Altered adenylyl cyclase activities and G-protein abnormalities in portal hypertensive rabbits

Abstract

Portal hypertension (PHT) is characterized by splanchnic hyperemia due to a reduction in mesenteric vascular resistance. We hypothesized that alterations in the activity of a guanine-nucleotide regulatory protein (G- protein) might be partially responsible for the marked circulatory disturbances observed in PHT. We, therefore, determined alterations in adenylyl cyclase/cAMP system in prehepatic portal hypertensive rabbits and correlated these changes to the activity of a G-protein. Basal and G-protein- stimulated adenylyl cyclase activities were lower in the PHT superior mesenteric artery (22-26%) and thoracic aorta (31-46%) membranes, but higher (178-321%) in portal vein. The functional activity of Giα proteins (pertussis toxin-catalyzed ADP-dependent ribosylation) increased in the PHT superior mesenteric artery and thoracic aorta, but decreased in portal vein. Immunodetection revealed an increase in the Giα protein subunits (Giα1/Giα2 and Giα3/Goα) in PHT thoracic aorta, without any change in Gsα proteins; and a decrease in the amount of Giα proteins in PHT portal vein. There was no change in the amount of Gsα/Giα in the PHT superior mesenteric artery. We conclude the hemodynamic alterations of PHT are associated with intrinsic alterations in G-protein-enzyme effector systems. These alterations are vessel specific and suggest a possible unique global derangement underlying the vasculopathy of PHT.