AbstractBoth the superficial epithelium and submucosal glands play a role in airway secretion. Electrophysiological experiments showed that extracellular ATP induced an initial transient increase in Cl– secretion followed by a prolonged inhibition of Na+ absorption in rabbit tracheal epithelium, which lacks submucosal glands. The response to ATP was mimicked by UTP or ATPγS in untreated normal epithelium, suggesting a P2U‐type receptor in the epithelium. Meanwhile, in tracheal epithelium from SO2‐induced bronchitic rabbit ATP induced a prolonged increase in Cl– secretion without a decrease in Na+ absorption, which was mimicked by adenosine or isoproterenol (ISP). The alteration in the bronchitic epithelium was shown to result from a newly expressed CFTR by both immunohistological and Northern blot analysis. Patch‐clamp experiments showed that ATP induced an initial Cl– current followed by K+ current in acinar cells of submucosal glands isolated from feline and human trachea. Although ISP alone or adenosine did not evoke any significant current responses, ISP augmented the ATP‐induced Cl– and K+ currents. A phosphodiesterase inhibitor, 3‐isobutyl‐1‐methylxanthine (IBMX), mimicked the augmentation by ISP. ATP also induced an increase in [Ca2+]i in acinar cells of submucosal glands, which was augmented by ISP. Mucus glycoprotein (MGP) secretion from isolated submucosal glands was also stimulated by ATP but not by adenosine. The ATP‐induced MGP secretion was augmented by ISP. These findings suggest that P2‐receptor stimulation and the resultant [Ca2+]i‐rise induce both electrolyte and MGP secretion, which is enhanced by [cAMP]i‐rise in airway submucosal glands. Drug Dev. Res. 52:170–177, 2001. © 2001 Wiley‐Liss, Inc.