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At least 613 records · Page 34Linked to original sources

PubMed1984

Photoalteration of calcium channel blockade in the cardiac Purkinje fiber.

Organic compounds that block calcium channel current (calcium antagonists) are important tools for the characterization of this channel. However, the practically irreversible nature of this block restricts the usefulness of this group of drugs. In this paper, we investigate the influence of light on calcium channel blockade by several organic compounds. Our results show that inhibition of calcium channel current by two dihydropyridine derivatives that contain an o-nitro moiety (nisoldipine and nifedipine) can be rapidly reversed by illumination. The energy range important to this reaction is for light wavelengths between 320 and 450 nm. Calcium channel inhibition by two other dihydropyridine derivatives (nicardipine and nitrendipine) as well as by D600, is not modulated by illumination. These results indicate that the photosensitivity of certain dihydropyridine calcium channel blockers make these compounds useful as reversible blockers of this channel.

Action Potentials↗

PubMed1991

Microvascular actions of calcium channel antagonists.

The microvascular actions of three calcium channel antagonists were studied in intact spontaneously hypertensive rats (SHR) provided with a dorsal striated muscle microcirculatory chamber. Verapamil and the dihydropyridine derivatives nifedipine and felodipine reduced mean arterial blood pressure (MAP) in a dose-dependent manner. They dilated arterioles of different sizes, with the most pronounced effect being on the smallest precapillary arterioles. Venular diameters were not affected by the calcium antagonists. Approximately 60% of the small arterioles showed a rhythmic pattern of vasodilatation and constriction. This pattern of spontaneous vasomotion was completely blocked by the calcium channel antagonists, especially those of the dihydropyridine type. It is concluded that (a) small precapillary arterioles play an important role in the vasodilator action of calcium channel antagonists, and (b) arteriolar vasomotion depends on vascular smooth muscle cell calcium influx.

Animals↗

PubMedDate not supplied

Effects of calcium channel blockers on potassium homeostasis.

The known effects of calcium channel blockers on various aspects of potassium homeostasis are reviewed. Regulation of potassium homeostasis requires both renal and external handling mechanisms. Signaling by calcium appears to mediate both of these. Calcium channels have been identified in adrenal glomerulosa cells, and cellular calcium entry has been demonstrated in vitro to be necessary for the synthesis and secretion of aldosterone. Calcium channel antagonists such as verapamil and nifedipine, at pharmacologic doses, can block aldosterone production. In vivo, however, only chronic administration of verapamil appears to attenuate aldosterone responsiveness to angiotensin II. Chronic administration of nifedipine does not have a dramatic effect on aldosterone production following potassium loading. Other studies have demonstrated improved extrarenal potassium disposal following treatment with calcium channel blocking agents. Clinically, there are no reports of either hyperkalemia or hypokalemia with the routine therapeutic use of these agents given alone. This review was prompted by the development of hyperkalemia in a patient with chronic renal failure following the initiation of therapy with the calcium channel blocker diltiazem: however, numerous other etiologies may also have contributed to the development of hyperkalemia in this case. Review of the data indicates that current evidence implicating this class of drugs in the pathogenesis of disordered potassium regulation remains equivocal.

Adrenal Cortex↗

PubMed1997

Evidence for antiaggressive property of some calcium channel blockers.

The effect of calcium channel blockers on foot shock induced (aggression (FSA) were studied in mice. Verapamil, (10, 20 and 40 mg kg-1 i.p.) diltiazem (20 and 40 mg kg-1 i.p.) and nifedipine (25 and 50 mg kg-1 i.p.) significantly reduced fighting episodes. Diltiazem and nifedipine blocked the amphetamine induced facilitation of FSA, while verapamil blocked both amphetamine as well as physostigmine induced facilitation of FSA. These findings suggest that calcium channel blockers possess antiaggressive activity, which may be attributed to decrease in central dopaminergic and/or cholinergic mechanism.

Aggression↗

PubMed1996

Diversity and function of presynaptic calcium channels in the brain.

