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, h as a vasodilator action by stimulating guanylate cyclase and ATP-sensi tive K+ channel. The aim of present study was to examine the effects o f chronic oral administration of a high dose of nicorandil on in vitro vascular reactivity. Nicorandil (30 mg/kg), at a dose 6-10-times high er than to decrease blood pressure in rat, was orally administered 2-t imes daily for 2-4 weeks to the rats. At the end of the administration period, thoracic aorta was isolated for in vitro study. Treatment wit h nicorandil for 4 weeks markedly reduced the relaxant effect of nicor andil itself and other vasodilators including sodium nitroprusside, ni tric 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 ni corandil and sodium nitroprusside was less in the aorta from nicorandi l-treated rat than in the vehicle-control rat. Chronic administration of nicorandil altered neither the contractile responses to norepinephr ine nor the vasodilator effect of verapamil. On the other hand, a 4-we ek treatment with a dose of nicorandil (2 mg/kg) sufficient to decreas e blood pressure in rat showed no change in aortic response. These res ults suggest that in vivo chronic treatment with a high dose of nicora ndil inactivates not only the guanylate cyclase activity but also the mechanism mediated by cGMP; it also attenuates the sensitivity of K+ c hannels to levcromakalim. Prolonged activation of the specific site ma y desensitize its site of action.