Nanoformulation of valsartan-loaded tablet attenuates L-NAME-induced hypertension: role of Nrf2/PPARγ/AT1 signaling pathway

• DOI: 10.1007/s00210-025-03993-4
• Publication Date: 2025-03-29T16:32:19Z
• Authors: Hanan Elimam; Khalid M. El-Say; Tarek A. Ahmed; Sylvie Marleau; Zakaria El-Khayat; Mona El-Banna; Jihan Hussein

Abstract Hypertension is the most common entity globally, marked by high prevalence and heterogeneous pathophysiology. Oxidative stress is a crucial area of investigation among potential etiologies. We examined the hypothesis that blocking the angiotensin type 1 (AT1) receptor with valsartan (VST) in self-nanoemulsifying delivery systems (SNEDS) and loads in liquisolid tablets (LST-1) or valsartan and hydrochlorothiazide (VST/HCTZ) in SNEDS and loads in liquisolid tablets (LST-2) in comparison with non-SNEDS liquisolid tablets (DCT-3 and DCT-4) would lead to an improvement in hypertension management. The present study aims to explore the molecular mechanisms underlying their effect in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Male Sprague–Dawley rats were given L-NAME (40 mg/kg/day) orally for three weeks to inhibit the endogenous synthesis of nitric oxide (NO). Concurrent treatment with VST or VST/HCTZ liquisolid tablets (20 mg/kg/day for three weeks) resulted in lowering blood pressure (BP), reversing the L-NAME-induced serum NO suppression, enhancing lipid profile, and improving oxidative status. The antioxidant defense of paraoxonase was significantly increased in the LST-1- and LST-2-treated rats compared to the L-NAME-treated rats by 135% and 90%, respectively. Furthermore, SNEDS-loaded VST or SNEDS-loaded VST/HCTZ liquisolid tablets significantly lowered the elevated level of AT1 (P < 0.05), showed a marked Nrf2 expression (P < 0.01) and overexpressed PPARγ (P < 0.05), and suppressed iNOS expression (P < 0.0001). These results highlight the remarkable benefits of the novel formula, “SNEDS-loaded VST and SNEDS-loaded VST/HCTZ,” as an alternative therapy in treating hypertension and its complications.

Graphical abstract

Schematic diagram showing the mechanism of SNEDS-loaded VST and SNEDS-loaded VST/HCTZ as potential treatment strategies for hypertension. This mechanism includes the reduction of iNOS expression, antioxidant activity, and AT1R normalization action through activation of the Nrf2/PPARγ signaling cascade.