DIFFERENTIAL-EFFECTS OF METHANOL ON RAT AORTIC SMOOTH-MUSCLE

The effects of methanol on isolated segments of rat aorta were investi gated. In the absence of any vasoactive agent, methanol (5-675 mM) fai led to alter basal tension. In rat aortic rings precontracted with hig h K+ (30 mM), methanol elicited a concentration-related relaxation at concentrations of from 5 to 675 mM. The K+-induced contraction in the presence of endothelium was more strongly inhibited by methanol than i n the absence of endothelium. The effective concentration producing ap proximately 50% of the maximal relaxation response (ED50) to methanol was about 96 mM. Methanol-induced relaxations could not be abolished e ither by 5 x 10(-5) M N-nitro-L-arginine methyl ester (L-NAME) or NG-n itro-L-arginine (L-NNA), both selective inhibitors of nitric oxide (NO ) formation; these relaxations were not potentiated by addition of exc ess L-arginine. An inhibitor of prostanoid synthesis, indomethacin (10 (-5) M), had no effects on methanol-induced relaxation. Removal of ext racellular Ca2+ ([Ca2+](o)) resulted in almost complete inhibition of the relaxant effects of methanol on rat aortic ring segments. Marked a ttenuation of the relaxation responses of intact arteries to methanol was obtained after buffering intracellular Ca2+ ([Ca2+](i)) with 10 mu M BAPTA-AM. In 5-hydroxytryptamine (5-HT, 2.5 mu M)- or phenylephrine (PE, 0.1 mu M)-precontracted rat aortic rings, methanol amplified con tractile responses to 5-HT and PE; these increased responses were conc entration dependent. No significant differences in these methanol pote ntiated responses were found between aorta with or without endothelial cells. The amplified rat aortic smooth muscle responses induced by me thanol after PE could be modified only by phentolamine, an antagonist of PE, while responses to 5-HT could be inhibited by methysergide (an antagonist of 5-HT) and by phentolamine, diphenhydramine, and haloperi dol. Pretreatment with 50, 200, and 500 mM methanol increased rat aort ic contractile responses induced by 5-HT and PE. Our results suggest t hat: (a) acute methanol exposure relaxes rat aortic smooth muscle cont ractile responses induced by high K+, leading to vessel relaxation. Th is relaxation effect of methanol is endothelium-dependent, clearly Ca2 + dependent, and independent of endogenous vasoditators such as acetyl choline, histamine, catecholamines, serotonin, or PG. (b) Methanol see ms to increase potassium current by shifting the potential towards mor e negative values in depolarized vascular muscle cell membranes, proba bly inducing hyperpolarization of the cell membranes leading to a repo larization. (c) In contrast to the relaxant responses, methanol proten tiates contractile response of rat aorta to 5-HT and PE. (C) 1998 Else vier Science Inc.