title: Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction.
abstract: BACKGROUND
  Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined.
  
  
  METHODS
  We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability.
  
  
  RESULTS
  In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W.
  
  
  CONCLUSIONS
  Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent.
authors.affiliation: Justus-Liebig-University Giessen, University of Giessen & Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Medical Clinic II/IV/V, Aulweg 130, 35392 Giessen, Germany.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Ketabchi
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Bakytbek
authors.initials: B
authors.lastname: Egemnazarov
authors.forename: S Mostafa
authors.initials: SM
authors.lastname: Shid-Moosavi
authors.forename: Gholam A
authors.initials: GA
authors.lastname: Dehghani
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Natascha
authors.initials: N
authors.lastname: Sommer
mesh_terms: D000138:Acidosis / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006935:Hypercapnia / Q000188:drug therapy / Q000503:physiopathology*; D000860:Hypoxia / Q000188:drug therapy / Q000503:physiopathology*; D007097:Imines / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D017693:Sodium Bicarbonate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007097:Imines; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D019335:Nitroarginine; D017693:Sodium Bicarbonate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III