Nobiletin, a citrus flavonoid, exhibits a wide range of biological activities. This study investigated the effect of nobiletin on vascular dysfunction and remodeling in L-NAME-induced hypertensive rats. Male Sprague-Dawley rats were given L-NAME (40 mg kg⁻¹) for five weeks to induce hypertension and treated with nobiletin (20 or 40 mg kg⁻¹) or captopril (5 mg kg⁻¹) for the last two weeks. Nobiletin or captopril significantly reduced blood pressure and the enhancement of the contractile response to sympathetic nerve stimulation in the mesenteric vascular beds of L-NAME rats (p < 0.05). Both agents improved the impairment of vasorelaxation responses to acetylcholine in mesenteric vascular beds and aortic rings in L-NAME rats (p < 0.05). Moreover, nobiletin and captopril decreased oxidative stress markers, restored the abnormality of plasma NOx and the protein expressions of eNOS, Nrf-2 and HO-1 observed in L-NAME rats (p < 0.05). Increases in aortic wall thickness, cross sectional area, vascular smooth muscle cells and collagen deposition that occurred in L-NAME rats were reduced by nobiletin or captopril (p < 0.05). These reductions were associated with the suppression of matrix metalloproteinase (MMP)-2 and MMP-9 protein expression (p < 0.05). These findings indicated that nobiletin had antihypertensive effects with amelioration of vascular alterations. The molecular mechanism is likely to involve the restoration of Nrf-2/HO-1/MMP signaling pathways.

Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by n-nitro l-arginine methyl ester (l-NAME) in rats. Male Sprague-Dawley rats were treated with l-NAME (40 mg/kg), l-NAME plus hesperidin (15 mg/kg), hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in l-NAME rats. l-NAME-induced cardiac remodeling, i.e., increases in wall thickness, cross-sectional area (CSA), and fibrosis in the left ventricular and vascular remodeling, i.e., increases in wall thickness, CSA, vascular smooth muscle cells, and collagen deposition in the aorta were attenuated by hesperidin or captopril. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), and enhancing plasma nitric oxide metabolite (NOx) in l-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF- β1 protein expression and the overexpression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was suppressed in l-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in l-NAME hypertensive rats. The possible mechanism may involve antioxidant and anti-inflammatory effects.

Diosmetin is a citrus flavonoid that has antioxidant and anti-inflammatory effects. This study examined the effect of diosmetin on blood pressure and vascular alterations and its underlying mechanisms in experimentally hypertensive rats. Male Sprague rats were administered Nω-nitro-l-arginine methyl ester L-NAME for five weeks and were given diosmetin at doses of 20 or 40 mg/kg or captopril (5 mg/kg) for two weeks. Diosmetin alleviated hypertension, improved endothelial dysfunction, and suppressed the overactivity of sympathetic nerve-mediated vasoconstriction in aorta and mesentery hypertensive rats (p < 0.05). Increases in plasma and aortic tissue malondialdehyde (MDA) and carotid superoxide generations and reductions of plasma superoxide dismutase, catalase, and nitric oxide in hypertensive rats were ameliorated by diosmetin (p < 0.05). Diosmetin increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in hypertensive rats. Furthermore, diosmetin mitigated hypertrophy and collagen accumulation of the aortic wall in L-NAME rats. It exhibited an anti-inflammatory effect by reducing interleukin-6 (IL-6) accumulation and by overexpressing the phospho-c-Jun N-terminal kinases (p-JNK) and the phospho-nuclear factor-kappaB (p-NF-κB) proteins in the aorta (p < 0.05). Captopril was a positive control substance and had similar effects to diosmetin. In summary, diosmetin reduced blood pressure and alleviated vascular abnormalities in L-NAME-treated rats. These effects might be related to antioxidant and anti-inflammatory effects as well as to the modulation of the expression of the Nrf2/HO1 and p-JNK/NF-κB proteins.