel recordings is associated with calcium antagonist receptor binding sites in osteoblast-like osteosarcoma cells. By using whole cell current recordings we now show that this channel is stimulated by the dihydropyridine calcium agonist drug BAY K 8644. A physiological relevance of these channels is apparent from the stereoselective, potent inhibition of parathyroid hormone-stimulated calcium uptake into osteoblast-like cells in culture by desmethoxyverapamil, a phenylalkylamine calcium antagonist. Secretion by these cells of the bone matrix protein osteocalcin is stimulated by BAY K 8644 and blocked by desmethoxyverapamil and nitrendipine. Evidence for a role of this channel in bone remodeling in intact animals comes from enhanced bone resorption in fetal rat bones observed with BAY K 8644 and stereoselective, potent blockade of resorption by desmethoxyverapamil.

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

PubMed1991

Physiopathology of neuronal voltage-operated calcium channels.

Voltage-operated calcium channels are multimeric transmembrane proteins crucially involved in control of calcium homeostasis. Multiple types of voltage-operated calcium channels have been described in both the nervous system and peripheral tissues. Different channels can be classified according to either their biophysical properties or their pharmacology, biochemical and molecular structure, and localization and functional role. Concentrating on neuronal cells, this paper reviews the different properties of low- and high-voltage activated channels, as well as various attempts to subdivide high-voltage activated channels into different subtypes (L, N, omega, P, etc.). The availability of selective drugs (such as dihydropyridines) and natural toxins (such as omega-Conotoxin, omega-agatoxin, and funnel-web spider toxins), which bind to specific channel subtypes, has greatly helped in channel classification. The emerging view is that there are many members of the family of voltage-operated calcium channels, each with its own molecular structure, a different pharmacology, a different localization, and possibly a different physiological role. Different calcium subtypes are selectively affected in human and animal diseases. The use of omega-Conotoxin has led to identification of the channel subtype (omega) specifically affected in Lambert-Eaton myasthenic syndrome (a human disease of neurotransmission), and has permitted development of new diagnostic approaches to the disease.

Autoimmune Diseases↗

PubMed1996

Single L-type calcium channel conductance with physiological levels of calcium in chick ciliary ganglion neurons.

1. Single L-type calcium channels in chick ciliary ganglion neurons were studied at high current resolution in cell-attached patch recordings using quartz-glass micropipettes. 2. A single open-channel current amplitude was observed when Ba2+ was the charge carrier with a conductance of 26 pS at 110 mM barium. However, with 110 mM calcium two current fluctuation amplitudes were observed. These were termed low and high fluctuation amplitudes, CaL and CaH, and had conductances of 8.8 and 12 pS, respectively. These two levels probably reflect two different channel species. CaL was identified as an L-type calcium channel on the basis of resistance to inactivation, conductance, and dihydropyridine sensitivity. 3. Single-channel current fluctuations could be detected with calcium concentrations as low as 1.0 mM. Although the unitary conductance (gamma) was much greater with barium than calcium at every concentration tested, the concentration dependence of conductance was similar for gamma Ba, gamma CaH and gamma CaL. Fitting the concentration dependencies of these conductances with a Langmuir isotherm gave KD estimates of 4.7, 5.6 and 5.0 mM for barium, CaL and CaH, respectively 4. The single-channel conductance of the L-type channel (gamma L) can be described by the relation: conductance (in pS) = 9.2/(1 + 5.6/[Ca]) where [Ca] is the external calcium concentration in the 1.0-110 mM range. Thus, at a physiological external calcium concentration of 2 mM the conductance is 2.4 pS. 5. Ca2+ transport through the L-type calcium channel is particularly sensitive to changes in external calcium concentration in the physiological range but approaches saturation at about 10 mM. this characteristic may optimize the responsiveness of the cell to small changes in ambient calcium concentrations while limiting excess entry in the presence of abnormally high calcium levels.

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

PubMed2001

Identification of membrane calcium channels essential for cytoplasmic and nuclear calcium elevations induced by vascular endothelial growth factor in human endothelial cells.

