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Vol. 281, Issue 3, 1247-1256, 1997
Department of Physiology, Botterell Hall, Queen's University,
Kingston, Ontario, Canada
Nifedipine antagonizes L-type Ca++ channels found
throughout the cardiovascular system, but also blocks Kv channels,
which are members of the same supergene family. We have examined
nifedipine actions on the human heart K+ channel (hKv1.5)
expressed in human embryonic kidney cells. Peak and steady-state
currents on depolarization were reduced by nifedipine with
Kd values of 18.6 ± 2.7 and 6.3 ± 0.5 µM respectively at +40 mV, and with Hill coefficients of
0.75 ± 0.04 and 0.93 ± 0.03. Block increased rapidly
between -10 mV and +10 mV, coincident with channel opening and
suggested an open channel block mechanism, which was confirmed by tail
current crossover on repolarization (unblock on channel closing). At
more positive potentials than +20 mV, block was relieved. The time
constants (
2) for nifedipine block of hKv1.5 were
concentration and voltage dependent. At +40 mV, 2 was
16.7 ± 0.8 (10 µM), and 4.8 ± 0.6 msec (50 µM),
(n = 4-8). Using a first order kinetic analysis,
apparent binding constants were 5.64 × 106
M
1 s1
(k+1, on-rate) and 37.5 s1
(k1, off-rate), with a
Kd of 6.65 µM, close to that obtained from
the dose-response curve. An increase in the off-rate
(k1) could explain relief of block >+20 mV.
The rank order of block under different patch configurations was
whole-cell 
outside-out > inside-out 
cell-attached
macropatches. Together, these suggested a binding site for nifedipine
at the extracellular pore of hKv1.5 or at a hydrophobic channel domain
within the lipid bilayer at a site that is more accessible from the
extracellular side.
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