YC-1 enhances the responsiveness of tolerant vascular smooth muscle to glyceryl trinitrate

A major limitation of the use of organic nitrates in cardiovascular medicin e is the development of tolerance, which has been attributed, in part, to a decrease in their metabolic activation in the vascular smooth muscle cell. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was shown to potentiate vascular smooth muscle responsiveness to glyceryl trinitrate (GTN), sodium nitroprusside, and the nitric oxide donor NOC 18, in organic nitrate-naive vascular smooth muscle. We used GTN-tolerant rabbit aortic ri ngs (RARs) to test the hypothesis that a non-vasorelaxant concentration of YC-1 enhances the ability of the prototypical organic nitrate GTN to relax vascular smooth muscle and elevate intravascular cGMP under conditions of G TN tolerance. Treatment with YC-1 (3 muM) produced a left shift of the GTN concentration-response curve and decreased the EC50 value for GTN-induced r elaxation in both GTN-tolerant and non-tolerant RARs (P < 0.05). Intravascu lar cGMP elevation induced by GTN was enhanced in the presence of YC-1 in G TN-tolerant and non-tolerant RARs (P < 0.05). These observations indicate t hat YC-1, or similarly acting drugs, may be useful in overcoming the tolera nce that develops during sustained GTN therapy, and that its mechanism may involve enhanced cGMP formation.