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EVALUATION OF CARDIOPROTECTIVE EFFECTS OF THE INCRITIN MIMETICS EXENATIDE AND VILDAGLIPTIN IN THE EXPERIMENT

Introduction: The results of experimental and clinical trials make it clear that incretin mimetics possess pleiotropic effects and demonstrate the value in terms of assessment of their potential opportunities as cardioprotectors. Goals: To study the cardioprotective effects of exenatide and vildagliptin on the model of doxorubicin-induced cardiomyopathy. Methods: The experiments on the Langendorf isolated rat heart were dedicated to the study of cardioprotactive activity of exenatide (10 mcg/kg/day) («Byetta®», Eli Lilly and Company, USA) and vildagliptin (0.2 mg/kg/day) («Galvus®», Novartis, Switzerland), on the contractile function of the isolated heart wich was previously perfused with doxorubicin (20 mg/kg, intraperitoneally before 48 hours). The evaluation of cardioprotactive activity was based on the findings of the functional trial with high-frequency stimulation (480 bmp) in hypercalcium (5 mmol) perfusion. The complex evaluation of the myocardial damage in the flowing perfusate from isolated hearts included the assessment of creatine phosphokinase isoenzyme (CPK-MB) and lactic dehydrogenase (LDH). The activity of lipid peroxidation (LPO) was evaluated by measuring the content of malondialdehyde (MDA) and diethenoid conjugant (DC). Results: Exenatide (10 mcg/kg/day) and vildagliptin (0.2 mg/kg/day) demonstrate a cardioprotactive effect on the model of doxorubicin-induced pathology, resulting in a decrease of diastolic dysfunction to 5.3±0.1 units and 6.5±0.2 units respectively, compared to control 8.3±0.1 units. The cardioprotactive effect was confirmed by 27% and 19% decrease in the levels of CPK-MB marker damage, and by 11.8% and 9.6% decrease in LDH levels respectively in exenatide and vildagliptin series, compared to control. The cardioprotactive effect was also confirmed by prevention of accumulation of lipid peroxidation products of MDA and DC in the ventricular myocardium. Conclusion: Exenatide (10 mcg/kg/day) and vildagliptin (0.2 mg/kg/day) decrease diastolic disfunction, resulting in the recovery of the contractile function of the heart, reduction of the “diastole defect” (StТТI), and the decrease in irreversible damages of cardiomyocytes.

Иллюстрации

Figure 1. Exercise tolerance test under submaximal electrical stimulation of a rat heart isolated by Langendorf. Са2+ concentration in perfusate – 5 mmol/L. Intact group.Pressure profile in the left ventricle (mmHg) at imposing qickened heartbeat (480 bpm) within 15 sec. Са2+ concentration in perfusate – 5 mmol/L. Doxorubicin (20 mg/kg ) given at a single dose within 48 hours (а). Intact group (b).

Table 1. Effects of incretin mimetics  exenatide and vildagliptin on indices of contractile function of the heart of rats with doxorudicine cardiomyopathy (M ± m; n = 10).

Note: LVL – left ventricular pressure (mmHg); + dp/dtmax – maximum contraction rate (mmHg/sec); -dp/dtmax maximum relaxation rate (mmHg/sec); HR – heart rate (bpm). Doxorubicin was administered intraperitoneally 48 hours before the experiment. The incretin mimetics  – exenatide and vildagliptin – were administered twice at an interval of 24 hours, respectively intramuscularly and intrahepatically. ** - p <0.005 in comparison with the group of intact animals *- p <0.005 in comparison with the control group.

Figure 2. Content of  creatine phosphokinase in the perfusate in groups under Exenatide (10 mcg /kg/day) and Vildagliptine (0.2 mg/kg/day) on the background of Doxorubicin myocardiopathy. * – р< 0.05 in comparison with the control. ** – р< 0.05  in comparison with the group of intact animals.

Figure 3. Content of  lactate dehydrogenase in the groups under Exenatide (10 mcg /kg/day) and Vildagliptine (0.2 mg/kg/day) on the background of Doxorubicin myocardiopathy. * – р< 0.05 in comparison with the control. ** – р< 0.05  in comparison with the group of intact animals.

Figure 4. Content of  malonic dialdehyde in the groups under Exenatide (10 mcg /kg/day) and Vildagliptine (0.2 mg/kg/day) on the background of Doxorubicin myocardiopathy. * – р< 0.05 in comparison with the control. ** – р< 0.05  in comparison with the group of intact animals.

Figure 5. Content of  diene conjugates in the groups under Exenatide (10 mcg /kg/day) and Vildagliptine (0.2 mg/kg/day) on the background of Doxorubicin myocardiopathy.* – р< 0.05 in comparison with the control. ** – р< 0.05  in comparison with the group of intact animals.

DOI: 10.18413/2313-8971-2017-3-2-57-63
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