Calcium channels in presynaptic nerve terminals are essential for neurotransmitter release, and current research has provided evidence for the involvement of a multitude of Ca2+ channel types. The diversity of Ca2+ channel structure and distribution in the brain suggests specific functional roles. Modulation by interaction with other proteins and/or by phosphorylation/dephosphorylation reactions enhances the regulatory impact of these channels on brain function.

Animals↗

PubMed2002

Antihistamine terfenadine inhibits calcium influx, cGMP formation, and NMDA receptor-dependent neurotoxicity following activation of L-type voltage sensitive calcium channels.

We have investigated the actions of the H1 receptor antagonist terfenadine on voltage sensitive calcium channels and calcium-mediated pathways. We found that terfenadine prevented N-methyl-D-aspartate (NMDA)-mediated excitotoxicity following stimulation of L-type voltage sensitive calcium channels by the specific agonist BayK8644. The neuroprotective effect of terfenadine was concentration-dependent, 10 and 100 nM terfenadine providing 50 and 100% neuroprotection, respectively. Neuroprotection was associated with a decrease in calcium influx via L-voltage sensitive calcium channels. Terfenadine fully reversed the increase in intracellular calcium induced by BayK8644, and delayed significantly the time necessary for this agonist to induce maximum intracellular calcium levels. Calcium-mediated biochemical pathways coupled to voltage sensitive calcium channels activation were also affected by terfenadine. This drug inhibited intracellular cGMP formation by BayK8644 in a concentration-dependent manner, 100 nM terfenadine reducing cGMP formation by 50% and 1 micro M terfenadine fully inhibiting cGMP synthesis. Terfenadine reduced NMDA receptor-mediated cGMP formation due to the release of glutamate following activation of calcium channels by BayK8644. Finally, we also show that terfenadine effectively reduced steady-state concentrations of both intracellular calcium and cGMP in unstimulated cultures in their usual growing conditions.

Journal Article↗

PubMed2005

A single CaVbeta can reconstitute both trafficking and macroscopic conductance of voltage-dependent calcium channels.

Voltage-dependent calcium-channel beta subunits (Ca(V)beta) strongly modulate pore-forming alpha(1) subunits by trafficking channel complexes to the plasma membrane and enhancing channel open probability (P(o)). Despite their central role, it is unclear whether binding of a single Ca(V)beta, or multiple Ca(V)betas, to an alpha(1) subunit governs the two distinct functions. Conventional experiments utilizing coexpression of alpha(1) and Ca(V)beta subunits have been unable to resolve the ambiguity due to difficulties in establishing their stoichiometry in functional channels. Here, we unambiguously establish a 1: 1 stoichiometry by covalently linking Ca(V)beta(2b) to the carboxyl terminus of alpha(1C) (Ca(V)1.2), creating alpha(1C).beta(2b). Recombinant L-type channels reconstituted in HEK 293 cells with alpha(1C).beta(2b) supported whole-cell currents to the same extent as channels reconstituted via coexpression of the individual subunits. Analysis of gating charge showed alpha(1C).beta(2b) fully restored channel trafficking to the plasma membrane. Co-transfecting Ca(V)beta(2a) with alpha(1C).beta(2b) had little further impact on function. To rule out the possibility that fused Ca(V)beta(2b) was interacting in trans with neighbouring alpha(1) molecules, alpha(1C).beta(2b) was cotransfected with alpha(1B) (Ca(V)2.2), and pharmacological block with nimodipine showed an absence of alpha(1B) trafficking. These results establish that association of a single Ca(V)beta with a pore-forming alpha(1) subunit captures the functional essence of HVA calcium channels, and introduce alpha(1)-Ca(V)beta fusion proteins as a powerful new tool to probe structure-function mechanisms.

Calcium Channels, L-Type↗

PubMed1996

Calcium-channel blockade and incidence of cancer in aged populations.

