Because beta-adrenergic agonist therapy may be useful clinically as a treatment to hasten the resolution of alveolar edema, this study was designed to examine the dose-dependent effects of beta-adrenergic agonist therapy on alveolar epithelial fluid clearance. The studies were done by instilling an isosmolar 5% albumin solution into the distal air spaces of both ex vivo rat and ex vivo human lungs that were inflated with 8 to 10 cm H2O with 100% oxygen and placed in a 37 degrees C humid incubator. Alveolar fluid clearance was measured by the progressive increase in concentration of protein over 1 or 4 h. Salmeterol, a new long-acting lipophilic agent, was more potent than terbutaline in stimulating alveolar fluid clearance from the ex vivo human lung. Therefore, salmeterol was used for these studies. The results indicated that: (1) basal, unstimulated alveolar fluid clearance in rat lungs was significantly faster than in human lungs (24 +/- 4% over 4 h in rat lungs compared with 11 +/- 2% over 4 h in human lungs, p < 0.05); (2) comparison of equivalent doses of beta-adrenergic stimulation indicated that stimulated clearance rates were also faster in rat lungs than in human lungs; (3) very low doses of salmeterol were effective in ex vivo rat lungs (10(-8) M); and (4) relatively low doses were effective in the ex vivo human lungs (10(-6) M) as a treatment for increasing alveolar fluid clearance. In summary, there are significant differences in the basal and stimulated rates of alveolar epithelial fluid clearance in rat and human lungs, although the ex vivo human studies may have underestimated maximal alveolar fluid clearance in the intact human lung. The human lung responds well to relatively low doses of beta-adrenergic agonist therapy, a finding with potentially important clinical implications for hastening the resolution of alveolar edema.