Clinically relevant concentrations of β2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury

Objective: To determine whether clinically relevant airspace concentrations of beta(2)-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether beta(2) 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 muL with salmeterol treatment, compared with 296 +/- 65 muL 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 muL with salmeterol compared with 119 +/- 51 muL in saline-treated rats 4 hrs after acid injury (p < .05). Conclusions: Clinically relevant airspace concentrations of beta(2)-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 beta(2)-adrenergic agonists improve outcome in patients with acute lung injury.