Mechanism of nitrate-induced vasodilation and tolerance

Various NO-forming compounds have in common that along with their mechanically relaxing effect, they increase the concentration of cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. This has been shown for nitroglycerin, NaNO2, nitroprusside-Na, 2'3'-dinitroadenosine-5'-ethylcarboxamide (B-744-99), and more recently for SIN-1, the vasoactive metabolite of molsidomine, and for nicorandil (SG-75). In isolated circular strips of bovine coronary arteries, suspended in a partially depolarizing Tyrode's solution containing 27 mM K+, these drugs produced dose-dependent relaxations which were slightly preceded by concomitant increases in cGMP levels, measured at various moments of drug action by freeze-clamping the strips, and by subsequent determinations of cyclic nucleotide levels by RIA. Levels of cyclic 3',5'-AMP were not significantly changed, except by B-744-99. Inhibition of cGMP hydrolysis by the addition of M & B 22,948 (2-o-propoxyphenyl-8-azapurin-6-one) augmented the nitrate-induced rises in cGMP as well as their relaxing effects on coronary arterial strips. In the presence of the vital stain methylene blue - which was shown in vitro to prevent nitrate-induced activation of guanylate cyclase, the enzyme which forms cGMP from GTP - the relaxant actions as well as the increases in cGMP produced by several of these nitro-compounds in coronary strips were almost abolished. The actions of organic nitrates appear to depend on their previous reduction to NO by a rate-limiting step involving cysteine, whereas those of nitroprusside and SIN-1 are probably independent of cysteine.(ABSTRACT TRUNCATED AT 250 WORDS)