title: Sildenafil Treatment Ameliorates the Maternal Syndrome of Preeclampsia and Rescues Fetal Growth in the Dahl Salt-Sensitive Rat.
abstract: Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus. There is currently no effective treatment, but sildenafil, a phosphodiesterase-5 inhibitor, has been proposed as a potential therapy to reduce blood pressure and improve uteroplacental perfusion in preeclamptic patients. We hypothesized that sildenafil would improve the maternal syndrome and fetal outcomes in the Dahl S rat model of superimposed preeclampsia. Dahl S rats were mated, and half received sildenafil (50 mg/kg per day, via food) from day 10 through day 20 of pregnancy. The untreated Dahl S rats had a significant rise in blood pressure and a 2-fold increase in urinary protein excretion from baseline to late pregnancy; however, sildenafil-treated Dahl S rats exhibited ≈40 mm Hg drops in blood pressure with no rise in protein excretion. Sildenafil also increased creatinine clearance and reduced nephrinuria and glomerulomegaly. Sildenafil treatment reduced the uterine artery resistance index during late pregnancy in the Dahl S rat and improved fetal outcomes (survival, weight, and litter size). In addition, 19% of all pups were resorbed in untreated rats, with no incidence of resorptions observed in the treated group. Furthermore, tumor necrosis factor-α, endothelin-1, and oxidative stress, which are characteristically increased in women with preeclampsia and in experimental models of the disease, were reduced in treated rats. These data suggest that sildenafil improves the maternal syndrome of preeclampsia and blood flow to the fetoplacental unit, providing preclinical evidence to support the hypothesis that phosphodiesterase type 5 inhibition may be an important therapeutic target for the treatment of preeclampsia.
authors.affiliation: From the Departments of Pharmacology and Toxicology (E.E.G., J.N.M., M.R.G., J.M.S.), Medicine (M.R.G.), and Physiology and Biophysics (J.P.G.), University of Mississippi Medical Center, Jackson.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Gillis
authors.affiliation: From the Departments of Pharmacology and Toxicology (E.E.G., J.N.M., M.R.G., J.M.S.), Medicine (M.R.G.), and Physiology and Biophysics (J.P.G.), University of Mississippi Medical Center, Jackson.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Mooney
authors.affiliation: From the Departments of Pharmacology and Toxicology (E.E.G., J.N.M., M.R.G., J.M.S.), Medicine (M.R.G.), and Physiology and Biophysics (J.P.G.), University of Mississippi Medical Center, Jackson.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garrett
authors.affiliation: From the Departments of Pharmacology and Toxicology (E.E.G., J.N.M., M.R.G., J.M.S.), Medicine (M.R.G.), and Physiology and Biophysics (J.P.G.), University of Mississippi Medical Center, Jackson.
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
authors.affiliation: From the Departments of Pharmacology and Toxicology (E.E.G., J.N.M., M.R.G., J.M.S.), Medicine (M.R.G.), and Physiology and Biophysics (J.P.G.), University of Mississippi Medical Center, Jackson. jsasser@umc.edu.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sasser
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000503:physiopathology; D011247:Pregnancy; D011270:Pregnancy, Animal; D051381:Rats; D020303:Rats, Inbred Dahl; D000068677:Sildenafil Citrate / Q000627:therapeutic use*; D013577:Syndrome; D014655:Vascular Resistance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D014665:Vasodilator Agents; D000068677:Sildenafil Citrate
keywords: endothelin-1; oxidative stress; phosphodiesterase-5 inhibitors; pregnancy; tumor necrosis factor-α