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

Crit Care Med. 2004 Jul;32(7):1470-6. doi: 10.1097/01.ccm.0000129489.34416.0e.


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.

Design: Prospective randomized laboratory investigation.

Setting: University-affiliated laboratory.

Subjects: Sprague Dawley rats.

Interventions: Dibutyryl cyclic adenosine monophosphate (cAMP), salmeterol, albuterol, and isoproterenol in normal rat lung. Salmeterol in a rat model of acid-induced lung injury.

Measurements and main 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Monophosphate / metabolism*
  • Adrenergic beta-Agonists / therapeutic use*
  • Albuterol / analogs & derivatives*
  • Albuterol / therapeutic use*
  • Animals
  • Extravascular Lung Water / drug effects*
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Pulmonary Edema / drug therapy*
  • Pulmonary Gas Exchange / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Distress Syndrome / drug therapy*
  • Salmeterol Xinafoate
  • Stereoisomerism


  • Adrenergic beta-Agonists
  • Adenosine Monophosphate
  • Salmeterol Xinafoate
  • Albuterol