Elimam Hanan, El-Say Khalid M, Ahmed Tarek A, Marleau Sylvie, El-Khayat Zakaria, El-Banna Mona, Hussein Jihan
Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt.
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 26. doi: 10.1007/s00210-025-03993-4.
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.
高血压是全球最常见的病症，具有高患病率和异质性病理生理学特征。氧化应激是潜在病因中一个关键的研究领域。我们检验了这样一个假设：与非自纳米乳化给药系统的液体制剂片（DCT - 3和DCT - 4）相比，自纳米乳化给药系统中载有缬沙坦（VST）的液体制剂片（LST - 1）或自纳米乳化给药系统中载有缬沙坦和氢氯噻嗪（VST/HCTZ）的液体制剂片（LST - 2），阻断1型血管紧张素（AT1）受体将有助于改善高血压的治疗。本研究旨在探索它们对N（G）-硝基-L-精氨酸甲酯（L-NAME）诱导的高血压大鼠产生作用的分子机制。雄性Sprague-Dawley大鼠口服L-NAME（40毫克/千克/天）三周，以抑制内源性一氧化氮（NO）的合成。同时用VST或VST/HCTZ液体制剂片（20毫克/千克/天，持续三周）进行治疗，可降低血压（BP），逆转L-NAME诱导的血清NO抑制，改善血脂状况，并改善氧化状态。与L-NAME处理的大鼠相比，LST - 1和LST - 2处理的大鼠中对氧磷酶的抗氧化防御能力分别显著提高了135%和90%。此外，载有SNEDS的VST或载有SNEDS的VST/HCTZ液体制剂片显著降低了升高的AT1水平（P < 0.05），显示出显著的Nrf2表达（P < 0.01）和过表达的PPARγ（P < 0.05），并抑制了iNOS表达（P < 0.0001）。这些结果突出了新型制剂“载有SNEDS的VST和载有SNEDS的VST/HCTZ”作为治疗高血压及其并发症的替代疗法的显著益处。
