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

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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 = 0 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 ±– 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] ± 50 μM with about 70% inhibition for [MK‐196] = I 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 μM ± [MK‐196] ± 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. The fast component may reflect a direct interaction of MK‐196 with an extracellular site of the Cl‐channel, whereas the slow one may reflect impairment of a metabolic pathway regulating the Cl‐permeability, or an interaction of MK‐196 with a cytoplasmic site of the anion permeation pathway.