Catecholamines trigger the switch from liquid secretion to absorption by perinatal lung, but regulation of Cl-and liquid secretion by pulmonary epithelia early in lung development (low [catecholamine]) is unknown. We looked for evidence for P1and P2receptors that mediate Cl-secretion in 14-d distal lungs and 14- and 18-d tracheas explanted from fetal rats (term = 22 d). We measured amiloride-insensitive transepithelial voltage changes induced by ATP, UTP, or adenosine. Explants were hyperpolarized by all three agonists and by terbutaline, aβ-adrenergic agonist and Cl-secretagogue. Whereas adenosine, ATP, or UTP injected into 14-d explant lumena, or adenosine added to the tracheal bath, induced hyperpolarization with EC50of 2-15 μM EC50, values for all three agonists in the distal lung bath or ATP or UTP in the tracheal bath were five times greater. By 18 d, EC50values for agonists in the bath were comparable to those for lumenal agonists (3-12μM). In contrast, microinjection of terbutaline into all explant lumena(final concentrationn = 3 × 10-5M) induced minimal hyperpolarization, whereas the same concentration in the bath raised bioelectric potential difference maximally. We conclude that1)β-adrenergic receptors are present on the basolateral membranes of cells of the pulmonary epithelium early in lung development, and2) adenosine, ATP, and UTP receptors are present in apical membranes throughout lung epithelial development, but basolateral receptors for these agaonists in distal lung or ATP/UTP in trachea function later in gestation. The putative distribution of P1and P2receptors suggests a role for agonists released from pulmonary epithelial cells in the regulation of liquid secretion early in lung development.Abbreviation: PD,potential difference (bioelectric)