title: Sildenafil attenuates placental ischemia-induced hypertension.
abstract: Preeclampsia is a complication of pregnancy that is marked by hypertension, proteinuria, and maternal endothelial dysfunction. A central factor in the etiology of the disease is the development of placental hypoxia/ischemia, which releases pathogenic soluble factors. There is currently no effective treatment for preeclampsia, but the phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been suggested, as PDE-5 is enriched in the uterus, and its antagonism could improve uteroplacental function. Here, we report in the reduced uterine perfusion pressure (RUPP) rat model that administration of oral sildenafil is effective in attenuating placental ischemia-induced hypertension during gestation. RUPP animals have significantly elevated arterial pressure compared with control animals (132 ± 3 vs. 100 ± 2 mmHg; P < 0.05). Administration of oral sildenafil (45 mg·kg⁻¹·day⁻¹) had no effect on blood pressure in control rats but decreased pressure in RUPP rats (115 ± 1 mmHg; P < 0.05). RUPP induced changes in placental sFlt-1, and vascular endothelial growth factor (VEGF) was unaffected by sildenafil administration, as was the decrease in free plasma VEGF. RUPP animals had a significant increase in medullary PDE-5/β-actin ratio (1 ± 0.14 vs. 1.63 ± 0.18; P < 0.05) expression with a resulting reduction in renal medullary cGMP (1.5 ± 0.15 vs. 0.99 ± 0.1 pmol/μg protein, P < 0.05) compared with controls. Although sildenafil had no effect on renal medullary cGMP in control animals, it significantly increased cGMP in RUPP animals (1.3 ± 0.1 pmol/μg protein; P < 0.05). These data suggest that sildenafil might provide an effective therapeutic option for the management of hypertension during preeclampsia.
authors.affiliation: Department of Physiology and the Cardiovascular Renal Research Center, The University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Eric M
authors.initials: EM
authors.lastname: George
authors.forename: Ana C
authors.initials: AC
authors.lastname: Palei
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dent
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D000199:Actins / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D062186:Arterial Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007511:Ischemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D021041:Placental Circulation / Q000187:drug effects; D011225:Pre-Eclampsia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000199:Actins; D000959:Antihypertensive Agents; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; C467498:vascular endothelial growth factor A, rat; D000068677:Sildenafil Citrate; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
keywords: phosphodiesterase-5; preeclampsia; pregnancy; soluble fms-like tyrosine kinase; vascular endothelial growth factor