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*

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Abstract
Objective: To determine whether clinically relevant airspace concentrations of β2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether β2 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 10−5M, salmeterol 10−6M, and isoproterenol 10−6M 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 10−6M (14.5 ± 3.0%, p < .05) and R-enantiomer 10−6M (15.0 ± 4.6%, p < .05), but there was no difference between the two groups. Intra-alveolar salmeterol 10−6M attenuated the degree of pulmonary edema following acid-induced lung injury. Extravascular lung water increased to only 180 ± 30 μL with salmeterol treatment, compared with 296 ± 65 μL 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 μL with salmeterol compared with 119 ± 51 μL in saline-treated rats 4 hrs after acid injury (p < .05). Conclusions: Clinically relevant airspace concentrations of β2-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 β2-adrenergic agonists improve outcome in patients with acute lung injury.