Dexmedetomidine Provides Cardioprotection During Early or Late Reperfusion Mediated by Different Mitochondrial K+-Channels

Abstract

Background: Cardioprotective interventions—such as pharmacological postconditioning—are a promising strategy to reduce deleterious consequences of ischemia and reperfusion injury (I/RI) in the heart, especially as timing and onset of myocardial infarction are unpredictable. Pharmacological postconditioning by treatment with dexmedetomidine (Dex), an α2-adrenoreceptor agonist, during reperfusion protects hearts from I/RI, independently of time point and duration of application during the reperfusion phase. The mitochondrial ATP-sensitive K+ (mKATP) and mitochondrial large-conductance calcium-sensitive potassium channel (mBKCa) play a pivotal role in mediating this cardioprotective effect. Therefore, we investigated whether Dex-induced cardioprotection during early or late reperfusion is mediated variously by these mitochondrial K+-channels. METHODS: Hearts of male Wistar rats were randomized into 8 groups and underwent a protocol of 15 minutes adaption, 33 minutes ischemia, and 60 minutes reperfusion in an in vitro Langendorff-system. A 10-minute treatment phase was started directly (first subgroup, early reperfusion) or 30 minutes (second subgroup, late reperfusion) after the onset of reperfusion. Control (Con) hearts received vehicle only. In the first subgroup, hearts were treated with 3 nM Dex, 100 µM mKATP-channel blocker 5-hydroxydecanoate (5HD) or 1 µM mBKCa-channel blocker Paxilline (Pax) alone or with respective combinations (5HD + Dex, Pax + Dex). Hearts of the second subgroup received Dex alone (Dex30’) or in combination with the respective blockers (5HD + Dex30’, Pax + Dex30’). Infarct size was determined with triphenyltetrazoliumchloride staining. Hemodynamic variables were recorded during the whole experiment. RESULTS: During early reperfusion (first subgroup), the infarct size reducing effect of Dex (Con: 57% ± 9%, Dex: 31% ± 7%; P< .0001 versus Con) was completely abolished by 5HD and Pax (52% ± 6%; Pax + Dex: 53% ± 4%; each P< .0001 versus Dex), while both blockers alone had no effect on infarct size (5HD: 54% ± 8%, Pax: 53% ± 11%). During late reperfusion (second subgroup) the protective effect of Dex (Dex30’: 33% ± 10%, P< .0001 versus Con) was fully abrogated by Pax (Pax + Dex30’: 58% ± 7%, P < .0001 versus Dex30’), whereas 5HD did not block cardioprotection (5HD + Dex30’: 36% ± 7%). Between groups and within each group throughout reperfusion no significant differences in hemodynamic variables were detected. CONCLUSIONS: Cardioprotection by treatment with Dex during early reperfusion seems to be mediated by both mitochondrial K+-channels, whereas during late reperfusion only mBKCa-channels are involved.

Intraoperative Dexmedetomidine Improves the Outcome of Pediatric Cardiac Surgery: A One-Year Cohort Study

“… 2 -adrenergic agonists are known to have a protective effect on myocardial ischemia by increasing cAMP levels and enhancing adenosine-induced coronary vasodilatation. Preconditioning with dexmedetomidine has been shown to attenuate myocardial ischemia/reperfusion injury by activating pro-survival kinases [ 19 , 20 ]. Both preconditioning and postconditioning with dexmedetomidine can therefore effectively protect the heart and brain from ischemia-reperfusion injury [ 21 , 22 ].…”

EDA2R knockdown alleviates myocardial ischemia/reperfusion injury through inhibiting the activation of the NF-κB signaling pathway

“…DEX is effective in attenuating the stress response to surgical stimulation and improving the oxygen supply-demand balance in the heart [25]. In addition, various studies have indicated that DEX exerts protective effects against I/R injury via direct action on the myocardium [26][27][28].…”

Etomidate Attenuates the Ferroptosis in Myocardial Ischemia/Reperfusion Rat Model via Nrf2/HO-1 Pathway

“…Postconditioning is considered to be a novel strategy to reduce myocardial damage during IR episodes (17, 18). Therefore, the present study aimed to explore the role of Eto postconditioning in MIRI rats.…”