title: Chronically elevated endothelin levels reduce pulmonary vascular reactivity to nitric oxide.
abstract: Although local tissue activation of the endothelin (ET) system contributes to the development of pulmonary hypertension, the impact of isolated chronic plasma hyperendothelinemia on the pulmonary circulation is unknown.
  
  
  METHODS
  Mini-osmotic pumps were implanted in rats to deliver ET-1 during 7 or 28 days. After in vivo hemodynamics, the lungs were isolated to derive pressure-flow relations. Small pulmonary arteries ( approximately 250 microm) were mounted on an isometric myograph to study their reactivity.
  
  
  RESULTS
  Plasma ET-1 approximately doubled (p < 0.05) after 7 and 28 days. Lung tissue ET-1 level increased fourfold after 7 days (p < 0.001) but was no longer significantly elevated after 28 days. Right ventricular systolic pressure was unaffected. The pulmonary pressure-flow relation shifted upward with a steeper slope (p < 0.05) at 7 days, but not after 28 days. Maximum dilatations to both acetylcholine (p < 0.01) and sodium nitroprusside (p < 0.001) were greatly reduced by approximately 50% after 28 days and were normalized by the addition of the nitric oxide synthase inhibitor L-NNA and the antioxidant N-acetyl-L-cysteine, respectively.
  
  
  CONCLUSIONS
  Chronic hyperendothelinemia reduces the pulmonary vasodilator reserve in response to nitric oxide. Correction by an antioxidant and L-NNA suggests that this relates to increased production of reactive oxygen species, which may have clinical relevance for conditions associated with chronic increase of ET. Further studies are required to determine if, in the long term, this could contribute to the development of pulmonary hypertension.
authors.affiliation: Montreal Heart Institute, and University of Montreal, Quebec, Canada.
authors.forename: Annik
authors.initials: A
authors.lastname: Migneault
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sauvageau
authors.forename: Louis
authors.initials: L
authors.lastname: Villeneuve
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: Normand
authors.initials: N
authors.lastname: Leblanc
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Dupuis
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D015918:Infusion Pumps, Implantable; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
chemical_list: D016232:Endothelins; D009569:Nitric Oxide