Cirrhosis is associated with development of tolerance to cardiac chronotropic effect of endotoxin in rats

Abstract

Sepsis is a common complication of cirrhosis with a high mortality. Cirrhosis is associated with cardiac chronotropic and inotropic dysfunction, which is known as cirrhotic cardiomyopathy and might be linked to endotoxaemia. This study was aimed to explore the hypothesis that the inflammatory response induced by administration of low dose of lipopolysaccharide (LPS) exacerbates cardiac chronotropic dysfunction in cirrhotic rats; and if so, whether this is associated with altered cardiac toll-like receptor expression. Cirrhosis was induced by surgical ligation of the bile duct in male Wister rats. Four weeks after bile duct ligation or sham surgery, the subjects were given intraperitoneal injection of either saline or LPS (0.1 mg/kg). Five hours after LPS injection, the atria were isolated and spontaneously beating rate and chronotropic responsiveness to β-adrenergic stimulation was assessed using standard organ bath. The expression of toll-like receptor 4 (TLR4) was assessed the atria using immunohistochemistry as well as quantitative RT-PCR. LPS injection could induce a significant hypo-responsiveness to adrenergic stimulation in sham-operated rats. However, in cirrhotic rats, the chronotropic responses did not change after acute injection of LPS. Immunohistochemical study showed that TLR4 is mainly expressed in the myocardium in control atria and its expression is markedly decreased in myocardial layer following chronic bile duct ligation. Our data showed that cirrhosis is associated with development of tolerance to cardiac chronotropic effect of LPS in rats and this might be caused by altered localization of TLR4 in myocardium.