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.
Laboratory of Hemodynamics & Cardiovascular Technology (LHTC), Institute of Bioengineering (Bâtiment MED), Station 9, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
Eur J Pharmacol. 2023 May 5;946:175654. doi: 10.1016/j.ejphar.2023.175654. Epub 2023 Mar 15.
Hypertension is the most common cause of left ventricular hypertrophy, contributing to heart failure progression. Candesartan (Cand) is an angiotensin receptor antagonist widely used for hypertension treatment. Structural modifications were previously performed by our group using Zinc (ZnCand) as a strategy for improving its pharmacological properties. The measurements showed that ZnCand exerts a stronger interaction with the angiotensin II receptor, type 1 (AT receptor), reducing oxidative stress and intracellular calcium flux, a mechanism implied in cell contraction. These results were accompanied by the reduction of the contractile capacity of mesangial cells. In vivo experiments showed that the complex causes a significant decrease in systolic blood pressure after 8 weeks of treatment in spontaneously hypertensive rats (SHR). The reduction of heart hypertrophy was evidenced by echocardiography, the histologic cross-sectional area of cardiomyocytes, collagen content, the B-type natriuretic peptide (BNP) marker and connective tissue growth factor (CTGF) and the matrix metalloproteinase 2 (MMP-2) expression. Besides, the complex restored the redox status. In this study, we demonstrated that the complexation with Zn(II) improves the antihypertensive and cardiac effects of the parental drug.
高血压是左心室肥厚的最常见原因，导致心力衰竭进展。坎地沙坦（坎地沙坦）是一种广泛用于治疗高血压的血管紧张素受体拮抗剂。我们之前使用锌（ZnCand）进行了结构修饰，作为改善其药理特性的策略。测量结果表明，ZnCand 与血管紧张素 II 受体 1（AT 受体）的相互作用更强，可减少氧化应激和细胞内钙通量，这是细胞收缩的一种机制。这些结果伴随着肾小球系膜细胞收缩能力的降低。体内实验表明，该复合物在自发性高血压大鼠（SHR）治疗 8 周后可显著降低收缩压。超声心动图、心肌细胞组织学横截面积、胶原含量、B 型利钠肽（BNP）标志物和结缔组织生长因子（CTGF）以及基质金属蛋白酶 2（MMP-2）的表达证明了心脏肥厚的减少。此外，该复合物还恢复了氧化还原状态。在这项研究中，我们证明了与 Zn(II) 的络合作用改善了母体药物的降压和心脏作用。
