Endogenous κ-Opioid Peptide Mediates the Cardioprotection Induced by Ischemic Postconditioning

Abstract

The aim of this study was to investigate the underlying mechanism that dynorphin, an endogenous kappa opioid receptor (κ-OR) agonist, triggers antiapoptotic effect of postconditioning (Postcon). In addition to vehicle treatment, Sprague Dawley rats (n = 6) underwent a 30-minute left anterior descending occlusion followed by 2 hours of reperfusion with or without a Postcon stimulus. The selective κ-OR antagonist nor-binaltorphimine (Nor-BNI) was administered intravenously 5 minutes before reperfusion. Infarct size was determined by using 2,3,5-triphenyltetrazolium chloride staining. Blood plasma concentrations of creatine kinase (CK) and lactate dehydrogenase (LDH) and myocardial caspase-3 activity were analyzed spectrophotometrically. Myocardial apoptosis was analyzed by the detection of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling. Immunoreactive dynorphin in blood serum and myocardium was measured by means of an antigen-competitive enzyme-linked immunosorbent assay. Infarction size, caspase-3 activity, apoptotic index, and CK and LDH levels were significantly higher in the ischemic/reperfusion group than in the vehicle group (P < 0.01). Postcon significantly reduced infarction size, caspase-3 activity, apoptotic index, CK and LDH levels (P < 0.01 vs. ischemic/reperfusion). Dynorphin content significantly increased after Postcon (P < 0.01). All the effects described above were abolished by Nor-BNI, with the exception of dynorphin content. We found that cardiac protection and antiapoptotic effect of Postcon is mediated by the activation of κ-OR. Effect of Postcon is mediated, at least partially, by enhanced dynorphin expression.

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

“…Nor-BNI was used at a dose 9 mg/kg as recommended by Birch et al (1987), and several recent reports demonstrated that even lower doses (0.3-2.0 mg/kg) of this antagonist inhibited κ-OR-mediated effects (Gross et al, 2010;Guo et al, 2011;Tong et al, 2011;LonghiBalbinot et al, 2011). BNTX at a dose of 0.7 mg/kg eliminated neither the infarct-sparing effect (Maslov et al, 2009) nor the antinociceptive effect of the selective δ 2 -OR agonist deltorphin II (Sofuoglu et al, 1993), but it increased the antinociceptive ED 50 value of the intrathecally administered δ 1 -OR agonist DPDPE 5.9-fold (Sofuoglu et al, 1993).…”

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

“…In contrast to studies implicating DOR and possibly MOR involvement, Guo et al . () report increased cardiac content of the KOR peptide dynorphin during ischaemic post‐conditioning in rats, in association with KOR‐antagonist sensitive protection.…”

Extracellular signalling molecules in the ischaemic/reperfused heart – druggable and translatable for cardioprotection?

“…The most important receptor for protection is the δ receptor. A specific δ receptor antagonist reduces cardioprotection markedly, whereas a κ receptor antagonist has little effects on ischaemic preconditioning (Schultz et al ., ; Aitchison et al ., ) and ischaemic postconditioning in rats (Jang et al ., ; Zatta et al ., ; Guo et al ., ), and during RIPC in rats (Wong et al ., ).…”