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. 2005 Oct;146(3):315-23.
doi: 10.1038/sj.bjp.0706331.

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

Seyed Ali Gaskari  1 , Hongqun Liu, Leila Moezi, Yang Li, Soon Koo Baik, Samuel S Lee
Affiliations

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

Seyed Ali Gaskari et al. Br J Pharmacol. 2005 Oct.

Abstract

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. 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. Dose-response curve for a beta-adrenergic agonist isoproterenol was constructed in the presence and absence of a CB-1 antagonist AM251 (1 microM). Cirrhotic muscles had a blunted response to isoproterenol, which was completely restored by AM251. Dose-response curves to anandamide, and CB-1 and CB-2 protein and mRNA expression in Western blot and reverse transcriptase-polymerase chain reaction experiments were not significantly different between cirrhotic and sham muscles. 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. Taken together, these results indicate a pathogenic role for increased local (neuronal) production of endocannabinoids, mediated by a G(i)-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.

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Figures

Figure 1
Figure 1
(a and b), Effect of 30 min preincubation with a CB-1 antagonist (AM251, 1 μM) and anandamide (0.3 μM) on isoproterenol dose–response curves of isolated papillary muscles. Values are the mean±s.e.m. of four to five rats per group. BDL, bile duct-ligated group; ANM, anandamide. *P<0.05 compared to maximum response of sham group. #P<0.05 compared to maximum response of BDL group.
Figure 2
Figure 2
Dose–response curves to anandamide in the presence and absence of a CB-1 antagonist (AM251, 1 μM) in isolated papillary muscles. Values are the mean±s.e.m. of four to five rats per group. BDL, bile duct-ligated group. *P<0.05 compared to maximum response of sham group. #P<0.05 compared to maximum response of BDL group.
Figure 3
Figure 3
mRNA expression of CB-1 and CB-2 receptors in ventricular homogenates by RT–PCR. BDL, bile duct-ligated group; PC, positive control (cerebellum for CB-1 and spleen for CB-2). There were no significant differences in band density of CB-1 or CB-2 between BDL and shams.
Figure 4
Figure 4
Western blot protein expression of CB-1 and CB-2 receptors and FAAH in ventricular homogenates. BDL, bile duct-ligated group. There were no significant differences between BDL and sham groups in these proteins.
Figure 5
Figure 5
(a and b), Effect of 30 min preincubation with an anandamide reuptake blocker (VDM11, 10 μM) and a CB-1 antagonist (AM251, 1 μM) or a CB-2 antagonist (AM630, 1 μM) on contractility of isolated papillary muscles at different frequencies of contraction. Values are the mean±s.e.m. of four to five rats per group. BDL, bile duct-ligated group. Tocrisolve, solvent used for VDM11. *P<0.05 compared to maximum response of sham-Tocrisolve group. #P<0.05 compared to maximum response of BDL-Tocrisolve group. +P<0.05 compared to maximum response of BDL-VDM11 group.
Figure 6
Figure 6
(a and b) Effect of 30 min preincubation with an anandamide reuptake blocker (AM404, 10 μM) and a CB-1 antagonist (AM251, 1 μM) or a CB-2 antagonist (AM630, 1 μM) on contractility of isolated papillary muscles at different frequencies of contraction. Values are the mean±s.e.m. of four to five rats per group. BDL, bile duct-ligated group. Tocrisolve, solvent used for AM404. *P<0.05 compared to maximum response of sham-Tocrisolve group. #P<0.05 compared to maximum response of BDL-Tocrisolve group.
Figure 7
Figure 7
(a and b) Effect of 30 min preincubation with an anandamide reuptake blocker (VDM11, 10 μM) and TTX (1 μM) or treatment with PTX (40 μg kg−1 body weight, i.v., 48 h before the experiment) on contractility of isolated papillary muscles at different frequencies of contraction. Values are the mean±s.e.m. of four to five rats per group. BDL, bile duct-ligated group; TTX, tetrodotoxin; PTX, pertussis toxin; Tocrisolve, solvent used for VDM11. *P<0.05 compared to maximum response of sham-Tocrisolve group. #P<0.05 compared to maximum response of BDL-Tocrisolve group.
Figure 8
Figure 8
Effect of 30 min preincubation with an NOS blocker (L-NAME, 10 μM) on contractility of isolated papillary muscles at different frequencies of contraction. Values are the mean±s.e.m. of four to five rats per group. BDL, bile duct-ligated; L-NAME, N-nitro-L-arginine-methyl ester. *P<0.05 compared to maximum response of sham-VDM11 group. #P<0.05 compared to maximum response of BDL-VDM11 group.
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