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H Schroder, DC Leitman, BM Bennett, SA Waldman and F Murad
Department of Medicine, Stanford University School of Medicine, Palo Alto, California.
Cultured rat lung fibroblasts were used to explore desensitization of guanylate cyclase to nitrovasodilators. The effect of pretreatment with glyceryl trinitrate (GTN) on the concentration-response curves of GTN and sodium nitroprusside (SNP) for cyclic GMP accumulation in intact cells and activation of guanylate cyclase in broken cell preparations was measured. Pretreatment of cells with 1 microM GTN for 3 h decreased cyclic GMP accumulation induced by GTN but had no effect on SNP-induced cyclic GMP accumulation. Pretreatment of cells with 100 microM GTN decreased the efficacy of GTN and SNP for cyclic GMP elevation by 89% and 40%, respectively. In contrast to results obtained with GTN, SNP slightly desensitized cyclic GMP accumulation induced by GTN and SNP. Pretreatment of cells with 100 nM atrial natriuretic peptide resulted in a 44% decrease in cyclic GMP accumulation induced by subsequent exposure to 10 nM atrial natriuretic peptide but had no effect on cyclic GMP elevation induced by nitrovasodilators. In experiments with crude preparations of soluble guanylate cyclase from cells pretreated with 1 mM GTN, activation of the enzyme by GTN and SNP was inhibited almost completely. Tolerance to GTN in intact cells could not be reversed by subsequent incubation with thiols such as cysteine, N- acetylcysteine or glutathione. However, overnight incubation of GTN- tolerant cells in media without added thiols resulted in complete recovery of responsiveness to GTN. Recovery of GTN-induced cyclic GMP accumulation was inhibited in a concentration-dependent manner by cycloheximide, suggesting that reversal of organic nitrate tolerance requires de novo synthesis of gyanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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