Improvement of the cardiovascular effect of methyldopa by complexation with Zn(II): Synthesis, characterization and mechanism of action

ACTIS DATO, AGUSTIN B.; PORTIANSKY, ENRIQUE L.; WILLIAMS, PATRICIA A. M.; MARTINEZ, V; DE GIUSTI, VERÓNICA; VELEZ RUEDA, JORGE O.; FERRER, EVELINA G.

Puerto Varas

Congreso; PANAM Physiological Sciences 2023; 2023

Chilean Society of Physiological Sciences (SCHCF) and Latin American Association of Physiological Sciences (ALACF).

Introduction: α-methyldopa (MD) is used for managing hypertension during pregnancy. Zinc deprivation hasbeen associated with many diseases.Objectives: The synthesis of a Zn coordination complex[Zn(MD)(OH)(H2O)2].H2O (ZnMD) provide apromising alternative pathway to improve the biological properties of MD.Methods: Fluorescence spectral studies were conducted toexamine the binding of complex with bovine serum albumin (BSA).  MD, ZnMD, and ZnCl2 wereadministered to spontaneous hypertensive rats (SHR) rats during 8 weeks and systolicblood pressure (SBP) and echocardiographic parameters were determined (CICUAL Protocolnumber: T02-02-2023). Ex vivo assays were conducted toevaluate oxidative stress parameters of cardiac tissues, and cross-sectionalarea (CSA) and collagen levels of left ventricular cardiomyocytes. Theexpression of NAD(P)H oxidase subunits (gp91phox and p47phox)and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis.Results: ZnMD exhibited a moderate affinity for bindingwith BSA, involving Van der Waals forces and hydrogen bonds. Upon treatment inSHR, a reduction in SBP was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week, respectively, n=4).ZnMD prevented myocardial hypertrophy, improved heart function and reducedcardiac fibrosis. In contrast, MD did not show noticeable differences in theseparameters. ZnMD regulated negatively the oxidative damage and increased SOD1expression, while MD did not show significant effect. Conclusion: Both MD and ZnMD have the potential to betransported by albumin. Our findings provide important evidence suggesting thatthis complex could be a potential therapeutic drug for the treatment ofhypertension and cardiac hypertrophy and dysfunction. Financing: This work was supported by: UNLP [X/871,V720], CONICET [PIP 1999], CICPBA and ANPCyT [PICT-2019-0945] Argentina. AADand VRM are fellowship holders of CONICET. ELP, VDG, and EGF are researchfellows of CONICET and PAMW is research fellow of CICPBAAcknowledgments: The authors thank to Leandro Di Cianni for thetechnical support to measure the blood pressure and Dr. Nadir Jori, for themeasurements of the RMN spectrum.