Effects of chronic oral administration of a high dose of nicorandil on in vitro contractility of rat arterial smooth muscle

Abstract

Nicorandil, which is structurally a nitrate and also a nicotinamide, has a vasodilator action by stimulating guanylate 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 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.