beta(2)-Adrenergic Stimulation Blunts Inhibition of Epithelial Ion Transport by Hypoxia of Rat Alveolar Epithelial Cells

Hypoxia impairs alveolar fluid clearance by inhibition of Na+ reabsorption, and also impairs beta(2) adrenergic signaling in alveolar epithelium. Since both are major rescue mechanisms preventing pulmonary edema, we studied whether acute and prolonged treatment with terbutaline would prevent hypoxic inhibition of ion transport. Short circuit currents (ISC) were measured on normoxic and hypoxic (1.5% O-2; 24h) primary rat alveolar type II (ATII) cells in absence and presence of terbutaline (1 to 100 mu M, 24h). Control and pre-treated cells were stimulated acutely with terbutaline. Transepithelial transport was measured as short circuit current (ISC) in Ussing chambers. Terbutaline induced a rapid decrease ISC (-20%) followed by a slow raise. The transient change in ISC was not inhibited by amiloride but was prevented after Cl- depletion indicating a Cl- current. The slow increase after this transient was amiloride-sensitive indicating a Na+ current. Total ISC, its amiloride-sensitive component, and the transient decrease upon terbutaline stimulation were decreased by hypoxia. 24h treatment with terbutaline stimulated these currents in normoxia and hypoxia, although stimulation was less in the latter. 24h treatment with terbutaline increased the capacity of Na+/K+-ATPase and ENaC as measured after permeabilization with amphotericin. These changes were not paralleled by altered mRNA expression. Acutely applied terbutaline induced a 4-fold increase in cAMP formation in normoxia; terbutaline-induced cAMP-formation was impaired by hypoxia (-20%). Pre-treatment with terbutaline for 24h decreased terbutaline-induced cAMP formation by 85%. Despite this desensitization, addition of terbutaline to terbutaline pre-treated cells caused a larger increase in Cl- and Na+ transport both in normoxia and hypoxia than in non pre-treated cells. These results indicate that beta(2) adrenergic stimulation increased Na+- and Cl- transport in ATII cells even in hypoxia thus restoring normal reabsorption. Copyright (C) 2010 S. Karger AG, Basel