RELAXANT EFFECT OF NICORANDIL ON THE TONIC CONTRACTION OF THE CANINE LARGE CORONARY-ARTERY INDUCED BY PHORBOL 12,13-DIBUTYLATE

The contractile response to a protein kinase C activator, phorbol 12,1 3-dibutylate, and the relaxant effect of nicorandil on this contractio n were studied in the canine isolated coronary artery. Phorbol 12,13-d ibutylate (10(-9) -3 x 10(-6) M) elicited slowly developing, dose-depe ndent and sustained contractions which were antagonized by a putative protein kinase C inhibitor, staurosporine. Removal of Ca2+ from the me dium or pretreatment with nifedipine (10(-6) M) partly inhibited the r esponse 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 subseq uent addition of cromakalim (10(-5) M) to the nitroglycerin-treated ri ngs (cromakalim alone inducing a partial relaxation of about 35%) caus ed nearly full relaxation. Methylene blue (5 x 10(-6) M) inhibited the relaxant response to lower (less than or equal to 10(-5) M) but not t o higher concentrations of nicorandil, while it antagonized the nitrog lycerin-induced relaxation at all concentrations used. The relaxant re sponse at higher concentrations of nicorandil (greater than or equal t o 3 x 10(-5) M) was antagonized by 10(-6) M of glibenclamide. These re sults 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 a ppears that nicorandil relaxes the contraction induced by phorbol 12,1 3-dibutylate through a nitrate-like mode of action, combined with a po tassium channel-opening activity.