title: Induced nitric oxide impairs relaxation but not contraction in endotoxin-exposed rat pulmonary arteries.
abstract: BACKGROUND
  Many patients with severe acute lung injury do not respond to nitric oxide (NO) inhalational therapy with alleviation of pulmonary arterial hypertension and hypoxemia, so this treatment remains controversial. MATERIALS AND METHODS.: We investigated in endotoxin-exposed Wistar rat pulmonary arteries whether endogenous NO alters contractile and relaxing responses, by electrochemical NO and isometric force measurements.
  
  
  RESULTS
  Receptor-independent contraction was similar in control and endotoxin-exposed arteries, while thromboxane analogue (TxA)-dependent contraction was less in the latter. Neither non-selective NO synthase (NOS) inhibition by N(G)-nitro-l-arginine (l-NA) or selective inducible-NOS2 inhibition by aminoguanidine (AG) improved TxA-induced contraction in endotoxin-exposed arteries. Acetylcholine-induced relaxation was impaired in endotoxin-exposed pulmonary arteries, despite a comparable acetylcholine-induced NO release in control arteries. Additionally, NO solution-induced relaxation of endotoxin-exposed arteries was impaired, but could be improved by l-NA or AG. Application of a phosphodiesterase-insensitive cyclic guanosine monophosphate analogue induced similar relaxation in both control and endotoxin-exposed arteries.
  
  
  CONCLUSIONS
  Endotoxin-associated NOS2-derived NO is thus associated with impaired NO-mediated relaxation, but does not underlie reduced receptor-mediated pulmonary contractile responses. An increased phosphodiesterase activity may underlie the former, so this route can be explored to replace or improve the effect of inhalational NO therapy in severe sepsis-induced acute lung injury in patients.
authors.affiliation: Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands. c.boer@vumc.nl
authors.forename: Christa
authors.initials: C
authors.lastname: Boer
authors.forename: A B Johan
authors.initials: AB
authors.lastname: Groeneveld
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Scheffer
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: de Lange
authors.forename: Nico
authors.initials: N
authors.lastname: Westerhof
authors.forename: Pieter
authors.initials: P
authors.lastname: Sipkema
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism* / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D045462:Endothelium-Dependent Relaxing Factors; D004731:Endotoxins; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006152:Cyclic GMP; D000109:Acetylcholine