Role of β3-adrenoceptors for intrahepatic resistance and portal hypertension in liver cirrhosis

Abstract

Increased intrahepatic resistance and splanchnic blood flow cause portal hypertension in liver cirrhosis. Nonselective β-adrenoceptor (β-AR) antagonists have beneficial effects on hyperdynamic circulation and are in clinical use. In this context, the role of the β3-AR is undefined. Here we investigated their expression and role in portal hypertension in patients and rats with liver cirrhosis. We analyzed cirrhotic human and rat tissues (liver, splanchnic vessels) and primary rat cells. Protein expression of β3-AR was determined by western blot and messenger RNA (mRNA) levels by reverse-transcription polymerase chain reaction (RT-PCR). Activities of Rho-kinase and the nitric oxide (NO) effector protein kinase G (PKG) were assessed by way of substrate phosphorylation (moesin, vasodilator-stimulated phosphoprotein [VASP]). Cyclic 3′,5′ adenosine monophosphate (cAMP) accumulation was determined by an enzyme-immunoassay kit. The effects of selective β3-AR agonists (CGP12177A, BRL37344) and antagonist (SR59230A) were investigated by collagen matrix contraction of hepatic stellate cells (HSCs), in situ liver perfusions, and in vivo hemodynamic parameters in bile duct ligation and carbon tetrachloride intoxication in cirrhotic rats. In cirrhosis of humans and rats, β3-AR expression is markedly increased in hepatic and in splanchnic tissues. Stimulation of β3-AR leads to relaxation of HSCs by way of cAMP accumulation, and by inhibition of Rho-kinase activity; any role ofNOand its effector PKG was not observed. β3-AR agonists decrease intrahepatic resistance and portal pressure in cirrhotic rats. Conclusion: There is a marked hepatic and mesenteric up-regulation of β3-ARs in human cirrhosis and in two different animal models of cirrhosis. The β3-AR-agonists should be further evaluated for therapy of portal hypertension. Copyright © 2009 by the American Association for the Study of Liver Diseases.