β2-Adrenergics in Hypoxia Desensitize Receptors but Blunt Inhibition of Reabsorption in Rat Lungs

Alveolar edema and decreased inspired Po-2 decrease the oxygen supply to alveolar epithelia, impairing beta(2)-adrenergic receptor (beta 2AR) signaling and alveolar reabsorption. beta 2AR agonists potently stimulate alveolar reabsorption. Thus, hypoxia impairs a major defense mechanism that provides protection from alveolar edema. Because in vivo data on the combined effects of prolonged hypoxia and beta 2AR agonist treatment on beta 2AR signaling are sparse, we tested whether in vivo hypoxia augments the inactivation of beta 2AR during prolonged stimulation. Rats were exposed to normoxia (N) and hypoxia (8% O-2; H), and were also treated with terbutaline (T; 2.5 mg/kg, intraperitoneal, twice daily) or saline (S) for 4 days. beta 2AR signaling was studied in alveolar epithelial (ATII) cells and in whole-lung tissue from treated rats. The terbutaline-stimulated formation of cyclic adenosine monophosphate was decreased by approximately 40% in whole lung and in ATII cells of NT, HS, and HT. The effects were not additive. The beta 2AR number was increased in HS, but decreased in NT and HT. Treatment increased the G-protein-coupled receptor kinase 2 protein in the plasma membranes of ATII cells, but did not affect G proteins. In vivo hypoxia significantly decreased total and amiloride-sensitive alveolar fluid reabsorption, which was prevented by acute alveolar treatment and 4 days of systemic terbutaline treatment. The alpha ENaC (subunit of epithelial Na channels) protein in plasma membranes was increased in HT, without effects on mRNA. These results indicate that prolonged alveolar hypoxia and treatment with terbutaline impaired beta 2AR signaling in alveolar epithelia and in whole lungs, and this signaling was not further impaired by hypoxia. Despite impaired beta 2AR signaling, treatment with terbutaline for 4 days prevented the inhibition of alveolar reabsorption caused by in vivo hypoxia.