The cannabinoid CB1 receptor antagonist, rimonabant, protects against acute myocardial infarction.
CB1 antagonism is associated with reduced doxorubicin-induced cardiotoxicity and decreased cerebrocortical infarction. Rimonabant, a selective CB1 receptor antagonist, was, before it was withdrawn, proposed as a treatment for obesity and reported to reduce cardiovascular risk by improving glucose and lipid profiles and raising adiponectin levels. The cardioprotective actions of rimonabant in 6-week-old C57BL/6J mice fed either high-fat (HFD) or standard diets (STD) for 8 weeks were investigated. At 14 weeks, mice received rimonabant (10 mg/kg/day, i.p.) or vehicle for 1 week and were then subjected to an in vivo acute myocardial infarction. The influence of rimonabant on infarct size (IS) in CB1 knockout (CB1-/-) and wild-type (CB1+/+) mice was also examined. C57BL/6J mice that had been maintained on STD or HFD exhibited 4.3 and 21.4% reductions in body weight following 7 days rimonabant treatment. Rimonabant reduced IS in both STD (29.6 +/- 3.5% vs. 49.8 +/- 6.9% in control, P < 0.05) and HFD (26.9 +/- 1.5% vs. 48.7 +/- 7% in control, P < 0.05) mice. In CB1-/- mice rimonabant failed to reduce body weight or IS (51.0 +/- 5.3% vs. 49.7 +/- 4.7% in control, P > 0.05), although significant reductions were seen in CB1+/+ mice (IS, 48.9 +/- 4.6% control vs. 30.5 +/- 3.1% rimonabant, P < 0.05). To exclude the possibility that weight loss alone induced cardioprotection, HFD mice were switched to STD for 7 days (HFD-STD), resulting in an 11.3 +/- 1.0% decrease in body weight compared to control (+2.1 +/- 1.1% in HFD). This, however, was not associated with IS reduction (39.1 +/- 3.9% HFD-STD vs. 40.0 +/- 5.3% HFD, P > 0.05). Serum and cardiac adiponectin levels were unaltered by rimonabant treatment. HL-1 cell death was not prevented by 1 or 7 days treatment with rimonabant. We conclude that rimonabant-induced infarct limitation may involve the CB1 receptor, although not necessarily cardiac CB1 receptors, and is unrelated to weight loss or altered adiponectin synthesis.
Lim
Shiang Y
SY
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK.
Davidson
Sean M
SM
Yellon
Derek M
DM
Smith
Christopher C T
CC
D052242:Adiponectin / Q000032:analysis / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant
D052242:Adiponectin; D004041:Dietary Fats; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant