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 μg kg−1 d−1) or vehicle for 12 weeks after coronary artery ligation or sham operation.
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 μl vs control: 820±40 μl vs HU-210: 790±50 μl; P<0.05) in rats with large myocardial infarction (MI).
Left-ventricular CB1 immunoactivity in rats 12 weeks after large MI was unaltered as compared with noninfarcted hearts.
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±5 mm Hg; P<0.05 vs control: 124±3 mm Hg; and P<0.001 vs AM-251: 114±3 mm Hg) and prevented endothelial dysfunction (ED) in aortic rings of rats with large MI (P<0.05).
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).
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.
British Journal of Pharmacology (2003) 138, 1251–1258. doi:10.1038/sj.bjp.0705156