Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A.
OBJECTIVE
β(3) -Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of β(3) -adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats.


METHODS
PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl(4) -treated cirrhotic rats before and during infusion of the selective β(3) -adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed.


RESULTS
At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose-dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective β(3) -adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, β(3) -adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats.


CONCLUSIONS
β(3) -Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target.
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Valentina
V
Vasina
Ferdinando
F
Giannone
Marco
M
Domenicali
Rocco
R
Latorre
Annalisa
A
Berzigotti
Paolo
P
Caraceni
Marco
M
Zoli
Fabrizio
F
De Ponti
Mauro
M
Bernardi
D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006439:Hemodynamics; D006975:Hypertension, Portal / Q000503:physiopathology*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011169:Portal Vein / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D058673:Adrenergic beta-3 Receptor Antagonists; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; C076252:amibegron