Direct comparison of the infarct-limiting and hemodynamic effects of various necroptosis inhibitors in the model of prolonged static cold storage of the donor rat heart

Objective. To investigate the effects of various necroptosis inhibitors on the morphological and functional characteristics of the myocardium in the model of prolonged cold preservation of the donor rat heart. Design and methods. Thirty eight Wistar rats were divided into the following groups: 1) control (n = 7), 2) dimethylsulfoxide (DMSO) (n = 7), 3) necrostatin-1s (n = 6), 4) necrosulfonamide (n = 6), 5) necrostatin-5 (n = 6), 6) necrostatin-1 (n = 6). Necroptosis inhibitors were administered by intraperitoneal injection 1 hour prior to the start of the experiment, previously dissolved in DMSO. HTK solution cooled to 4 °C was used as a preservative solution. The functional state of the myocardium was assessed by continuous recording of intraventricular pressure, heart rate and coronary flow velocity. Morphological changes in the myocardium were assessed by the size of myocardial necrosis, measured planimetrically after the end of 8-hour ischemia and 2-hour reperfusion. Results. All investigated necroptosis inhibitors significantly improved the morphological and functional state of the myocardium, which manifested itself in a significantly smaller amount of myocardial necrosis in the groups of necroptotic inhibitors in comparison with control groups and DMSO. Thus, in the groups of necrosulfonamide and necrostatin-1s, myocardial necrosis size was 31 ± 8,7 % and 27 ± 8,2 %, respectively; in necrostatin-5 and necrostatin-1 groups — 37 ± 9,2 % and 34 ± 7,8, respectively, which is lower than in control groups and DMSO (58 ± 8,6 % and 60 ± 7,6 %, respectively, p < 0,05). Also, diastolic intraventricular pressure was lower and pulse intraventricular pressure and coronary flow velocity were higher during the reperfusion period in the groups of necroptosis inhibitors compared to control group and DMSO group (p < 0,05). We did not find any significant differences between necroptosis inhibitors regarding cardioprotective activity in the model of prolonged cold preservation of the donor heart. Conclusions. All inhibitors of necroptosis equally improved the morphological and functional state of the myocardium in the model of prolonged static cold storage of the donor heart.

MIR-223, necroptosis, intraventricular pressure, pulmonary arterial hypertension, hemodynamic effects, cold preservation of the donor heart, cardioprotection, myocardial ischemia and reperfusion injury, necroptosis inhibitors

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