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Abstract
Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP) in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL)-induced cirrhosis received vehicle (citrate buffer) or streptozotocin (diabetic, BDL/STZ). The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist) and overcome by NaF (a G protein activator). The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation.
Highlights
Liver cirrhosis is characterized by increased intrahepatic resistance and splanchnic hyperemia with elevated portal pressure, the so-called portal hypertension [1]
There were no significant differences in glucose, body weight (BW), mean arterial pressure (MAP), portal pressure (PP), and heart rate (HR) between bile duct ligation (BDL) rats perfused with Krebs solution (BDL/K, n = 10), 45 mM D-glucose (BDL/G, n = 9), or 45 mM D-glucose and NaF (BDL/ G+NaF, n = 7)
The parameters were similar among BDL/ STZ rats perfused with Krebs solution (BDL/STZ/K, n = 7), 45 mM D-glucose (BDL/STZ/G, n = 9), 45 mM D-glucose and NaF (BDL/STZ/G+NaF, n = 6), or OPC-31260 (BDL/STZ/ OPC-31260, n = 8) (P.0.05)
Summary
Liver cirrhosis is characterized by increased intrahepatic resistance and splanchnic hyperemia with elevated portal pressure, the so-called portal hypertension [1]. Portal-systemic collaterals develop to divert portal blood flow to the systemic circulation, among which gastroesophageal varices are the most prominent [2]. A vascular endothelium-derived factor mediating vasodilation and angiogenesis, participates in the development of portal hypertension and varices [3,4]. Variceal hemorrhage is the most dreadful and challenging complication [5]. The current treatment strategy aims to reduce portal inflow, portal pressure and/or constrict collateral vasculature. Factors that alter collateral vascular contractility may contribute to the control of variceal hemorrhage
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