We studied the regulatory mechanism of Na+ absorption in fetal distal lung epithelium (FDLE), using patch clamp and single cell imaging techniques. A beta 2-agonist activated a 28 pS non-selective cation channel (NSCC) by: 1) producing a dependency of the NSCC activity on the cytosolic [Cl-] ([Cl-]c); 2) inducing a reduction in the [Cl-]c from 45 to 25 mM which directly activated the beta 2-treated NSCC. The beta 2-agonist-induced decrease in [Cl-]c was caused by activation of Ca(2+)-activated K+ channel and cAMP-activated Cl- channel. A development of the [Cl-]c-dependency and a reduction in [Cl-]c act as a second messenger of the beta 2 agonist signal transduction pathway in this Na+ transporting epithelium.