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Results for “Calcium Channel Agonists”

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PubMed1996

Stimulus properties of the L-type calcium channel agonist BAY k 8644 in rats.

Calcium (Ca(2+)) channels appear to be involved in the regulation of ethanol (EtOH) intake, as indicated by the effectiveness of both L-type Ca(2+) channel antagonists and agonists in reducing EtOH intake in animals. The present study was aimed to investigate rewarding/aversive and discriminative stimulus effects of the Ca(2+) channel agonist BAY k 8644, a compound showing pronounced anti-alcohol effects in rats. Therefore, a series of conditioned taste aversion (CTA), conditioned place preference (CPP) and two-lever drug discrimination (DD) experiments were conducted in Wistar rats, with (+/-)-BAY k 8644 and its enantiomers. After i.p. application, (+/-)-BAY k 8644 (0.0625-1mg/kg), (-)-BAY k 8644 (0.125-1mg/kg) and (+)-BAY k 8644 (2.5-20mg/kg) all induced a dose-dependent CTA. The minimal effective doses (MED) for (+/-)-, (-)- and (+)-BAY k 8644 were 0.25, 0.25 and 10mg/kg, respectively. In a CPP study, however, (+/-)-BAY k 8644 (0.25-2mg/kg, i.p.) showed neither aversive nor rewarding stimulus properties. Rats were trained to discriminate (-)-BAY k 8644 (0.3mg/kg, i.p.), the enantiomer acting as a high potency Ca(2+) channel agonist, from vehicle, in a two-lever DD procedure (ED(50)) value: 0.05mg/kg); full generalisation: 0.1mg/kg). The (-)-BAY k 8644 cue dose-dependently generalized to (+/-)-BAY k 8644 and (+)-BAY k 8644, the enantiomer acting as a low potency Ca(2+) channel antagonist, with ED(50) values of 0.06 and 0.28mg/kg, respectively. Both (+/-)- and (+)-BAY k 8644 produced full generalization at 1mg/kg, the latter compound showing an inverted U-shaped curve (i.e., this was the only dose showing >80% drug lever selection). The stimulus patterns of BAY k 8644 and its enantiomers appear to resemble the anti-alcohol profiles of these compounds. Therefore, commonalities between the stimulus properties of the agonistic and antagonistic enantiomers might provide a clue for the mechanism underlying the anti-alcohol effects of L-type Ca(2+) channel antagonists and agonists.

Journal Article↗

PubMed1993

Effect of calcium channel agonist (BAY K8644) on volatile anesthetic-mediated depression in neonatal rabbit papillary muscle.

Heart muscle is dependent on the entry of calcium from the extracellular fluid to support contraction, and neonatal hearts are particularly sensitive to reductions in transsarcolemmal entry of calcium. Accordingly, this study evaluated the ability of the calcium channel agonist BAY K8644 to prevent or reverse the myocardial depressant effects of halothane or isoflurane in right ventricular papillary muscles from neonatal rabbits. The ability of BAY K8644 to reverse reductions in force (F) and dF/dt (halothane and isoflurane) or prevent reduction (halothane) was studied. Halothane decreased F to 24 +/- 2% of baseline values (p = 0.001). The addition of BAY K8644 reversed F to only 54 +/- 3% of baseline (p = 0.001 vs. baseline and p = 0.002 vs. halothane alone). Isoflurane decreased F to 20 +/- 2% of baseline (p = 0.001) with a return to 45 +/- 4% of baseline with the addition of BAY K8644 (p = 0.0001 vs. baseline and p = 0.0025 vs. isoflurane alone). With BAY K8644 in the bath prior to the addition of halothane, halothane decreased F to 38 +/- 4% of baseline (p = 0.001). dF/dt mirrored changes in F in all studies. These data show that a calcium channel agonist is only partially effective in modulating volatile anesthetic-induced depression in neonatal rabbit ventricular papillary muscle.

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

PubMed1986

BAY k 8644, a calcium channel agonist, reverses hypotension in endotoxin-shocked rats.

