Enhanced G-protein-induced relaxation in portal hypertensive rats: Role of nitric oxide

Abstract

generalized reduced vascular resistance.1,2 The reasons for Portal hypertension (PHT) is characterized by splanchnic the decreased vascular resistance include exaggerated endohyperemia due to a reduction in mesenteric vascular resisthelial function with enhanced synthesis and/or release of tance. The reasons for the decreased resistance include an vasoactive substance (such as prostacyclin and nitric oxide) increased responsiveness to a vasodilator substance. Because and altered vascular responsiveness to vasoconstrictor subthe activation of an inhibitory guanine nucleotide regulatory stances (such as vasopressin, angiotensin, norepinephrine, (Gi) protein can result in endothelium-dependent relaxation, and methoxamine). [3][4][5][6][7][8] Nitric oxide (NO), a potent endothewe tested the hypothesis that exaggerated Gi-protein induced lium-derived relaxing factor, is one of the major vasoactive relaxation via a nitric oxide (NO)-dependent pathway partly substances implicated in the pathogenesis of the reduced reflects the enhanced Gi-protein expression in PHT vessels.vascular resistance in PHT. [7][8][9][10] The altered vascular respon-PHT was created in Sprague-Dawley rats by a partial portalsiveness and circulatory abnormalities of PHT can be partially vein ligation. Control animals were sham operated. Using corrected following the inhibition of NO synthase (NOS) isolated vascular rings in the absence or presence of an intact with specific NOS inhibitors. [10][11][12][13][14][15] This suggests that enhanced endothelium, N G -nitro-L-arginine methyl ester (L-NAME), and NO production is a major modulator of the exaggerated vaspertussis toxin, dose response relationships for sodium fluocular response in PHT. ride (NaF; range, 0. 1-4 mmol/L), a Gi protein activator, wereAlthough the exact etiology of the enhanced NO response determined in a cumulative manner. Gi-protein expression in PHT remains unclear, it is possible that an overproduction was determined by Western blotting. NaF caused a doseof NO is not a primary but is a secondary event to enhanced dependent relaxation in both sham and portal hypertensive endothelial shear stress, pressure, or endotoxemia. [15][16][17][18] Most pre-contracted vessels, an effect that was significantly inhibstudies to date have been unable to detect endotoxemiaited by pertussis toxin, endothelial denudation, and L-NAME.induced NOS expression in PHT animal models which do not Concentrations of NaF greater than 4 mmol/L caused contracinvolve any hepatic parenchymal dysfunction 19-21 ; however, tions, an effect that was unaffected by L-NAME. The NaFinduced NOS expression has been demonstrated in cirrhotic induced relaxation response was significantly greater in PHT models of PHT, particularly with ascites. [22][23] In prehepatic vessels as compared with sham concomitant with increased models of PHT, basal calcium-dependent endothelial NOS Gi-protein expression in PHT vessels. These data suggest that (eNOS) activity is significantly increased in hypertensive vesthe enhanced endothelia...