BACKGROUND: Calcium-channel blockers can alter apoptosis, a mechanism for destruction of cancer cells. We examined whether the long-term use of calcium-channel blockers is associated with an increased risk of cancer. METHODS: Between 1988 and 1992 we carried out a prospective cohort study of 5052 people aged 71 years or more and who lived in three regions of Massachusetts, Iowa, and Connecticut USA. Those taking calcium-channel blockers (n = 451) were compared with all other participants (n = 4601). The incidence of cancer was assessed by survey of hospital discharge diagnoses and causes of death. These outcomes were validated by the cancer registry in the one region where it was available. Demographic variables, disability, cigarette smoking, alcohol consumption, blood pressure, body-mass index, use of other drugs, hospital admissions for other causes, and comorbidity were all assessed as possible confounding factors. FINDINGS: The hazard ratio for cancer associated with calcium-channel blockers (1549 person-years, 47 events) compared with those not taking calcium-channel blockers (17225 person-years, 373 events) was 1.72 (95% CI 1.27-2.34, p = 0.0005), after adjustment for confounding factors. A significant dose-response gradient was found. Hazard ratios associated with verapamil, diltiazem, and nifedipine did not differ significantly from each other. The results remained unchanged in community-specific analyses. The association between calcium-channel blockers and cancer was found with most of the common cancers. INTERPRETATION: Calcium-channel blockers were associated with a general increased risk of cancer in the study populations, which suggested a common mechanism. These observational findings should be confirmed by other studies.

Aged↗

PubMed1995

Interaction of Ro 40-5967 and verapamil with the stably expressed alpha 1-subunit of the cardiac L-type calcium channel.

The interaction of the nondihydropyridine calcium channel antagonist Ro 40-5967 with the stably expressed class C alpha 1-subunit of the cardiac L-type calcium channel was investigated and compared with that of verapamil by using the whole cell patch clamp configuration. Both compounds blocked the Ba++ inward current. The IC50 values at a holding potential of -80 or -40 mV were 4.9 and 1.4 microM for Ro 40-5967 and 250 and 15.5 microM for verapamil. Both Ro 40-5967 and verapamil induced a partial tonic block at a holding potential of -80 mV. The block increased with high depolarization rates. Both Ro 40-5967 and verapamil shifted the steady-state inactivation curve by more than 20 mV to hyperpolarized membrane potentials and decreased the inactivation rate constant. The effect of Ro 40-5967, but not that of verapamil, was attenuated by intracellular dialysis with GTP gamma S. The affinity for verapamil was not affected by replacing Ba++ by Ca++, but was increased by the coexpression of the beta 3-subunit. These results indicate that both compounds interact with high affinity with the inactivated channel state, but may interact additionally with the open channel.

Animals↗

PubMed1990

Calcium channel blockers in affective illness: role of sodium-calcium exchange.

Available evidence suggests that verapamil and perhaps other calcium channel blockers are effective in treating mania but not unipolar depression. This article briefly reviews the clinical experience and reexamines potential mechanisms. It is proposed that antimanic efficacy is primarily related to inhibition of sodium-calcium counterexchange rather than calcium channel blockade.

Bipolar Disorder↗

PubMed1999

Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids.

Calcium influx through store-operated calcium release-activated calcium channels (CRAC) is required for T cell activation, cytokine synthesis, and proliferation. The CD95 (Apo-1/Fas) receptor plays a role in self-tolerance and tumor immune escape, and it mediates apoptosis in activated T cells. In this paper we show that CD95-stimulation blocks CRAC and Ca(2+) influx in lymphocytes through the activation of acidic sphingomyelinase (ASM) and ceramide release. The block of Ca(2+) entry is lacking in CD95-defective lpr lymphocytes as well as in ASM-defective cells and can be restored by retransfection of ASM. C2 ceramide, C6 ceramide, and sphingosine block CRAC reversibly, whereas the inactive dihydroceramide has no effect. CD95-stimulation or the addition of ceramide prevents store-operated Ca(2+) influx, activation of the transcriptional regulator NFAT, and IL-2 synthesis. The block of CRAC by sphingomyelinase metabolites adds a function to the repertoire of the CD95 receptor inhibiting T cell activation signals.

