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

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

Research output: Contribution to journalArticle

94 Citations (Scopus)

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 β-adrenergic agonist isoproterenol was constructed in the presence and absence of a CB-1 antagonist AM251 (1 μM). 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.

Original languageEnglish
Pages (from-to)315-323
Number of pages9
JournalBritish Journal of Pharmacology
Volume146
Issue number3
DOIs
Publication statusPublished - 2005 Oct 1

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Endocannabinoids
Bile Ducts
Cardiomyopathies
Muscles
Isoproterenol
Fibrosis
Adrenergic Agonists
Muscle Relaxation
Papillary Muscles
Pertussis Toxin
Tetrodotoxin
Reverse Transcriptase Polymerase Chain Reaction
Tachycardia
Ligation
Sprague Dawley Rats
Proteins
Western Blotting
Messenger RNA
AM 251
anandamide

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Gaskari, Seyed Ali ; Liu, Hongqun ; Moezi, Leila ; Li, Yang ; Soon, Koo Baik ; Lee, Samuel S. / Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. In: British Journal of Pharmacology. 2005 ; Vol. 146, No. 3. pp. 315-323.
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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 β-adrenergic agonist isoproterenol was constructed in the presence and absence of a CB-1 antagonist AM251 (1 μM). 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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Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. / Gaskari, Seyed Ali; Liu, Hongqun; Moezi, Leila; Li, Yang; Soon, Koo Baik; Lee, Samuel S.

In: British Journal of Pharmacology, Vol. 146, No. 3, 01.10.2005, p. 315-323.

Research output: Contribution to journalArticle

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