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The Journal of pharmacology and experimental therapeutics

Effects of nicorandil on cytosolic calcium concentrations and on tension development in the rabbit femoral artery.


PMID 8113988

Abstract

By using front-surface fluorometry and fura-2-loaded strips of the rabbit femoral artery, the effects of 2-nicotinamidoethyl nitrate (nicorandil) on cytosolic Ca++ concentration ([Ca++]i) and on tension development were measured simultaneously, and findings were compared with those of SG-209 (2-nicotinamidoethyl acetate), nitroglycerin and cromakalim. During contraction induced by 25 mM K(+)-depolarization or by 3 x 10(-7) M noradrenaline stimulation, application of nicorandil, nitroglycerin or cromakalim, decreased [Ca++]i and tension, in a concentration-dependent manner. With a given amount of reduction in [Ca++]i, the extent of relaxation was in the following order: nitroglycerin > nicorandil > cromakalim. The [Ca++]i-tension relations of the relaxations induced by nitroglycerin and cromakalim were shifted to the right and to the left from that observed with the nicorandil-induced relaxation, respectively. During the contraction induced both by 25 mM K(+)-depolarization and by 3 x 10(-7) M noradrenaline, glibenclamide almost fully antagonized cromakalim- and SG-209-induced relaxation, and partially antagonized the nicorandil-induced relaxation, but not the nitroglycerin-induced relaxation. In the absence of extracellular Ca++, the noradrenaline-induced contraction due to release of Ca++ from the intracellular store was inhibited by nicorandil and by nitroglycerin. Cromakalim and SG-209 had no such effects. Both nitroglycerin and nicorandil increased intracellular cyclic GMP content. We suggest that nicorandil relaxes the rabbit femoral artery both by directly reducing [Ca++]i and by directly controlling Ca++ sensitivity of the contractile apparatus, through second messengers. The reduction of [Ca++]i involves inhibition of the release of stored Ca++ and Ca++ influx, the latter due in part to opening of ATP-sensitive K+ channels.

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