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004 ENDOCANNABINOID SYSTEM OVERACTIVITY AND CIRRHOTIC CARDIOMYOPATHY IN A RAT MODEL OF CIRRHOSIS SA Gaskari, H Liu, H Honar, SS Lee Baseline cardiac function is normal in cirrhotic patients but its responsiveness to stressful stimuli is blunted. This phenomenon is termed 'cirrhotic cardiomyopathy'. Previously, we have provided in vitro pharmacological evidence suggesting a role for increased local cardiac production of endocannabinoids in a rat model of cirrhosis. We aimed to further clarify the role of endocannabinoid system in pathogenesis of cirrhotic cardiomyopathy in an in vivo setting. Furthermore, we examined cardiomyocytes as possible source for local endocannabinoid production in the cirrhotic rat heart.
Liver Unit, Gastrointestinal Research Group, Department of Medicine, University of Calgary, Calgary, Alberta
Cirrhosis was induced in male Sprague-Dawley rats by bile duct-ligation (BDL), whereas controls underwent a sham operation. Four weeks after surgery, under ketamine/xylasine anesthesia, we measured left ventricular (LV) volume and pressure by an intraventricular microprobe, cardiac output (CO) by thermodilution, mean arterial pressure (MAP), and heart rate (HR). Effect of intravenous administration of AM251 (cannabinoid receptor-1 antagonist, 3 mg/kg) and capsazepine (vanilloid receptor-1 antagonist, 3 mg/kg) were explored. In another set of experiments, contractile response of isolated cardiomyocytes to VDM11 (anandamide reuptake blocker) was measured.
AM251 administration significantly increased MAP and LV dP/dT while it significantly decreased left ventricular end-diastolic volume (LVEDV) in BDL rats. This treatment had no significant effect in the sham group. Capsazepine treatment did not induce a significant change in MAP, LV dP/dT, and LVEDV in BDL and sham animals. Treatment of isolated cardiomyocytes with VDM11 did not change their contractile function.
These findings confirm the direct CB1-mediated cardiac effect of endocannabinoid system overactivity in cirrhosis. Absent VDM11 response in isolated cardiomyocytes does not support their role in local production of endocannabinoids; however, this issue requires further investigation.