de Almeida Camila Leandra Bueno, Cechinel-Filho Valdir, Boeing Thaise, Mariano Luísa Nathália Bolda, Silva Luísa Mota da, Andrade Sérgio Faloni de, de Souza Priscila
Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Itajaí, SC 88302-901, Brazil.
Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Itajaí, SC 88302-901, Brazil.
Chem Biol Interact. 2018 Jan 5;279:227-233. doi: 10.1016/j.cbi.2017.11.021. Epub 2017 Dec 1.
Although the acute diuretic effect of nothofagin has been recently demonstrated, its effects after dose-repeated treatment have not yet been explored. For that, male Wistar normotensive (NTR) and spontaneously hypertensive rats (SHR) were orally treated, once a day, with vehicle (VEH: distilled water; 1 ml/kg), hydrochlorothiazide (HCTZ; 10 mg/kg) or nothofagin (NOT; 1 mg/kg). The cumulative diuretic index and urinary electrolytes excretion were measured each 24 h. On the last day of the experiment (7th day), urine, blood and kidney samples were collected for biochemical and molecular analyzes. The urinary volume of both NTR and SHR were significantly increased with the treatment with NOT (from the second to the seventh day of treatment), with final values reaching an increase of 56% and 82%, respectively, when compared with VEH-treated group. This effect was associated with increased levels of urinary excretion of Na and Cl, without any changes on K excretion. None of the treatments modified urinary pH or density values. Importantly, neither the NOT nor the HCTZ caused any change in body weight following the dose-repeated treatment, and also did not provoke an electrolytic disturbance. Regarding the renal analyzes, when compared with the vehicle-treated NTR group, the activity of superoxide dismutase (SOD) and the reduced glutathione (GSH) levels in kidney homogenates of the SHR group were decreased, while the generation of lipid hydroperoxides were significantly increased. The daily treatment with NOT was able to restore the GSH levels and SOD activity, as well as reduced the lipoperoxidation in the kidney homogenates obtained from SHR animals. Finally, NOT significantly augmented the levels of nitrite, a marker of nitric oxide production, in the plasma obtained from SHR group when compared with the vehicle-treated only NTR. This study revealed the prolonged diuretic and saluretic effect of nothofagin in normotensive and hypertensive rats. Our data also showed the renal protective effects of nothofagin by the improvement of antioxidative capacity, as well as by the augmented bioavailability of plasma nitric oxide in the hypertensive group.
尽管最近已证实诺托法金具有急性利尿作用，但其重复给药后的效果尚未得到研究。为此，将雄性Wistar正常血压大鼠（NTR）和自发性高血压大鼠（SHR）每天口服给予溶媒（VEH：蒸馏水；1 ml/kg）、氢氯噻嗪（HCTZ；10 mg/kg）或诺托法金（NOT；1 mg/kg）。每24小时测量累积利尿指数和尿电解质排泄量。在实验的最后一天（第7天），收集尿液、血液和肾脏样本进行生化和分子分析。与溶媒处理组相比，NOT处理使NTR和SHR的尿量均显著增加（从处理的第二天到第七天），最终值分别增加了56%和82%。这种作用与Na和Cl尿排泄水平增加有关，而K排泄无任何变化。所有处理均未改变尿pH值或密度值。重要的是，NOT和HCTZ重复给药后均未引起体重变化，也未引发电解质紊乱。关于肾脏分析，与溶媒处理的NTR组相比，SHR组肾脏匀浆中的超氧化物歧化酶（SOD）活性和还原型谷胱甘肽（GSH）水平降低，而脂质氢过氧化物的生成显著增加。每天给予NOT能够恢复SHR动物肾脏匀浆中的GSH水平和SOD活性，并减少脂质过氧化。最后，与仅用溶媒处理的NTR相比，NOT显著提高了SHR组血浆中亚硝酸盐（一氧化氮产生的标志物）的水平。本研究揭示了诺托法金在正常血压和高血压大鼠中具有持久的利尿和促尿钠排泄作用。我们的数据还表明，诺托法金通过提高抗氧化能力以及增加高血压组血浆一氧化氮的生物利用度而具有肾脏保护作用。
