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The effects of organic nitrates on tone and tissue cyclic nucleotide levels were studied, using canine coronary, mesenteric and renal arteries, and femoral veins. Glyceryl trinitrate (GTN) relaxed all vascular tissues examined and increased tissue cyclic GMP (cGMP) levels in a concentration-dependent manner, but GTN induced no significant changes in cyclic AMP (cAMP) levels. An increase in cGMP levels induced by 10 microM of GTN in coronary arteries was observed before the onset of relaxation. Methylene blue, an inhibitor of guanylate cyclase, inhibited the relaxant effect of GTN and decreased cGMP levels. In contrast, M & B 22,948, an inhibitor of cGMP phosphodiesterase, not only enhanced relaxation by GTN, but also increased cGMP levels. Other organic nitrates, pentaerythritol tetranitrate (PETN), nicorandil (NIC), and isosorbide dinitrate (ISDN), also relaxed coronary arteries and increased cGMP levels in a concentration-dependent manner. A significant correlation was observed between percentage increases in cGMP levels and percentage relaxation by 10 microM of GTN, PETN, NIC, and ISDN (r = 0.952, p less than 0.001). Plasma concentrations of 4 organic nitrates inversely correlated with percentage increases in cGMP levels by 10 microM of these agents in coronary arteries (r = -0.845, p less than 0.001). These results suggest that an increase in cGMP is responsible for relaxation in vascular smooth muscles by organic nitrates, and that therapeutic plasma concentrations may be estimated by the degree of increase in cGMP levels induced by their administration.
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