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PubMed1995

Voltage-dependence of Ca2+ agonist effect of YC-170 on cardiac L-type Ca2+ channels.

1. We investigated the voltage-dependence of the agonist actions of YC-170, a dihydropyridine (DHP) derivative, on cardiac L-type Ca2+ channels in rabbit ventricular cells, using the patch clamp technique. The characteristics of YC-170 were compared with those of other DHP Ca2+ agonists (Bay K 8644, CGP 28392). Ca2+ channel activities were elicited by depolarizing pulses to 0 mV from a holding potential (HP) of either -80 mV or -40 mV. 2. YC-170 (10 microM) increased Ca2+ channel activities when HP was set at -80 mV. However, decreasing HP to -40 mV abolished the agonist action. The agonist effect of Bay K 8644 (1 microM) on Ca2+ channels was elicited to the same extent at either HP. CGP 28392 (10 microM) also increased Ca2+ channel activities at both HPs, but its agonist effect was significantly larger at an HP of -80 mV than at -40 mV. 3. All of the three DHP Ca2+agonists prolonged open times of Ca2+ channels, but the prolongation did not correspond to the voltage-dependence of Ca2+ agonist effects of the three DHPs. 4. YC-170 markedly reduced the closed time of the Ca2+ channel when the HP was at -80 mV, but prolonged it at HP of -40 mV. Bay K 8644 reduced closed times at an HP of -80 mV. At an HP of -40 mV, Bay K 8644 slightly reduced closed times. CGP 28392 reduced closed times at an HP of -80 mV and prolonged those at an HP of -40 mV. Thus the voltage-dependence of the agonist effects of these agents was in good agreement with the voltage-dependence of changes in closed times of Ca2+ channel. 5. Two mechanisms may be involved in the agonist action of YC-170; a prolongation of open times, and a reduction of closed times of Ca2+ channels, i.e. an increase in reopening. The former mechanism is not dependent on Hp and the latter mechanism is highly dependent on HP. Thus, the voltage-dependence of the agonist action may be attributed to the voltage-dependence of their enhancing effect on reopening of Ca2+ channels.

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

PubMed1996

Inhibitory effect of calcium channel blockers on human mesangial cell growth: evidence for actions independent of L-type Ca2+ channels.

Calcium channel blockers (CCB) are known to affect the outcome of glomerulosclerosis in vivo and to suppress mesangial cell proliferation and cytokine production in vitro. It is uncertain, however, whether (i) human adult mesangial cells (HMC) express L-type Ca2+ channels and (ii) whether the effect of CCB on HMC is mediated by inhibition of L-type Ca2+ channels. In single cell preparations of HMC, the L-type Ca2+ channel agonist Bay K 8644 and K+-depolarization of the cell membrane caused a transient increase of cytosolic free Ca2+ ([Ca2+]i) in 60 to 80% of the cells. The CCB verapamil and nifedipine partially inhibited the effect of Bay K 8644 and K+-depolarization on [Ca2+]i. Binding experiments confirmed these functional studies by showing specific binding at the phenylalkylamine binding site of L-Type Ca2+ channels. Quiescent HMC were stimulated with fetal calf serum (FCS) or growth factors (platelet derived growth factor A/B, epidermal growth factor, angiotensin II, endothelin 1) in the presence of various concentrations (10(-10) to 10(-5) M) of different CCB: either (R)-verapamil, (S)-verapamil or the raceme of verapamil, and nifedipine or diltiazem, respectively. In addition, the enantiomers of devapamil were studied, because their action on the L-type Ca2+ channel is more stereoselective than that of the enantiomers of verapamil. At high concentrations (10(-6) to 10(-5) M) (R,S)-verapamil decreased cell numbers in cultures of quiescent HMC, increased LDH in the supernatant, and caused loss of trypan blue exclusion (cytotoxicity). At lower concentrations (R,S)-verapamil showed no cytotoxicity, but had two effects: (1.) concentration dependent (down to 10(-8) M) inhibition of indices of cell proliferation, that is, (i) stimulated (FCS or growth factor) 3H-thymidine incorporation and (ii) increment in cell number; and (2.) inhibition of indices of cell or matrix protein synthesis, that is, (i) stimulated 3H-methionine incorporation and (ii) 3H-proline incorporation. At equimolar concentrations the dihydropyridine nifedipine was equipotent with verapamil, whereas the benzothiazepine diltiazem was conspicuously less effective. Even at the lowest effective concentration (10(-8) M) comparison of (R)- and (S)-verapamil showed no significant difference between the enantiomer with weak or with strong effect on L-type Ca2+ channels, and this was true even when the more stereoselective enantiomers of devapamil were tested. These observations argue against the notion that effects of CCB result from specific interaction with L-type Ca2+ channels. The data are more consistent with the idea that interactions with targets other than L-type Ca2+ channels are involved.

