Beta adrenergic agents stimulate Na- and water reabsorption in the lung, whereas hypoxia inhibits transport. It is therefore of importance to know whether hypoxia impairs beta adrenergic signalling in lung alveolar epithelium thus diminishing its stimulatory action. To test this, A549 cells were exposed to hypoxia (1.5% O2) ± ter-butaline (TERB) for 24 hours. Acute TERB (15min, 1mM IBMX) treatment of hypoxia-exposed cells increased cAMP production in normoxia (40%) and hypoxia (20%), whereas 24h TERB pre-treatment (10mM) blunted cAMP production. Beta-2 receptor density, measured as 125Iodo-cyano-pindolol (ICYP) binding was decreased by about 25% after 24h hypoxia. TERB-pre-treatment decreased ICYP-binding by 90% indicating receptor down regulation in normoxia and hypoxia. Whereas beta 2-receptor mRNA-expression (RT-PCR) was not affected by TERB- and hypoxia-pre-treatment, adenylyl cyclase-3 mRNA was decreased by about 20%; 24h TERB had no effect. The phosphodiesterase 3A (PDE3A) mRNA was decreased in hypoxia by 50% but not by pre-treatment with TERB. These results indicate that hypoxia impairs beta-adrenergic signalling. However, the decrease in PDE3A by hypoxia might allow significant accumulation of cAMP even when receptor density and cyclase are reduced indicating that TERB might be effective despite receptor down regulation in hypoxia.