Daily treatment with sildenafil reverses endothelial dysfunction and oxidative stress in an animal model of insulin resistance

被引:39
作者
Behr-Roussel, Delphine [2 ]
Oudot, Alexandra [2 ]
Caisey, Stephanie [2 ]
Coz, Olivier L. E. [2 ]
Gorny, Diane [2 ]
Bernabe, Jacques [2 ]
Wayman, Chris [3 ]
Alexandre, Laurent [2 ]
Giuliano, Francois A. [1 ]
机构
[1] Hop Raymond Poincare, Dept Phys Med & Rehabil, Neurouroandrol Unit, F-92380 Garches, France
[2] Pelvipharm, Domaine CNRS, F-91190 Gif Sur Yvette, France
[3] Pfizer Global Res & Dev, Sandwich CT13 9NJ, Kent, England
关键词
D O I
10.1016/j.eururo.2007.11.018
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Objectives: Patients with insulin resistance exhibit endothelial dysfunction with decreased nitric oxide (NO) production and increased oxidative stress. We postulated that daily sildenafil improved endothelial function in fructose-fed rats. Methods and results: Wistar rats were fed a standard or fructose-enriched diet (FFR) for 9 wk. From weeks 6-8, sildenafil was administered twice daily (sc, 20 m g/kg), followed by a 1-wk washout. Concentration-response curves (CRCs) to endothelium-dependent (acetylcholine [Ach] and A23187) and -independent (sodium nitroprusside [SNP]) relaxing agents were performed on isolated precontracted aortas and superior mesenteric arteries (SMAs). Vascular cyclic guanosine monophosphate (cGMP) content, urinary excretion of nitrates/ nitrites (NOx) and 8-isoprostanes (IPT), and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were evaluated. Relaxations to ACh were significantly reduced in aortas and SMAs of FFR. Sildenafil restored ACh-induced relaxations in aortas and provoked a significant leftward shift of the CRC to ACh in SMAs, whereas it did not modify the enhanced relaxations to SNP in FFR. IL-6, TNF-alpha, vascular cGMP, and urinary NOx levels were not modified by the fructose or sildenafil treatment. Urinary IPT levels were significantly elevated in FFR and normalized by sildenafil. Conclusions: Endothelial dysfunction and oxidative stress associated with insulin resistance can be reversed by daily sildenafil, even 1 wk after treatment cessation. (c) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:1272 / 1281
页数:10
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