Diabetes Diminishes the Portal-Systemic Collateral Vascular Response to Vasopressin via Vasopressin Receptor and Gα Proteins Regulations in Cirrhotic Rats

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.

Diabetes enhances the intrahepatic vascular response to endothelin‐1 in cirrhotic rats: association with the ETA receptor and pERK up‐regulation

“…Similarly, when the splanchnic circulation was examined, the SMA was not significantly different between cirrhotic rats with or without diabetes. Another piece of evidence that we have published previously is that diabetes brings about a decrease in the portal‐systemic collateral vascular responses of cirrhotic rats , which is the opposite of the relevant influence on intrahepatic vascular response found in the current study. Since PP is determined by the net influence exerted by SMA flow, intrahepatic vascular resistance and portal‐systemic collateral vascular resistance, our findings demonstrate a complex interplay among these three factors.…”

Synthesis and Biological Evaluation of Substituted Desloratadines as Potent Arginine Vasopressin V2 Receptor Antagonists

“…The receptor stimulates adenylate cyclase, which results in the production of cyclic AMP [5]. Thus, there is potential to develop a vasopressin V2 receptor antagonist for the treatment of disorders such as congestive heart failure [6,7,8,9], hypertension [10,11], renal disease [12,13], edema [14,15], liver cirrhosis [16,17], hyponatremia [18,19,20,21,22], inappropriate antidiuretic hormone secretion (SIADH) syndrome [23] and any state involving excessive retention of water.…”