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Vol. 292, Issue 3, 939-943, March 2000
-Cells
Department of Pharmacology, University of South Alabama, College of
Medicine, Mobile, Alabama
It has been shown that mibefradil (Ro 40-5967) exerts a selective
inhibitory effect on T-type Ca2+ currents, although at
higher concentrations it can antagonize high voltage-activated
Ca2+ currents. The action of mibefradil on Ca2+
channels is use- and steady-state-dependent and the binding site of
mibefradil on L-type Ca2+ channels is different
from that of dihydropyridines. By using conventional whole-cell and
perforated patch-clamp techniques, we showed that mibefradil has an
inhibitory effect on both T- and L-type Ca2+
currents in insulin-secreting cells. However, the effect on
L-type Ca2+ currents was time-dependent and
poorly reversible in perforated patch-clamp experiments. By using mass
spectrometry, we demonstrated that mibefradil accumulates inside cells,
and furthermore, a metabolite of mibefradil was detected. Intracellular
application of this metabolite selectively blocked the
L-type Ca2+ current, whereas mibefradil exerted
no effect. This study demonstrates that mibefradil permeates into cells
and is hydrolyzed to a metabolite that blocks L-type
Ca2+ channels specifically by acting at the inner side of
the channel.
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