Effect of Chronic Continuous Normobaric Hypoxia on Functional State of Cardiac Mitochondria and Tolerance of Isolated Rat Heart to Ischemia and Reperfusion: Role of µ and δ2 Opioid Receptors

Abstract

Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to ischemia/reperfusion injury in vivo and this effect is mediated via µ and δ2 opioid receptors (ORs) activation. CNH has also been shown to be cardioprotective in isolated rat heart. In this study, we hypothesize that this cardioprotective effect of CNH is mediated by activation of µ and δ2 ORs and preservation of mitochondrial function. Hearts from rats adapted to CNH (12 % oxygen) for 3 weeks were extracted, perfused in the Langendorff mode and subjected to 45 min of global ischemia and 30 min of reperfusion. Intervention groups were pretreated for 10 min with antagonists for different OR types: naloxone (300 nmol/l), the selective δ OR antagonist TIPP(ψ) (30 nmol/l), the selective δ1 OR antagonist BNTX (1 nmol/l), the selective δ2 OR antagonist naltriben (1 nmol/l), the selective peptide μ OR antagonist CTAP (100 nmol/l) and the selective κ OR antagonist nor-binaltorphimine (3 nmol/l). Creatine kinase activity in coronary effluent and cardiac contractile function were monitored to assess cardiac injury and functional impairment. Additionally, cardiac tissue was collected to measure ATP and to isolate mitochondria to measure respiration rate and calcium retention capacity. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the postischemic recovery of contractile function. Additionally, CNH improved mitochondrial state 3 and uncoupled respiration rates, ADP/O, mitochondrial transmembrane potential and calcium retention capacity and myocardial ATP level during reperfusion compared to the normoxic group. These protective effects were completely abolished by naloxone, TIPP(ψ), naltriben, CTAP but not BNTX or nor-binaltorphimine. These results suggest that cardioprotection associated with adaptation to CNH is mediated by µ and δ2 opioid receptors activation and preservation of mitochondrial function.

[D-Ala2, D-Leu5] Enkephalin Attenuates Hepatic Ischemia–Reperfusion Injury in Cirrhotic Rats

“…Since the delta opioid receptor (DOR) was discovered by scientists, its role was investigated in neurological diseases and pain control fields (11). It was reported that the IRI in the heart (21), spinal cord (22), and brain (23) could be alleviated and neurological recovery promoted when DOR was activated by DADLE. Like other organs, the liver also contains many DORs (24).…”

New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB

“…Myocardial reperfusion injury and its therapy are under research in cardiology. Nowadays, there is increasing evidence that opioid receptors are an emerging therapeutic target in I/R injury and cardioprotection [ 23 , 24 ]. Small clinical studies using opioid receptor agonists in the reperfusion setting during coronary artery bypass surgery demonstrated beneficial effects in reducing myocardial injury [ 3 ].…”

Participation of bradykinin, cannabinoid, and vanilloid receptors in the infarct-limiting effect of adaptation to normobaric hypoxia

“…Последовательная активация рецепторов (опиоидных или брадикининовых) и Gi/o-белков приводит к запуску внутриклеточного киназного механизма, выключающего протеинкиназу С, NO-синтазу, тирозинкиназы, и в последствии к активации АТФ-чувствительных калиевых каналов митохондрий [27]. Результатом последнего является ингибирование открытия поры, регулирующей проницаемость митохондрий (MPTP), повышение устойчивости митохондрий к ионам кальция, улучшение энергетического метаболизма мито-хондрий и, таким образом, снижение чувствительности клетки к повреждающему действию ишемии и реперфузии [28].…”