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

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

Morgan Eric E; Stader Sonya M; Hodnichak Cheryl M; Mavrich Kate E; Folkesson Hans G; Maron Michael B

American journal of physiology. Lung cellular and molecular physiology

2003

2003-09

We previously found that prolonged isoproterenol (Iso) infusion in rats impaired the ability of beta-adrenoceptor (beta-AR) agonists to increase alveolar liquid clearance (ALC). Here, we determined if postreceptor defects in beta-AR signaling contribute to this impairment. Iso was infused using subcutaneous miniosmotic pumps (4, 40, or 400 microg. 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 microg. 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 microg. 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 microg. 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 microg. kg-1. h-1. These data demonstrate that prolonged beta-AR agonist exposure can impair alveolar epithelial beta-AR signaling downstream of the beta-AR.

8-Bromo Cyclic Adenosine Monophosphate/pharmacology; Adenylyl Cyclases/metabolism; Adrenergic; Adrenergic beta-Agonists/*pharmacology; Animals; beta/*metabolism; Colforsin/pharmacology; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases/metabolism; Cyclic AMP/metabolism; Extravascular Lung Water/metabolism; Isoproterenol/*pharmacology; Male; Pulmonary Alveoli/*drug effects/*metabolism; Pulmonary Edema/metabolism; Rats; Receptors; Respiratory Mucosa/drug effects/metabolism; Signal Transduction/drug effects; Sprague-Dawley

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