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Results for “Calcium Channel Agonists”

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At least 19 recordsLinked to original sources

PubMed1992

Interaction of U-50,488H with calcium channel agonists and antagonists in different cardiac tissues.

1. The present study examined the interaction of U-50,488H (specific k-agonist) with diltiazem (calcium channel antagonist) or Bay K 8644 (calcium channel agonist) on isolated left and right atria of the rat. 2. The inhibitory effects of U-50,488H on left and right atria were unaffected by the k-receptor antagonist MR-2266 (10(-7) and 5 x 10(-7) M) suggesting that they were not mediated via opioid receptors. 3. The inhibitory cardiac effects induced by U-50,488H were antagonized in presence of Bay K 8644. The negative inotropic response to the maximum concentration of U-50,488H used in presence of two concentrations of Bay K 8644 (10(-9), 3 x 10(-9) M) were 19 +/- 0.9% and 9 +/- 0.1% reductions in contractility respectively. These values were significantly (P < 0.001) lower than that obtained with the k-agonist alone (76 +/- 3.6%). Similar results were obtained for the negative chronotropism of right atria. 4. The inhibitory effect of U-50,488H was potentiating in the presence of diltiazem (5 x 10(-8) or 10(-7) M). The IC50 values for U-50,488H obtained in the left (22 +/- 2 x 10(-6) M) and right atria (610 +/- 40 x 10(-6) M) were significantly (P < 0.001) decreased in the presence of diltiazem. 5. These data demonstrate that transmembrane calcium influx may play an important role in the inhibitory cardiac effects of U-50,488H, which may be independent of k-receptor stimulation.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1993

[Estimation of free calcium level within synaptosomes by using fura-2 and the effect of calcium channel agonist and antagonist].

The cytosolic free calcium concentration [Ca2+]i in synaptosomes was determined with the fluorescent indicator fura-2, the effects of calcium channel agonist and antagonist on intracellular Ca2+ level were studied. The cytosolic ionized calcium concentrations in resting status were between 200 nmol/L and 400 nmol/L. Cytosolic Ca2+ was elevated following increases in Ca2+ concentration in the medium, plasma membrane depolarizations induced by KCl, and the addition of glutamate and NMDA. On the other hand, the increase of cytosolic Ca2+ induced by KCl was decreased by verapamil and that induced by NMDA was decreased by MgCl2. A few critical problems in [Ca2+]i detection were also discussed.

Animals↗

PubMed1994

Identical inhibitory modulation of A-type potassium currents by dihydropyridine calcium channel agonists and antagonists.

We have studied the interaction of dihydropyridine (DHP) Ca2+ channel agonists and antagonists with A-type K+ channels in whole-cell patch-clamp recordings from bovine adrenal zona fasciculata cells. At concentrations from 1 to 100 microM, DHP antagonists [nimodipine and (+)-Bay K 8644] and agonists [(-)-Bay K 8644 and RS 30026] each reversibly reduced A-type K+ current (IA) amplitude and markedly accelerated the apparent rate of IA inactivation. Unlike their actions on Ca2+ channels, the effects of DHP agonists and antagonists on IA were qualitatively indistinguishable. Inhibition of IA by DHPs was not accompanied by changes in the voltage-dependent steady state inactivation of IA or the kinetics of recovery subsequent to repolarization. The effects of DHPs on peak IA and inactivation kinetics were not use dependent. The DHPs were much less effective in cells where fast N-type inactivation had spontaneously diminished with time. These actions of DHPs on IA are in marked contrast to their voltage-dependent modulation of L-type Ca2+ currents, indicating that fundamentally different mechanisms are involved. Rather than directly occluding A-type K+ channels, the drugs may enhance the voltage-independent rate of inactivation. This could occur through interaction of the DHP with a site on the amino-terminal inactivation domain or the DHP binding site at the inner mouth of the channel. Regardless of the mechanism involved, the identical modulation by DHP agonists and antagonists is a distinctive feature of A-type K+ channels in adrenal zona fasciculata cells.

