TERFENADINE BLOCKS TIME-DEPENDENT CA2-PIG VENTRICULAR MYOCYTES(, NA+,AND K+ CHANNELS IN GUINEA)

Terfenadine, which blocks delayed rectifier K+ channels (I-K), is stru cturally related to diphenylalkylamine L-type Ca2+ channel (I-Ca) bloc kers and has been reported to render Purkinje fibers inexcitable. We u sed standard whole-cell patch clamp techniques in isolated guinea pig ventricular myocytes to investigate the direct effect of terfenadine o n I-Ca after discovering that the upstrokes of early afterdepolarizati ons in guinea pig myocytes were inhibited by the drug at concentration s 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 ob tained. All experiments were controlled for time of intracellular dial ysis. 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 m V after 10 min exposure [peak at 0 mV in K+-deficient dialysis solutio n -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 completel y blocked after 15 min drug exposure. Ten minutes of exposure to terfe nadine (3 x 10(-6)M) also caused near-complete blockade of peak I-Na w hen 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 e ffect was much less pronounced when I-Na was measured from a holding p otential of -90 mV. After exposure to terfenadine 3 x 10(-6)M, I-K den sity, measured as peak tail current at -40 mV after 300-ms depolarizat ions, was also reduced but not eliminated at membrane potentials betwe en -20 and +60 mV. In contrast, exposure to terfenadine caused no sign ificant change in the current-voltage relationship after 300-ms steps from -90 to +60 mV. Terfenadine had no effect on time constants of dec ay of I-K or I-Ca. These results suggest that terfenadine blocks sever al time- and voltage-dependent channels, possibly by binding to a comm on protein structure, not related to ion selectivity, that is primaril y associated with time-dependent activation of channel conductance.