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 microM, 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.