Animals↗

PubMed1999

Complex influence of the L-type calcium-channel agonist BayK8644(+/-) on N-methyl-D-aspartate responses and neuronal survival.

Past studies have implicated calcium influx through the N-methyl-D-aspartate class of ionotropic glutamate receptors as a key factor in excitotoxicity. Here, primary cultures of hippocampal neurons were exposed to N-methyl-D-aspartate with or without the L-type calcium channel agonist BayK8644(+/-). Calcium influxes were monitored with Fura-2 microfluorescent imaging and 45Ca measurements, and survival was assayed through cell counts. While 100 microM BayK8644 alone evoked a moderate elevation of intraneuronal calcium concentrations ([Ca2+]i), it dramatically attenuated the larger calcium influxes triggered by 500 microM N-methyl-D-aspartate. This attenuation was non-competitive and reversible; it was not inhibited by charybdotoxin or cyclosporin A. In spite of this attenuation of [Ca2+]i responses, 5-min exposures to BayK8644 produced much greater neurotoxicity 24 h later than did doses of N-methyl-D-aspartate evoking larger [Ca2+]i increases. This neurotoxicity was not observed with potassium-mediated depolarization or cobalt; indeed, both reversed the neurotoxicity of BayK8644. The relevant conclusions are two-fold: BayK8644 inhibits influx of calcium through a ligand-gated glutamate receptor, and BayK8644 exhibits considerable neurotoxicity. The former effect does not appear to depend upon the major metabolic pathways that modulate N-methyl-D-aspartate channels and thus may involve a direct allosteric interaction with the N-methyl-D-aspartate receptor. The toxicity of BayK8644 depends, at least partially, upon its activation of voltage-gated (cobalt-sensitive) calcium channels. However, the reversal of this toxicity by depolarization suggests that depolarization can be beneficial to neuronal survival through mechanisms other than calcium influx through voltage-gated calcium channels.

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

PubMed2004

L-type calcium channel agonist induces correlated depolarizations in mice lacking the beta2 subunit nAChRs.

Retinal waves are mediated in part by activation of nicotinic receptors containing the beta2 subunit. Mice deficient in beta2 containing nAChRs have maintained firing of action potentials but do not support correlated waves. As a result, beta2-/- mice have inhibited refinement of circuits within the retina as well as retinal projections to the CNS. Previously, we observed that correlated increases in calcium reminiscent of retinal waves could be induced in beta2-/- retina by pharmacological application of the L-type calcium channel agonist, FPL-64176. Here, we characterize FPL-induced activity patterns in beta2-/- retina using both whole cell and multielectrode array recordings. FPL-induced strong depolarizations in previously non-spiking beta2-/- retinal ganglion cells. Though these strong depolarizations were likely to underlie the FPL-induced calcium transients, they led to highly variable effects on the spiking of individual retinal ganglion cells. In addition, induced spiking activity had significantly weaker nearest-neighbor correlations than WT mice. Initial attempts of intraocular injections of FPL in beta2-/- mice did not rescue eye-specific layer formation. These findings indicate that activity induced by FPL is not sufficient for driving eye-specific segregation in beta2-/- mice.

Animals↗

PubMed1987

Induction of seizures in mice by intracerebroventricular administration of the calcium channel agonist BAY k 8644.

The calcium channel agonist BAY k 8644 was used to investigate the role of the calcium ion (Ca2+) in epileptogenesis. Intracerebroventricular administration of the compound induced murine seizures that were reversed by calcium channel inhibitors (CCIs) but not by anticonvulsants such as carbamazepine, pentobarbital, and diazepam. The seizures were exacerbated by phenytoin and valproic acid. Chronic administration of CCI's, previously shown to produce down-regulation of the binding of the CCI [3H]nitrendipine, resulted in augmentation of BAY k 8644-induced seizures.

