Activation of peripheral δ2 opioid receptors increases cardiac tolerance to ischemia/reperfusion injury Involvement of protein kinase C, NO-synthase, KATP channels and the autonomic nervous system

Aims: This study aims to investigate the role of peripheral delta(2) opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, K-ATP channels and the autonomic nervous system in delta(2) cardioprotection. Main methods: Deltorphin II and various inhibitors were administered in vivo prior to coronary artery occlusion and reperfusion in a rat model. The animals were monitored for the development of arrhythmias. infarct development and the effects of selected inhibitors. Key findings: Pretreatment with peripheral and delta(2) specific opioid receptor (OR) antagonists completely abolished the cardioprotective effects of deltorphin II. In contrast, the selective delta(1) OR antagonist 7-benzylidenenaltrexone (BNTX) had no effect. The protein kinase C (PKC) inhibitor chelerythrine and the NO-synthase inhibitor L-NAME (N-nitro-L-arginine methyl ester) also reversed both deltorphin II effects. The nonselective ATP-sensitive K+ (K-ATP) channel inhibitor glibenclamide and the selective mitochondria K-ATP channel inhibitor 5-hydroxydecanoic acid only abolished the infarct-sparing effect of deltorphin II. Inhibition of tyrosine kinase (TK) with genistein. the ganglion blocker hexamethonium and the depletion of endogenous catecholamine storage with guanethidine reversed the antiarrhythmic action of deltorphin II but did not change its infarct-sparing action. Significance: The cardioprotective mechanism of deltorphin II is mediated via stimulation of peripheral 82 opioid receptors. PKC and NOS are involved in both its infarct-sparing and antiarrhythmic effects. Infarct-sparing is dependent upon mitochondrial K-ATP channel activation while the antiarrhythmic effect is dependent upon TK activation. Endogenous catecholamine depletion reduced antiarrhythmic effects but did not alter the infarct-sparing effect of deltorphin II. Published by Elsevier Inc.