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Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses endothelial dysfunction and oxidative stress associated with the metabolic syndrome

Background

Patients with metabolic syndrome exhibit generalized endothelial dysfunction with decreased NO production and increased vascular oxidative stress. We postulated that chronic treatment with sildenafil could upregulate the NOS/cGMP pathway and improve endothelial function in fructose-fed rats.

Materials and methods

Wistar rats (n = 10–14 per group) were fed a standard chow (CONT) or a 60% fructose/5% fat (% by weight)-enriched diet for 8 weeks (FFR). From week 5 through 8, sildenafil was administered twice a day (sc, 20 mg/kg, FFR+SIL), thus reaching clinically relevant plasma concentrations circa 20 nM unbound known to give efficacy in man (Pfizer Inc., data on file), 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 A23187) and -independent (SNP) relaxants in presence of indomethacin. Urinary 8-isoprostanes (IPT) and plasma levels of IL-6 and TNF-α were also evaluated.

Results

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 A23187 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) even after one week of wash-out from treatment. 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 A23187 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 nor TNF-α 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).

Conclusion

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 that may be of benefit in vascular cardio-metabolic indications.

Acknowledgements

This study was supported by an independent investigator research grant from Pfizer.

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Correspondence to Behr-Roussel Delphine.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Delphine, BR., Oudot, A., Caisey, S. et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses endothelial dysfunction and oxidative stress associated with the metabolic syndrome. BMC Pharmacol 7, S28 (2007). https://doi.org/10.1186/1471-2210-7-S1-S28

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Keywords

  • Metabolic Syndrome
  • Endothelial Dysfunction
  • Isometric Tension
  • Leftward Shift
  • Enrich Diet