The hypotension and depressed myocardial function frequently observed in endotoxin-induced shock are difficult to overcome pharmacologically. In this paper we demonstrate that the calcium channel agonist BAY k 8644 potently elevates blood pressure in endotoxin-shocked rats. A one time dose as low as 10 micrograms/kg of BAY k 8644 significantly elevated mean arterial pressure (MAP) in endotoxin-treated hypotensive rats while having minimal effects in normal rats. The maximum BAY k-induced percentage increase in MAP was greater in endotoxin-treated rats when compared with saline-treated control (153% vs. 120% increase respectively). BAY k 8644 also caused a dose-dependent decrease in heart rate of 37% in endotoxin-treated rats and 39% in control rats (NS vs. control). No differences in the regulatory properties of [3H]nitrendipine binding sites were discerned comparing control and endotoxin-treated rats. Thus, the enhanced activity of BAY k 8644 in hypotensive rats was not due to augmented affinity for the cardiac dihydropyridine binding site. These results demonstrate that the use of calcium channel agonists might represent a unique pharmacologic approach in pathologic states characterized by hypotension and diminished cardiac function.

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

PubMed1987

Crystal structure of a 1,4-dihydropyridine with enantiomers showing opposite effects on calcium channels: structural features of calcium channel agonists and antagonists.

The structure of the calcium channel modulator isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-5-nitro- 3-pyridinecarboxylate has been determined by X-ray analysis. Structural and stereochemical features are discussed in relation to previously determined structures of calcium agonists and antagonists of the 1,4-dihydropyridine type, and in relation to a newly proposed model for the dihydropyridine binding site.

Calcium Channel Blockers↗

PubMedDate not supplied

Effects of a novel calcium channel agonist dihydropyridine analogue, Bay k 8644, on pig coronary artery: biphasic mechanical response and paradoxical potentiation of contraction by diltiazem and nimodipine.

Bay k 8644 is a structural analogue of the 1,4-dihydropyridines whose pharmacological actions on heart and vascular smooth muscle are opposite from those of nifedipine and other similar calcium antagonists. We have examined the action of Bay k 8644 ("calcium channel agonist") on isolated porcine coronary artery rings. The interactions between Bay k 8644 and the vasodilators isosorbide dinitrate (ISDN), diltiazem, and nimodipine were quantitated. Bay k 8644 produced a biphasic, dose-dependent mechanical response, with contraction occurring over the concentration range of 1-350 nM (ED50 = 11.4 nM) and relaxation observed at concentrations greater than 350 nM (IC50 = 5.7 microM). ISDN, diltiazem, and nimodipine relaxed, in a dose-dependent manner, maximal Bay k 8644-induced contractions. When the coronary rings were pretreated for 25-90 min with 80% inhibitory concentrations of these vasodilators, there was little or no effect by ISDN on Bay k 8644-induced contractions; however, there was a surprising potentiation by diltiazem and by nimodipine. Pretreatment of coronary rings with higher concentrations of ISDN or diltiazem caused an inhibition of Bay k 8644-induced contraction, while pretreatment with higher concentrations of nimodipine caused further potentiation of contraction elicited by Bay k 8644. Bay k 8644 increased the tension developed in response to high potassium (potential-operated channel activation) or histamine (receptor-operated channel activation). To account for the biphasic response to Bay k 8644 (dose-dependent contraction and relaxation), and the unexpected potentiation of Bay k 8644-induced contraction by nimodipine and by diltiazem, a molecular model is proposed for vascular smooth muscle in which Bay k 8644 functions as a partial calcium channel agonist at two functionally distinct 1,4-dihydropyridine "receptor sites."

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

PubMed1994

Effect of the calcium channel agonist Bay K8644 on mechanical and electrical responses of frog skeletal muscle.

The effects of Bay K8644, a Ca2+ channel agonist, on the mechanical and electrical properties of frog skeletal muscle fibers were investigated. At relatively low concentrations, such as 10(-6) and 10(-5) M, Bay K8644 significantly potentiated the maximum amplitudes of twitch responses, and this effect was not reversed in the presence of the calcium channel antagonist nitrendipine. At higher concentrations, such as 10(-4) M, Bay K8644 depressed the amplitudes of twitch responses, and nitrendipine did not change this effect. At all concentrations, Bay K8644 greatly reduced the area under the tetanic force versus time curve, and this effect was not modified by the concomitant application of Bay K8644 and nitrendipine. Intracellular recordings revealed that the depressing effect of Bay K8644 on tetanic contractions was due to the blockade of sodium action potentials. In conclusion, the present results suggest that the modulation of twitch responses by calcium channel agonist and antagonists, at the concentration range used, is not related to the expected modulation of voltage-sensitive slow calcium channels in frog skeletal muscle fibers, and tetanic contractions are depressed by the calcium channel agonist Bay K8644 through its effect on sodium channels.

