Sevoflurane Confers Additive Cardioprotection to Ethanol Preconditioning Associated With Enhanced Phosphorylation of Glycogen Synthase Kinase-3? and Inhibition of Mitochondrial Permeability Transition Pore Opening
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Published:25th Mar 2020
Objective: The purposes of this study were to investigate whether sevoflurane (SEVO) enhances moderate-dose ethanol (EtOH) preconditioning and whether this additional cardioprotection is associated with glycogen synthase kinase-3? (GSK-3?), protein kinase B (Akt), mammalian target of rapamycin (mTOR), 70-kDa ribosomal s6 kinase-1 (p70s6K), and/or mitochondrial permeability transition pore (MPTP) opening. Design: In vitro study using an isolated heart Langendorff preparation. Setting: University research laboratory. Participants: Male guinea pigs (n = 170). Interventions: Isolated perfused guinea pig hearts underwent 30-minute ischemia and 120-minute reperfusion (control). The EtOH group received 5% EtOH in the drinking water for 8 weeks. Anesthetic preconditioning was elicited by a 10-minute exposure to 2% SEVO in EtOH (EtOH + SEVO group) or non-EtOH (SEVO group) hearts. The inhibition of GSK-3? phosphorylation and mTOR was achieved with LY294002 and rapamycin, respectively. GSK-3?, Akt, mTOR, and p70s6K expressions were determined by western blot. Calcium-induced MPTP opening was assessed in isolated calcein-loaded mitochondria. Measurements and Main Results: After ischemia-reperfusion, the EtOH, SEVO, and EtOH + SEVO groups had higher left ventricular developed pressure recovery and lower end-diastolic pressure versus the control group. Infarct size was smaller in the EtOH and SEVO groups versus control and even smaller in the EtOH + SEVO group. Phosphorylation of GSK-3? and Akt, but not mTOR and p70s6K, was increased in the EtOH and SEVO groups. Phosphorylation of GSK-3?, but not mTOR and p70s6K, was further increased in the EtOH + SEVO group. The EtOH and SEVO groups exhibited a smaller calcium-induced MPTP opening, and the EtOH + SEVO presented an even smaller MPTP opening. Conclusions: SEVO and chronic EtOH preconditioning offer additive cardioprotection. This effect is associated with an increased GSK-3? phosphorylation and an inhibition of MPTP opening.