TY - JOUR

T1 - Indacrinone (MK-196) - a specific inhibitor of the voltage-dependent Cl- permeability in toad skin

AU - Durr, J. E.

AU - Larsen, E. H.

PY - 1986

Y1 - 1986

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0022610984&partnerID=8YFLogxK

U2 - 10.1111/j.1748-1716.1986.tb07887.x

DO - 10.1111/j.1748-1716.1986.tb07887.x

M3 - Journal article

C2 - 3088914

AN - SCOPUS:0022610984

VL - 127

SP - 145

EP - 153

JO - Acta Physiologica Scandinavica

JF - Acta Physiologica Scandinavica

SN - 0001-6772

IS - 2

ER -