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

PubMed1992

Bay K-8644 in different solvents acts as a transient calcium channel antagonist and a long-lasting calcium channel agonist.

This report describes the effect of Bay K-8644 dissolved in various solvents on two types of calcium channel currents in neuroblastoma cells. Transient calcium channel (T channel) currents were not affected by Bay K-8644 dissolved in ethanol (EtOH) or polyethylene glycol (PEG). However, at the same concentration of 0.6 microM, Bay K-8644 dissolved in dimethylsulfoxide (DMSO) (Bay K-8644/DMSO) decreased the T channel current by 50%. The concentration of all three solvents in the bath was fixed at 0.3% to reach different final concentrations of Bay K-8644. At this fixed solvent concentration, the inhibitory effect of Bay K-8644/DMSO on T channel currents was dose-dependent; the solvents alone did not have any effect on T channel currents; and DMSO pretreatment of cells did not render the T channel current sensitive to Bay K-8644 dissolved in EtOH or PEG. Bay K-8644/DMSO was dried using a flash evaporator and redissolved in EtOH or PEG. Dried Bay K-8644 that was redissolved in EtOH or PEG to achieve a final concentration of 0.6 microM inhibited T channel currents by 39 or 35%, respectively. Furthermore, Bay K-8644 (10 nM) increased L channel currents by 80% with DMSO, but only 30% with EtOH as the solvent. These results show that in neuroblastoma cells Bay K-8644/DMSO, within the concentration range examined, is a T channel antagonist and more effective L channel agonist than Bay K-8644 dissolved in the two other solvents.

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

PubMed1990

Calcium and contractile responses to phorbol esters and the calcium channel agonist, Bay K 8644, in arteries from hypertensive rats.

This study examined the calcium dependency of contractions in arteries from rats made hypertensive by aortic coarctation and in rats with genetic hypertensive (stroke-prone spontaneously hypertensive rats). Mesenteric artery and aortic strips were suspended in tissue baths for isometric force recording and contractions to two drugs were characterized: 1) a phorbol ester, TPA (12-O-tetrade-canoylphorbol-13-acetate), and 2) the calcium channel agonist, Bay K 8644. Thoracic aortae and mesenteric arteries from hypertensive rats were more sensitive to the contractile properties of the protein kinase C activator TPA than comparable arteries from normotensive rats. In thoracic aortae from coarcted rats, the contractile activity of Bay K 8644 was potentiated compared to normotensive values. In the presence of 19.2 mmol/L KCl, responses to Bay K 8644 in thoracic aortae from normotensive rats were potentiated and did not differ from coarcted values. In contrast, contractions to Bay K 8644 and TPA in abdominal aortae obtained below the coarctation were not different from normotensive values. Upon exposure to 26.2 mmol/L KCl, contractions to Bay K 8644 in abdominal aortae were potentiated and those in aortae from coarcted rats did not differ from sham values. Contractile responses to both drugs were blocked by nifedipine and verapamil and responses were attenuated in calcium-free solution. We conclude that calcium channel function and its regulation by protein kinase C contribute to altered vascular reactivity in hypertension. Further, these abnormalities have a pressure dependency, because they did not occur in abdominal aortae from coarcted rats.

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

PubMed1986

Bay K 8644, a voltage-sensitive calcium channel agonist, facilitates secretion of atrial natriuretic polypeptide from isolated perfused rat hearts.

Effects of Bay K 8644, a voltage-sensitive calcium channel agonist, on atrial natriuretic polypeptide (ANP) secretion from isolated rat hearts perfused with Krebs-Henseleit solution were investigated. After a ninety-min period for stabilization, coronary sinus effluents were collected every two min and ANP levels were measured by radioimmunoassay. The basal secretory rate of ANP was 1.65 +/- 0.15 ng/min (mean +/- standard error). Bay K 8644 stimulated ANP secretion dose-dependently. This stimulatory action was blocked by simultaneous administration of nifedipine, its competitive antagonist. Heart rate was also increased by Bay K 8644 administration. In the gel filtration study, the major secretory form of ANP corresponded to alpha-rat ANP, a 28-amino acid peptide. These results suggest that voltage-sensitive calcium channels are involved in two principal biological properties, contraction and ANP secretion, of atrial cardiocytes.

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

PubMed1986

Calcium channel agonists and antagonists regulate protein phosphorylation in intact synaptosomes.