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

PubMed2004

New 1,4-dihydropyridines endowed with NO-donor and calcium channel agonist properties.

A new series of calcium channel agonists structurally related to Bay K8644, containing NO donor furoxans and the related furazans unable to release NO, is described. The racemic mixtures were studied for their action on L-type Ca(2+) channels expressed in cultured rat insulinoma RINm5F cells. All the products proved to be potent calcium channel agonists. All the racemic mixtures, with the only exception of the carbamoyl derivatives 9, 12 endowed with scanty solubility, were separated by chiral chromatography into the corresponding enantiomers; the (+) enantiomers were found to be potent agonists while the (-) ones were feeble antagonists. The racemic mixtures were also assessed for their positive inotropic activity on electrically stimulated rat papillary muscle and for their ability to increase Ca(2+) entry into the vascular smooth muscle of rat aorta strips. The cyanofuroxan 8 proved to be an interesting product with dual Ca(2+)-dependent positive inotropic and NO-dependent vasodilating activity.

Animals↗

PubMed1992

Will the calcium channel agonist BAY K8644 inhibit halothane-induced impairment of calcium current?

The inhaled anesthetics impair transsarcolemmal calcium entry (ICa) in myocardial cells, although the mechanism of this interaction is not known. This inhibition of calcium entry has been implicated in the myocardial depression of the volatile anesthetics. To further characterize this interaction and to evaluate whether a calcium channel agonist could attenuate or prevent the inhibition of calcium entry, the effect of the calcium channel agonist BAY K8644 on the impairment of ICa by halothane was evaluated in single guinea pig ventricular myocytes. Calcium currents were evoked by means of the whole-cell voltage-clamp technique. Baseline peak ICa was higher in the cells exposed to 5 microM BAY K8644 (311 vs 206 pA/cm2, P less than 0.04). On exposure to 1% halothane, peak ICa was impaired to an identical degree whether or not cells were exposed to BAY K8644 (78% and 79% of baseline value). This is consistent with the suggestion that the effects of these agents on ICa are nonspecific. However, the increase in ICa suggests that appropriate calcium channel agonists might serve to ameliorate the myocardial depressant effects of halothane.

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

PubMed1986

Exaggerated Dahl salt-sensitive kidney response to calcium channel agonist isomer of Bay k 8644, but not to calcium channel antagonist isomer of Bay k 8644.

We examined the influence of calcium channel agonist and antagonist optical isomers of BAY-K-8644 on the renal vascular resistance, glomerular filtration rate and sodium excretion of isolated perfused kidneys from Dahl salt-sensitive (DS) and salt-resistance (DR) rats previously stabilized on high- and low-NaCl regimens. The agonist isomer affected these parameters at a lower concentration and to a greater degree in the high-salt DS rat kidneys than in the other three groups. The antagonist isomer also reversed agonist-induced changes to the greatest degree in the high-salt DS rat kidneys. However, the low-salt DS and high-salt DR rat kidneys appeared to be slightly more reactive to these isomers than the low-salt DR rat kidneys, suggesting that hereditary predisposition and dietary NaCl may contribute independently to renal responsiveness to calcium channel-active agents.

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

PubMed1988

Calcium channel agonists and antagonists: effects of chronic treatment on pituitary prolactin synthesis and intracellular calcium.

