Involvement of Endothelin 1 in Remote Preconditioning-Induced Cardioprotection through connexin 43 and Akt/GSK-3β Signaling Pathway.

The present study was aimed to explore the role of endothelins in remote preconditioning (RP)-induced myocardial protection in ischemia-reperfusion (IR) injury. RP stimulus was given by subjecting hind limb to four cycles of ischemia and reperfuion (5 minutes each) using blood pressure cuff in male rats. Following RP, hearts were isolated and subjected to 30 minutes of ischemia and 120 minutes of reperfusion on Langendorff apparatus. The extent of myocardial injury was determined by measuring the levels of LDH-1, CK-MB and cardiac troponin T (cTnT) in coronary effluent; caspase-3 activity and Bcl 2 expression in heart (apoptosis); infarct size by triphenyl tetrazolium chloride and contractility parameters including left ventricular developed pressure, dp/dt _max dp/dt _min and heart rate. RP reduced ischemia reperfusion-induced myocardial injury, increased the levels of endothelin 1 (in blood), Akt-P, GSK-3β-P and P-connexin 43 (in hearts). Pretreatment with ET _A receptor antagonist, BQ 123 (1 and 2 mg/kg), ET _B receptor antagonist, BQ 788 (1 and 3 mg/kg) and dual inhibitor of ET _A and ET _B receptor, bonsentan (25 and 50 mg/kg) abolished these effects of RP. However, the effects of bonsentan were more pronounced in comparison to BQ 123 and BQ 788. It is concluded that RP stimulus may release endothelin 1 in the blood, which may activate myocardial ET _A and ET _B receptors to trigger cardioprotection through connexin 43 and Akt/GSK-3β pathway.