Activation of peripheral delta‐2 opioid receptors increases tolerance to ischemia/reperfusion injury

Abstract

We investigated the role of peripheral δ2 opioid receptors (OR) in cardiac tolerance to ischemia/reperfusion injury and examined the contribution of Protein Kinase C (PKC), tyrosine kinase (TK), potassium ATP (KATP) channels and the autonomic nervous system in δ2 cardioprotection. Deltorphin II and inhibitors were administered prior to coronary artery occlusion and reperfusion in a rat model. Rats were monitored for the development of arrhythmias and infarct development. Pretreatment with δ2 specific OR antagonist naltriben completely abolished the cardioprotective effects of Deltorphin II. In contrast the selective δ1 OR antagonist 7‐Benzylidenenaltrexone had no effect. The PKC inhibitor chelerythrine and the nitric oxide synthase (NOS) inhibitor L‐NAME (N‐nitro‐L‐arginine methyl ester) also reversed both Deltorphin II effects. The nonselective KATP channel inhibitor glibenclamide and the selective mitochondrial KATP channel inhibitor 5‐hydroxydecanoic acid abolished the infarct‐sparing effect of Deltorphin II. Inhibition of 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. The cardioprotective mechanism of Deltorphin II is mediated via stimulation of peripheral δ2 opioid receptors.