Relaxant effect of nicorandil on the tonic contraction of the canine large coronary artery induced by phorbol 12,13-dibutylate.

Abstract

The contractile response to a protein kinase C activator, phorbol 12,13-dibutylate, and the relaxant effect of nicorandil on this contraction were studied in the canine isolated coronary artery. Phorbol 12,13-dibutylate (10(-9)-3 x 10(-6) M) elicited slowly developing, dose-dependent and sustained contractions which were antagonized by a putative protein kinase C inhibitor, staurosporine. Removal of Ca2+ from the medium or pretreatment with nifedipine (10(-6) M) partly inhibited the response to phorbol 12,13-dibutylate. Nicorandil (10(-7)-3 x 10(-4) M) produced full relaxation at its maximum effect in rings precontracted with phorbol 12,13-dibutylate (10(-7) M). Nitroglycerin (10(-9)-3 x 10(-5) M) caused only a partial relaxation (to about 30%), but subsequent addition of cromakalim (10(-5) M) to the nitroglycerin-treated rings (cromakalim alone inducing a partial relaxation of about 35%) caused nearly full relaxation. Methylene blue (5 x 10(-6) M) inhibited the relaxant response to lower (< or = 10(-5) M) but not to higher concentrations of nicorandil, while it antagonized the nitroglycerin-induced relaxation at all concentrations used. The relaxant response at higher concentrations of nicorandil (> or = 3 x 10(-5) M) was antagonized by 10(-6) M of glibenclamide. These results suggest that the contraction induced by phorbol 12,13-dibutylate may be related to an activation of protein kinase C and, in part, to increases in the Ca2+ influx via voltage-dependent Ca2+ channels. It appears that nicorandil relaxes the contraction induced by phorbol 12,13-dibutylate through a nitrate-like mode of action, combined with a potassium channel-opening activity.