Propranolol modulates the collateral vascular responsiveness to vasopressin via a G(α)-mediated pathway in portal hypertensive rats.

Abstract

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 x kg(-1) of body weight x 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 portal-systemic 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.

• Authors: Jing-Yi Lee, Teh-Ia Huo, Hui-Chun Huang, Fa-Yauh Lee, Han-Chieh Lin, Chiao-Lin Chuang, Ching-Chih Chang, Sun-Sang Wang, Shou-Dong Lee
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 121 Issue 12 Pg. 545-54 (Dec 2011) ISSN: 1470-8736 [Electronic] England
• PMID: 21736560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Antihypertensive Agents
• GTP-Binding Protein alpha Subunits
• Vasoconstrictor Agents
• Arginine Vasopressin
• Suramin
• Propranolol

Topics

• Adrenergic beta-Antagonists (administration & dosage, pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Arginine Vasopressin (antagonists & inhibitors, pharmacology)
• Collateral Circulation (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Interactions
• GTP-Binding Protein alpha Subunits (antagonists & inhibitors, genetics, physiology)
• Gene Expression Regulation (drug effects)
• Hemodynamics (drug effects)
• Hypertension, Portal (physiopathology)
• Liver Circulation (drug effects, physiology)
• Male
• Propranolol (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Suramin (pharmacology)
• Vasoconstrictor Agents (pharmacology)