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 diphenylalkylamine 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 greater than or equal to 10(-6)M. 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 x 10(-6)M) 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 0 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 x 10(-6)M) 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 x 10(-6)M, 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.