Postreceptor defects in alveolar epithelial β-adrenergic signaling after prolonged isoproterenol infusion

Abstract

We previously found that prolonged isoproterenol (Iso) infusion in rats impaired the ability of β-adrenoceptor (β-AR) agonists to increase alveolar liquid clearance (ALC). Here, we determined if postreceptor defects in β-AR signaling contribute to this impairment. Iso was infused using subcutaneous miniosmotic pumps (4, 40, or 400 μg · kg-1 · h-1) in rats for 48 h. At this time, forskolin-stimulated ALC was measured by mass balance. Forskolin-stimulated ALC [33.4 ± 2.1%/h (mean ± SE) in vehicle-infused rats] was reduced by 25 and 38%, respectively, after the 40 and 400 μg · kg-1 · h-1 Iso infusions. The ability of forskolin to increase cAMP was reduced by 70% in alveolar type II (ATII) cells isolated from rats infused with 400 μg · kg-1 · h-1 Iso. Additionally, the ability of the stable cAMP analog 8-bromoadenosine-3′,5′-cyclic monophosphorothioate, Sp-isomer, to increase ALC (48.7 ± 3.0% in vehicle-infused rats) was reduced by 25 and 51%, respectively, after the 40 and 400 μg · kg-1 · h-1 infusions. Finally, the ability of cAMP to increase protein kinase A activity was eliminated in ATII cells isolated from rats infused with Iso at 400 μg · kg-1 · h-1. These data demonstrate that prolonged β-AR agonist exposure can impair alveolar epithelial β-AR signaling downstream of the β-AR.