PRL synthesis by GH cells in culture has previously been shown to increase when calcium is added to cultures grown in calcium-depleted medium or when cultures are treated for 18 h or longer with the dihydropyridine calcium channel agonist BAY K8644, whereas the antagonist nimodipine inhibits PRL. The experiments described here were designed to test whether differences in PRL synthesis caused by the dihydropyridines are due to changes in PRL mRNA levels, whether structurally different classes of calcium channel blockers alter PRL production, and whether long term treatment with calcium channel agonists and antagonists alters intracellular free calcium, [Ca2+]i. PRL synthesis and PRL mRNA levels were increased similarly by BAY K8644 and decreased in parallel by the dihydropyridine antagonist nimodipine, while overall protein and RNA synthesis were not changed by either the agonist or antagonist. Two calcium channel blockers which act at different sites on L-type channels than the dihydropyridines also inhibited PRL synthesis without affecting GH; 5 microM verapamil reduced PRL by 64% and 15 microM diltiazem by 89%. Partial depolarization with 5-25 mM KCl increased PRL synthesis up to 2-fold. The intracellular free calcium ion concentration was estimated by Quin 2 and averaged 142 nM for control cultures in normal medium, and 128 and 168 nM for cultures treated 72 h with nimodipine or BAY K8644, respectively. Nimodipine totally prevented the calcium rise obtained upon depolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

BAY-K-8644, a calcium channel agonist, induces a rise in cytoplasmic free calcium and iodide discharge in thyroid cells.

BAY-K-8644, a calcium channel agonist, induces a rise in cytoplasmic free calcium and iodide discharge in cultured porcine thyroid cells. The cytoplasmic free calcium concentration, [Ca2+]i, was measured using aequorin, a calcium-sensitive photoprotein. BAY-K-8644, a dihydropyridine derivative, acts as a Ca channel agonist and induces a rise in [Ca2+]i and iodide discharge; 0.5 nM BAY-K-8644 is a minimal dose to effect a rise in [Ca2+]i and iodide discharge and 50 nM BAY-K-8644 produces the maximal effect. The data indicate that BAY-K-8644-induced iodide discharge is mediated by a rise in [Ca2+]i.

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

PubMed1990

RS 30026: a potent and effective calcium channel agonist.

1. A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine-induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2. RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2 nM. 3. Compounds were also evaluated for their effects on guinea-pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10(-9) and 10(-6) M (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10(-6) M (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10(-10) and 10(-7) M. 4. Calcium channel currents in single embryonic chick myocytes were recorded by whole-cell voltage clamp techniques. RS 30026 (100 nM-500 nM) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nM) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nM) were much less marked. 5. Analysis of the activation characteristics of currents showed parallel shifts in the activation curve to more negative potentials in the presence of 50 nm Bay K 8644, with a much smaller shift in the presence of 500nm Bay K 8644. RS 30026 (100 and 500nM) caused concentration-dependent shifts in the activation of the calcium channel currents with an increase of the slope of the curve. 6. RS 30026 appears to be the most potent and effective calcium channel agonist described to date.

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

PubMed1991

(+)-S-12967 and (-)-S-12968: 1,4-dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries.

1. The actions of (+)-S-12967 and (-)-S-12968 two isomers of a new 1,4-dihydropyridine (DHP) derivative, were studied on 125 mM K(+)-, Ca(2+)- and noradrenaline-induced contractions in rat isolated mesenteric resistance arteries and compared to those of nifedipine. 2. The action of (+)-S-12967 and (-)-S-12968 was slow in onset in contrast to nifedipine. Both isomers had a dual contractile and relaxant action in arteries contracted with 125 mM K+; however, the (-)-isomer was about 300 times more potent than the (+)-isomer. The response to 125 mM K+, being depressed by 70%, recovered within 20 to 30 min for all DHP derivatives. All vessels were treated with 1 x 10(-6) M phenoxybenzamine thus excluding the possibility that the contraction is mediated by activation of amine-receptors. 3. Both (+)-S-12967 and (-)-S-12968 at low concentrations potentiated responses induced by Ca2+ in arteries activated by 125 mM K+ and inhibited the responses at higher concentrations. (+)-S-12967 and (-)-S-12968 had no contractile action in arteries kept in normal buffer. Nifedipine had only an inhibitory action on vessel responses to 125 mM K+ and Ca2+. 4. Both isomers and nifedipine depressed the maximal vessel response to noradrenaline by about 20% and 44%, respectively. 5. The results confirm that DHP calcium antagonists selectively inhibit vascular smooth muscle responses induced by high potassium and that the potency of 1,4-DHP isomers may vary considerably. Furthermore, since the agonistic/antagonistic properties on the calcium channel were shared by both stereoisomers of the 1,4-DHP molecule and apparently dependent on their concentration and the vascular smooth muscle membrane potential, it suggests that the agonistic action of 1,4-DHPs may be ascribed to functional characteristics of their binding site regulating the Ca2l -channel.

