TRANSPORT OF INSULIN ACROSS RABBIT NASAL-MUCOSA INVITRO INDUCED BY DIDECANOYL-L-ALPHA-PHOSPHATIDYLCHOLINE

To investigate the short-term effects of didecanoyl-L-alpha-phosphatid ylcholine 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 t he 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 measur ed across an exposed tissue area of 0.44 cm2. Morphological and physio logical examinations revealed a typical respiratory epithelium contain ing amiloride-sensitive Na+ channels and diphenylamine-2-carboxylate-s ensitive 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 transmucosa l conductance (by 43-53%) and decreased potential difference (to 0-2 m V) to new steady-state values within 10-15 min. Control unidirectional rate constants for permeation of sucrose, polyethylene glycol 4000, a nd insulin were low and varied according to the molecular size. After addition of didecanoyl-L-alpha-phosphatidylcholine, unidirectional rat e 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 bee n applied to the mucosal side for 15 min. The results suggest that did ecanoyl-L-alpha-phosphatidylcholine may increase the transepithelial a bsorption of insulin by facilitating a paracellular passage through a reversible opening of tight junctions.