Indacrinone (MK-196) - a specific inhibitor of the voltage-dependent Cl- permeability in toad skin
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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 ≤ -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] = 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 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 intertaction of MK-196 with a cytoplasmic site of the anion permeation pathway.
Originalsprog | Engelsk |
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Tidsskrift | Acta physiologica Scandinavica |
Vol/bind | 127 |
Udgave nummer | 2 |
Sider (fra-til) | 145-153 |
Antal sider | 9 |
ISSN | 0001-6772 |
DOI | |
Status | Udgivet - 1986 |
ID: 367300622