This study examined whether hyperglucagonism may promote an altered sensitivity to norepinephrine (NE) and contribute to systemic vasodilation in rats with portal hypertension due to portal vein stenosis. Three groups of male Sprague-Dawley rats were studied, portal hypertensive, normal controls, and hyperglucagonemic controls. Systemic vascular reactivity was studied by constructing dose-response curves of systemic vascular resistance (SVR) during infusions of increasing doses of NE and calculating NE ED50, the dose of NE that caused 50% of the maximal increase in SVR. Measurement of SVR was based on simultaneous measurements of arterial pressure and cardiac output (CO). Repeated measurements of CO were performed by indicator dilution curves of indocyanine green by means of a fiber-optic catheter placed in the carotid artery. Portal hypertensive rats had a decreased systemic sensitivity to NE, shown by a significant increase in NE ED50 compared with normal controls (60 +/- 8 micrograms vs. 25 +/- 3 micrograms; P less than 0.001). Glucagon levels were markedly increased in the portal hypertensive group (332 +/- 51 pg/ml vs. 176 +/- 22 pg/ml in controls; P less than 0.005). Glucagon infusion in normal rats achieved levels similar to those observed in portal hypertension (305 +/- 48 pg/ml; NS). Systemic vascular sensitivity to NE was also impaired in these hyperglucagonemic normal animals, as shown by an abnormal NE ED50 (69 +/- 16 micrograms; P less than 0.001 vs. controls) that was almost identical to that observed in portal hypertension. These results are consistent with the hypothesis that a reduced sensitivity to NE can contribute to systemic vasodilation in portal hypertension and suggest that hyperglucagonism can play a key role in its pathogenesis.