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Doxorubicin-associated Сardiomyopathy: New Approaches to Pharmacological Correction Using 3-(2,2,2-trimethylhydrazinium) Propionate Derivatives

Introduction: The search for new compounds with cardioprotective activity amongst the 3-(2,2,2-trimethylhydrazinium) propionate derivatives looks promising.

Research objectives: to study cardioprotective effects of the 3-(2,2,2-trimethylhydrazinium) propionate derivatives.

Methods: The cardioprotective effect of the derivatives (nicotinate, 5-hydroxynicotinate) of 3-(2,2,2-trimethylhydrazinium) propionate) and reference medicine meldonium in the case of doxorubicin (DOX) (20 mg/kg, intraperitoneally for 48 hours) cardiomyopathy was evaluated by the results of a functional test with high-frequency stimulation (480 bpm).

To provide integral validation for the development of the simulated pathological processes, biochemical and morphological studies of the heart were carried out. For a biochemical evaluation of myocardial damage in the homogenisate, the isoenzyme creatinine kinase MB (CK-MB) and lactate dehydrogenase (LDH) were determined.

Results: The derivatives nicotinate and 5-hydroxynicotinate of 3-(2,2,2-trimethylhydrazinium) propionate) exert a cardioprotective effect on a doxorubicin pathology model, which is expressed in a decreased coefficient of diastolic dysfunction (StTTI) to the level of 5.8±0.1 ru and 4.6±0.2 ru in comparison with that in the control group 8.3±0.1 ru and reference medicine meldonium 6.5±0.1 ru, respectively.

The cardioprotective effect was confirmed by decreased levels of markers of damage to CK-MB and LDH and a decreased diameter of cardiomyocytes compared to those in the control group.

Conclusion: The derivatives of 3-(2,2,2-trimethylhydrazinium) propionate (nicotinate, 5-hydroxynicotinate) 3-(2,2,2-trimethylhydrazinium) propionate reduce diastolic dysfunction and irreversible damage to cardiomyocytes in case of doxorubicin-associated cardiomyopathy.

Иллюстрации

Figure 1. Chemical structures of 3-(2,2,2-trimethylhydrazinium) propionate derivatives.

Figure 2A. Loading test with submaximal electrostimulation of the isolated Langendorf rat heart. Key: The dynamics of pressure in the left ventricle (mm Hg) with the cardiac stimulation (480 beats per minute) for 11 seconds. Concentrations of Ca2+ in the perfusate 5 mmol/l. Intact group (a). Doxorubicin (20 mg/kg) once per 48 hours (b). From top to bottom: scale 1 – left ventricular pressure (LVP in mm Hg); scale 2 – cardiac pacing (480 beats per minute for 11 seconds); scale 3 – the rate of change of the LDVP (+dP/dtmax, -dP/dtmax, mm Hg/sec)

Figure 2B. Loading test with submaximal electrostimulation of the isolated Langendorf rat heart. Key: The dynamics of pressure in the left ventricle (mm Hg) with the cardiac stimulation (480 beats per minute) for 11 seconds. Concentrations of Ca2+ in the perfusate 5 mmol/l. Intact group (a). Doxorubicin (20 mg/kg) once per 48 hours (b). From top to bottom: scale 1 – left ventricular pressure (LVP in mm Hg); scale 2 – cardiac pacing (480 beats per minute for 11 seconds); scale 3 – the rate of change of the LDVP (+dP/dtmax, -dP/dtmax, mm Hg/sec)

Table 1. Effect of CTK-733 (189 mg/kg/day), CTK-735 (199.1 mg/kg/day) and meldonium (90 mg/kg/day) on functional, biochemical and morphological indices in case of DOX -induced cardiotoxicity (M±m; n = 10)

Key: The coefficient of diastolic dysfunction StITT (ru), creatine kinase CK-MB (IU/L), lactate LDH (IU/L), ** – р<0.05 compared to the group of intact animals; * – р<0.05 compared to the control.

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