THE ENDOTHELIAL AND NON-ENDOTHELIAL MECHANISM RESPONSIBLE FOR ATTENUATED VASOCONSTRICTION IN CIRRHOTIC RATS

The pathogenesis of the vasodilatation associated with liver cirrhosis is not fully understood, but it has recently been postulated that it may be related to an increase in nitric oxide production. The aim of t his study was to compare the response of isolated aortic rings from no rmal and cirrhotic rats to two vasoconstrictors, phenylephrine and U46 619, a thromboxane analogue. Biliary cirrhosis was induced by ligation of the common bile duct; a sham operation was performed in control an imals. Five weeks later, the aorta was removed and dissected into ring s for study in organ chambers. Concentration-response curves were obta ined for the two vasoconstrictors from rings with intact endothelium a nd from rings denuded of endothelium. We found that the vasoconstricti on produced by phenylephrine was decreased in cirrhotic vessels both w ith and without endothelium, but the response to U46619 was not modifi ed by cirrhosis. Concentration-response curves for phenylephrine were also obtained from rings in which the synthesis of nitric oxide and pr ostaglandins was inhibited by N-G-monomethyl-L-arginine and indomethac in, respectively. Nitric oxide synthase inhibition restored normal con tractility of the rings with and without endothelium. This beneficial effect was not observed when cyclo-oxygenase activity was blocked with indomethacin. This study suggests that cirrhotic vessels are hyporeac tive to vasoconstrictors and that this effect is mediated through incr eased nitric oxide production. The improvement observed after inhibiti on of the nitric oxide pathway in denuded rings led us to suggest that cirrhosis also induces nitric oxide synthase in smooth muscle cells, as previously observed by others in septic animals.