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

• Published in: Membranes (Basel) 2023-01, Vol.13 (1), p.63
• Main Authors: Popov, Sergey V., Mukhomedzyanov, Alexandr V., Maslov, Leonid N., Naryzhnaya, Natalia V., Kurbatov, Boris K., Prasad, N. Rajendra, Singh, Nirmal, Fu, Feng, Azev, Viacheslav N.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AMP-activated protein kinase; Calcium conductance; Cardiology; Cardiomyocytes; Channel opening; Channels; Clinical medicine; Coronary artery; Coronary vessels; Deltorphin II; Drug dosages; Drugs; Extracellular signal-regulated kinase; Guanylate cyclase; Heart; Ischemia; Janus kinase; KATP channels; Kinases; Laboratory animals; Membrane permeability; Mitochondrial permeability transition pore; Myocardial infarction; Narcotics; Nitric-oxide synthase; Occlusion; Opioid receptors; Ostomy; Peptides; Pharmacology; Potassium; Potassium channels (calcium-gated); Potassium conductance; Protein kinase A; Protein kinase C; Proteins; Reactive oxygen species; Receptors; Reperfusion; Software; Veins & arteries
• ISSN: 2077-0375; 2077-0375
• DOI: 10.3390/membranes13010063

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.