Improvement in the antihypertensive and cardiac effects of olmesartan by complexation with Zn(II) in spontaneously hypertensive rats.

VELEZ RUEDA OMAR; FERRER , EVELINA; MARTÍNEZ, VALERIA; DE GIUSTI, V.C.; RESTREPO-GUERRERO, ANDRÉS GONZALO; PORTIANSKY, E.L.; WILLIAMS, P.A.M.

La Plata

Congreso; ISHR-Lat 2022. Congreso anual de la Sección Latinoamericana de la International Society for Heart Research.; 2022

International Society for Heart Research

In this study, modification of the structure of the commercial drug olmesartan by Zn(II) complexation, [Zn(Olme)(H2O)2] (ZnOlme), is presented. It displayed enhanced antihypertensive and cardiac effects.After 8 weeks of treatment in SHR male rats, ZnOlme has a better blood pressure-lowering activity compared with olmesartan and this effect was noticeable even in the first weeks of treatment, while ZnCl2 did not show significant reduction. ZnOlme also reduced left ventricle (LV) weight, left ventricle/tibia lenght ratio (LV/TL) and, at cellular level, attenuated cardiomyocyte enlargement suggesting that it has the potential to prevent LV hypertrophy. Besides, ZnOlme reduced the interstitial fibrosis (assessed by measuring the contents of collagen type I and III). The recovery of heart function was also evidenced by fractional shortening (diastolic left ventricular diameter/systolic left ventricular diameter) determinations.Furthermore, not only olmesartan treatment reduced oxidative stress but also ZnOlme treatment significantly prevented reactive oxygen species (ROS) generation; the production of ROS was significantly higher in non-treated rats. In addition, as an indication of oxidative damage, the generation of thiobarbituric acid reactive substance (TBARS) was assessed. In agreement with ROS results, ZnOlme exerted a significant decrease in the lipid peroxidation. Additionally, administration of ZnOlme markedly enhanced glutathione (GSH) content in heart tissues compared to control and olmesartan. Thus, it can be concluded that ZnOlme increased the antioxidant capacity and prevented cardiac oxidative stress.Our results demonstrate that continuous oral administration of ZnOlme in SHR has a better antihypertensive effect and grant an improvement of cardioprotection through antioxidant activity. These findings indicate that metallodrugs that can reduce the effects of oxidative stress and generate more efficient therapeutic agents for cardiovascular diseases.