Effects of Neurokinins on Ion Transport and Sulfated Macromolecule Release in the Isolated Ferret Trachea

Abstract

The secretory actions of substance P (SP) were studied by examining its effects on ion transport and sulfated macromolecule release in the isolated ferret trachea. Responses to serosally administered SP were unmasked by thiorphan, suggesting that SP administered by this route was degraded by neutral endopeptidase. Therefore, the serosal actions of neurokinins and neurokinin analogues were studied in tissues pretreated with thiorphan. In thiorphan-treated tissues, SP dose-dependently increased the short-circuit current (Isc) with a maximum increase of 0.50 +/- 0.07 mueq/cm2.h above baseline. The SP-induced increase in Isc was inhibited by bumetanide but not by amiloride, suggesting the involvement of electrogenic Cl- secretion. The direct measurement of ion fluxes, however, failed to detect a significant unilateral movement of Cl- from the serosa to mucosa, probably due to a relatively small and transient increase in Isc produced by SP. Instead, SP (10(-6) M) induced large, electroneutral secretion of Na+ and Cl-. In addition, SP stimulated sulfated macromolecule output. The rank order of potency in increasing both Isc and sulfated macromolecule release among neurokinins and their analogues was SP = SP-methyl ester greater than neurokinin A greater than neurokinin B greater than senktide. These findings indicate that the secretory responses to SP are probably mediated by NK-1 receptors.