Role of beta3-adrenoceptors for intrahepatic resistance and portal hypertension in liver cirrhosis.
Increased intrahepatic resistance and splanchnic blood flow cause portal hypertension in liver cirrhosis. Nonselective beta-adrenoceptor (beta-AR) antagonists have beneficial effects on hyperdynamic circulation and are in clinical use. In this context, the role of the beta(3)-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 beta(3)-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 beta(3)-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, beta(3)-AR expression is markedly increased in hepatic and in splanchnic tissues. Stimulation of beta(3)-AR leads to relaxation of HSCs by way of cAMP accumulation, and by inhibition of Rho-kinase activity; any role of NO and its effector PKG was not observed. beta(3)-AR agonists decrease intrahepatic resistance and portal pressure in cirrhotic rats.


CONCLUSIONS
There is a marked hepatic and mesenteric up-regulation of beta(3)-ARs in human cirrhosis and in two different animal models of cirrhosis. The beta(3)-AR-agonists should be further evaluated for therapy of portal hypertension.
Trebicka
Jonel
J
Department of Internal Medicine I, University of Bonn, Bonn, Germany. jonel.trebicka@ukb.uni-bonn.de
Hennenberg
Martin
M
Schulze Pröbsting
Andrea
A
Laleman
Wim
W
Klein
Sabine
S
Granzow
Michaela
M
Nevens
Frederik
F
Zaagsma
Johan
J
Heller
Jörg
J
Sauerbruch
Tilman
T
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology*; D008103:Liver Cirrhosis / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000502:physiology*; D014655:Vascular Resistance
D011412:Propanolamines; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D011433:Propranolol; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; C033394:CGP 12177