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

PubMed1993

[Calcium signals in blood cells].

Stimulation of blood cells by binding of agonists to receptors initiates cellular calcium signals. The signals appear as transient increases of the cytosolic concentration of ionized calcium. The signals influence secretion, adhesion, phagocytosis, movements and proliferation of the blood cells. The calcium signals are controlled by other signalling systems that regulate calcium transporting devices located in the plasma membrane and the membranes that surround the cellular calcium stores. Calcium ions are transported through channels, pumps, or exchangers located in the cellular membranes. Several calcium transporters are subjected to cellular feedback mechanisms. A few pathological disorders of the calcium signal system are known.

Animals↗

PubMed1997

Calcium handling by vascular myocytes in hypertension.

Calcium ions (Ca2+) trigger the contraction of vascular myocytes and the level of free intracellular Ca2+ within the myocyte is precisely regulated by sequestration and extrusion mechanisms. Extensive evidence indicates that a defect in the regulation of intracellular Ca2+ plays a role in the augmented vascular reactivity characteristic of clinical and experimental hypertension. For example, arteries from spontaneously hypertensive rats (SHR) have an increased contractile sensitivity to extracellular Ca2+ and intracellular Ca2+ levels are elevated in aortic smooth muscle cells of SHR. We hypothesize that these changes are due to an increase in membrane Ca2+ channel density and possibly function in vascular myocytes from hypertensive animals. Several observations using various experimental approaches support this hypothesis: 1) the contractile activity in response to depolarizing stimuli is increased in arteries from hypertensive animals demonstrating increased voltage-dependent Ca2+ channel activity in hypertension; 2) Ca2+ channel agonists such as Bay K 8644 produce contractions in isolated arterial segments from hypertensive rats and minimal contraction in those from normotensive rats; 3) intracellular Ca2+ concentration is abnormally increased in vascular myocytes from hypertensive animals following treatment with Ca2+ channel agonists and depolarizing interventions, and 4) using the voltage-clamp technique, the inward Ca2+ current in arterial myocytes from hypertensive rats is nearly twice as large as that from myocytes of normotensive rats. We suggest that an alteration in Ca2+ channel function and/or an increase in Ca2+ channel density, resulting from increased channel synthesis or reduced turnover, underlies the increased vascular reactivity characteristic of hypertension.

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

PubMed2006

Aldosterone increases voltage-gated sodium current in ventricular myocytes.

The role of aldosterone in the pathogenesis of heart failure (HF) is still poorly understood. Recently, aldosterone has been shown to modulate the function of cardiac Ca(2+) and K(+) channels, thus playing a role in the electrical remodeling process. The goal of this work was to investigate the role of aldosterone on the cardiac Na(+) current (I(Na)). We analyzed the effects of aldosterone on I(Na) in isolated adult mouse ventricular myocytes, using the whole cell patch-clamp technique. After 24 h incubation with 1 microM aldosterone, the I(Na) density was significantly increased (+55%), without alteration of the biophysical properties and the cell membrane capacitance. Aldosterone (10 nM) increased the I(Na) by 23%. In 24-h coincubation experiments, with the use of actinomycin D, cycloheximide, or brefeldin A, the effect of aldosterone on I(Na) was abolished. Spironolactone (mineralocorticoid receptor antagonist, 10 microM) prevented the 1 microM aldosterone-dependent I(Na) increase, whereas RU-38486 (glucocorticoid receptor antagonist, 10 microM) did not. The action potential duration (APD) was longer in aldosterone-treated (APD(90): +53%) than in control myocytes. In addition, the L-type Ca(2+) current was also upregulated (+48%). We performed quantitative RT-PCR measurements and Western blots to quantify the mRNA and protein levels of Na(v)1.5 and Ca(v)1.2 (main channels mediating cardiac I(Na) and I(Ca)), but no significant difference was found. In conclusion, this study shows that aldosterone upregulates the cardiac I(Na) and suggest that this phenomenon may contribute to the HF-induced electrical remodeling process that may be reversed by spironolactone.

