We previously demonstrated that 48-h isoproterenol (Iso) infusion in rats impaired the ability of beta-adrenoceptor (beta-AR) agonists to increase alveolar liquid clearance (ALC). In this study, we determined whether this impairment persisted over longer time periods by infusing 400 mug.kg(-1).h(-1) Iso by osmotic minipump for 24-144 h (n = 6-7/group). ALC in control rats was 19.0 +/- 2.4 (SD)% of instilled volume absorbed per hour. In Iso-infused rats, ALC was elevated at 24 h (34.9 +/- 2.4%) and decreased at 48 h (15.2 +/- 4.4%) and had recovered to 24 h values at 96 h (37.3 +/- 3.8%) and 144 h (35.2 +/- 3.3%). Plasma Iso concentrations remained elevated at all Iso infusion times. Peripheral lung beta(2)-AR expression exhibited a parallel time course, with a reduction in expression observed at 48 h, followed by an increase to 24 h values at 96 and 144 h. Propranolol prevented the increase in ALC observed at 96 and 144 h, indicating that the recovery in ALC was mediated by a recovery of beta-AR function and beta-AR signaling. ALC at 96 and 144 h could not be further increased by terbutaline, indicating that ALC was maximally stimulated. These data indicate that recovery of beta-AR-stimulated ALC can occur in the continued presence of Iso and is mediated by a recovery of the ability of the distal lung epithelium to respond to beta-AR stimulation.