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 (PGI2) has been shown to be elevated in portal hypertensive rabbits, we studied whether PGI2 could mediate the reduced sympathetic response. We measured the change in the superior mesenteric artery resistance (Rsma) 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 PGI2 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 Rsma response (ED50). Portal hypertensive rabbits had significantly higher ED50 (310 +/- 4.1 mg/kg) than normotensive rabbits (150 +/- 4.1 mg/kg, P less than 0.01). Cyclooxygenase blockade resulted in marked reduction of the ED50 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 ED50 (80 +/- 2.5 mg/kg) and PGI2 infusion at 300 ng/kg/min increased the ED50 further (160 +/- 7.5 mg/kg/min, P less than 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 PGI2 will cause a dose-related decrease in sympathetic response.(ABSTRACT TRUNCATED AT 250 WORDS)
Sitzmann
J V
JV
Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
Li
S S
SS
Lin
P W
PW
D000818:Animals; D016861:Cyclooxygenase Inhibitors; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000494:pharmacology*; D006975:Hypertension, Portal / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology; D009638:Norepinephrine / Q000494:pharmacology*; D011817:Rabbits; D012016:Reference Values; D013152:Splanchnic Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol; D009638:Norepinephrine; D007213:Indomethacin