Mechanisms of nitrate-induced vasodilatation and tolerance

Nitrovasodilators have been found to relax vascular smooth muscle by stimulating soluble guanylate cyclase and thus by increasing the formation of cyclic GMP (cGMP). This nucleotide is responsible for relaxation, most likely by decreasing cytosolic free Ca2+ by one or several mechanisms. Repeated administration of organic nitrates causes tolerance development characterized by a diminished relaxing effect and an attenuated rise in cGMP. Experiments in isolated circular strips from bovine coronary arteries were performed in order to study the mechanism of tolerance development. It was found that after nitroglycerin (NG) pretreatment the response of the coronary strips to NG was less sensitive with respect to relaxation and increases in cGMP. These strips were also cross-tolerant against isosorbide-5-mononitrate, which by itself caused only little tolerance. With NG, the degree of tolerance development depended on the time and the concentration of NG pre-exposure. NG was found to stimulate guanylate cyclase (GC) in coronary supernatant provided that cysteine was added to the incubation medium. As in the intact strips, activation of GC by NG was attenuated when supernatants were preincubated with NG. It was found that addition of cysteine during incubation lessened the degree of desensitization but did not prevent it completely. Similarly, in coronary strips, tolerance development was lower when N-acetylcysteine was present during pre-exposure of the strips with NG. Considerably more effective in preventing tolerance development by about 50% was L-2-oxothiazolidine-4-carboxylate (OTC), a substance that easily penetrates into the cell and is transformed into cysteine by 5-oxo-prolinase.(ABSTRACT TRUNCATED AT 250 WORDS)