Vascular tolerance to nitroglycerin and cyclic GMP generation in rat aortic smooth muscle

Recent reports have suggested that cyclic guanosine 3', 5'-monophosphate (cGMP) may mediate drug-induced vascular smooth muscle relaxation. This hypothesis was examined by correlating increases in cGMP formation with vascular smooth muscle relaxation after sensitivities to nitroglycerin and nitroprusside were altered. Both nitroglycerin and nitroprusside produced a concentration-dependent increase in rat aortic cGMP levels, which preceded relaxation. A specific inhibition of nitroglycerin relaxation was accomplished by pretreating helical rat aortic strips with 5.5 X 10(-4) M nitroglycerin for 1 hr (in vitro nitroglycerin tolerance). Both nitroglycerin and nitroprusside were inhibited by pretreating tissues with 10(-5) M methylene blue for 1 hr. Whenever nitroglycerin or nitroprusside relaxation was inhibited, there was a corresponding inability to generate cGMP. Vascular tissues derived from nitroglycerin-tolerant animals (in vivo tolerance) exhibited a profile of cGMP reduction that closely resembled that of the in vitro model. Vascular smooth muscle relaxation induced by 8-bromoguanosine-3', 5'-monophosphoric acid was not inhibited by either in vitro nitroglycerin tolerance or methylene blue, suggesting that the subsequent action of cGMP, once formed, is not impaired. The results of this study support the contention that cGMP generation may be an important step in the promotion of vascular smooth muscle relaxation by nitroglycerin and nitroprusside.