Amer Ahmed E, El-Sheakh Ahmed R, Hamed Mohamed F, El-Kashef Hassan A, Nader Manar A, Shehatou George S G
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa City, Dakahliya, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahliya, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Dakahliya, Egypt.
Eur J Pharm Sci. 2021 Jan 1;156:105580. doi: 10.1016/j.ejps.2020.105580. Epub 2020 Sep 30.
This study was undertaken to investigate the possible ameliorative influences of febuxostat (FEB) on vitamin D3 plus nicotine (VDN)-induced vascular calcification (VC) in Wistar rats. VDN rats received a single dose of vitamin D3 (300.000 IU/kg, I.M) and two oral doses of nicotine (25 mg/kg) on day 1. They were then administrated FEB, in two doses (10 and 15 mg/kg/day, orally), or the drug vehicle, for 4 weeks. Age-matched normal rats served as control. At the end of the experiment, body weight, kidney function parameters, serum ionic composition, cardiovascular measures, aortic calcium deposition and aortic levels of oxidative stress markers, interleukin 1β (IL-1β), runt-related transcription factor 2 (Runx2) and osteopontin (OPN) were determined. Aortic immunoexpressions of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP-9) and α-smooth muscle actin (α-SMA) were evaluated. FEB significantly restored body weight loss, ameliorated kidney function and diminished serum disturbances of calcium and phosphorus in VDN rats. Moreover, FEB reduced VDN-induced elevations in aortic calcium deposition, SBP and DBP. FEB (15 mg/kg) markedly decreased left ventricular hypertrophy and bradycardia in VDN group. Mechanistically, FEB dose-dependently improved oxidative damage, decreased levels of IL-1β and Runx2, lessened expression of TNF-α, iNOS and MMP-9 and enhanced expression of OPN and α-SMA in VDN aortas relative to controls. These findings indicate that FEB, mainly at the higher administered dose (15 mg/kg), successfully attenuated VDN-induced VC. FEB may be useful in reducing VC in patients at high risk, including those with chronic kidney disease and diabetes mellitus.
本研究旨在探讨非布司他（FEB）对维生素D3加尼古丁（VDN）诱导的Wistar大鼠血管钙化（VC）可能的改善作用。VDN大鼠在第1天接受单剂量维生素D3（300,000 IU/kg，肌肉注射）和两剂口服尼古丁（25 mg/kg）。然后，它们接受两剂FEB（10和15 mg/kg/天，口服）或药物赋形剂，持续4周。年龄匹配的正常大鼠作为对照。实验结束时，测定体重、肾功能参数、血清离子组成、心血管指标、主动脉钙沉积以及主动脉氧化应激标志物、白细胞介素1β（IL-1β）、 runt相关转录因子2（Runx2）和骨桥蛋白（OPN）的水平。评估主动脉中肿瘤坏死因子-α（TNF-α）、诱导型一氧化氮合酶（iNOS）、基质金属蛋白酶-9（MMP-9）和α-平滑肌肌动蛋白（α-SMA）的免疫表达。FEB显著恢复了VDN大鼠的体重减轻，改善了肾功能，并减轻了血清钙和磷的紊乱。此外，FEB降低了VDN诱导的主动脉钙沉积、收缩压和舒张压升高。FEB（15 mg/kg）显著降低了VDN组的左心室肥厚和心动过缓。从机制上讲，与对照组相比，FEB剂量依赖性地改善了氧化损伤，降低了IL-1β和Runx2的水平，减少了TNF-α、iNOS和MMP-9的表达，并增强了VDN主动脉中OPN和α-SMA的表达。这些发现表明，FEB主要在较高给药剂量（15 mg/kg）时成功减轻了VDN诱导的VC。FEB可能有助于降低高危患者的VC，包括慢性肾病和糖尿病患者。
