Abstract 1181: Daily Treatment with Sildenafil Reverses Endothelial Dysfunction and Oxidative Stress in an Animal Model of Metabolic Syndrome
Patients with metabolic syndrome exhibit generalized endothelial dysfunction with decreases in NO production and increases in oxidative stress. We postulated that chronic treatment with sildenafil could upregulate the NOS/cGMP pathway and improve endothelial function in fructose-fed rats. Wistar rats (n=10–14 per group) were fed a standard chow (CONT) or a 60 % fructose/5% fat-enriched diet for 8 weeks (FFR). From week 5 through 8, sildenafil was administered twice a day (sc, 20 mg/kg, FFR+SIL), then a 1-week wash-out period from sildenafil was observed. Isometric tension studies were performed on isolated aortic and superior mesenteric arterial (SMA) rings precontracted with noradrenaline to build concentration-response curves (CRC) to endothelium-dependent (ACh and A23 187) and -independent (SNP) relaxants in presence of indomethacin. Vascular cGMP content, urinary excretion of nitrates and nitrites (NOx) and 8-isoprostanes (IPT), and plasma levels of IL-6 and TNF-α were also evaluated. Relaxations to ACh were reduced in aortas of FFR (10−5 M: -102.6±-2.4% vs -89.2±4.7, p<0.001) while only slightly affected in SMA rings. Relaxations to A23 187 were significantly reduced both in aortic and SMA rings of FFR. In aortas, sildenafil treatment restored normal endothelium-dependent relaxations to ACh (10−5 M: -104.2±3.0%, p<0.001). In SMA rings, a leftward shift of the CRC to ACh could be detected (pD2: -8.12±0.11 vs -8.60±0.08, p<0.05). Relaxations to A23 187 were also restored by sildenafil in both aortic and SMA rings of FFR. Enhanced compensatory endothelium-independent relaxations to SNP in FFR were not modified by sildenafil treatment. Neither IL-6, TNF-α, vascular cGMP nor urinary NOx levels were modified by the fructose or sildenafil treatment. Urinary IPT levels was normalized by the sildenafil treatment (FFR: 2.07±0.36 vs CONT:0.95±0.14 vs FFR+SIL: 0.88±0.13 ng/ml/24 h, p<0.05). Endothelial dysfunction and oxidative stress associated with the metabolic syndrome can be reversed in FFR by a chronic treatment with sildenafil, even 7 days after treatment has ceased. This sustained improvement in endothelial function suggests that chronic administration of sildenafil may lead to structural and molecular changes within the vascular wall.