title: Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury.
abstract: OBJECTIVE
  To determine whether clinically relevant airspace concentrations of beta2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether beta2 agonist therapy decreased pulmonary edema in experimental acute lung injury.
  
  
  METHODS
  Prospective randomized laboratory investigation.
  
  
  METHODS
  University-affiliated laboratory.
  
  
  METHODS
  Sprague Dawley rats.
  
  
  METHODS
  Dibutyryl cyclic adenosine monophosphate (cAMP), salmeterol, albuterol, and isoproterenol in normal rat lung. Salmeterol in a rat model of acid-induced lung injury.
  
  
  RESULTS
  Basal alveolar fluid clearance was 7.6 +/- 2.2 %/hr. Maximal cAMP-dependent alveolar fluid clearance rate was 32.9 +/- 10.9 %/hr (p <.05). Racemic albuterol 10(-5) M, salmeterol 10(-6) M, and isoproterenol 10(-6) M each stimulated alveolar fluid clearance to a level comparable to maximal cAMP-dependent alveolar fluid clearance. Compared with basal rates, alveolar fluid clearance was increased by both racemic albuterol 10(-6) M (14.5 +/- 3.0%, p <.05) and R-enantiomer 10(-6) M (15.0 +/- 4.6%, p <.05), but there was no difference between the two groups. Intra-alveolar salmeterol 10 (-6) M attenuated the degree of pulmonary edema following acid-induced lung injury. Extravascular lung water increased to only 180 +/- 30 microL with salmeterol treatment, compared with 296 +/- 65 microL in saline-treated rats 4 hrs after acid injury (p <.05). This decrease in lung water was accompanied by a 2.4-fold increase in the rate of alveolar fluid clearance at 4 hrs in the salmeterol-treated group. Lung endothelial permeability, expressed as extravascular plasma equivalents, was reduced to 64 +/- 9 microL with salmeterol compared with 119 +/- 51 microL in saline-treated rats 4 hrs after acid injury (p <.05).
  
  
  CONCLUSIONS
  Clinically relevant airspace concentrations of beta2-adrenergic agonists a) stimulate maximal cAMP-dependent airspace fluid clearance in normal lungs and b) reduce pulmonary edema in acid aspiration-induced lung injury by increasing alveolar fluid clearance and decreasing endothelial permeability. Clinical studies are required to determine whether beta2-adrenergic agonists improve outcome in patients with acute lung injury.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.forename: James A
authors.initials: JA
authors.lastname: Frank
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D015633:Extravascular Lung Water / Q000187:drug effects*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D011654:Pulmonary Edema / Q000188:drug therapy*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D000068299:Salmeterol Xinafoate; D013237:Stereoisomerism
chemical_list: D000318:Adrenergic beta-Agonists; D000249:Adenosine Monophosphate; D000068299:Salmeterol Xinafoate; D000420:Albuterol