Endocannabinoids protect the rat isolated heart against ischaemia.
1 The purpose of this study was to determine whether endocannabinoids can protect the heart against ischaemia and reperfusion. 2 Rat isolated hearts were exposed to low-flow ischaemia (0.5-0.6 ml min(-1)) and reperfusion. Functional recovery as well as CK and LDH overflow into the coronary effluent were monitored. Infarct size was determined at the end of the experiments. Phosphorylation levels of p38, ERK1/2, and JNK/SAPK kinases were measured by Western blots. 3 None of the untreated hearts recovered from ischaemia during the reperfusion period. Perfusion with either 300 nM palmitoylethanolamide (PEA) or 300 nM 2-arachidonoylglycerol (2-AG), but not anandamide (up to 1 micro M), 15 min before and throughout the ischaemic period, improved myocardial recovery and decreased the levels of coronary CK and LDH. PEA and 2-AG also reduced infarct size. 4 The CB(2)-receptor antagonist, SR144528, blocked completely the cardioprotective effect of both PEA and 2-AG, whereas the CB(1)-receptor antagonist, SR141716A, blocked partially the effect of 2-AG only. In contrast, both ACEA and JWH015, two selective agonists for CB(1)- and CB(2)- receptors, respectively, reduced infarct size at a concentration of 50 nM. 5 PEA enhanced the phosphorylation level of p38 MAP kinase during ischaemia. PEA perfusion doubled the baseline phosphorylation level of ERK1/2, and enhanced its increase upon reperfusion. The cardioprotective effect of PEA was completely blocked by the p38 MAP kinase inhibitor, SB203580, and significantly reduced by the ERK1/2 inhibitor, PD98059, and the PKC inhibitor, chelerythrine. 6 In conclusion, endocannabinoids exert a strong cardioprotective effect in a rat model of ischaemia-reperfusion that is mediated mainly through CB(2)-receptors, and involves p38, ERK1/2, as well as PKC activation.
Lépicier
Philippe
P
Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, Canada H3C 3J7.
Bouchard
Jean-François
JF
Lagneux
Caroline
C
Lamontagne
Daniel
D
D000577:Amides; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D015153:Blotting, Western; D001892:Camphanes / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control; D010169:Palmitic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology; D011493:Protein Kinase C / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077285:Rimonabant; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D000577:Amides; D001095:Arachidonic Acids; D015415:Biomarkers; D001892:Camphanes; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D007093:Imidazoles; D010169:Palmitic Acids; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; C110630:SR 144528; C119325:arachidonyl-2-chloroethylamide; C005958:palmidrol; C094503:glyceryl 2-arachidonate; D007770:L-Lactate Dehydrogenase; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000077285:Rimonabant