Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts.
The aim of the present study was to document the presence of cannabinoid receptors in the rat heart, and to assess the cardioprotective properties of CB(1)- and CB(2)-receptor agonists. Rat isolated hearts were exposed to low-flow ischemia and reperfusion, with selective cannabinoid agonists administered prior to and during the ischemic period. In some hearts, RT-PCR, Western blots, and immunohistological techniques were used to identify and localize both cannabinoid-receptor subtypes. The effect of cannabinoids on infarct size was evaluated in additional hearts using TTC staining. Protein and mRNA for both CB(1)- and CB(2)-receptors were found in rat heart extracts. CB(1)-receptors were localized almost exclusively on arterial and capillary endothelial cells in intact hearts, whereas CB(2)-receptors appeared on cardiomyocytes and endothelial cells of larger arteries. Both the CB(1)-agonist, ACEA (50 nM), and the CB(2)-agonist, JWH015 (50 nM), reduced infarct size. However, only the cardioprotective effect of the CB(1)-agonist was blocked by the NO-synthase inhibitor, N(G)-nitro-L-arginine (30 microM). In conclusion, CB(1)-receptors are present mainly on endothelial cells in the rat heart, and exert their effect through production of NO. In contrast, CB(2)-receptors present on cardiomyocytes exert a cardioprotective effect independent of this endothelial factor.
Lépicier
Philippe
P
Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada H3C 3J7.
Lagneux
Caroline
C
Sirois
Martin G
MG
Lamontagne
Daniel
D
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D015153:Blotting, Western; D004727:Endothelium / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001095:Arachidonic Acids; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C119325:arachidonyl-2-chloroethylamide; D009569:Nitric Oxide; D012313:RNA; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C402944:JHW 015