Vascular endothelial growth factor (VEGF) is mitogenic for endothelial cells and has been shown to induce angiogenesis and endothelial cell migration through stimulation of endothelial tyrosine-kinase receptors. Here, using confocal microscopy and the patch-clamp technique on endothelial cells, membrane permeability to calcium as well as cytoplasmic and nuclear free calcium levels have been investigated in the first stages of tyrosine-kinase receptor activation by VEGF. VEGF (0.5nM) as well as inositol trisphosphate (IP3) induced an activation of membrane calcium-permeable channels exhibiting a similar low conductance in the range of 10 pS. The VEGF-triggered activation of these calcium channels, mediated by IP3 and involving the intracellular calcium stores, results in an increase in both cytoplasmic and nuclear calcium levels in endothelial cells, potentially modulating gene expression. Finally, the effect of Ni2+, a calcium channel blocker, on endothelial cell proliferation has been studied. The results show that inhibition of extracellular calcium influx significantly inhibits VEGF-induced cell proliferation. In the process of cell stimulation by VEGF, and possibly by other growth factors, activation of calcium channels could then be a key step in calcium-regulated gene expression and cell activation. These results suggest that the use of calcium channel blockers could be a novel way of prevention or reversion of VEGF-induced tumoral angiogenesis.

Calcium↗

PubMed1997

A dihydropyridine-sensitive voltage-dependent calcium channel in the sarcolemmal membrane of crustacean muscle.

Single-channel currents through calcium channels in muscle of a marine crustacean, the isopod Idotea baltica, were investigated in cell-attached patches. Inward barium currents were strongly voltage-dependent, and the channels were closed at the cell's resting membrane potential. The open probability (Po) increased e-fold for an 8.2 mV (+/- 2.4, n = 13) depolarization. Channel opening were mainly brief (< 0.3 ms) and evenly distributed throughout 100-ms pulses. Averaged, quasimacroscopic currents showed fast activation and deactivation and did not inactivate during 100-ms test pulses. Similarly, channel activity persisted at steadily depolarized holding potentials. With 200 mM Ba2+ as charge carrier, the average slope conductance from the unitary currents between +30 and +80 mV, was 20 pS (+/- 2.6, n = 12). The proportion of long openings, which were very infrequent under control conditions, was greatly increased by preincubation of the muscle fibers with the calcium channel agonist, the dihydropyridine Bay K8644 (10-100 microM). Properties of these currents resemble those through the L-type calcium channels of mammalian nerve, smooth muscle, and cardiac muscle cells.

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

PubMed2001

Model organisms: new insights into ion channel and transporter function. L-type calcium channels regulate epithelial fluid transport in Drosophila melanogaster.

The neuropeptide CAP2b stimulates fluid transport obligatorily via calcium entry, nitric oxide, and cGMP in Drosophila melanogaster Malpighian (renal) tubules. We have shown by RT-PCR that the Drosophila L-type calcium channel alpha1-subunit genes Dmca1D and Dmca1A (nbA) are both expressed in tubules. CAP2b-stimulated fluid transport and cytosolic calcium concentration ([Ca2+]i) increases are inhibited by the L-type calcium channel blockers verapamil and nifedipine. cGMP-stimulated fluid transport is verapamil and nifedipine sensitive. Furthermore, cGMP induces a slow [Ca2+]i increase in tubule principal cells via verapamil- and nifedipine-sensitive calcium entry; RT-PCR shows that tubules express Drosophila cyclic nucleotide-gated channel (cng). Additionally, thapsigargin-induced [Ca2+]i increase is verapamil sensitive. Phenylalkylamines bind with differing affinities to the basolateral and apical surfaces of principal cells in the main segment; however, dihydropyridine binds apically in the tubule initial segment. Immunocytochemical evidence suggests localization of alpha1-subunits to both basolateral and apical surfaces of principal cells in the tubule main segment. We suggest roles for L-type calcium channels and cGMP-mediated calcium influx in both calcium signaling and fluid transport mechanisms in Drosophila.

Animals↗

PubMed1992

Prevention of calcium overload and down-regulation of calcium channels in rat heart by SR 33557, a novel calcium entry blocker.

The effect of SR 33557, a novel calcium entry blocker, on calcium overload, and regulation of calcium channels and beta-adrenergic receptors was investigated in the rat heart. Calcium overload and infarct-like lesions were produced by a large dose of isoproterenol (40 mg/kg, subcutaneously) to rats. Calcium overload was maximal 8 hours after administration of isoproterenol (control: 5.7 mmol Ca2+/kg dry weight, isoproterenol: 34.9 mmol Ca2+/kg dry weight). At that time, a decrease in the total number of beta-adrenergic receptors (-27%) and calcium channels (-20% and -23%) was observed. Intravenous injection of SR 33557 (0.5-10 mg/kg), 30 minutes before administration of isoproterenol, attenuated the increase in calcium content in a dose-related manner, such that 5 mg/kg SR 33557 reduced calcium overload by 50%. At this dose, SR 33557 had no effect on the number of beta-adrenergic receptors but prevented the decrease in the number of calcium channels. The total number of binding sites and the dissociation constants of each radioligand were estimated from saturation isotherms. The dissociation constants were unchanged when animals given isoproterenol or SR 33557 and isoproterenol were compared to the control group. The results indicate that SR 33557 is able to protect against the calcium overload induced by sympathetic over-stimulation. This over-stimulation of the sympathetic system causes a down-regulation of the number of active beta-adrenergic receptors and calcium channels. The down-regulation of calcium channels is selectively reduced by earlier administration of SR 33557.

