Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats

1 Cardiac contractility in cirrhosis is normal at baseline but hyporesponsive to stimuli, a phenomenon known as ` cirrhotic cardiomyopathy'. The pathogenesis remains unclear. Endocannabinoids are vasoactive, but have not previously been examined in the cirrhotic heart. We therefore aimed to systematically clarify a possible role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy. 2 Cirrhosis was induced in Sprague - Dawley rats by bile duct ligation; controls underwent a sham operation. At 4 weeks after operation, isolated left ventricular papillary muscle contractility was studied. 3 Dose - response curve for a beta- adrenergic agonist isoproterenol was constructed in the presence and absence of a CB- 1 antagonist AM251 ( 1 mu M). Cirrhotic muscles had a blunted response to isoproterenol, which was completely restored by AM251. 4 Dose- response curves to anandamide, and CB- 1 and CB- 2 protein and mRNAexpression in Western blot and reverse transcriptase - polymerase chain reaction experiments were not significantly different between cirrhotic and sham muscles. 5 Force - frequency relationship studies were performed in cirrhotic and normal muscles. At higher frequencies, anandamide reuptake blockers ( VDM11 and AM404) significantly enhanced muscle relaxation in cirrhotic muscles, but not in controls. This effect was completely blocked by AM251 and pertussis toxin, whereas tetrodotoxin partially reversed it. 6 Taken together, these results indicate a pathogenic role for increased local ( neuronal) production of endocannabinoids, mediated by a Gi- protein- dependent CB- 1- responsive pathway in cirrhotic cardiomyopathy. The increased tachycardia- stress- induced release of endocannabinoids may help explain why contractility is normal at baseline but attenuated with stress.