(+)-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.
Department of Pharmacology, University of Aarhus, Denmark.
D
D
Prieto
M J
MJ
Mulvany
N C
NC
Nyborg
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014655:Vascular Resistance / Q000187:drug effects
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C067838:S 11568; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine