Splanchnic vasodilatation and vascular hyporesponsiveness to vasopressors are characteristic features of patients with cirrhosis. Although the vascular response to different vasopressors has been shown to be attenuated in cirrhosis, alterations on the receptor level are discussed controversially. Thus, impaired postreceptor signaling has been postulated. However, so far this has not been studied in human splanchnic vessels. Therefore, we assessed the vascular response of human hepatic arteries after activating the G-protein-dependent signal transduction pathway by stimulation with angiotensin II, the thromboxane A 2 analog U46619, or by G-protein activation with NaF/AlCl 3 . After endothelium denudation, cumulative isometric concentration contraction curves were obtained for hepatic arteries from 32 cirrhotic patients undergoing liver transplantation and from 40 organ donors after stimulation with either angiotensin II (10 ؊11 -10 ؊5 mol/L), U46619 (10 ؊10 -10 ؊6 mol/L) or AlCl 3 (30 mol/L)/NaF (10 ؊4 -3 ؋ 10 ؊2 mol/L). Hepatic arteries from cirrhotic patients were markedly less responsive to angiotensin II (P < .0001) than those from organ donors. Both stimulation of the G-protein phospholipase C pathway via the thromboxane A 2 receptor and receptor-independent Gprotein stimulation with AlCl 3 /NaF, induced an intact contractile response. In conclusion, the G-protein-dependent signal transduction system itself is unaltered in cirrhosis. Hence, the cause of the hyporesponsiveness to some vasoconstrictors in cirrhosis appears to be a receptor-specific phenomenon localized upstream from the G-protein level. (HEPATOLOGY 2001;34:884-888.)Peripheral and splanchnic vasodilatation leading to hyperdynamic circulation are characteristic hemodynamic features in patients with cirrhosis and in animal models with portal hypertension. 1-3 Supposedly, this is caused by an impaired vascular response to different vasoconstrictors as found in animal models with cirrhosis. [4][5][6][7][8][9][10] Recently, hyporesponsiveness of human hepatic arteries from patients with cirrhosis to vasoconstrictors such as the ␣ 1 -agonist methoxamine, 11 vasopressin, 12 or 5-hydroxytryptamine 12 has also been found. However, the exact pathophysiologic basis of the vascular hyporesponsiveness in cirrhosis has so far not been elucidated. Because vascular hyporesponsiveness has been shown to persist after inhibition of nitric oxide synthesis and endothelium removal 11,13 it cannot be solely explained by increased formation of nitric oxide in cirrhosis.Vascular hyporeactivity in cirrhosis involves different Gprotein-linked transmembrane receptors including the ␣ 1 -adrenoceptor, 6,10,11 the angiotensin II type 1 (AT 1 ) receptor, 5,14-16 and the vasopressin receptor. 12 Stimulation of these receptors predominantly induces smooth muscle contraction by G-protein (␣-subunit)-dependent activation of phospholipase C (PLC). This catalyzes formation of inositol 1,4,5-triphosphate (IP 3 ) and 1,2-diacylglycerol, which induces Ca 2ϩ mobilization and protein ki...