To investigate the short-term effects of didecanoyl-L-alpha-phosphatidylcholine on the nasal mucosa and the mechanism by which didecanoyl-L-alpha-phosphatidylcholine enhances the nasal absorption of insulin, an in vitro model was developed. The mucosa from the posterior part of the rabbit nasal septum was mounted in an Ussing chamber and incubated in bicarbonate Ringer solution at 37 degrees C. Potential difference, transmucosal conductance, and unidirectional tracer fluxes were measured across an exposed tissue area of 0.44 cm2. Morphological and physiological examinations revealed a typical respiratory epithelium containing amiloride-sensitive Na+ channels and diphenylamine-2-carboxylate-sensitive Cl- channels. Spontaneous potential difference (10.8 +/- 0.4 mV [n = 50]; serosa positive) and transmucosal conductance (10.5 +/- 0.4 mS/cm2 [n = 50]) were stable for several hours. Mucosal addition of 0.1-0.5% didecanoyl-L-alpha-phosphatidylcholine increased transmucosal conductance (by 43-53%) and decreased potential difference (to 0-2 mV) to new steady-state values within 10-15 min. Control unidirectional rate constants for permeation of sucrose, polyethylene glycol 4000, and insulin were low and varied according to the molecular size. After addition of didecanoyl-L-alpha-phosphatidylcholine, unidirectional rate constants for the three compounds all increased 3- to 5.5-fold. The didecanoyl-L-alpha-phosphatidylcholine effects on potential difference and transmucosal conductance were reversible after a recovery period of at least 40 min when didecanoyl-L-alpha-phosphatidylcholine had been applied to the mucosal side for 15 min. The results suggest that didecanoyl-L-alpha-phosphatidylcholine may increase the transepithelial absorption of insulin by facilitating a paracellular passage through a reversible opening of tight junctions.