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Abstract: Aims: This study aims to investigate the role of peripheral δ2 opioid receptors in cardiac tolerance to ischemia/reperfusion injury and to examine the contribution of PKC, TK, KATP channels and the autonomic nervous system in δ2 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 δ2 specific opioid receptor (OR) antagonists completely abolished the cardioprotective effects of deltorphin II. In contrast, the selective δ1 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+ (KATP) channel inhibitor glibenclamide and the selective mitochondrial KATP 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 δ2 opioid receptors. PKC and NOS are involved in both its infarct-sparing and antiarrhythmic effects. Infarct-sparing is dependent upon mitochondrial KATP 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. [Copyright &y& Elsevier]

SUMMARY1. The κ1 and κ2 opioid receptor agonists U-62066 (8 mg/kg, i.p.) and (–)-bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti-arrhythmic properties against adrenaline-induced dysrhythmias in rats. 2. In contrast, (+)-bremazocine has no effect on adrenaline-induced dysrhythmias. 3. The κ1 opioid receptor agonists U-50 488 (110 nmol) and [D-Ala2]-dynorphin A (20 nmol) and the κ2 opioid receptor agonist (–)-bremazocine (30 nmol) exhibit pro-arrhythmic properties following intracerebroventricular administration. 4. Prior administration of the κ opioid receptor antagonist nor-binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro-arrhythmic (BNI, i.c.v., 14 nmol) as well as anti-arrhythmic (BNI, 10 mg/kg, i.p.) effects of the κ opioid receptor agonists. 5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti-arrhythmic actions of the κ1 opioid receptor agonist U-62066 following systemic administration. 6. It is suggested that the anti-arrhythmic effects of U-62066 and (–)-bremazocine are associated with the activation of peripheral κ opioid receptors and do not depend on the activation of κ opioid receptors in the autonomic nervous system. [ABSTRACT FROM AUTHOR]

It was established that adaptation to chronic continuous normobaric hypoxia (CCNH) increases cardiac tolerance to ischemia and reperfusion. It was performed coronary artery occlusion (20 min) and reperfusion (3 h) in Wistar rats. CCNH promoted a decrease in the infarct size/area at risk ratio in 2-fold. CCNH promoted an increase in the nitrite/nitrate levels in blood serum and myocardium. Pretreatment with protein kinase C (PKC) inhibitor chelerythrine, NO-synthase (NOS) inhibitor L-NAME, iNOS inhibitor S-methylisothiourea, KATP channel blocker glibenclamide, mitoKATP channel blocker 5-hydroxydecanoic acid abolished the infarct-reducing effect of CCNH. The non-selective tyrosine kinase inhibitor genistein attenuated but not eliminated infarct-sparing effect of CCNH. The nNOS inhibitor 7-nitroindazole, sarcKATP channel blocker HMR 1098, MPT pore inhibitor atractyloside, PI3 kinase inhibitor wortmannin did not reverse infarct-limiting effect of CCNH. It was concluded that infarct-reducing effect of CCNH is mediated via PKC, iNOS activation and mitoKATP channel opening. While nNOS, PI3 kinase, sarcKATP channel, MPT pore are not involved in the development of CCNH-induced cardiac tolerance to impact of ischemia-reperfusion.