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(+)‐S‐12967 and (–)‐S‐12968: 1,4‐dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries
Author(s) -
Prieto Dolores,
Mulvany Michael J.,
Nyborg Niels C.B.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb09850.x
Subject(s) - agonistic behaviour , dihydropyridine , calcium channel , calcium , pharmacology , chemistry , voltage dependent calcium channel , stereochemistry , biology , medicine , endocrinology , psychiatry , aggression
1 The actions of (+)‐S‐12967 and (–)‐S‐12968 two isomers of a new 1,4‐dihydropyridine (DHP) derivative, were studied on 125 m m 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 m m K + ; however, the (–)‐isomer was about 300 times more potent than the (+)‐isomer. The response to 125 m m K + , being depressed by 70%, recovered within 20 to 30 min for all DHP derivatives. All vessels were treated with 1 × 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 Ca 2+ in arteries activated by 125 m m 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 m m K + and Ca 2+ . 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 Ca 2+ ‐channel.