Indacrinone (MK-196)--a specific inhibitor of the voltage-dependent Cl- permeability in toad skin

Abstract

The effect of indacrinone (MK-196) on Cl- transport through toad (Bufo bufo) skin epithelium was studied by the voltage clamping technique. At the transepithelial potential, V = 50 mV (serosal bath grounded) the unidirectional fluxes, governed by a Cl- self-exchange diffusion pathway, were not affected by 1 mM racemic MK-196 in the outer bath. Likewise at V = o mV, the unidirectional fluxes as well as the active (net) inward flux of Cl- were unaffected by MK-196. Voltage clamping the epithelium in the physiological range of potentials activated a Cl- specific passive conductance that saturated for V less than or equal to -90 mV. The influx and efflux of Cl- through this pathway were inhibited by MK-196, and the (passive) Cl- current was inhibited in a dose-dependent way for [MK-196] greater than or equal to 50 microM with about 70% inhibition for [MK-196] = 1 mM. The maximum Cl- conductance was decreased without shifting the position along the V-axis of the inverted S-shaped conductance-voltage relationship. The time constants for the voltage-stimulated Cl- conductance activation were not affected by MK-196 (50 microM less than or equals [MK-196] less than or equals 1 mM). The (+) and (-) isomers and racemic MK-196 affected the voltage-dependent Cl- conductance in similar ways. It is concluded that MK-196 has the properties of a Cl- channel blocker which is specific for the voltage-dependent Cl- permeability of the epithelium. The time course for development of inhibition exhibited a fast (min) and a slow (h) component.(ABSTRACT TRUNCATED AT 250 WORDS)