Ischemia and reperfusion provokes barrier failure of the coronary microvasculature through activation of the endothelial contractile machinery and formation of intercellular gaps, leading to myocardial edema development that jeopardizes functional recovery of the heart. In vivo studies have shown that cannabinoid receptor (CBR) activation protects reperfused hearts against reperfusion injury.

The aim of the present study is to investigate whether CBR activation with the non specific CBR agonist R1-Methanandamide (R1M) can protect coronary endothelium against reperfusion induced gap formation.

Cultured rat coronary endothelial monolayers were submitted to conditions of simulated ischemia (40min; pH6.4) and reperfusion (40min; pH7.4). Stimulation of cannabinoid receptors during reperfusion significantly reduced reperfusion-induced gap formation (gaps[a.U.]: control:28321; R1M [10mM]:17210*; n=8–14;*p<0.05 vs. control). This effect is mediated through activation of CB1 receptors, since application of the CB1 receptor antagonist AM251 [250nM] during reperfusion completely abolished the R1M mediated protection (p<0.05; n=8). Whereas the protection could be further enhanced if AM630 [300nM], a CB2 receptor antagonist, was added to the reperfusion medium simultaneously to R1M application (p<0.05; n=8).

In conclusion, activation of endothelial cannabinoid receptors protects the coronary endothelium against reperfusion-induced gap formation. This protection is mediated through CB1 receptors whereas CB2 receptor activation blunts this protective effect.