title: Dehydroepiandrosterone upregulates soluble guanylate cyclase and inhibits hypoxic pulmonary hypertension.
abstract: OBJECTIVE
  It has been reported that dehydroepiandrosterone is a pulmonary vasodilator and inhibits chronic hypoxia-induced pulmonary hypertension. Additionally, dehydroepiandrosterone has been shown to improve systemic vascular endothelial function. Thus, we hypothesized that chronic treatment with dehydroepiandrosterone would attenuate hypoxic pulmonary hypertension by enhancing pulmonary artery endothelial function.
  
  
  RESULTS
  Rats were randomly assigned to five groups. Three groups received food containing 0, 0.3, or 1% dehydroepiandrosterone during a 3-wk-exposure to simulated high altitude (HA). The other 2 groups were kept at Denver's low altitude (LA) and received food containing 0 or 1% dehydroepiandrosterone. Dehydroepiandrosterone dose-dependently inhibited hypoxic pulmonary hypertension (mean pulmonary artery pressures after treatment with 0, 0.3, and 1% dehydroepiandrosterone=45+/-5, 33+/-2*, and 25+/-1*# mmHg, respectively. *P<0.05 vs. 0% and # vs. 0.3%). Dehydroepiandrosterone (1%, 3 wks) treatment started after rats had been exposed to 3-wk hypoxia also effectively reversed established hypoxic pulmonary hypertension. Pulmonary artery rings isolated from both LA and HA rats treated with 1% dehydroepiandrosterone showed enhanced relaxations to acetylcholine and sodium nitroprusside, but not to 8-bromo-cGMP. In the pulmonary artery tissue from dehydroepiandrosterone-treated LA and HA rats, soluble guanylate cyclase, but not endothelial nitric oxide synthase, protein levels were increased.
  
  
  CONCLUSIONS
  These results indicate that the protective effect of dehydroepiandrosterone against hypoxic pulmonary hypertension may involve upregulation of pulmonary artery soluble guanylate cyclase protein expression and augmented pulmonary artery vasodilator responsiveness to nitric oxide.
authors.affiliation: Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver Colorado 80262, United States. masahiko.oka@uchsc.edu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Vijaya
authors.initials: V
authors.lastname: Karoor
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Homma
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Nagaoka
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakao
authors.forename: Scott M
authors.initials: SM
authors.lastname: Golembeski
authors.forename: Jennifer
authors.initials: J
authors.lastname: Limbird
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Imamura
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Gebb
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fagan
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000627:therapeutic use*; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004958:Estradiol / Q000097:blood; D006162:Guanylate Cyclase / Q000032:analysis / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000201:enzymology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013739:Testosterone / Q000097:blood; D015854:Up-Regulation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D013739:Testosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D000109:Acetylcholine