Terfenadine, which blocks delayed rectifier K+ channels (Ik), is structurally related to diphenylalkylamine L-type Ca2+ channel (ICa) 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 ICa after discovering that the upstrokes of early afterdepolarizations in guinea pig myocytes were inhibited by the drug at concentrations > or = 10(-6)M. Some data analyzing the effect of terfenadine on time-dependent Na+ channels (INa) and IK also were obtained. All experiments were controlled for time of intracellular dialysis. Terfenadine (3 x 10(-6)M) reduced peak ICa (measured in either K+-containing or Cs+-substituted intracellular solutions from holding potentials of -40 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 ICa was almost completely blocked after 15 min drug exposure. Ten minutes of exposure to terfenadine (3 x 10-6M) also caused near-complete blockade of peak INa when INa 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 INa was measured from a holding potential of -90 mV. After exposure to terfenadine 3 x 10 (-6)M, IK 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 IK or ICa. 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.