Animals↗

PubMed2003

The neuronal beta 4 subunit increases the unitary conductance of L-type voltage-gated calcium channels in PC12 cells.

beta subunits of voltage-gated calcium channels influence channel behavior in numerous ways, including enhancing the targeting of alpha1 subunits to the plasma membrane and shifting the voltage dependence of activation and inactivation. Of the four beta subunits that have been identified, beta 4 is of particular interest because mutation of its alpha1 subunit interaction domain produces severe neurological defects. Its differential distribution in the hippocampus prompted us to examine whether this subunit was responsible for the heterogeneity of hippocampal L-type calcium channels. To study the functional effects of the beta 4 subunit on native L-type calcium channels, we transfected beta 4 cDNA subcloned out of embryonic hippocampal neurons into PC12 cells, a cell line that contains the beta 1, beta 2, and beta 3 subunits but not the beta 4 subunit. Cell-attached single-channel recordings of L-type channel activity from untransfected and transfected PC12 cells compared with recordings obtained from hippocampal neurons revealed an effect of the beta 4 subunit on single-channel conductance. L-type channels in untransfected PC12 cells had a significantly smaller conductance (19.8 picosiemens (pS)) than L-type channels in hippocampal neurons (22 pS). After transfection of beta 4, however, L-type single-channel conductance was indistinguishable between the two cell types. Our data suggest that calcium channel beta 4 subunits affect the conductance of L-type calcium channels and that native hippocampal L-type channels contain the beta 4 subunit.

Animals↗

PubMed1991

Pharmacology of calcium channels in cardiac muscle, vascular muscle, and neurons.

The properties of voltage-dependent calcium channels in muscle cells and neurons have been studied using the whole-cell patch clamp technique. Cardiac muscle cells, vascular muscle cells, and neurons all have multiple types of calcium channels, and the different types have different pharmacological properties. The predominant calcium current in most cardiac and vascular muscle cells is carried through L-type calcium channels, which are potently and completely blocked by dihydropyridine drugs; the block is voltage-dependent, and is more potent at depolarized holding potentials where the calcium current is partly inactivated. In neurons, much less of the high-threshold calcium channel current is blocked by dihydropyridines, because much of it is carried through N-type calcium channels, which are not blocked by dihydropyridines but are blocked by the peptide toxin omega-conotoxin GVIA. In addition to L-type and N-type calcium channels, rat neurons have a third type of high-threshold calcium channel that is not blocked by either omega-conotoxin or dihydropyridines. Some neurons also have a fourth type of calcium current, a low threshold current carried by T-type calcium channels.

Animals↗

PubMed2000

Differential involvement of L-type calcium channels in epileptogenesis of rat hippocampal slices during ontogenesis.

Organic calcium channel antagonists block epileptiform activity in adult tissue, suggesting an essential role of L-type channels in epileptogenesis in the mature CNS. By contrast, this remains doubtful for neonatal tissue, as the density of calcium channels changes markedly with ontogenesis. The paper addresses this question by exploring the antiepileptic efficacy of the L-type calcium channel blockers verapamil and nifedipine in low-Mg(2+)-epilepsy in rat hippocampal slices of different postnatal (PN) ages. Field (CA3, CA1) and membrane potentials (CA3) were recorded. Washout of Mg(2+) induced epileptiform potentials, which were blocked age-dependently: Verapamil suppressed activity in all preparations of PN1-5 and PN13-30+, but only in 70% of PN6-12. Nifedipine depressed activity in >75% of slices of PN13-30+, but only in 33% of PN1-12. The findings indicate a role of L-type calcium channels in epileptogenesis from PN13 onwards, with phenylalkylamine-sensitive calcium channels also being involved during PN1-5.

Age Factors↗

PubMedDate not supplied

Cardiovascular alterations in rat fetuses exposed to calcium channel blockers.

Preclinical toxicologic investigation suggested that a new calcium channel blocker, Ro 40-5967, induced cardiovascular alterations in rat fetuses exposed to this agent during organogenesis. The present study was designed to investigate the hypothesis that calcium channel blockers in general induce cardiovascular malformations indicating a pharmacologic class effect. We studied three calcium channel blockers of different structure, nifedipine, diltiazem, and verapamil, along with the new agent. Pregnant rats were administered one of these calcium channel blockers during the period of cardiac morphogenesis and the offspring examined on day 20 of gestation for cardiovascular malformations. A low incidence of cardiovascular malformations was observed after exposure to each of the four calcium channel blockers, but this incidence was statistically significant only for verapamil and nifedipine. All four agents were associated with aortic arch branching variants, although significantly increased only for Ro 40-5967 and verapamil.

