Prostacyclin mediates splanchnic vascular response to norepinephrine in portal hypertension

Portal hypertension is characterized by increased splanchnic blood flow. This hyperemia may be related to the documented in vitro impaired sympathetic response in portal hypertension. Because prostacyclin (PGI 2) has been shown to be elevated in portal hypertensive rabbits, we studied whether PGI 2 could mediate the reduced sympathetic response. We measured the change in the superior mesenteric artery resistance ( R SMA) to norepinephrine infusion in chronic portal vein ligated (PHT) and normotensive rabbits, in both portal hypertensives and normals following cyclooxygenase blockade with 8 mg/kg indomethacin, and finally in portal hypertensive, cyclooxygenase-blocked rabbits with a constant IV infusion of PGI 2 at 200 or 300 ng/kg/min. Dose-response curves were obtained and statistical comparisons were based on the dose of norepinephrine producing 50% of maximal R SMA response (ED 60). Portal hypertensive rabbits had significantly higher ED 50 (310 ± 4.1 mg/kg) than normotensive rabbits (150 ± 4.1 mg/kg, P < 0.01). Cyclooxygenase blockade resulted in marked reduction of the ED 50 in both groups and ablated the difference between normotensive and PHT rabbits (20 ± 2.4 and 20 ± 2.8 mg/kg/min, respectively). Prostacyclin infusion at 200 ng/kg/min increased the ED 50 (80 ± 2.5 mg/kg) and PGI 2 infusion at 300 ng/kg/min increased the ED 50 further (160 ± 7.5 mg/kg/min, P < 0.01 vs cyclooxygenase-blocked only rabbits). These results provide the first in vivo evidence of reduced splanchnic sensitivity to norepinephrine in portal hypertension and demonstrate that PGI 2 will cause a dose-related decrease in sympathetic response. Also, cyclooxygenase blockade will ablate the differences between normal and portal hypertensive animals, an effect reversed by exogenous PGI 2. We conclude that PGI 2 is one of the modulators of sympathetic vascular response in portal hypertensive and normal rabbits and that the diminished response in portal hypertension may be related to higher endogenous prostacyclin.