大鼠门静脉高压和肝硬化：β3 肾上腺素能受体激动剂 SR58611A 的作用。
Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A.
机构信息
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
出版信息
Br J Pharmacol. 2012 Nov;167(5):1137-47. doi: 10.1111/j.1476-5381.2012.02074.x.
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.
背景与目的
β(3) -肾上腺素能受体参与生理和病理条件下血管张力的调节。我们旨在评估β(3) -肾上腺素能受体药理学调节对门静脉压力(PP)和全身血液动力学的影响及其在肝硬化大鼠肝脏和肠系膜血管中的表达。
实验方法
在对照和 CCl(4) 处理的肝硬化大鼠中，在输注选择性β(3) -肾上腺素能受体激动剂 SR58611A 之前和期间，通过有创评估 PP、中心静脉压(CVP)和全身血液动力学。还从肝脏、心脏、门静脉和肠系膜动脉采集组织样本，用于免疫组织化学和分子生物学分析。评估了 SR58611A 对分离的门静脉的作用。
主要结果
在基线时，肝硬化大鼠表现出门静脉高压、CVP 降低和高动力循环。SR58611A 在肝硬化大鼠中诱导出显著的、剂量依赖性的 PP 降低，但在对照组中没有。尽管两组均表现出剂量依赖性的平均动脉压降低，但这种作用与肝硬化大鼠的心脏指数(CI)降低和指示性外周血管阻力(PVRI)不变有关，而对照组动物的 CI 增加和 PVRI 降低有关。用选择性β(3) -肾上腺素能受体拮抗剂 SR59230 预处理可防止所有 SR58611A 诱导的肝硬化大鼠的变化。SR58611A 浓度依赖性地使肝硬化大鼠的门静脉舒张，舒张程度明显大于健康大鼠；SR59230A 预处理完全阻止了 SR58611A 诱导的肝硬化门静脉舒张。最后，在肝硬化和对照组动物的肝脏、心脏和门静脉中鉴定出β(3) -肾上腺素能受体；它们在肝硬化大鼠中的表达增加。
结论和意义
β(3) -肾上腺素能受体在实验性肝硬化门静脉高压中发生改变，可能是一个新的治疗靶点。
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