Abnormalities, Drug-Induced↗

PubMed1993

G-protein modulation of ion permeation through N-type calcium channels.

N-type calcium channels in cell membranes are inhibited by neurotransmitters such as noradrenaline, luteinizing hormone-releasing hormone (LHRH), gamma-aminobutyric acid (GABA) and glutamate. Although GTP-binding proteins (G proteins) are probably the common mediators of such inhibition, it is unclear exactly how G proteins alter the operation of the channel. Various experiments have shown changes in channel gating. Here we show that inward current carried by Na+ through N-type channels was far less inhibited by LHRH or by internal GTP-gamma S than was current carried by Ba2+. With external Ba2+ and internal Cs+, LHRH inhibited the Ba(2+)-carried inward limb of the instantaneous current-voltage curve much more than the Cs(+)-carried outward limb. Noise analysis showed that LHRH or GTP-gamma S decrease single-channel current carried by Ba2+. These results suggest that alteration of the ion permeation pathway contributes significantly to G-protein inhibition of N-type Ca2+ channels.

Animals↗

PubMed1991

Two types of calcium channels are expressed in adult bovine chromaffin cells.

1. Calcium channel activity was recorded in chromaffin cells in the cell-attached condition, using 110 mM-Ba2+ as the permeant ion. 2. One type of calcium channel had a conductance of 16 pS, was completely inactivated at a holding potential of -20 mV and was insensitive to dihydropyridine agonists and antagonists. These characteristics correspond to a calcium channel of the N-type. 3. A second type of calcium channel was active at holding potentials of -30 mV and above, had a channel conductance of 31 pS, and was sensitive to the dihydropyridine agonist, Bay K 8644. The channel opened along two dominant modes with characteristic time constants of 0.5 and 5 ms. The main effect of Bay K 8644 was to increase the probability of both short and long openings with no change in their relative proportions (6 to 1 respectively). These characteristics correspond to a calcium channel of the L-type. 4. omega-Conotoxin affected the activity of both N- and L-type channels. It drastically reduced the number of N-type channel openings and produced complex changes in L-type channel activity. Long openings were less frequent and the conductance during short openings was slightly smaller than that measured in the presence of Bay K 8644. 5. The discussion focuses on modulation of L-type channel activity. Openings of L-type channels are rarely recorded in the cell-attached configuration under control conditions. Addition of Bay K 8644 is needed to reveal the presence of L-type channels. By contrast, L-type currents recorded in the whole-cell configuration are always observed and are insensitive to Bay K 8644. These results indicate that L-type channels are normally inoperable in chromaffin cells.

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

PubMed2002

Tubular and cellular localization of the cardiac L-type calcium channel in rat kidney.

BACKGROUND: The mRNAs of several types of calcium channels have been identified in intact rat kidney, and L-type calcium channels cause changes in intracellular calcium in primary cultures of distal tubule cells. The aim of this study was to evaluate the tubular and cellular distribution of the alpha1C subunit of the L-type calcium channel in intact kidney. METHODS: RT-PCR and Northern blot analysis were used to assess the regional abundance of the mRNA of this channel. Immunocytochemistry combined with confocal microscopy and surface biotinylation were applied to determine the tubular and cellular localization of the protein. RESULTS: Northern blot and RT-PCR analysis indicated that the mRNA of the alpha1C subunit of the cardiac L-type calcium channel was present in whole rat kidney, kidney tubules and kidney cell lines. Western blot of lysates from whole kidney, kidney tubules or cell lines revealed bands of approximately 190 kD for the alpha1C subunit and approximately 60 kD for the beta3 subunit. Confocal immunohistochemistry indicated that the alpha1C subunit of this channel was co-expressed in cells of the distal tubule that express calbindin-D28K, but not in intercalated cells. The alpha1C subunit was also highly expressed in both outer and inner medullary collecting ducts. Serial confocal microscopic images or surface biotinylation experiments determined that the channel was predominantly on the basolateral membrane but had some distribution on the apical membrane. CONCLUSIONS: The distribution and cellular localization of the alpha1C subunit of cardiac L-type calcium channel suggest it is probably involved in intracellular and membrane calcium signaling.

Animals↗