Protein phosphorylation in intact synaptosomes is highly sensitive to alterations in calcium fluxes and was used to probe the possible mechanism of action of the calcium channel agonist BAY K 8644 and antagonists verapamil and nifedipine. These agents (at 1 microM) all increased the basal phosphorylation of a specific set of 4 synaptosomal phosphoproteins termed P139, P124, P96 and P60, but did not alter depolarization-dependent protein phosphorylation. The increases could not be explained by a direct stimulation of protein kinases and appears unrelated to the known effects of these drugs on K+-stimulated neurotransmitter release. This finding may reveal a possible new mechanism of action for drugs which interact with calcium channels.

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

PubMed2003

Calcium channel agonist, (+/-)-Bay K8644, causes an immediate increase in the striatal 1-methyl-4-phenylpyridinium level following systemic administration of the dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, in Balb/c mice.

In vivo formation of 1-methyl-4-phenylpyridinium ion (MPP(+)) in the striatum, and dopaminergic neurotoxicity following systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the presence and absence of calcium channel agonist (+/-)-Bay K8644 were analyzed in Balb/c mice. We used HPLC-photodiode array detection, HPLC-electrochemical detection and spectrofluorimetric procedures to measure striatal MPP(+) and dopamine (DA) and for the assay of monoamine oxidase-B (MAO-B) activity, respectively. Systemic administration of (+/-)-Bay K8644 resulted in a significant increase in striatal MAO-B activity. An MPTP-induced decrease in striatal MAO-B activity was attenuated by pre-treatment with (+/-)-Bay K8644 initially, but not on the 3rd day. MPP(+) formation in the striatum following systemic administration of MPTP was significantly increased by the pre-treatment of the agonist initially (30 min), but was not different afterwards (at 60 and 90 min). Nevertheless, the total MPP(+) formed over a 90 min period was found to be comparable. (+/-)-Bay K8644 administration prior to MPTP failed to influence the MPTP-induced striatal DA depletion on the 3rd day. While the transient effect of (+/-)-Bay K8644 on striatal MAO-B is reflected as an immediate increase in the levels of MPP(+) in the striatum, it failed to affect MPTP-induced DA neurotoxicity in Balb/c mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2002

Spinal cord regeneration induced by a voltage-gated calcium channel agonist.

Regeneration in the central nervous system (CNS) is prohibitive. This is likely due to an interplay of cellular (gene expression, growth factors) and environmental (inhibition by CNS myelin) factors. Calcium supports various intracellular functions, and multiple in vitro studies have shown a role of calcium in axonal growth. In this study, we examine the role of a calcium agonist, S(-)-Bay K 8644, in promoting or impeding CNS growth in vivo, in an effort to understand further the relationship between the voltage-gated L type calcium channel and regeneration. Using a well-established rat spinal cord model of regeneration, we have injected various doses of S(-)-Bay K 8644 (30-240 M) around the injured spinal cord. Our results demonstrate that S(-)-Bay K 8644 enhances regeneration in a dose-dependent fashion. In addition, at very specific concentrations, the same agonist has no effect on or even inhibits regeneration. We conclude that spinal regeneration is highly dependent on intracellular calcium concentration. Furthermore, depending on the dose used, the effect of calcium agonist supplementation on spinal regeneration can be supportive or inhibitory.

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

PubMed1985

The calcium channel agonist, Bay K 8644, inhibits renin release from rat kidney cortical slices.

The effects of Bay K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) -pyridine-5-carboxylate], a calcium channel agonist, on renin release in rat kidney cortical slices were examined. Bay K 8644 produced a dose-related inhibition of renin release in the presence of 15 mM potassium. The inhibitory effect of Bay K 8644 on this release was abolished when calcium was excluded from the incubation medium. Nifedipine exerted a concentration-dependent blocking action on the inhibition of renin release by Bay K 8644. These findings support the proposal that calcium influx into the renin secretory cells is an inhibitory signal for renin release.

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

PubMed1989

Age influences responses of rat isolated aorta and pulmonary artery to the calcium channel agonist, Bay K 8664, and to potassium and calcium.

