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Vol. 294, Issue 2, 562-570, August 2000
Department of Pharmacology, University of Connecticut Health
Center, Farmington, Connecticut
We tested the assumption that nifedipine blocks L-type calcium
current [ICa(L)] at +10 mV and unmasks
Na+/Ca2+ exchange-triggered contractions
in guinea pig isolated ventricular myocytes. Voltage-clamp pulses
elicited ICa(L) at +10 mV and evoked contractions in myocytes superfused with Tyrode's solution (35°C). Nifedipine blocked ICa(L) with an
IC50 of 0.3 µM; this decreased to 50 nM at a holding
potential of 
40 mV, indicating preferential block of inactivated
L-type Ca2+ channels. Use-independent block of
ICa(L) increased with concentration (10-100
µM) and application time when nifedipine was rapidly applied (t1/2 = ~0.2 s) during rest
intervals (5-30 s). The fraction of use-dependent block of
ICa(L) diminished with increasing drug concentration. Nifedipine also accelerated
ICa(L) inactivation on the first test pulse.
The combination of 30 µM nifedipine/30 µM Cd2+ (Nif
30/Cd 30) was as effective as 100 µM nifedipine to suppress ICa(L) on the first test pulse at +10 mV.
The incidence of complete block of contractions, as for complete block
of ICa(L), increased as a function of
nifedipine concentration and application time. Neither nifedipine nor
Nif 30/Cd 30 affected Na+/Ca2+ exchange
current at +10 to +100 mV. Contractions at +100 mV, although as
large as those at +10 mV, were delayed in onset and resistant to
nifedipine or Nif 30/Cd 30. We conclude that nifedipine-sensitive ICa(L) triggers contractions at +10 mV,
whereas nifedipine-resistant Na+/Ca2+ exchange
current initiates those at +100 mV.
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