Action Potentials↗

PubMed2000

D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade.

In spite of the recognition that striatal D(2) receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D(2) receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca(2+) currents through L-type Ca(2+) channels, resulting in diminished excitability. This modulation is mediated by G(beta)(gamma) activation of phospholipase C, mobilization of intracellular Ca(2+) stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D(2) receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.

Action Potentials↗

PubMed1999

Changes of cardiac calcium homeostasis in spontaneously hypertensive rats.

The aim of the present study was to assess the alterations in cardiac Ca2+ homeostasis induced by hypertension using electrically paced right ventricular strips from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2 Basal contractile force was higher in SHR than in WKY. Similarly, the beta-adrenoceptor agonist isoprenaline (10 nM-10 microM) induced a concentration-dependent positive inotropic effect that was higher in SHR than in WKY, which was in turn inhibited by the beta-adrenoceptor antagonist propranolol (1 microM) in both strains. 3 Preincubation of strips with the L-type Ca2+ channel blockers, nifedipine (1 microM) or verapamil (10 microM), markedly inhibited the isoprenaline response, the inhibition being higher in SHR than in WKY. However, this inhibition was minor by the T-type Ca2+ channel blocker mibefradil (10 microM). 4 Bay K 8644 (10 nM-10 microM), a L-type Ca2+ channel activator induced a concentration-dependent positive inotropic effect, that was greater in SHR than WKY. 5 Nifedipine and verapamil (both 0.1 nM-10 microM) inhibited in a concentration-dependent way the inotropic effect induced by 0.3 microM isoprenaline or 1 microM Bay K 8644. The inhibition was higher in SHR than in WKY. Mibefradil (0.1 nM-10 microM) only clearly inhibited the isoprenaline and Bay K 8644 inotropic effects at 10 microM in both strains. 6 The inhibitor of the sarcoplasmic reticulum Ca2+ release, ryanodine (10 nM-10 microM), was a more effective depressor of isoprenaline-induced response in SHR than in WKY. 7 These results suggest that cardiac Ca2+ homeostasis in SHR ventricular strips is altered compared with those of WKY, showing an increased Ca2+ entry through L-type Ca2+ channels and release from sarcoplasmic reticulum; the participation of T-type Ca2+ channels are irrelevant in this tissue.

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

PubMed1998

L-Type calcium channels mediate a slow excitatory synaptic transmission in rat midbrain dopaminergic neurons.

Patch pipettes were used to record whole-cell synaptic currents under voltage-clamp in dopaminergic neurons in slices of rat substantia nigra pars compacta and ventral tegmental area. We report that dihydropyridines (DHPs), L-type Ca2+ channel antagonists, depressed a slow EPSC (EPSCslow) evoked by a train of focally delivered electrical stimuli. In fact, the amplitude of the EPSCslow was reduced by the DHP antagonists nifedipine (1-100 microM), nimodipine (1-100 microM), and isradipine (30 nM-100 microM) in a concentration-dependent and reversible manner. On the other hand, Bay-K 8644 (1 microM), an L-type Ca2+ channel agonist, increased the EPSCslow. The DHPs depressed the EPSCslow only when the high-frequency stimulation that was used to evoke this synaptic current lasted >70 msec. On the other hand, Bay-K 8644 increased the amplitude of the EPSCslow only when it was evoked by a train <70 msec. Moreover, the DHPs did not affect the EPSCfast, the IPSCfast, and the IPSCslow. The inhibition of the EPSCslow caused by the DHPs is attributed to presynaptic mechanisms because (1) the inward current generated by exogenously administered glutamate was not affected and (2) the EPSCslow was reduced to a similar degree even when the activation state of postsynaptic L-type Ca2+ channels was changed by holding the neurons at -100, -60, and +30 mV. Finally, a DHP-sensitive component of the EPSCslow could even be detected after the blockade of N-, Q-, and P-type Ca2+ channels by the combination of omega-conotoxin GVIA, omega-agatoxin IVA, and omega-conotoxin MVIIC. Taken together, these results indicate that under certain patterns of synaptic activity, L-type Ca2+ channels regulate the synaptic release of excitatory amino acids on the dopaminergic neurons of the ventral mesencephalon.

