Antihypertensive Effects of Diosmetin in Hypertension-Induced Cardiovascular Abnormalities in Rats.

Abstract

Introduction: Hypertension is associated with cardiovascular dysfunction and remodeling. Diosmetin, a flavonoid isolated from citrus seeds, has various biological properties. This work investigated the effects of diosmetin on cardiovascular parameters and classical and non-classical renin-angiotensin systems (RAS) in two-kidney one-clip (2K-1C) rats.

Methods: 2K-1C hypertension was induced by placing a silver clip on the left renal artery. Three weeks after induction, rats were orally gavage with either vehicle, diosmetin (20 or 40 mg/kg), or telmisartan (5 mg/kg) for four weeks. Blood pressure (BP) was monitored weekly while vascular function and histomorphology studies were performed at the end of the study. Oxidative stress markers and RAS parameters, including serum angiotensin-converting enzyme (ACE) activity and plasma angiotensin II and angiotensin I-7 (Ang-(1-7)) concentrations, were also measured. The expression levels of angiotensin II type 1 receptor (AT₁R), transforming growth factor-β (TGF-β), and Mas receptor protein were assessed. A molecular docking analysis was performed to analyze the potential interactions between diosmetin and the human angiotensin I converting enzyme.

Results: In this in vivo study on the 2K-1C rats, diosmetin exhibited antihypertensive effects in the 2K-1C model via modulation of the RAS. Diosmetin at doses of 20 and 40 mg/kg decreased BP by 11.73% and 23.17%, respectively. Diosmetin also improved vascular function by reducing sympathetic nerve-mediated vasoconstriction and restoring endothelium-mediated vasodilation in the mesentery and aortic rings. The thickening of the left ventricle and aorta in hypertensive rats was alleviated by diosmetin treatment. RAS parameters and oxidative stress markers were improved in the diosmetin-treated group compared to the untreated group. Additionally, diosmetin treatment restored the overexpression of the AT₁R and TGF-β while reducing Mas receptor expression in cardiac and aortic tissue. The molecular docking analysis confirmed that diosmetin can bind to the active site of ACE.

Conclusion: Diosmetin restored hemodynamic alterations associated with the improvement of vascular function. It also ameliorated left ventricular-aortic hypertrophy in hypertensive rats. These effects could be attributed to its capacity to modulate classical and non-classical RAS.