CARDIOPROTECTIVE EFFECTS OF NECROSTATIN‑1S AND NECROSULFONAMIDE IN THE MODEL OF PROLONGED STATIC COLD STORAGE OF THE DONOR RAT HEART

Objective. To investigate the effects of necroptosis inhibitors — necrosulfonamide and necrostatin‑1s — on morphofunctional characteristics of the myocardium in the model of prolonged cold preservation of the donor rat heart. Design and methods. The study was performed on 27 Wistar rats. The animals were divided into the following groups: 1) control (n = 7), 2) dimethylsulfoxide (DMSO, n = 6), 3) necrostatin‑1s (n = 8), 4) necrosulfonamide (n = 6). All test compounds were administered intraperitoneally 1 hour before the start of the experiment. Histidine-tryptophan-ketoglutarate (HTK) solution cooled to 4 °C was used as a preservative agent. DMSO was used as a solvent for necrostatin‑1s and necrosulfonamide. During the experiment, left ventricular pressure, heart rate and coronary flow were recorded. At the end of 8‑hour of ischemia and 2‑hour of reperfusion, myocardial infarct size was planimetrically evaluated. Results. Necrostatin-1s and necrosulfonamide show cardioprotective effects, as evidenced by the significantly lower levels of myocardial necrosis in these groups, as well as the best indices of intracardiac hemodynamics during reperfusion. In the groups of necrosulfonamide and necrostatin‑1s, myocardial infarct size was 32,2 ± 9,6 and 29,0 ± 9,2 %, respectively, which is significantly lower than in control groups and DMSO (54,4 ± 6,6 and 59,2 ± 5,6 %, respectively, p < 0,05). During reperfusion in necrosulfonamide and necrostatin‑1s groups, higher values of pulse intraventricular pressure and coronary flow rates were recorded, as well as lower diastolic intraventricular pressure, compared to control group and DMSO (p < 0,05). Conclusions. Necroptosis inhibitors necrostatin‑1s and necrosulfonamide improve morphofunctional characteristics of the myocardium state during prolonged cold preservation of the donor heart.

1. Dmitriev Y, Minasyan S, Vasina L, Demchenko E, Galagudza M. Effects of inhibitors of necroptosis and autophagy on morphofunctional characteristics of the myocardium during static cold storage of donor rat heart. Bulletin of Experimental Biology and Medicine. 2015;159(6):792–795. https://doi.org/10.1007/s10517–015–3078–3

2. Takahashi N, Duprez L, Grootjans S, Cauwels A, Nerinckx W, Du Hadaway J et al. Necrostatin‑1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Disease. 2012;3: e437. doi:10.1038/cddis.2012.176

3. Smith C, Davidson S, Lim S, Simpkin J, Hothersall J, Yellon D. Necrostatin: A potentially novel cardioprotective agent? Cardiovasc Drugs Ther. 2007;21:227–233. doi:10.1007/s10557–007–6035–1

4. Dmitriev Y, Minasian S, Demchenko E, Galagudza M. Study of cardioprotective effects of necroptosis inhibitors on isolated rat heart subjected to global ischemia-reperfusion. Bulletin of Experimental Biology and Medicine. 2013; 155(2):245–248. https://doi.org/10.1007/s10517–013–2124–2.

5. Oerlemans M, Liu J, Arslan f, OudenBen K, Middelaar P, Doevendans PA et al. Inhibition of RIP1‑dependent necrosis prevents adverse cardiac remodeling after myocardial ischemiareperfusion in vivo. Basic Res. Cardiol. 2012;107(4):270. doi:10.1007/s00395–012–0270–8

6. Zhao H, Jaffer T, Eguchi S, Wang Z, Linkermann A, Ma D. Role of necroptosis in the pathogenesis of solid organ injury. Cell Death and Disease. 2015;6: e1975. doi:10.1038/cddis.2015.316

7. Pavlovsky A, Lian D, Huang X, Yin Z, Haig A, Jevnikar A et al. RIPK3‑mediated necroptosis regulates cardiac allograft rejection. Am J Transpl. 2014;14(8): 1778–1790. doi:10.1111/ajt.12779