Animals↗

PubMed1988

Increased vascular response to calcium channel agonist by Dahl S rat kidney.

We examined responses to the calcium channel agonist, BAY-K 8644, of isolated perfused kidneys from Dahl salt-sensitive (DS) and -resistant (DR) rats that had been stabilized on high (HI) and low (LO) NaCl intakes. Mean arterial pressures of DS/HI rats exceeded those of the other three groups. BAY-K 8644 significantly increased the renal vascular resistance (RVR) of DS/HI and DS/LO kidneys, by 38 and 12%, respectively, but did not increase RVR of DR/HI or DR/LO kidneys significantly (6 and 2%, respectively). Increases in RVR and decreases in glomerular filtration rate of DS/HI kidneys exceeded those of DR/HI kidneys. Increases in the RVR of DS/LO kidneys exceeded those of DR/LO kidneys. Experiments utilizing the separate calcium channel agonist and antagonist enantiomers of BAY-K 8644 corroborated these findings, but at lower concentrations. "Chemical sympathectomy" with 6-hydroxydopamine increased the reactivity of kidneys from only high-NaCl animals to BAY-K 8644 without regard to Dahl S or R status. In conclusion, the DS kidney vasculature manifests an increase in responsiveness to this calcium channel agonist, independently of antecedent NaCl loading or high blood pressure. However, a high antecedent salt intake or hypertension enhances vascular responsiveness of the DS kidney to BAY-K 8644.

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

PubMed1987

Evidence for distinct calcium channel agonist and antagonist binding sites in intact cultured embryonic chick ventricular cells.

To determine whether calcium channel agonists and antagonists bind to distinct pharmacologically active sites, the binding of dihydropyridine calcium channel agonists and antagonists was related to calcium flux and contractile state in primary monolayer cultures of spontaneously contracting chick embryo ventricular cells. Equilibrium binding studies using the antagonist (+)-[3H]PN200-110 demonstrated equilibrium binding to intact, beating cells consistent with a single class of binding sites (KD, 1.1 nM; Bmax, 40 fmol/mg protein). Membrane depolarization of the intact cells by incubation in 30 mM potassium caused a 91% increase in the apparent number of (+)-PN200-110 binding sites (Bmax 76 fmol/mg protein), but no significant change in the KD (1.2 nM). The (+)-PN200-110 produced a concentration-dependent decrease in calcium uptake (IC50 2.2 nM) and contractile amplitude (IC50 5.6 nM). The calcium channel agonist, (+/-)-[3H]BAY k 8644, bound to two distinct binding sites with high affinity (KD 1.0 nM) and low affinity (KD 1.9 microM). The (+/-)-BAY k 8644 produced biphasic modulation of calcium flux and contractile state. At concentrations of 100 nM or less, (+/-)-BAY k 8644 increased calcium flux and contractile amplitude, consistent with drug interaction with the high affinity agonist site. However, at higher concentrations, the stimulatory effect of (+/-)-BAY k 8644 on calcium flux and contractile amplitude was abolished, a finding that is consistent with drug interaction with the low affinity antagonist site.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1985

Calcium channel agonist BAY k8644 enhances anterior pituitary secretion in rat and monkey.

