[d-Ala2,d-Leu5]-enkephalin (DADLE) and morphine-induced postconditioning by inhibition of mitochondrial permeability transition pore, in human myocardium

Abstract

The aim of the study was to examine the cardioprotective effect of morphine and Delta 2 opioid D-Ala2-Leu5 enkephalin(DADLE) administered, at early reoxygenation, in isolated human myocardium exposed to hypoxia–reoxygenation. Then,we tested the involvement of mitochondrial permeability transition pore in morphine and DADLE-induced postconditioning.Human right atrial trabeculae were obtained during cardiac surgery (coronary artery bypass and aortic valve replacement).Isometrically contracting isolated human right atrial trabeculae were exposed to 30-min hypoxia and 60-min reoxygenation(control group). In treatment groups, morphine 0.5 mmol, DADLE 10 nmol, DADLE 50 nmol and DADLE 100 nmol were administered during the first 15 min of reoxygenation. In two additional groups, morphine and DADLE 100 nmol were administered in the presence of atractyloside 50 mmol, the mitochondrial permeability transition pore opener. The force of contraction at the end of 60-min reoxygenation period (FoC60 expressed as % of baseline) was compared (mean+standard deviation) between the groups by an analysis of variance. Morphine (FoC60: 81+9% of baseline), DADLE50 nmol (FoC60: 76+11% of baseline) and DADLE 100 nmol (FoC60: 81+4% of baseline) increased significantly (P,0.001) the FoC60 as compared with the control group (FoC60: 53+3% of baseline). DADLE 10 nmol did not modify the FoC60 (50+9% of baseline; P ¼ 0.60 versus control group). The enhanced recovery of FoC60 induced by morphine and DADLE 100 nmol were abolished in the presence of atractyloside (FoC60: respectively 57+6% and 44+7% of baseline;P, 0.001). In conclusion, the administration of morphine and DADLE, in early reoxygenation period, protected human myocardium, in vitro, against hypoxia–reoxygenation injury, at least in part, by the inhibition of mitochondrial permeability transition pore opening.

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

“…While there are few studies in humans, one investigation applying PET, supports expression of both MORs and DORs in human heart (Villemagne et al ., ), and more recent analysis identifies all three subtypes on human myocardial cells (Sobanski et al ., ), with the DORs and MORs also expressed on sparse individual nerve fibres, and KORs on intrinsic cardiac adrenergic cell‐like structures. This expression profile is consistent with beneficial responses to MOR and DOR agonists in isolated human myocardium (Bell et al ., ; Lemoine et al ., ; Fuardo et al ., ) and patients (Xu et al ., ; Wong et al ., ) (Table ). Myocardial expression of opioid receptors also appears modifiable under pathological conditions: I–R induces DOR mRNA and protein, together with KOR mRNA in myocardial area‐at‐risk in pigs (Karlsson et al ., ).…”

‘Opioidergic postconditioning’ of heart muscle during ischemia/reperfusion injury

“…Previous studies on the influence of opioids in human cardiac tissue utilized mainly the OR modulators applied before the lethal hypoxic period [8,15]. The novelty of our study is that morphine and DADLE were applied at the reperfusion that makes the study protocol compatible with usual clinical circumstances.…”

“…Morphine was the first opioid with proven cardioprotective effect [6]. More recently, several investigators have demonstrated in an animal model of I/R injury that beneficial effect is mediated via the d-OR pathway [7][8][9]. However, the class of ORs responsible for this effect in humans remains unknown [10].…”

Sufentanil attenuates impairment of the endothelium-dependent vasodilation induced by hypoxia–reoxygenation in the rat coronary artery

“…When used at the beginning of reperfusion, drugs such as opioids may provide cardioprotective effects during cardiopulmonary bypass (Fuardo et al 2013;Zhai et al 2012;Zhang et al 2013). Results of our pilot study suggested that a new postconditioning method, the infusion of sufentanil into the aortic root, can attenuate myocardial I/R injury in patients with mitral valve replacement (Zuo et al 2014) .…”