Effects of (+)-S-12967 and (−)-S-12968, two enantiomers of a new slow-acting 1,4-dihydropyridine, on rat coronary resistance arteries

Abstract

The action of (+)-S-12967 and (−)-S-12968, two isomers of a new 1,4-dihydropyridine molecule (2-(7-amino-2,5-dioxaheptyl)-3-ethoxycarbonyl-4-(2,3-dichlorophenyl)-5-methoxycarbonyl-6-methyl 1,4-dihydropyridine), was studied on responses of rat isolated coronary resistance arteries (i.d. about 230 μm) to K +, Ca 2+, and 5-hydroxytryptamine (5-HT). Both isomers slowly relaxed coronary arteries contracted with 125 mM K +, reaching a maximal effect in about 2 h. In contrast, the maximal relaxing effect of nifedipine was obtained within 20 min. The response to 125 mM K + did not recover within the 2-h washout period in vessels exposed to the isomers but returned to pre-drug levels within 40 min in vessels exposed to nifedipine. Nifedipine was 4 times more potent than the (−)-isomer which again was about 200 times more potent the (+)-isomer. The IC 50[M] values were approximately 1 nM, 4 nM and 0.8 μM, respectively. The relaxing effect of the isomers, which has a pK a of 8.6, was dependent on the extracellular pH being greater at high than low pH. Both isomers antagonized the vessel responses to K + and Ca 2+ and 5-HT. Higher concentrations of the isomers were required to antagonize responses to K + and 5-HT than to Ca 2+, probably due to the more depolarized state of the vascular smooth muscle in the latter experiments. In conclusion, the results demonstrate extracellular pH dependence as well as stereoselectivity regarding potency of (+)-S-12967 and (−)-S-12968 in rat coronary arteries. Both isomers may be characterized as slow-acting 1,4-dihydropyridine vasodilators.