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 microM 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 microM. Although 10 microM promethazine did not change the inactivation time constants of INa, it shifted the steady-state inactivation curve (h infinity 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.
Tanaka
H
H
Department of Laboratory Medicine, Kyoto Prefectural University of Medicine, Japan.
Habuchi
Y
Y
Nishimura
M
M
Sato
N
N
Watanabe
Y
Y
D000465:Algorithms; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D011398:Promethazine / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*
D015222:Sodium Channels; D011398:Promethazine