CB 1 cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction (original) (raw)

2003, British Journal of Pharmacology

1 To study the long-term effects of altered cannabinoid receptor activity on myocardial and vascular function, Wistar rats were treated with the selective CB 1 antagonist AM-251 (0.5 mg kg À1 d À1 ), the potent synthetic cannabinoid HU-210 (50 mg kg À1 d À1 ) 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 (Po0.05) and increased the left-ventricular operating volume (AM-251: 930740 ml vs control: 820740 ml vs HU-210: 790750 ml; Po0.05) in rats with large myocardial infarction (MI). 3 Left-ventricular CB 1 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 CB 1 receptors, increased the left-ventricular end-diastolic pressure (LVEDP, Po0.05). However, it prevented the drop in left-ventricular systolic pressure (HU-210: 14275 mm Hg; Po0.05 vs control: 12473 mm Hg; and Po0.001 vs AM-251: 11473 mm Hg) and prevented endothelial dysfunction (ED) in aortic rings of rats with large MI (Po0.05). 5 Compared with AM-251, HU-210 prevented the decline in the maximal rate of rise of leftventricular pressure and the maximum pressure-generating ability (Po0.05). In rats with small MI, HU-210 increased cardiac index (Po0.01) and lowered the total peripheral resistance (Po0.05). 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 CB 1 antagonism promotes remodeling despite unchanged myocardial CB 1 expression. index; dP/dt max , maximal rate of rise of left-ventricular systolic pressure; ED, endothelial dysfunction; HR, heart rate; HU-210, {-}-11-OH-D 9 tetrahydrocannabinol dimethylheptyl; LVEDP, left-ventricular end-diastolic pressure; MAP, mean arterial pressure; MI, myocardial infarction; SVI, stroke volume index; TPRI, total peripheral resistance index