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EFFECTS OF CB1 BLOCKADE IN CARDIAC CONTRACTILITY OF CIRRHOTIC RATS AT REST AND IN RESPONSE TO HEMORRHAGE
SA Gaskari, H Liu, H Honar, SS Lee
Liver Unit, Gastrointestinal Research Group, Department of Medicine, University of Calgary, Calgary, AB, Canada
Baseline cardiac function is normal in cirrhosis but its responsiveness to stressful stimuli is blunted. Previously, we have provided in vitro evidence suggesting a role for increased local cardiac production of endocannabinoids acting on cannabinoid receptor-1 (CB1) in a rat model of cirrhosis. We aimed to clarify the effect of CB1 blockade on cardiac function of cirrhotic rats in vivo at rest and in response to hemorrhage.
Cirrhosis was induced in male Sprague_Dawley rats by bile duct-ligation (BDL), whereas controls underwent a sham operation. 4 weeks after surgery, under pentobarbital anesthesia, we measured left ventricular (LV) pressure and volume by an intraventricular microprobe, mean arterial pressure (MAP), and heart rate (HR). In two sets of experiments AM251 (CB1 antagonist) was administered acutely (3 mg/kg, iv bolus) or chronically (4 mg/kg/day, SC, for two days). Controlled hemorrhage was induced from femoral artery.
Acute AM251 administration significantly increased MAP and LV dP/dT while it significantly decreased LV end-diastolic volume in BDL rats. Hemorrhage induced a significant decrease in MAP, LV pressure, and LV dP/dT in BDL rats. These changes were not restored in the vehicle treated BDL rats. However, chronic administration of AM251 significantly improved their cardiac response to hemorrhage. This was shown by a significant increase in MAP, LV pressure, and LV dP/dT after induction of hemorrhage. LV dP/dT response to hemorrhage is shown in the figure. These treatments had no significant effect in the sham group.
These findings confirm the CB1-mediated cardiac effect of endocannabinoid system overactivity in cirrhosis in an in vivo setting. Furthermore, it suggests a beneficial role for CB1 blockade in improving cardiac response to hemorrhage in cirrhotic rats.
