Abstract

We tested the assumption that nifedipine blocks L-type calcium current [I_Ca(L)] at +10 mV and unmasks Na⁺/Ca²⁺ exchange-triggered contractions in guinea pig isolated ventricular myocytes. Voltage-clamp pulses elicited I_Ca(L) at +10 mV and evoked contractions in myocytes superfused with Tyrode's solution (35°C). Nifedipine blocked I_Ca(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 ofI_Ca(L) increased with concentration (10–100 μM) and application time when nifedipine was rapidly applied (t_1/2 = ∼0.2 s) during rest intervals (5–30 s). The fraction of use-dependent block ofI_Ca(L) diminished with increasing drug concentration. Nifedipine also acceleratedI_Ca(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 suppressI_Ca(L) on the first test pulse at +10 mV. The incidence of complete block of contractions, as for complete block of I_Ca(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-sensitiveI_Ca(L) triggers contractions at +10 mV, whereas nifedipine-resistant Na⁺/Ca²⁺ exchange current initiates those at +100 mV.