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

PubMed2000

Increased expression of L-type calcium channels in vascular smooth muscle cells at spastic site in a porcine model of coronary artery spasm.

Coronary artery spasm is caused primarily by increased contractility of vascular smooth muscle. Excessive Ca2+ entry into vascular smooth muscle cells (VSMCs) may be one of the key mechanisms for the spasm, but no study has ever directly examined the possible alterations of Ca2+ channels in the spastic coronary artery. Here we show that L-type Ca2+ channels are excessively expressed at the spastic site of the coronary artery. In a porcine model of coronary spasm with balloon injury, both receptor-mediated stimulation of L-type Ca2+ channels by serotonin and direct stimulation of the channels by Bay K 8644 (a dihydropyridine Ca2+ channel agonist) repeatedly induced coronary spasm in vivo, which was abolished by pretreatment with nifedipine, a dihydropyridine Ca2+ channel antagonist. In a single VSMC freshly dispersed from coronary arteries in vitro, patch-clamp experiments showed that current density of L-type Ca2+ channel current was significantly increased in VSMCs from the spastic site compared with that from the control site even when the channels were maximally stimulated by Bay K 8644. There was no difference in the sensitivity of the channels to Bay K 8644. These results indicate that functionally available L-type Ca2+ channels are excessively expressed at the spastic site of the coronary artery in our porcine model, suggesting that increased expression of L-type Ca2+ channels and concomitant increase in Ca2+ entry into VSMCs through the channels may contribute, at least in part, to the pathogenesis of coronary artery spasm.

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

PubMed1995

Inhibition of arteriole alpha 2- but not alpha 1-adrenoceptor constriction by acidosis and hypoxia in vitro.

We have found that hypoxia and acidosis inhibit constriction by alpha 2D-adrenoceptors but not by alpha 1D-adrenoceptors on arterioles of rat skeletal muscle, facilitating local metabolic control of blood flow. When activated by full agonists like norepinephrine, this alpha 2D-constriction relies on Ca2+ influx through dihydropyridine-sensitive, voltage-operated Ca2+ channels (VOC), while alpha 1D-constriction does not. The purpose of the present study was to examine the dose sensitivity of this selective metabolic inhibition of alpha 2D-constriction and determine whether inhibition of VOCs is involved. Changes in lumen diameter of microcannulated arterioles isolated from rat skeletal muscle (107 +/- 3 microns control diam) were measured by videomicroscopy for bath-added agents. Decreases in pH (7.4-7.0) or PO2 (70 to 10 mmHg) caused graded inhibition of alpha 2D-adrenoceptor constriction (UK-14304 plus prazosin); the half-maximum inhibitory concentration for acidosis was 7.1 and for PO2 was 24 mmHg. alpha 1D-Adrenoceptor constriction by the respective full and partial alpha 1-agonists, phenylephrine (PE) and St-587 (both plus rauwolscine), was unaffected. Because St-587 but not PE constriction was dependent on VOC activation, the sensitivity of alpha 2D- but not alpha 1D-constriction to acidosis and hypoxia appeared to be independent of reliance on VOCs. This was examined directly; contractile sensitivity to KCl and the VOC agonist, SDZ-202-791, was unaffected by pH 7.0 or PO2 10 mmHg. These data suggest that alpha 2D-constriction is sensitive to inhibition by hypoxia and acidosis through a mechanism that does not involve direct blockade of dihydropyridine-sensitive Ca2+ channels.

