The blood pressure responses to intravenous infusions of norepinephrine and angiotensin II, sympathetic and nonsympathetic vasoconstricting agents, respectively, were measured in 20 patients with cirrhosis (10 Child-Pugh grade A and 10 Child-Pugh grades B or C) and in 20 healthy subjects. The log PD20 (dose of agonist required to raise blood pressure by 20 mm Hg) for norepinephrine was 4.78 +/- 0.36 (mean +/- S.D.) in patients with severe cirrhosis and 4.36 +/- 0.37 in controls, p less than 0.01. Log PD20 for angiotensin II was 3.16 +/- 1.06 in patients with severe cirrhosis and 1.97 +/- 0.74 in controls, p less than 0.01. Cardiovascular responses to selective sympathetic agonists were measured in 10 other cirrhotic patients (all Child-Pugh grades B or C) and in 10 healthy controls. Log PD20s for phenylephrine, an alpha-1 adrenoceptor agonist, and for alphamethylnorepinephrine; an alpha-2 adrenoceptor agonist, were increased in cirrhosis (phenylephrine = 5.35 +/- 0.49 vs. 4.95 +/- 0.35, p less than 0.05; alphamethylnorepinephrine = 4.05 +/- 0.26 vs. 3.44 +/- 0.55, p less than 0.001). In contrast, log CD20 (dose of agonist required to raise the heart rate by 20 beats/min) for isoproterenol, a beta-adrenoceptor agonist, was similar in cirrhotic patients and controls (2.81 +/- 0.38 vs. 2.94 +/- 0.45, p = 0.49). These studies demonstrate that pressor reactivity to both sympathetic and nonsympathetic agonists is impaired in severe cirrhosis, that the impaired sympathetic responses are not caused by generalized sympathetic desensitization and that the site common to the four agonists with impaired responses is the peripheral vascular smooth muscle.