Actis Dato Agustin B, Martinez Valeria R, Velez Rueda Jorge O, Portiansky Enrique L, De Giusti Verónica, Ferrer Evelina G, Williams Patricia A M
CEQUINOR-CONICET-CICPBA-UNLP, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, Bv. 120 N◦ 1465, 1900 La Plata, Argentina.
CIC-CONICET-UNLP, Facultad de Médicas, Universidad Nacional de La Plata, 60 y 120, 1900 La Plata, Argentina.
J Trace Elem Med Biol. 2024 Jan;81:127327. doi: 10.1016/j.jtemb.2023.127327. Epub 2023 Oct 21.
the antihypertensive drug α-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)(HO)]·HO (ZnMD) provide a promising alternative pathway to improve the biological properties of MD.
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 ZnCl 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 and p47) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis.
The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG 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.
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.
抗高血压药物α-甲基多巴（MD）是孕期治疗高血压广泛使用的药物之一。锌缺乏与多种疾病有关。在此背景下，合成锌配位络合物[Zn(MD)(OH)(HO)]·HO（ZnMD）为改善MD的生物学特性提供了一条有前景的替代途径。
合成ZnMD并对其进行物理化学表征。进行荧光光谱研究以检测配体和金属与牛血清白蛋白（BSA）的结合情况。在8周内给自发性高血压大鼠（SHR）分别施用MD、ZnMD和ZnCl，测定血压和超声心动图参数。进行体外试验以评估活性氧（ROS）、硫代巴比妥酸反应性物质（TBARS）和一氧化氮（NO）的水平。还评估了左心室心肌细胞的横截面积（CSA）和胶原蛋白水平。此外，通过蛋白质印迹分析定量NAD(P)H氧化酶亚基（gp91和p47）和超氧化物歧化酶1（SOD1）的表达。
该络合物与BSA结合表现出中等亲和力，显示出自发相互作用（由负的ΔG值表明）和中等亲和力（由亲和常数确定）。结合过程涉及范德华力和氢键的形成。用MD和ZnMD治疗后，观察到SHR的收缩压降低，ZnMD比MD更有效（治疗第8周时分别为122±8.1 mmHg和145±5.6 mmHg）。ZnMD治疗可预防心肌肥大，改善心脏功能并减少心脏纤维化，左心室质量、缩短分数和组织学研究等参数证明了这一点。相比之下，MD在这些参数上没有明显差异。ZnMD通过降低ROS水平和脂质过氧化以及心脏NAD(P)H氧化酶，并增加SOD1表达来负面调节氧化损伤，而MD没有显著效果。此外，与MD治疗相比，ZnMD治疗的心脏一氧化氮水平更高。
MD和ZnMD都有被白蛋白转运的潜力。我们的研究结果提供了重要证据，表明这种络合物可能是治疗高血压和心脏肥大及功能障碍的潜在治疗药物。