Animals↗

PubMed2001

Structural understanding of the transmembrane domains of inositol triphosphate receptors and ryanodine receptors towards calcium channeling.

Inositol 1,4,5-triphosphate receptors (Insp(3)Rs) and ryanodine receptors (ryRs) act as cationic channels transporting calcium ions from the endoplasmic reticulum to cytosol by forming tetramers and are proteins localized to the endoplasmic reticulum (ER). Despite the absence of classical calcium-binding motifs, calcium channeling occurs at the transmembrane domain. We have investigated putative calcium binding motifs in these sequences. Prediction methods indicate the presence of six transmembrane helices in the C-terminal domain, one of the three domains conserved between Insp(3)R and ryR receptors. The recently identified crystal structure of the K(+) channel, which also forms tetramers, revealed that two transmembrane helices, an additional pore helix and a selectivity filter are responsible for selective K(+) ion channeling. The last three TM helices of Insp(3)R and ryR are particularly well conserved and we found analogous pore helix and selectivity filter motif in these sequences. We obtained a three-dimensional structural model for the transmembrane tetramer by extrapolating the distant structural similarity to the K(+) channels.

Amino Acid Motifs↗

PubMed1989

Voltage-dependent calcium channels in skeletal muscle transverse tubules. Measurements of calcium efflux in membrane vesicles.

Transverse tubule membranes isolated from rabbit skeletal muscle consist mainly of sealed vesicles that are oriented primarily inside out. These membranes contain a high density of binding sites for 1,4-dihydropyridine calcium channel antagonists. The presence of functional voltage-dependent calcium channels in these membranes has been demonstrated by their ability to mediate 45Ca2+ efflux in response to changes in membrane potential. Fluorescence changes of the voltage-sensitive dye, 3,3'-dipropyl-2,2'-thiadicarbocyanine, have shown that transverse tubule vesicles may generate and maintain membrane potentials in response to establishing potassium gradients across the membrane in the presence of valinomycin. A two-step procedure has been developed to measure voltage-dependent calcium fluxes. Vesicles loaded with 45Ca2+ are first diluted into a buffer designed to generate a membrane potential mimicking the resting state of the cell and to reduce the extravesicular Ca2+ to sub-micromolar levels. 45Ca2+ efflux is then measured upon subsequent depolarization. Flux responses are modulated with appropriate pharmacological specificity by 1,4-dihydropyridines and are inhibited by other calcium channel antagonists such as lanthanum and verapamil.

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

PubMed1992

Lambert-Eaton myasthenic syndrome without anti-calcium channel antibody: adverse effect of calcium antagonist diltiazem.

A 59 year old man with ischaemic heart disease, developed the clinical and electromyographic changes of the Lambert-Eaton myasthenic syndrome after taking calcium antagonist, diltiazem. The symptoms appeared periodically with a rise and fall in serum level of diltiazem. Extensive search was made for systemic neoplasms and autoimmune diseases without success. Serum antibody to voltage operated calcium channel was not detected.

Autoantibodies↗

PubMed1985

Anaesthetic implications of calcium channel blockers.