A calcium channel agonist BAY k8644 was applied to anterior pituitary (AP) cells in vitro. BAY k8644 (0.1-10 microM) stimulated prolactin and growth hormone (GH) release from monolayer AP cultures; the calcium channel antagonist D-600 (1-10 microM) completely blocked this effect. By utilizing a perifusion system, we observed an immediate and sustained amplification of prolactin (2.9-fold), growth hormone (2.3-fold), and luteinizing hormone (LH, 1.6-fold) release during the 1-h application of BAY k8644 (3 microM). A hypophysiotrophic peptide pulse 4 h after the BAY k8644 was removed confirmed that the cells remained responsive to their natural secretagogues. In another perifusion study 10-3,000 nM BAY k8644 produced a graded increase in prolactin release that was maintained over the 30-min exposure period. Finally, individual primate mammotrophs and somatotrophs showed a marked enlargement of hemolytic plaque area, an index of hormone release, 1 h after BAY k8644 (1 microM). We conclude that this synthetic dihydropyridine enhances the rate of prolactin, GH, and LH release from AP cells of two species. Because this is the first synthetic calcium channel agonist, structure-function studies characterizing calcium channel activation and exocytosis are now feasible.

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

PubMed2003

Calcium channel agonist, (+/-)-Bay K8644, causes a transient increase in striatal monoamine oxidase activity in Balb/c mice.

We investigated in vivo effects of the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl] pyridine-3-carboxylic acid ((+/-)-Bay K8644) on mitochondrial monoamine oxidase (MAO) activity and striatal dopamine (DA) content employing fluorimetric and HPLC-electrochemical procedures, respectively. (+/-)-Bay K8644 administration resulted in visible behavioral dysfunctions in mice. A reversible dose-independent inhibition of striatal DA levels and a significant increase in the brain mitochondrial MAO-A and -B activities were observed in animals treated with the calcium agonist. A positive relationship between the rise in the enzyme activity and decrease in DA content in (+/-)-Bay K8644 treated animals indicates a direct, but transient effect of this channel activator on DA metabolism, which may be related to acute behavioral syndromes exhibited following administration of the drug. Moreover, a direct involvement of L-type dihydropyridine sensitive calcium channels is indicated in this action, since nicardipine could effectively attenuate (+/-)-Bay K8644-induced behavioral aberrations, or block the striatal DA depletion and the increase in MAO activity. The present results have far-reaching implications in neuropharmacological research, where co-treatment of calcium channel drugs and MAO inhibitors are warranted.

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

PubMed1995

Influence of BAY k-8644, a calcium channel agonist, on the anticonvulsant activity of conventional anti-epileptics against electroconvulsions in mice.

BAY k-8644, an agonist at the dihydropyridine binding site of the L-type voltage dependent calcium channel, at the dose of 5 mg/kg (s.c.) did not significantly affect the threshold for electroconvulsions, but impaired the protective efficacy of flunarizine (15 and 20 mg/kg, i.p.) in the electroconvulsive test. Interestingly, the calcium channel agonist (at 1 and 5 mg/kg) distinctly diminished the protection offered by conventional anti-epileptic drugs (carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock-induced seizures in mice. A pharmacokinetic interaction does not seem to be involved in the effect of BAY k-8644, since total plasma levels of these anti-epileptics (measured by immunofluorescence) were not affected by the calcium channel agonist. The only anti-epileptic drug resistant to BAY k-8644 (up to 5 mg/kg) was valproate, whose ED50 (in mg/kg) was not changed in the presence of the calcium channel agonist. Further, BAY k-8644 (5 mg/kg) did not influence the flunarizine (a calcium channel blocker)-induced potentiation of the protective action of valproate against maximal electroshock-induced convulsions. The calcium channel agonist (5 mg/kg) reversed the flunarizine-induced augmentation of the anticonvulsive activity of carbamazepine. It may be concluded that carbamazepine, diphenylhydantoin and phenobarbital partially exert their anticonvulsive effects via blockade of calcium influx whilst valproate does not seem to. In this context, the flunarizine-induced potentiation of the anticonvulsive activity of valproate is probably independent of calcium channel blockade.

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