Cirrhotic cardiomyopathy: an endocannabinoid connection?
Cirrhotic cardiomyopathy: an endocannabinoid connection?
复制标题
肝硬化心肌病：与内源性大麻素有关吗？
DOI：
10.1038/sj.bjp.0706332
复制
发表时间：
2005
影响因子：
7.3
通讯作者：
Kunos,George
中科院分区：
文献类型：
--
作者：
Pacher,Pál;Bátkai,Sándor;Kunos,George
It has been known for over half a century that liver cirrhosis is associated with abnormal cardiovascular function (Ma & Lee, 1996; Moller & Henriksen, 2002). Portal hypertension caused by tissue scarring is associated with hyperdynamic circulation, manifested by increased heart rate and cardiac output and reduced splanchnic and systemic vascular resistance with low normal or decreased arterial blood pressure. Although the mechanism of peripheral vasodilation in liver cirrhosis, including the possible role of nitric oxide and other endothelium-dependent factors, has been intensively investigated during the past decades, the results have been disappointingly inconclusive (Ma & Lee, 1996; Moller & Henriksen, 2002). Recent studies have suggested that endocannabinoids and their receptors could play an important role in the hypotension associated with various pathologic states including cardiogenic, haemorrhagic and endotoxic shock (reviewed in Pacher et al., 2005), as well as advanced liver cirrhosis (Batkai et al., 2001; Ros et al., 2002). In these latter studies, intravenous administration of the CB1 antagonist SR141716 increased arterial blood pressure in cirrhotic rats primarily through a vascular mechanism, as suggested by the parallel increase in total peripheral resistance (Ros et al., 2002) and decreased mesenteric blood flow (Batkai et al., 2001). The involvement of vascular CB1 receptors was further indicated by the increased expression of CB1 receptors in vascular endothelial cells from cirrhotic compared to normal livers (Batkai et al., 2001) and the increased relaxation of mesenteric arteries from cirrhotic compared to normal rats in response to the endocannabinoid anandamide (arachidonoyl ethanolamide, AEA)(Domenicali et al., 2005). Also, circulating macrophages and platelets from cirrhotic animals and patients have elevated levels of endocannabinoids and, when isolated and injected into normal rats, these cells elicit SR141716-sensitive hypotension (Batkai et al., 2001; Ros et al., 2002). Patients with cirrhosis often have endotoxemia as lipopolysaccharide generated by normal intestinal bacteria, which is known to stimulate the synthesis of AEA in macrophages (Di Marzo et al., 1999; Liu et al., 2003), gains access to the systemic circulation as a result of its impaired hepatic elimination. On the basis of previous in vitro and in vivo studies of the effects of AEA on blood pressure, it was widely held that the predominant haemodynamic effect in vivo is vascular. However, in these earlier studies the direct cardiac effects were not evaluated. More recent detailed in vivo haemodynamic analyses clearly indicate, however, that AEA-induced hypotension is of predominantly cardiac origin due to a CB1-mediated decrease in cardiac contractility (Batkai et al., 2004; Pacher et al., 2005), which has also been documented in isolated cardiac preparations in vitro (Bonz et al., 2003). The results presented by Gaskari et al.(2005) in this issue implicate a similar endocannabinoid and CB1 receptor-mediated mechanism in the abnormal myocardial contractility associated with liver cirrhosis.Experimental and clinical studies during the past decades have strongly suggested the existence of latent heart failure with impaired responsiveness to standardized pharmacological or physiological stress, termed ‘cirrhotic cardiomyopathy’or CCMP, with pathophysiologic and clinical features distinct from alcoholic cardiomyopathy (Ma & Lee, 1996; Moller & Henriksen, 2002). CCMP is characterized by decreased β-adrenergic responsiveness, defective excitation-contraction coupling and conductance abnormalities, despite the increased baseline cardiac output. This is an …
