Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: β(3) -Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target.

Figure 1

Effect of increasing doses of SR58611A on portal pressure (PP) (A), central venous pressure (CVP) (B) and pressure gradient between PP and CVP (C) in healthy control and cirrhotic rats (n= 6, except for the highest dose where n= 5).⁺P < 0.05 versus baseline level; *P < 0.05 between cirrhosis and healthy controls.

Figure 2

Effect of increasing doses of SR58611A on mean arterial pressure (MAP) (A), cardiac index (CI) (B) and indicized peripheral vascular resistance (PVRI) (C) in healthy control and cirrhotic rats (n= 6, except for the highest dose where n= 5). ⁺P < 0.05 versus baseline level; *P < 0.05 between cirrhosis and healthy controls.

Figure 3

Effect of pretreatment with SR59230A on portal pressure (PP) (A), mean arterial pressure (MAP) (B), cardiac index (CI) (C) and indicized peripheral vascular resistance (PVRI) (D) in cirrhotic rats (n= 6, except for the highest dose where n= 5) exposed to increasing doses of SR58611A. *P < 0.05 between the groups.

Figure 4

Concentration-dependent responses to SR58611A administered cumulatively (CRC) in healthy control and cirrhotic rats (n= 6 per group), with or without pretreatment with the β₃-adrenoceptor antagonist SR59230A in isolated rings of rat portal vein; *P < 0.05 and **P < 0.01 between cirrhosis + SR58611A and healthy controls + SR58611A; ^§P < 0.05 and ^§§P < 0.01 between cirrhosis + SR58611A and cirrhosis + SR58611A pretreated with SR59230A.

Figure 5

Effect of increasing doses of SR58611A on portal vein vasodilatation in control and cirrhotic rats (n= 4). *P < 0.01 versus baseline level; **P < 0.001 between cirrhosis and healthy controls.

Figure 6

Representative pictures of tissue sections of liver (A, B), portal vein (C, D) and mesenteric artery (E, F) from a healthy control rat (A, C and E) and from a cirrhotic rat (B, D and F). Scale bar: 50 (A–B) and 25 µm.

Figure 7

Western blot analysis of β₃-adrenoceptor and β-actin protein in liver tissue from healthy control and cirrhotic rats. (A) Representative SDS-polyacrylamide gel, showing β₃-adrenoceptor (upper line) and β-actin (lower line). (B) Densitometric analysis of β₃-adrenoceptor protein bands normalized to β-actin. Data are expressed as mean ± SEM. n= 5. *P < 0.05 versus healthy controls.

Figure 8

RT-PCR analysis of β₃-adrenoceptor and β-actin mRNA expression in heart tissue from healthy and cirrhotic animals. Column graph refers to the densitometric analysis of β₃-adrenoceptor cDNA bands normalized to the expression of β-actin. Data are expressed as mean ± SEM; n= 5, *P < 0.05 versus healthy animals.