Protective role of nebivolol via AKT1/Hif-1α/eNOS signaling pathway: nephrotoxicity caused by methotrexate in a rat model.

Methotrexate (MTX) is an antineoplastic and anti-inflammatory agent, which is used in severe diseases. Its use should be limited due to side effects such as nephrotoxicity, myelotoxicity, and hepatotoxicity. Nebivolol (NBV), which is a beta-blocker used in the treatment of hypertension, also contributes to vasodilation in tissues by activating the endothelial nitric oxide synthase (eNOS) enzyme. The purpose of this study is to research the effect of NBV on MTX-induced nephrotoxicity through the AKT1/hypoxia-inducible factor 1-alpha (Hif-1α)/eNOS signaling pathway. The rats were randomly divided into three groups of eight each. The groups were control, MTX, and MTX + NBV. A single dose of 20 mg/kg MTX was given intraperitoneally to the rats on the first day of the study and 10 mg/kg NBV was given orally to the treatment group for 7 days. At the end of the study, rats' blood and kidney tissues were taken for histopathological, immunohistochemical, and biochemical examinations. MTX administration significantly decreased the expression levels of AKT1, eNOS, and Hif-1α compared with the control group (p < 0.001 for all), and NBV treatment increased these values compared with the MTX group (p < 0.001 for all). In conclusion, NBV treatment ameliorated the MTX-induced nephrotoxicity via AKT1/Hif-1α/eNOS signaling pathway.

Allopurinol treatment reduced vascular remodeling and improved vascular functions in monocrotaline-induced pulmonary hypertensive rats.

Increased oxidative stress and high uric acid are implicated in the pathogenesis of pulmonary hypertension (PH). This provides opportunity to benefit from drugs like allopurinol which suppresses both contributing factors. Therefore, we aimed to investigate the effects of allopurinol in preventing as well as reversing the pathological changes occurring in monocrotaline (MCT)-induced rat model of PH. Male rats were assigned into three groups based on the follow-up time: 7, 21 and 35 days. Time-matched controls of each group received single injections of MCT (60 mg/kg) intraperitoneally. Test groups consisted of rats who were treated with MCT on day 0 plus oral allopurinol (60 mg/kg) daily for 7 or 21 days. 35-day group received allopurinol for two weeks starting on the 22nd day following MCT injection. At the end of all-time points, rats were killed and basal pulmonary perfusion pressure, Fulton index, pulmonary arterial wall thickness and pulmonary arterial relaxations along with oxidative stress markers (MDA, SOD, XO), NO and uric acid levels were measured in all groups. MCT-injected rats had evidence of raised oxidative stress (high MDA and XO, low SOD levels) which was reversed by allopurinol co-treatment in all-time groups. Marked elevation of uric acid seen in 21- and 35 day-groups was also reversed by allopurinol. Reduced NO levels of 21 and 35 days were unchanged in allopurinol treated groups. Apart from an increase in arterial wall thickening which was maintained in all-time groups, no alterations in other cardiovascular parameters were observed in 7-day group. However, basal lung perfusion pressure and Fulton index significantly increased, while arterial relaxations decreased in 21- and 35-day groups. Co-treatment with allopurinol for 21 days improved these functional alterations, whereas late allopurinol treatment failed to affect them. Our results indicate that early treatment of MCT-induced PH with allopurinol ameliorated the impaired functional characteristics via suppressing the increased oxidative stress and uric acid, while treatment started after progression of the disease had no significant effect.