CB1 cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infaretion

I To study the long-term effects of altered cannabinoid receptor activity on myocardial and vascular function, Wistar rats were treated with the selective CB1 antagonist AM-251 (0.5 mg kg(-1)d(-1)), the potent synthetic cannabinoid HU-210 (50 mug kg(-1)d(-1)) or vehicle for 12 weeks after coronary artery ligation or sham operation. 2 AM-251 further reduced the pressure-generating capacity, shifted the pressure volume curve to the right (P<0.05) and increased the left-ventricular operating volume (AM-251: 930+/-40 mul vs control: 820+/-40 mul vs HU-210: 790+/-50 mul; P<0.05) in rats with large myocardial infarction (MI). 3 Left-ventricular CB1 immunoactivity in rats 12 weeks after large MI was unaltered as compared with noninfarcted hearts. 4 Cannabinoid receptor activation through HU-210, a cannabinoid that alters cardiovascular parameters via CB1 receptors, increased the left-ventricular end-diastolic pressure (LVEDP, P<0.05). However, it prevented the drop in left-ventricular systolic pressure (HU-210: 142+/-5mmHg; P<0.05 vs control: 124+/-3mm Hg; and P<0.001 vs AM-251: 114+/-3mmHg) and prevented endothelial dysfunction (ED) in aortic rings of rats with large MI (P<0.05). 5 Compared with AM-251, HU-210 prevented the decline in the maximal rate of rise of left-ventricular pressure and the maximum pressure-generating ability (P<0.05). In rats with small MI, HU-210 increased cardiac index (P<0.01) and lowered the total peripheral resistance (P<0.05). 6 The study shows that during the development of congestive heart failure post-large MI, cannabinoid treatment increases LVEDP and prevents hypotension and ED. Presumed CB1 antagonism promotes remodeling despite unchanged myocardial CB1 expression.