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

Abstract

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.