It has been suggested that glucagon contributes to the pathogenesis of portal hypertension by increasing portal blood flow. This study examined this issue by assessing the hemodynamic effects of a pharmacological dose of glucagon (1 mg, intravenously) in patients with cirrhosis and portal hypertension (n = 10) and in subjects without significant liver disease (controls = n = 5). Patients with cirrhosis had much higher glucagon levels than control subjects (875 f 167 vs. 186 f 25 pg/ml, p < 0.01) and showed blunted hemodynamic responses after glucagon administration. This occurred despite greater circulating glucagon levels, probably because of a significant prolongation of the plasma half-life of exogenously administered glucagon (4.9 f 0.4 vs. 2.7 2 0.1 min, p < 0.1). Control subjects had marked increases in heart rate (+19% f 4%, p < 0.01), cardiac index ( + 16% f 4%, p = 0.01) and arterial pressure ( + 10% f 3%, p c 0.05), but corresponding changes in patients with cirrhosis (+7% f 1%, +6% f 1%, and +6% f 2%, respectively) were significantly less pronounced (p = 0.05), and there was a negative correlation between basal glucagon levels and the response of heart rate to glucagon injection (r = -0.804, p < 0.001). Resistance to the systemic effects of glucagon in cirrhosis may thus be cawed by a down-regulation of vascular glucagon receptors. In addition, glucagon administration caused a significant increase in portal pressure (from 18.1 k 1.1 to 19.0 f 1.2 mm Hg, p c 0.01), as well as in azygos blood flow (from 0.54 f 0.03 to 0.64 f 0.04 L/min, + 19% -t 4%, p < 0.021, reflecting increased portocollateral blood flow. These findings are consistent with the hypothesis that glucagon is one of the factors contributing to the splanchnic vasodilatation and increased portal pressure of cirrhosis.