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Blockade of Na+ current by promethazine in guinea‐pig ventricular myocytes

1 To elucidate the antiarrhythmic mechanism of promethazine, its effects on the fast Na+ current (INa) were examined in single guinea‐pig ventricular myocytes by whole‐cell voltage clamp methods. 2 Promethazine blocked INa with a KD of 42.6 μm and Hill's coefficient of 1.1 at a holding potential of — 140 mV. 3 The INa blockade was enhanced at a less negative holding potential of − 80 mV with a change of KD to 4.4 μm. Although 10 μm promethazine did not change the inactivation time constants of INa, it shifted the steady‐state inactivation curve (h∞ curve) toward more negative potentials by 19.5 mV with the slope factor unaffected. 4 Double pulse experiments revealed that the development of blockade followed two‐exponential functions having time constants of 7 and 220 ms at − 20 mV. 5 Promethazine slowed the repriming of INa. This was associated with the development of slow phase having a time constant of 1160 ± 59 ms. 6 Promethazine produced a profound use‐dependent block when the cell was repeatedly stimulated with interpulse intervals shorter than 1 s. However, short pulses of 2 ms duration hardly produced such a use‐dependent block. Hence, open channel blockade is considered to play a minor role in the promethazine action on INa. 7 These results suggest that promethazine blocks cardiac INa in a manner similar to class I antiarrhythmic drugs and that this effect may account for its antiarrhythmic action.