Evidence for an endothelium-derived hyperpolarizing factor in the superiormesenteric artery from rats with cirrhosis

In cirrhosis, in splanchnic arteries, endothelium-dependent relaxation may persist even if overactive nitric oxide synthase (NOS) and cyclooxygenase ( COX) are inhibited. In normal arteries, a significant endothelium-dependent relaxation to acetylcholine persists after NOS/COX inhibition, This relaxa tion is caused by smooth muscle cell (SMC) membrane hyperpolarization, whic h is sensitive to a combination of the potassium channel blockers apamin an d charybdotoxin, and is mediated by an endothelium-derived hyperpolarizing factor (EDHF). The aim of this study was to detect EDHF and evaluate its pa thophysiologic role in isolated superior mesenteric arteries from cirrhotic rats. Arterial rings were obtained and exposed to N-w-nitro-L-arginine (L- NNA, a NOS inhibitor) and indomethacin (a COX inhibitor). Acetylcholine-ind uced membrane potential responses and concentration-response curves to the relaxant of acetylcholine were obtained with and without apamin plus charyb dotoxin. Acetylcholine-induced responses were measured in certain rings fro m endothelium-denuded arteries, Contractions caused by the alpha (1)-adreno ceptor agonist phenylephrine were obtained in cirrhotic and normal rings wi th and without apamin and charybdotoxin. Significant acetylcholine-induced, endothelium-dependent, apamin- and charybdotoxin-sensitive, SMC membrane h yperpolarization and relaxation were found. An apamin- and charybdotoxin-se nsitive hyporesponsiveness to the contractile action of phenylephrine was f ound in cirrhotic rings. In conclusion, in cirrhotic rats, in the superior mesenteric artery exposed to NOS/COX-inhibitors, an EDHF exists that may re place NOS/COX products to induce endothelium-dependent arterial relaxation.