Contractile hyporesponsiveness of hepatic arteries in humans with cirrhosis: Evidence for a receptor-specific mechanism

Splanchnic vasodilatation and vascular hyporesponsiveness to vasopressors a re characteristic features of patients with cirrhosis. Although the vascula r response to different vasopressors has been shown to be attenuated in cir rhosis, alterations on the receptor level are discussed controversially. Th us, impaired postreceptor signaling has been postulated. However, so far th is has not been studied in human splanchnic vessels. Therefore, we assessed the vascular response of human hepatic arteries after activating the G-pro tein-dependent signal transduction pathway by stimulation with angiotensin II, the thromboxane A(2) analog U46619, or by G-protein activation with NaF /AlCl3. After endothelium denudation, cumulative isometric concentration co ntraction curves were obtained for hepatic arteries from 32 cirrhotic patie nts undergoing liver transplantation and from 40 organ donors after stimula tion with either angiotensin II (10(-11)-10(-5) mol/L), U46619 (10(-10)-10( -6) mol/L) or AlCl3 (30 mu mol/L)/NaF (10(-4)-3 x 10(-2) mol/L). Hepatic ar teries from cirrhotic patients were markedly less responsive to angiotensin II (P < .0001) than those from organ donors. Both stimulation of the G-pro tein phospholipase C pathway via the thromboxane A(2) receptor and receptor -independent G-protein stimulation with AlCl3/NaF, induced an intact contra ctile response. In conclusion, the G-protein-dependent signal transduction system itself is unaltered in cirrhosis. Hence, the cause of the hyporespon siveness to some vasoconstrictors in cirrhosis appears to be a receptor-spe cific phenomenon localized upstream from the G-protein level.