Responses of isolated ring preparations of aorta and pulmonary artery from young (2 months) and aged (19-21 months) rats have been obtained to five contractile agents with differing mechanisms of action. The potencies (negative log EC50 values), but not the absolute maximum contractions (mN/mm2), for potassium, calcium (in K+-depolarized preparations), and the calcium channel activator, Bay K 8644, were all reduced in preparations from aged, compared with young, rats, and this reduction was more pronounced in aorta than in pulmonary artery. In contrast, the age of the rats had no influence on responses (potency or maximum contractions) to caffeine or the ionophore, A23187, indicating that the contractile ability of the preparations per se was retained in the aged rats. Aortic preparations from young rats contracted to Bay K 8644 without prior depolarization, whereas those from aged rats required partial depolarization (with 6 mM KCl) before consistent contractile responses to Bay K 8644 could be obtained. It is concluded that the influence of age on vascular contractions varies (a) between contractile agents, depending on their mechanisms of action and (b) between blood vessel types. To explain the reduced potencies of Bay K 8644, potassium, and calcium in aorta from aged rats, it is postulated that the resting membrane potential may be more negative in the preparations from the aged rats.

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

PubMed1989

Partitioning and location of Bay K 8644, 1,4-dihydropyridine calcium channel agonist, in model and biological membranes.

Several lines of evidence suggest that nonspecific drug interaction with the lipid bilayer plays an important role in subsequent recognition and binding to specific receptor sites in the membrane. The interaction of Bay K 8644, a 1,4-dihydropyridine (DHP) calcium channel agonist, with model and biological membranes was examined at the molecular level using small angle x-ray diffraction. Nonspecific drug partitioning into the membrane was examined by radiochemical assay. Nonspecific binding characteristics of [3H] Bay K 8644 were determined in both dipalmitoyl phosphatidylcholine (DPPC) vesicles above and below their thermal phase transition (Tm) and rabbit skeletal muscle light sarcoplasmic reticulum (LSR). In DPPC, the partition coefficient, Kp, was 14,000 above the Tm (55 degrees C) versus 160 in the gel phase (2 degrees C). The Kp determined in LSR membranes was 10,700. These values for both DPPC and LSR membranes can be compared with Kp = 290 in the traditional octanol/buffer system. Using small-angle x-ray diffraction, the equilibrium position of the electron-dense trifluoromethyl group of Bay K 8644 in DPPC (above Tm) and purified cardiac sarcolemmal (CSL) lipid bilayers was determined to be consistently located within the region of the first few methylene segments of the fatty acyl chains of these membranes. This position is similar to that observed for the DHP calcium channel antagonists nimodipine and Bay P 8857. We suggest this particular membrane location defines a region of local drug concentration and plane for lateral diffusion to a common receptor site. Below the DPPC membrane Tm, Bay K 8644 was shown to be excluded from this energetically favored position into the interbilayer water space. Heating the DPPC bilayer above the Tm (55 degrees C) showed that this exclusion was reversible and indicates that drug-membrane interaction is dependent on the bilayer physical state. The absence of any specific protein binding sites in these systems allows us to ascertain the potentially important role that the bulk lipid phase may play in the molecular mechanism of DHP binding to the specific receptor site associated with the calcium channel.

1,2-Dipalmitoylphosphatidylcholine↗

PubMedDate not supplied

Effects of intracoronary Bay k 8644, a calcium channel agonist, in anesthetized dogs.

Bay k 8644, a new dihydropyridine calcium channel activator has been shown to have positive inotropic and vasoconstrictor properties following intravenous (i.v.) administration. In the present study, intracoronary administration of Bay k 8644 was used to isolate drug effects on regional myocardial blood flow and contractility independent of systemic hemodynamic actions in beta-adrenoceptor-blocked anesthetized dogs. Intracoronary infusion of Bay k 8644 (1.5, 3.7, 7.4, 14.8 micrograms/min) produced significant increases in contractility (percentage of segment shortening) in the drug-perfused region. Peak positive dP/dt, an index of global contractility, was increased in parallel with increases of regional contractility. No other changes in systemic hemodynamics occurred. Transmural tissue blood flow distribution as measured by radioactive microspheres was also unchanged by Bay k 8644. Intracoronary infusion of KB-944, a nondihydropyridine calcium channel blocking agent, increased coronary blood flow and decreased regional segment shortening and peak positive dP/dt. KB-944 inhibited increases in contractility produced by Bay k 8644. Thus, Bay k 8644 was shown to have a direct positive inotropic effect in vivo which was inhibited by calcium channel blockade.

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

PubMed1996

The calcium channel agonist BAY k 8644 reduces ethanol intake and preference in alcohol-preferring AA rats.