Acidosis↗

PubMed1995

Enhancement by muscarinic agonists of a high voltage-activated Ca2+ current via phosphorylation in a snail neuron.

1. In previous work we have shown that in the snail Helix aspersa neuron F1 carbamylcholine (CCh) and other muscarinic agonists enhance the inward current carried through high voltage-activated Ca2+ channels by Ba2+ (HVA-ICa). It was also found that cyclic nucleotides, inositol trisphosphate or arachidonic acid are not involved in this modulation. Moreover, despite the effect of CCh being blocked by intracellular injection of EGTA, neither protein kinase C nor Ca(2+)-calmodulin-dependent protein kinase II appeared to play a role. 2. In the present paper, the intracellular mechanism of this muscarinic modulation was investigated further by studying the effects of inhibitors of Ser-Thr protein phosphatases (PP) on both the HVA-ICa of neuron F1 and its enhancement by CCh. 3. Intracellular injections in the F1 neuron of either microcystin LR or okadaic acid, both inhibitors of PP1 and PP2A, mimic the action of CCh on the HVA-ICa and occlude the effects of CCh on this current. In contrast, cyclosporin A, an inhibitor of PP2B (calcineurin), affects neither the HVA Ca2+ current itself nor its modulation by CCh. 4. The efficacy of PP inhibitors was tested in F1 neurons in which serotonin (5-HT) induces an inward current involving intracellular increases in cAMP and a protein kinase A-dependent closing of K+ channels. We found that intracellular injection of either microcystin LR or okadaic acid mimicked the 5-HT-induced inward current and occluded the effect of further application of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

[Single channel analysis of Ca2+ channel-agonistic action of dihydropyridine derivatives: voltage-dependent effects of YC-170 and BAY K 8644].

Voltage-dependent effects of YC-170, a dihydropyridine derivative, on rabbit cardiac L-type Ca2+ channels were investigated and compared with those of a dihydropyridine Ca2+ agonist, BAY K 8644, using patch clamp techniques. Single Ca2+ channel activities were elicited by depolarizing pulses to O mV from holding potentials (HPs) of -80 mV and -40 mV. With a HP of -80 mV, YC -170 (10 microM) increased a mean open time of the Ca2+ channel (vector o) from 0.50 +/- 0.03 ms to 1.2 +/- 0.05 ms (mean +/- S.E., n = 5), and increased NPo value of the Ca2+ channel by 710 +/- 96% (n = 5) of the control value. On the other hand, with a HP of -40 mV, YC-170 had little effects on NPo value (94 +/- 6.6% of the control value, n = 5), although YC-170 increased vector o from 0.64 +/- 0.05 ms to 1.2 +/- 0.11 ms. BAY K 8644 increased NPo values to almost the same degree with both HPs (920 +/- 93% with a HP of -80 mV, n = 5, and 990 +/- 85% with a HP of -40 mV, n = 5). BAY K 8644 (1 microM) remarkably increased vector o with both HPs (from 0.66 +/- 0.09 ms to 3.3 +/- 0.50 ms, n = 3, with a HP of -80 mV and from 0.68 +/- 0.06 ms to 4.9 +/- 1.2 ms, n = 4, with a HP of -40 mV). Although YC-170 and BAY K 8644 increased vector o with both HPs, YC-170 failed to produce the Ca2+ agonistic effect with less negative HP (-40 mV). Thus, another mechanism differing from prolongation of the open time may be involved in the agonistic action of YC-170. YC-170 increased markedly the frequency of openings of Ca2+ channels with a HP of -80 mV and decreased it with a HP of -40 mV. BAY K 8644 increased it slightly with a HP of -40 mV and did not change it with a HP of -80 mV. Analysis using closed time histograms also revealed that YC-170 enhanced reopenings of Ca2+ channels with a HP of 80 mV and suppressed it with a HP of -40 mV, BAY K 8644 enhanced it with both HPs. Two mechanisms may be involved in the agonistic action of dihydropyridine Ca2+ agonists. One is prolongation of the open time of Ca2+ channels and the other is an enhancement of reopenings of Ca2+ channels. The former mechanism may not be voltage dependent and the latter mechanism may be voltage dependent.

