O. Kuromaru et K. Sakai, RELAXANT EFFECT OF NICORANDIL ON THE TONIC CONTRACTION OF THE CANINE LARGE CORONARY-ARTERY INDUCED BY PHORBOL 12,13-DIBUTYLATE, Archives internationales de pharmacodynamie et de therapie, 330(1), 1995, pp. 25-38
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.