Clinical uses of calcium channel blockers are expanding. In addition to the established uses in patients with arrhythmias, angina pectoris or hypertension, newer and to some extent investigational uses indicate widespread application. For instance, their use has been reported in hypertrophic cardiomyopathy and cold cardioplegia, as well as in pulmonary hypertension, antiplatelet therapy, asthma, achalasia and oesophageal spasm, increased intraocular pressure and in cerebral vasospasm. Their use in obstetrical practice has been proposed. Thus, the presentation of a patient who is treated with calcium channel blockers and who requires anaesthesia will become more common. Calcium channel blockers may, under certain circumstances, potentiate haemodynamic and MAC depressive effects of inhalation agents. There is also evidence that the effects of neuromuscular blocking agents may be potentiated. The anaesthetist should be aware that the potential for interactions exists with digoxin, propranolol, quinidine, theophylline or dantrolene. Of interest and some significance are the anaesthetic implications of pathophysiological alterations that can be induced by calcium channel blockers, by affecting lower oesophageal tone, intracranial hypertension, bronchomotor tone (asthma), muscular dystrophy, neuromuscular function, hypoxic pulmonary vasoconstriction, malignant hyperthermia, inhibition of platelet aggregation and hyperkalemia. Despite these significant potential anaesthetic implications and because, at this time, in some instances withdrawal has clearly demonstrated increase in the signs of myocardial ischaemia, it would not seem necessary to recommend preoperative discontinuation of calcium channel blocker medication in patients presenting for anaesthesia. It is, however, appropriate that there is a high index of awareness of potential problems, unless there is some modification in inhalation anaesthetic concentrations and neuromuscular blocker dosage. Monitoring of cardiovascular and neuromuscular functions is essential. Calcium channel blockers would appear to be currently the drugs of choice for angina pectoris, arrhythmias or hypertension in patients with associated chronic obstructive pulmonary disease.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Calcium channel blockers in veterinary medicine.

Calcium channel blockers are becoming increasingly popular in veterinary medicine for the treatment of systemic hypertension, cardiac arrhythmias, and hypertrophic cardiomyopathy. Calcium is vital to many cellular functions and thus stringent regulation of intracellular calcium concentrations is required. Pharmacologic manipulation of the regulatory mechanisms has the potential to alter cellular function in all body systems. In human medicine, calcium channel blockers are being evaluated for, among other things, use in treating glaucoma, deep vein thrombosis, and pulmonary hypertension, in renal transplantation, and for prevention of reperfusion injury. The potentially beneficial effects of these drugs have often been overshadowed by adverse effects including hypotension, inappetence, bradycardia, conduction abnormalities, and decreased cardiac output. With the introduction of sustained-release formulations (diltiazem) and 2nd generation calcium channel blockers (amlodipine) many of these effects have been attenuated or eliminated. This paper will review the functions of calcium and the calcium channels as well as discussing the classes and current and potential uses of the various calcium channel blockers.

Animals↗

PubMed1983

Calcium channels resistant to organic calcium entry blockers in a rabbit vein.

We compared the effects of calcium entry blockers on myogenic tone with the effects of these compounds on agonist- and depolarization-induced mechanical responses in isolated rings of the rabbit facial vein. The development of intrinsic tone in response to distension of the vessel wall and its potentiation by increasing the ambient temperature were antagonized by MnCl2 (0.5 mM) but not verapamil, diltiazem, or nifedipine. Similarly, the contractile response to histamine was blocked by MnCl2 but was unaffected by moderate concentrations of the organic calcium entry blockers. The histamine contractile response elicited at 34 degrees C (a condition which abolishes intrinsic tone) was also refractory to verapamil (10(-6) M). Verapamil, diltiazem, and nifedipine antagonized the contractile response to calcium in depolarized facial vein rings. Thus both extrinsic and intrinsic contractile responses in the rabbit facial vein depend on an extracellular source of calcium. The distension-operated channels are unique in exhibiting a marked temperature sensitivity. However, receptor- and distension-operated calcium channels can be distinguished from the voltage-operated channels in their insensitivity to the organic calcium entry blockers.

Animals↗

PubMed2002

Differential effects of organic calcium-channel blockers on diastolic SR calcium-handling in the frog heart.

1. Gradual loss of sarcoplasmic reticular (SR) calcium during a rest-period is responsible for the rest-induced decay (RID) of force in mammalian myocardium. Effect of verapamil and diltiazem on a similar RID in the frog myocardium suggests a new mechanism of action of these drugs. 2. Strips of frog-ventricle were paced at 0.2 Hz and the rhythm was interrupted by varying rest-periods ranging from 10 to 180 s. In control conditions, the amplitude of the post-rest beat was significantly lower than that of the pre-rest beat for rest-periods more than 40 s (RID). 3. Verapamil and diltiazem (which are organic calcium-channel blockers (OCCB)) changed the pattern of RID in the control solution to a 'rest-induced potentiation' (RIP) in the same preparation while another OCCB nifedipine and the inorganic calcium-channel blocker cadmium did not alter the post-rest phenomenon. 4. We propose that verapamil and diltiazem produce an RIP due to either blockade of SR calcium-leak during rest or enhancement of SR calcium-uptake during rest.

Animals↗