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

PubMed1996

The effects of ketamine on Ca2+ movements in A7r5 vascular smooth muscle cells.

To investigate the effects of ketamine on Ca2+ movement to and from intracellular Ca2+ stores and across plasma membranes, 45Ca2+ fluxes were studied in permeabilized and intact A7r5 smooth muscle cells, an established cell line derived from embryonic rat aorta. Monolayers of A7r5 cells were loaded with 45Ca2+, and the radioactivity in the collected medium and the residual activity were measured by liquid scintillation counting. Ketamine had no effect on 45Ca2+ uptake and passive leak of the nonmitochondrial Ca2+ pool in permeabilized A7r5 cells. Ketamine 1 mM had no inhibitory effect on the inositol 1,4,5-trisphosphate (InsP3, 1 microM)-induced Ca2+ release from the intracellular stores. In intact A7r5 cells, ketamine did not alter the Ca2+ extrusion from these cells under resting conditions. Addition of 10 nM vasopressin resulted in a transient Ca2+ release from the intracellular stores. Ketamine inhibited this vasopressin-induced Ca2+ release, but did not enhance Ca2+ extrusion through the plasma membrane in the period after the vasopressin effect. These results indicate that ketamine inhibits agonist-induced Ca2+ release from intracellular stores, but has no effect on Ca(2+)-uptake into intracellular stores or on Ca2+ extrusion through the plasma membrane in A7r5 smooth muscle cells.

Anesthetics, Dissociative↗

PubMed1998

Isolation of a member of the neurotoxin/cytotoxin peptide family from Xenopus laevis skin which activates dihydropyridine-sensitive Ca2+ channels in mammalian epithelial cells.

We have used a sensitive bioassay of calcium-mediated volume changes in mammalian absorptive intestinal epithelial cells to screen extracts of the skin of the amphibian Xenopus laevis for the presence of factors affecting ion transport. A 66-residue peptide, purified using reversed-phase high performance liquid chromatography techniques, caused isotonic volume reduction of guinea pig jejunal villus cells in suspension. This volume reduction required extracellular Ca2+ and was prevented by the dihydropyridine-sensitive Ca2+ channel blocker niguldipine. Structural analysis demonstrated the presence of eight cysteines and a primary structure homologous to that of the neurotoxin/cytotoxin family found in the venom of certain poisonous snakes. The structure of the peptide was identical to that of xenoxin-1 purified from dorsal gland secretions of X. laevis (Kolbe, M., Huber A., Cordier, P., Rasmussen, U., Bouchon, B., Jaquinod, M., Blasak, R., Detot, E., and Kreil, G. (1993) J. Biol. Chem. 268, 16458-16464). Xenoxin-1 (10 nM) caused volume changes that required extracellular Ca2+ and were comparable in magnitude and direction to changes caused by BayK-8644 (100 nM), a dihydropyridine-sensitive Ca2+ channel agonist. The initial rate of dihydropyridine-sensitive 45Ca2+ influx was substantially increased by xenoxin-1. Staurosporine (10 nM) prevented volume changes caused by ATP (250 microM) but had no effect on volume changes caused by BayK-8644 or xenoxin-1. We conclude that xenoxin-1 directly activated dihydropyridine-sensitive Ca2+ channels in villus cells and that a mammalian homologue to xenoxin-1 may exist.

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

PubMed1991

Effects of Bay K 8644, a Ca2+ channel agonist, on [3H]norepinephrine release in hypothalamus of spontaneously hypertensive rats.

We describe the effects of Bay K 8644, a dihydropyridine-sensitive Ca2+ channel agonist, on [3H]norepinephrine (NE) release from the hypothalamus of spontaneously hypertensive rats (SHR). The electrical stimulation-evoked [3H]NE release was greater in hypothalamic slice of SHR than in those of Wistar Kyoto (WKY) rats. Bay K 8644 (10(-6) M) significantly increased the stimulation-evoked [3H]NE release in SHR. However, the agonist showed no significant effects in normotensive WKY rats. The results suggest that the dihydropyridine-sensitive Ca2+ channels might participate actively in the regulation of the central sympathetic tone of hypertension.

