The Infarct-Reducing Effect of the δ2 Opioid Receptor Agonist Deltorphin II: The Molecular Mechanism

Abstract

The search for novel drugs for the treatment of acute myocardial infarction and reperfusion injury of the heart is an urgent aim of modern pharmacology. Opioid peptides could be such potential drugs in this area. However, the molecular mechanism of the infarct-limiting effect of opioids in reperfusion remains unexplored. The objective of this research was to study the signaling mechanisms of the cardioprotective effect of deltorphin II in reperfusion. Rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The ratio of infarct size/area at risk was determined. This study indicated that the cardioprotective effect of deltorphin II in reperfusion is mediated via the activation of peripheral δ2 opioid receptor (OR), which is most likely localized in cardiomyocytes. We studied the role of guanylyl cyclase, protein kinase Cδ (PKCδ), phosphatidylinositol-3-kinase (PI3-kinase), extracellular signal-regulated kinase-1/2 (ERK1/2-kinase), ATP-sensitive K+-channels (KATP channels), mitochondrial permeability transition pore (MPTP), NO synthase (NOS), protein kinase A (PKA), Janus 2 kinase, AMP-activated protein kinase (AMPK), the large conductance calcium-activated potassium channel (BKCa-channel), reactive oxygen species (ROS) in the cardioprotective effect of deltorphin II. The infarct-reducing effect of deltorphin II appeared to be mediated via the activation of PKCδ, PI3-kinase, ERK1/2-kinase, sarcolemmal KATP channel opening, and MPTP closing.

δ-Opioid Receptor as a Molecular Target for Increasing Cardiac Resistance to Reperfusion in Drug Development

“…These data indicate that AMPK, Jak-2, PKA, and NOS are not involved in the deltorphininduced cardiac tolerance to reperfusion injury (Figure 1). The PKA inhibitor H-89 did not affect the deltorphin II-induced increase in the cardiac tolerance to reperfusion [38]. Therefore, the signaling mechanism of the cardioprotective effect of deltorphin II differs from that of morphine.…”

“…Therefore, the signaling mechanism of the cardioprotective effect of deltorphin II differs from that of morphine. Wortmannin, a PI3K inhibitor, and PD98059, an inhibitor of the signal cascade consisting of MEK1/2 and ERK1/2, abolished the infarct-sparing effect of the peptide δ 2 -OR agonist [38]. It should be noted that all of the indicated inhibitors did not affect the infarct size in the reperfusion of the heart.…”

“…Indeed, it was found that chelerythrine, an inhibitor of most PKC isoforms, abolishes the infarct-limiting effect of deltorphin II during reperfusion [38]. Rottlerin, a selective PKCδ inhibitor, also reversed the cardioprotective effect of deltorphin II (Figure 1).…”

“…It was previously found that the non-selective µand δ-OR agonist D-Ala 2 ,Leu 5 ,Arg 6 enkephalin (dalargin, 0.1 mg/kg) administered to rats before a coronary artery occlusion increased the cGMP level in the area at risk [39]. Deltorphin II had the same effect on the reperfusion of the heart; under the impact of this peptide, the cGMP level in the area at risk increased by two-fold [38]. The sources of cGMP in the cell are soluble guanylyl cyclase (GC) [40] and the atrial natriuretic peptide (ANP) receptor [41].…”

The Signaling Mechanism of Remote Postconditioning of the Heart: Prospects of the Use of Remote Postconditioning for the Treatment of Acute Myocardial Infarction

“…We found that blocking peripheral opioid receptors completely abolished the infarct-reducing effect of RPost induced by hind limb I/R in rats [ 20 ]. It was detected that opioid peptide deltorphin II can mimic RPost [ 30 , 31 ].…”