title: Downregulation of hypoxic vasoconstriction by chronic hypoxia in rabbits: effects of nitric oxide.
abstract: Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange. Chronic alveolar hypoxia results in vascular remodeling and pulmonary hypertension. Previous studies have reported conflicting results of the effect of chronic alveolar hypoxia on pulmonary vasoreactivity and the contribution of nitric oxide (NO), which may be related to species and strain differences as well as to the duration of chronic hypoxia. Therefore, we investigated the impact of chronic hypoxia on HPV in rabbits, with a focus on lung NO synthesis. After exposure of the animals to normobaric hypoxia (10% O(2)) for 1 day to 10 wk, vascular reactivity was investigated in ex vivo perfused normoxic ventilated lungs. Chronic hypoxia induced right heart hypertrophy and increased normoxic vascular tone within weeks. The vasoconstrictor response to an acute hypoxic challenge was strongly downregulated within 5 days, whereas the vasoconstrictor response to the thromboxane mimetic U-46619 was maintained. The rapid downregulation of HPV was apparently not linked to changes in the lung vascular NO system, detectable in the exhaled gas and by pharmacological blockage of NO synthesis. Treatment of the animals with long-term inhaled NO reduced right heart hypertrophy and partially maintained the reactivity to acute hypoxia, without any impact on the endogenous NO system being noted. We conclude that chronic hypoxia causes rapid downregulation of acute HPV as a specific event, preceding the development of major pulmonary hypertension and being independent of the lung vascular NO system. Long-term NO inhalation partially maintains the strength of the hypoxic vasoconstrictor response.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany. Norbert.Weissman@innere.med.uni-giessen.de
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Nollen
authors.forename: Boris
authors.initials: B
authors.lastname: Gerigk
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardeschir Ghofrani
authors.forename: Ralph Theo
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Andreas
authors.initials: A
authors.lastname: Gunther
authors.forename: Karin
authors.initials: K
authors.lastname: Quanz
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Jörg
authors.initials: J
authors.lastname: Hänze
authors.forename: Frank
authors.initials: F
authors.lastname: Rose
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000208:Acute Disease; D000818:Animals; D001944:Breath Tests; D002908:Chronic Disease; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011817:Rabbits; D013995:Time; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase