Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 946, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2023.175654
Keywords
Hypertension; Zn-candesartan; Cardiac hypertrophy; Oxidative stress
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Hypertension is the main cause of left ventricular hypertrophy and can lead to heart failure. Candesartan, an angiotensin receptor antagonist, is commonly used for hypertension treatment. Our study focused on the structural modification of candesartan using zinc (ZnCand) to enhance its pharmacological properties. The results showed that ZnCand exhibited stronger interaction with the AT1 receptor, reducing oxidative stress and intracellular calcium flux. Additionally, in vivo experiments demonstrated that ZnCand effectively reduced systolic blood pressure and heart hypertrophy in SHR rats, while restoring the redox status.
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 (AT1 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.
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