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

PubMed1989

Effects of the Ca agonists Bay K 8644 and CGP 28392 on vascular smooth muscle tone.

1. Nifedipine (5 x 10(-9) M) reduced and the Ca agonists CGP 28392 (10(-6) M) and Bay K 8644 (10(-7) M) increased the contractions elicited by K+ in segments of rat aorta, whereas those caused by noradrenaline (NA) were unaffected. 2. CGP 28392 and Bay K 8644 evoked concentration-dependent contractions in segments moderately depolarized with 15 mM K+; these responses were reduced by nifedipine. 3. 45Ca uptake induced by 50 mM K+ or NA (10(-7) M) was reduced by nifedipine (10(-6) M). Bay K 8644 (10(-6) M) only increased the 45Ca uptake induced by K+, which was inhibited by nifedipine (10(-6) M). 4. These results indicate that in this vascular preparation: (a) Ca agonists only activate voltage-dependent Ca channels (VDCs), the potency of Bay K 8644 being higher than of CGP 28392, and (b) VDCs and receptor-operated Ca channels have different pharmacological properties.

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

PubMed2005

Characterization of single L-type Ca2+ channels in myocytes isolated from the cricket lateral oviduct.

The single Ca2+ channel activity was obtained from cell-attached patch recordings with the use of pipettes filled with 100 mM Ba2+ as the charge carrier in myocytes isolated from the lateral oviduct of cricket Gryllus bimaculatus. The following results were obtained. (1) The channel had a unitary conductance of 18 pS. (2) The open time histogram of the channel could be fitted with a single exponential while the closed time histogram could be fitted with the sum of two exponentials, suggesting that there are at least one open state and two closed states for this channel. (3) The open probability of the channel increased with increasing membrane depolarization. (4) The mean current reconstructed by averaging individual current trace responses inactivated slowly and the current-voltage relationship for the peak mean current showed a bell-shaped relation. (5) The dihydropyridine (DHP) Ca2+ antagonist, nifedipine, reduced the mean current by increasing the proportion of "blank" sweeps. On the other hand, the DHP Ca2+ agonist, Bay K 8644, increased the mean current by increasing the mean open-times of the channel. These results confirm a presence of DHP-sensitive L-type Ca2+ channel in myocytes isolated from the lateral oviduct of cricket G. bimaculatus.

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

PubMed2003

L-type calcium channel activation up-regulates the mRNAs for two different sodium channel alpha subunits (Nav1.2 and Nav1.3) in rat pituitary GH3 cells.

Calcium entry through L-type Ca2+ channels has been shown to increase the number of Na+ channels in GH3 cells, a clonal line of rat pituitary cells. To test whether this Ca2+ influx affects the levels of Na+ channel mRNAs, we first examined which Na+ channel subunits are expressed in GH3 cells. By using RT-PCR with specific primers, we detected transcripts for four alpha subunits (Nav1.1, Nav1.2, Nav1.3 and Nav1.6) and two auxiliary subunits (beta1 and beta3) of Na+ channels in total RNA from control GH3 cells. Next, we optimized the RT-PCR conditions to allow detection of cDNAs in the linear range of the assay. These conditions were then used to assess the transcript levels of Na+ channels after chronic exposure (72 h) of GH3 cells to the L-type Ca2+ channel blocker nimodipine (1 microM) or the L-type channel agonist Bay K 8644 (0.5 microM). Nimodipine treatment caused a moderate reduction (approximately 30%) of the mRNA for Nav1.2 and a marked reduction (approximately 70%) of the mRNA for Nav1.3, whereas treatment with Bay K 8644 produced 90-130% increases in these same mRNAs. There were no concomitant changes in the mRNAs for Nav1.1 and Nav1.6. Moreover, beta1 and beta3 mRNA levels were also unchanged. Thus, GH3 cells express multiple Na+ channel subunits and L-type Ca2+ channel activity up-regulates in a specific way the mRNAs for Nav1.2 and Nav1.3. These findings improve our knowledge on the molecular diversity of Na+ channels in pituitary cells and extend the actual view about the regulation of Na+ channel gene expression by Ca2+ influx.

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