2-Arachidonylglycerol Acting on CB1 Cannabinoid Receptors Mediates Delayed Cardioprotection Induced by Nitric Oxide in Rat Isolated Hearts

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Abstract

Endocannabinoids have been implicated in protective effects in the heart and brain, but the mechanism of possible infarct-size–reducing effects remains controversial. Using a model of delayed preconditioning (PC), rats received the nitric oxide (NO) donor nitroglycerin (0.15 mg/h/kg) for 24 hours via transdermal application. Two days later, rat isolated perfused hearts were subjected to global, no-flow ischemia (20 min), and reperfusion (120 min). Cannabinoid receptor antagonists were given before no-flow throughout the protocol. Endocannabinoids were detected by liquid chromatography and mass spectrometry. NO-induced PC reduced the left ventricular infarct size from 40.9±3.9% to 27.5±3.8% (P<0.05). Treatment with the specific CB1 cannabinoid receptor antagonist AM-251 (0.3 μM) prevented the protective effect of PC on infarct size (40.2±4.7%, P>0.05 vs. controls). On the contrary, the specific CB2 receptor antagonist AM-630 (0.3 μM) did not alter infarct size (31.6±6.3%, P>0.05 vs. PC alone). Recovery of left ventricular developed pressure and coronary flow was incomplete in control and NO-pretreated hearts and not consistently altered by cannabinoid receptor antagonists. PC increased the heart tissue content of the endocannabinoid 2-arachidonylglycerol (2-AG) from 4.6±1.0 nmol/g in controls to 12.0±2.1 nmol/g (P<0.05). Tissue levels of the endocannabinoid arachidonylethanolamide (anandamide) remained unchanged (19.8±3.9 pmol/g vs. 19.5±4.8 pmol/g). 2-AG (1 μM) or its metabolically stable derivative noladinether (0.1 μM), given 30 minutes before ischemia/reperfusion in unpreconditioned hearts, mimicked the cardioprotective effects of PC and reduced infarct size.

We conclude that delayed PC through transdermal nitroglycerin application increases the production of the endocannabinoid 2-AG which elicits protective effects against myocardial infarction via CB1 cannabinoid receptors which represents one new mechanism of NO-mediated PC.

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