sr-144528 and Myocardial-Ischemia

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.

Topics: Amides; Animals; Arachidonic Acids; Biomarkers; Blotting, Western; Camphanes; Cannabinoid Receptor Modulators; Endocannabinoids; Ethanolamines; Glycerides; Heart; Imidazoles; L-Lactate Dehydrogenase; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; p38 Mitogen-Activated Protein Kinases; Palmitic Acids; Piperidines; Protein Kinase C; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction

We have examined the involvement of the endocannabinoid system in the cardioprotection triggered by lipopolysaccharide (LPS). Rats were treated with saline or LPS (10 microg x Kg(-1)). 24 h later, hearts were excised, retrogradely perfused, submitted to a low-flow ischaemia (0.6 ml x min(-1)) for 90 min and reperfused for 60 min. Some hearts were perfused with either SR 141716A (a cannabinoid CB(1), receptor antagonist 1 microM), SR 144528 (a CB2 receptor anagonist microM), NNLA (3 microM) or sodium nitroprusside (1 microM) 5 min before ischaemia and during the ischaemic period. The cardioprotective effects of LPS treatment, in terms of infarction and functional recovery, were not altered by the perfusion of SR 141716A but abolished by both SR 144528 and NNLA. Finally, SR 144528 abolished the beneficial effects of SNP perfusion. Our results suggest an involvement of endocannabinoids, acting through the CB2 receptors, in the cardioprotection triggered by LPS against myocardial ischaemia. This could be attributed to a relationship between cannabinoids and NO.

Topics: Animals; Camphanes; Cannabinoid Receptor Modulators; Heart; Lipopolysaccharides; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Piperidines; Protective Agents; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant