title: Response to inhaled nitric oxide (NO) is not associated with changes of plasma cGMP levels in patients with acute lung injury.
abstract: BACKGROUND
  A clinically relevant increase of PaO subset2 or decrease of pulmonary vascular resistance (PVR) upon inhalation of NO (iNO) does occur in only 60 to 80% of patients with acute lung injury. The mechanisms for divergent responses of different patients have not yet been fully elucidated. Since NO mediates its pulmonary effects by stimulating soluble guanylate cyclase, thereby increasing levels of cyclic guanosinemonophosphate (cGMP), we hypothesized that pulmonary cGMP production upon iNO might be suppressed in patients not responding to iNO treatment.
  
  
  METHODS
  After approval by the local ethical committee and after informed consent had been obtained, both arterial and mixed-venous cGMP levels were analyzed in 13 patients in whom iNO was administered to treat pulmonary hypertension and/or hypoxemia due to acute respiratory distress syndrome (n = 11) or reperfusion injury following lung transplantation (n = 2). Both cardiorespiratory variables and cGMP concentrations were documented simultaneously at baseline, 15 min after inhalation of 8 ppm of NO, and 15 min after withdrawal of NO, respectively.
  
  
  RESULTS
  Inhaled NO resulted in a significant increase in PaO(2)/FiO(2) and a decrease in PVR. Arterial and mixed venous concentration of cGMP (median) also increased significantly upon iNO from 2.5 to 6.5 nM (p <0.05) and from 3.0 to 5.7 nM (p <0.05), respectively. Theses effects were fully reversible after withdrawal of iNO. No gradients between arterial and mixed venous cGMP concentrations were detected (p = 0.12). Regression analysis showed no relationship between baseline arterial cGMP concentrations and changes of either PaO(2)/FiO(2) (p = 0. 62) or PVR (p = 0.91). Similarly, no relationship was found between the rise of arterial cGMP concentration subsequent to iNO and corresponding changes of PaO(2) (p = 0.40) or PVR (p = 0.74), respectively.
  
  
  CONCLUSIONS
  Inhalation of NO significantly stimulates soluble guanylate cyclase within the lungs in patients with acute lung injury. However, neither baseline cGMP nor its rise during treatment with inhaled NO can predict the clinical efficacy of iNO in humans. Furthermore, the fact that increased cGMP concentrations were detected during administration of iNO in mixed venous blood (i.e. pulmonary inflow) strongly suggest that the pharmacological effects of iNO are not fully selective for the lungs, but may also affect extrapulmonary organs.
authors.affiliation: Klinik für Anästhesiologie der Ludwig-Maximilians-Universität München, Klinikum Grosshadern, Marchioninistr. 15, D-81377 München, Germany. Bernhard.Zwissler@Ana.Med.Uni-Muenchen.De
authors.forename: B
authors.initials: B
authors.lastname: Zwissler
authors.forename: G
authors.initials: G
authors.lastname: Kemming
authors.forename: M
authors.initials: M
authors.lastname: Merkel
authors.forename: G
authors.initials: G
authors.lastname: Wolfram
authors.forename: M
authors.initials: M
authors.lastname: Kleen
authors.forename: O
authors.initials: O
authors.lastname: Habler
authors.forename: M
authors.initials: M
authors.lastname: Haller
authors.forename: J
authors.initials: J
authors.lastname: Briegel
mesh_terms: D000208:Acute Disease; D000280:Administration, Inhalation; D000328:Adult; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000097:blood*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000627:therapeutic use*; D011652:Pulmonary Circulation; D012131:Respiratory Insufficiency / Q000097:blood / Q000188:drug therapy*
chemical_list: D001993:Bronchodilator Agents; D009569:Nitric Oxide; D006152:Cyclic GMP