Applying a 12-h limited access, two-bottle choice procedure, antialcohol effects of the 1,4-dihydropyridine (DHP) L-type calcium (Ca2+) channel agonist BAY k 8644 were investigated in alcohol-preferring AA rats. In this Wistar line, selectively bred for a high 10% v/v ethanol (EtOH) preference in a free choice situation, effects on EtOH preference and intake, as well as on food and total fluid intake were evaluated for racemic BAY k 8644 (0.1-1 mg/kg IP; 0.25-2 mg/kg PO), its agonistic (-)-enantiomer (0.1-1 mg/kg IP and PO) and its antagonistic (+)-enantiomer (10-50 mg/kg IP and PO). Irrespective of route of application, BAY k 8644 was found to be effective in reducing both EtOH intake and preference (minimal effective dose: 0.5 mg/kg; maximum effect: approximately 60% of baseline levels). The (+)-enantiomer, acting as a low-potency Ca2+ channel antagonist, also reduced EtOH intake and preference, but the effects were not very selective as food intake was also substantially reduced. Moreover, the effects were only obtained at relatively high doses (50 mg/kg). The essential enantiomer involved in the antialcohol effects of BAY k 8644 seems to be the (-)-enantiomer, acting as a strong Ca2+ channel agonist. This latter compound was potent (minimal effective dose: 0.3 mg/kg), very effective in reducing EtOH intake (maximum effect: 29% of baseline level) and preference (26% of baseline) and apparently more selective. Although slightly decreasing over days, effects of (-)-BAY k 8644 on EtOH intake and preference were shown to remain after repeated treatment (10 successive days, 0.3 mg/kg IP). Interestingly, the acute antialcohol effects of (-)-BAY k 8644 (0.3-1 mg/kg IP) could not be antagonized with the DHP L-type Ca2+ channel antagonists nimodipine (0.01-1 mg/kg IP) and (-)-nimodipine (1-30 mg/kg IP). The present results suggest that a mechanism of action other than L-type Ca2+ channel agonism is involved in the antialcohol effects of (+/-)- and (-)-BAY k 8644. Alternatively, it is possible that the previously described antialcohol effects of DHP Ca2+ channel antagonists are not related to antagonistic activity at Ca2+ channels. Finally, it cannot be excluded that a mechanism unrelated to Ca2+ channels is responsible for the antialcohol effects of both DHP Ca2+ channel agonists and antagonists.

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

PubMed1999

Calcium channel agonist (-)-BAY k 8644 suppresses free and limited access intake of alcohol in genetic drinking rats.

Drugs which possess selective actions on a given voltage operated calcium (Ca2+) channel (VOCC) are reportedly involved in the pharmacological actions of alcohol. Recently it was shown that the 1,4-dihydropyridine (-)-BAY k 8644, an L-type VOCC agonist, reduces alcohol intake relatively selectively in the genetic drinking AA rat. This study determined whether (-)-BAY k 8644 would alter volitional alcohol drinking in two other genetic models of alcoholism, male P rats and a new strain of male and female high ethanol preferring (HEP) rats. By use of a standard 10-day preference test for water versus 3 to 30% alcohol, the maximally preferred concentration of alcohol was first determined for each rat individually, i.e. 9%, 13% or 15%. Then the rats were allowed free access over 24 h or limited access to alcohol for only 2 h, during which time the intakes of water and preferred solution of alcohol were recorded. After the drinking patterns stabilized for 4 days, saline, a solutol vehicle solution or (-)-BAY k 8644 was administered: (1) in a dose of 0.125, 0.25 or 0.5 mg/kg given intraperitoneally twice daily for 4 days during free access to alcohol; and (2) for 3 days in a dose of 0.125 or 0.25 mg/kg given subcutaneously 30 min prior to 2 h of limited access to alcohol. Fluid intakes were recorded for either 4 or 8 days after limited and free access conditions, respectively. Whereas the control solutions were without effect during 24 h access, (-)-BAY k 8644 caused a significant dose-dependent suppression of up to 80% in absolute g/kg and proportion of alcohol to total fluid consumed; this decline persisted in the post drug period. During the limited access paradigm, (-)-BAY k 8644 similarly reduced alcohol drinking maximally within the first 15 min of presentation of alcohol; again, this reduction persisted over the remaining 105 min of alcohol access. Also, individual levels of blood alcohol declined concurrently with the suppression of drinking. These results demonstrate that (-)-BAY k 8644 possesses a short latency of action on alcohol intake and that its salutary effects on drinking persist after the drug is terminated. Finally, the hypothesis that L-type calcium channel agonists may be useful as a therapeutic adjunct in the treatment of alcoholism is extended.

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