Effects of nicorandil on cytosolic calcium concentrations and on tension development in the rabbit femoral artery.
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.
Abe
S
S
Division of Clinical Nutrition, Graduate School of Health and Nutrition Sciences, Nakamura-Gakuen, Japan.
Nishimura
J
J
Nakamura
M
M
Kanaide
H
H
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D019806:Cromakalim; D006152:Cyclic GMP / Q000032:analysis; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; C035663:SG 209; D005996:Nitroglycerin; D006152:Cyclic GMP; D011188:Potassium; D005905:Glyburide; D002118:Calcium; D009638:Norepinephrine