Terfenadine blocks time-dependent Ca²⁺, Na⁺, and K⁺ channels in guinea pig ventricular myocytes

Terfenadine, which blocks delayed rectifier K⁺ channels (I_K), is structurally related to diphenylal-kylamine L-type Ca²⁺ channel (I_Ca) blockers and has been reported to render Purkinje fibers inexcitable. We used standard whole-cell patch clamp techniques in isolated guinea pig ventricular myocytes to investigate the direct effect of terfenadine on I_Ca after discovering that the upstrokes of early afterdepolarizations in guinea pig myocytes were inhibited by the drug at concentrations ≥10^-6M. Some data analyzing the effect of terfenadine on time-dependent Na⁺ channels (I_Na) and I_K also were obtained. All experiments were controlled for time of intracellular dialysis. Terfenadine (3 × 10^-6M) reduced peak I_Ca (measured in either K⁺-containing or Cs⁺-substituted intracellular solutions from holding potentials of -40 mV) at all membrane potentials between - 30 and + 60 mV after 10 min exposure [peak at o mV in K⁺-deficient dialysis solution -4.2 ± 2.3 pA/pF (mean ± SD, n = 5) versus - 13.02 ± 4.33 pA/pF in control solution (n = 5), P < 0.01], and I_Ca was almost completely blocked after 15 min drug exposure. Ten minutes of exposure to terfenadine (3 × 10^-6M) also caused near-complete blockade of peak I_Na when I_Na was measured at -40 mV after 300 ms conditioning pulses from a holding potential of -40 to potentials between -60 and -90 mV. The effect was much less pronounced when I_Na was measured from a holding potential of -90 mV. After exposure to terfenadine 3 × 10^-6M, I_K density, measured as peak tail current at - 40 mV after 300-ms depolarizations, was also reduced but not eliminated at membrane potentials between -20 and +60 mV. In contrast, exposure to terfenadine caused no significant change in the current-voltage relationship after 300-ms steps from -90 to +60 mV. Terfenadine had no effect on time constants of decay of I_K or I_Ca. These results suggest that terfenadine blocks several time- and voltage-dependent channels, possibly by binding to a common protein structure, not related to ion selectivity, that is primarily associated with time-dependent activation of channel conductance.