title: Impact of a long-term sildenafil treatment on pressor response in conscious rats with insulin resistance and hypertriglyceridemia.
abstract: BACKGROUND
  Insulin resistance constitutes a risk factor for endothelial dysfunction and subsequent cardiovascular diseases including hypertension. Daily treatment with phosphodiesterase type 5 (PDE5) inhibitors has beneficial effects on endothelial function in men with increased cardiovascular risk. Endothelium-dependent vasomotor function is ultimately linked to blood pressure (BP) regulation. We postulated that sildenafil would ameliorate BP and biological markers of endothelial function in fructose-fed rats (FFRs).
  
  
  METHODS
  Wistar rats were fed a standard chow or a 60% fructose-enriched diet containing 12% fat for 8 weeks (FFR). From week 6 through 8, sildenafil (twice a day subcutaneously, 20 mg/kg) was administered followed by a 1-week washout period. At the end of the washout period, BP was recorded using radiotelemetry following cumulative infusion of norepinephrine (from 50 to 400 ng/kg/min).
  
  
  RESULTS
  FFR displayed both an impaired glucose tolerance and elevated triglyceridemia. The latter was corrected by sildenafil treatment. Resting BP was similar in all rats, whereas pressor responses were significantly enhanced in FFR (maximal increase in mean BP to norepinephrine: 25.6 +/- 3.8 vs. 40.8 +/- 4.0 mm Hg, P < 0.05) and normalized by sildenafil treatment (24.9 +/- 5.3 mm Hg, not significant vs. control). Urinary levels of 8-isoprostanes and thromboxane B(2) were increased in FFR and corrected by sildenafil treatment.
  
  
  CONCLUSIONS
  Thus, chronic treatment with sildenafil normalized BP regulation in an experimental model of insulin resistance and hypertriglyceridemia while restoring normal excretion of urinary biological markers of oxidative stress and cyclooxygenase-derived vasoconstrictors. The modulation of ROS and cyclooxygenase-derived vasoconstrictors generation by a chronic treatment with sildenafil may represent an added benefit beyond PDE5 inhibition.
authors.affiliation: Pelvipharm, Orsay, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Behr-Roussel
authors.forename: Alexandra
authors.initials: A
authors.lastname: Oudot
authors.forename: Sandrine
authors.initials: S
authors.lastname: Compagnie
authors.forename: Diane
authors.initials: D
authors.lastname: Gorny
authors.forename: Olivier
authors.initials: O
authors.lastname: Le Coz
authors.forename: Jacques
authors.initials: J
authors.lastname: Bernabe
authors.forename: Chris
authors.initials: C
authors.lastname: Wayman
authors.forename: Laurent
authors.initials: L
authors.lastname: Alexandre
authors.forename: François
authors.initials: F
authors.lastname: Giuliano
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003243:Consciousness / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005632:Fructose / Q000494:pharmacology; D006339:Heart Rate / Q000502:physiology; D015228:Hypertriglyceridemia / Q000378:metabolism / Q000503:physiopathology*; D007279:Injections, Subcutaneous; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D014665:Vasodilator Agents; D005632:Fructose; D000068677:Sildenafil Citrate; D011451:Prostaglandin-Endoperoxide Synthases