Volume 7 Supplement 1

3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

Daily treatment with sildenafil, an inhibitor of cGMP-dependent phosphodiesterase, normalizes the exaggerated hemodynamic response to norepinephrine in fructose-fed rats

  • Delphine Behr-Roussel1Email author,
  • Alexandra Oudot1,
  • Sandrine Compagnie1,
  • Diana Gorny1,
  • Olivier Le Coz1,
  • Jaques Bernabé1,
  • Chris Wayman2,
  • Laurent Alexandre1 and
  • Francois Giuliano3
BMC Pharmacology20077(Suppl 1):P5

DOI: 10.1186/1471-2210-7-S1-P5

Published: 25 July 2007

Background

Enhanced responsiveness of the vascular smooth muscle cell to vasoconstrictor stimuli has been described in insulin-resistant states. Fructose overload leads to the development of the metabolic syndrome and its associated cardiovascular disorders including hypertension. We postulated that chronic treatment with sildenafil would regulate the abnormally increased pressor response to a norepinephrine challenge in fructose-fed rats. Material and methods Wistar rats were fed a standard chow (CONT, n = 12) or a 60% fructose-enriched diet containing 5% fat (% by weight) for 8 weeks (FFR, n = 12). From week 5 through 8, sildenafil (twice a day sc, 20 mg/kg) was administered (FFR+SIL, n = 14), thus reaching clinically relevant plasma concentrations circa 20 nM unbound (Pfizer Inc., data on file), followed by a 1-week wash-out period (W9). On W9, in a sub-group of these conscious rats (n = 5) that had previously been implanted with telemetric devices, AP was recorded following cumulative infusion of noradrenaline (NA 50, 100, 200, 400 ng/kg/min). In all rats, urinary 8-isoprostane (IPT) and TxB2 levels were determined during a 24-hour period. Tissue ET-1 content was measured in segments of aortic and mesenteric artery.

Results

Fasting glycemia was unchanged in all rats while triglyceridemia were elevated in FFR compared to CONT (2.0 ± 0.4 mM vs 1.2 ± 0.2, p < 0.05) and corrected by sildenafil treatment (1.3 ± 0.2, NS vs CONT). Resting AP was similar in all rats. Pressor responses to NA were exacerbated in FFR (maximal increase from basal MAP: +22.8 ± 1.7 vs +38.0 ± 7.3 mmHg, respectively, p < 0.05) and normalized by sildenafil treatment (+24.9 ± 5.2 mmHg, NS vs CONT). Vascular ET-1 levels were not modified by the fructose nor sildenafil treatment whereas the increased production of urinary IPT and TxB2 in FFR versus CONT (2.07 ± 0.36 ng/ml/24 h vs 0.88 ± 0.13 and 12.86 ± 1.91 pg/ml/24 h vs 7.25 ± 0.59, respectively, p < 0.05) were corrected following sildenafil treatment (0.95 ± 0.14 ng/ml/24 h and 8.74 ± 1.06 pg/ml/24 h, respectively, NS vs CONT).

Conclusion

In FFR, pressor responses to NA were potentiated, suggesting enhanced responsiveness of the vascular smooth muscle cell to vasoconstrictor stimuli. Chronic treatment with sildenafil was able to normalize the hemodynamic response to norepinephrine while restoring normal excretion of urinary biological markers of oxidative stress and vasoactive mediators in FFR. Both IPT and TxB2 could be considered as surrogate markers of endothelial function in clinical trials addressing cardiovascular risks.

Declarations

Acknowledgements

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

Authors’ Affiliations

(1)
Pelvipharm, Gif-sur-Yvette
(2)
Pfizer Global Research and Development
(3)
Department of Neurological Rehabilitation, AP-HP Raymond Poincaré hospital

Copyright

© Behr-Roussel et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

Advertisement