Effects of chronic oral administration of a high dose of nicorandil on in vitro contractility of rat arterial smooth muscle.
Nicorandil, which is structurally a nitrate and also a nicotinamide, has a vasodilator action by stimulating cyclase and ATP-sensitive K+ channel. The aim of present study was to examine the effects of chronic oral administration of a high dose of nicorandil on in vitro vascular reactivity. Nicorandil (30 mg/kg), at a dose 6-10-times higher than to decrease blood pressure in rat, was orally administered 2-times daily for a 2-4 weeks to the rats. At the end of the administration period, thoracic aorta was isolated for in vitro study. Treatment with nicorandil for 4 weeks markedly reduced the relaxant effect of nicorandil itself and other vasodilators including sodium nitroprusside, nitric oxide, endothelium-derived relaxing factor released by carbachol, 8-Br-cyclic guanosine 3',5'-monophosphate (cGMP), a K+ channel opener, levcromakalim, and forskolin. Increase in cGMP content induced by nicorandil and sodium nitroprusside was less in the aorta from nicorandil-treated rat than in the vehicle-control rat. Chronic administration of nicorandil altered neither the contractile responses to norepinephrine nor the vasodilator effect of verapamil. On the other hand, a 4-week treatment with a dose of nicorandil (2 mg/kg) sufficient to decrease blood pressure in rat showed no change in aortic response. These results suggest that in vivo chronic treatment with a high dose of nicorandil inactivates not only the guanylate cyclase activity but also the mechanism mediated by cGMP; it also attenuates the sensitivity of K+ channels to levcromakalim. Prolonged activation of the specific site may desensitize its site of action.
Trongvanichnam
K
K
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, University of Tokyo, Japan.
Mitsui-Saito
M
M
Ozaki
H
H
Karaki
H
H
D000284:Administration, Oral; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil