In helical strips of dog coronary arteries contracted with prostaglandin F2 alpha, relaxant responses to atrial natriuretic peptide (ANP), nitric oxide (NO), nitroglycerin and 8-bromo cyclic GMP were markedly inhibited or abolished by treatment with a high concentration of sodium nitroprusside, whereas the responses to beraprost and papaverine were not influenced. A similar suppression of the responses to ANP, NO, and sodium nitroprusside was observed after treatment with nitroglycerin. The relaxations induced by NO and nitroglycerin were abolished by methylene blue and oxyhemoglobin, whereas the response to ANP was not influenced. The sodium nitroprusside-induced relaxation was significantly potentiated by methylene blue but was abolished by oxyhemoglobin. The increase in cyclic GMP caused by ANP and nitroglycerin was not influenced by treatment with sodium nitroprusside, despite the fact that the responses to ANP and nitroglycerin were suppressed. It can be concluded that ANP and nitroglycerin or sodium nitroprusside share the same mechanism of action on intracellular processes occurring after the synthesis of cyclic GMP in dog coronary artery smooth muscle cells and that cross-tachyphylaxis between nitroglycerin, sodium nitroprusside, and ANP in the mechanical response is not associated with an impaired production of cyclic GMP.