CB(1) cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction.
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(-1) d(-1)), the potent synthetic cannabinoid HU-210 (50 micro g 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 micro l vs control: 820+/-40 micro l vs HU-210: 790+/-50 micro l; P<0.05) 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, 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). 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 CB(1) antagonism promotes remodeling despite unchanged myocardial CB(1) expression.
Wagner
Jens A
JA
Department of Medicine and Cardiology, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. j.wagner@medizin.uniwuerzburg.de
Hu
Kai
K
Karcher
Jan
J
Bauersachs
Johann
J
Schäfer
Andreas
A
Laser
Martin
M
Han
Hong
H
Ertl
Georg
G
D000818:Animals; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000150:complications* / Q000209:etiology*; D007022:Hypotension / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control*; D009203:Myocardial Infarction / Q000150:complications; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D043882:Receptors, Cannabinoid