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

Background the antihypertensive drug alpha-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(H2O)(2)]H2O (ZnMD) provide a promising alternative pathway to improve the biological properties of MD.Methods ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl2 were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91(phox) and p47(phox)) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis.Results The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative Delta G values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 +/- 8.1 mmHg and 145 +/- 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment.Conclusion Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.

Automated summary

The zinc coordination complex ZnMD, synthesized in this study, showed promising effects in treating hypertension and cardiac hypertrophy. It was more effective than the antihypertensive drug MD in reducing blood pressure and preventing myocardial hypertrophy. ZnMD also exhibited protective effects on the heart by reducing oxidative damage and regulating the expression of oxidative enzymes. These findings suggest that ZnMD has the potential to be developed as a therapeutic drug for hypertension and cardiac dysfunction.