Impact of a long-term sildenafil treatment on pressor response in conscious rats with insulin resistance and hypertriglyceridemia.
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.
Behr-Roussel
Delphine
D
Pelvipharm, Orsay, France.
Oudot
Alexandra
A
Compagnie
Sandrine
S
Gorny
Diane
D
Le Coz
Olivier
O
Bernabe
Jacques
J
Wayman
Chris
C
Alexandre
Laurent
L
Giuliano
François
F
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*
D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D014665:Vasodilator Agents; D005632:Fructose; D000068677:Sildenafil Citrate; D011451:Prostaglandin-Endoperoxide Synthases