Propranolol modulates the collateral vascular responsiveness to vasopressin via a G_α-mediated pathway in portal hypertensive rats

Gastro-oesophageal variceal haemorrhage is one of the most dreadful complications of portal hypertension and can be controlled with vasoconstrictors. Nevertheless, sympathetic tone abnormality and vascular hyporesponsiveness in portal hypertension may impede the haemostatic effects of vasoconstrictors. Propranolol, a β-blocker binding the G-protein-coupled adrenoceptor, is a portal hypotensive agent. However, whether propranolol influences the collateral vasoresponse is unknown. Portal hypertension was induced by PVL (portal vein ligation) in Sprague-Dawley rats. In an acute study with an in situ perfusion model, the collateral responsiveness to AVP (arginine vasopressin) was evaluated with vehicle, propranolol (10 μmol/l), propranolol plus suramin (100 μmol/l, a G_α inhibitor) or suramin pre-incubation. G_α mRNA expression in the splenorenal shunt, the most prominent intra-abdominal collateral vessel, was measured. In the chronic study, rats received DW(distilled water) or propranolol (10 mg kg^-1 of body weight day^-1) for 9 days. Then the concentration-response relationship of AVP and G_α mRNA expression were assessed. Propranolol pre-incubation elevated the perfusion pressure changes of collaterals in response to AVP, which was inhibited by suramin. The splenorenal shunt G_αq and G_α11 mRNA expression were enhanced by propranolol. The group treated with propranolol plus suramin had a down-regulation of G_α11 as compared with the propranolol group. Chronic propranolol treatment reduced mean arterial pressure, PP (portal pressure) and the perfusion pressure changes of collaterals to AVP. G_αs expression was up-regulated. In conclusion, propranolol pre-incubation enhanced the portalsystemic collateral AVP responsiveness in portal hypertensive rats, which was related to G_αq and G_α11 up-regulation. In contrast, the attenuated AVP responsiveness by chronic propranolol treatment was related to G_αs up-regulation. The G_α signalling pathway may be a therapeutic target to control variceal bleeding and PP in portal hypertension.