INHIBITION OF ION CURRENTS IN MEMBRANE OF SENSORY NEURON BY THE ANTIARRHYTHMIC DRUG BK-129 AND SELECTED CA(2+) ENTRY BLOCKERS

1) The inhibitory effects of the prospective antiarrhythmic drug BK 12 9 on Ca2+ and Na+ inward currents (I-Ca, and I-Na, respectively) and o n fast inactivating and slow noninactivating K+ outward currents (I-Kf , I-Ks, respectively) were tested in young rat sensory neurons by modi fied whole cell voltage clamp technique in vitro. The effects were com pared to those of nifedipine, verapamil and local anesthetic carbisoca ine. Both BK 129 and carbisocaine are basic carbanilates. 2) At a freq uency of test pulses of 0.2 Hz apparent dissociation constants (pD(2)) of BK 129 to channels conducting I-Ca, I-Na, I-Kf, and I-Ks were 5.31 3, 4.429, 3.985, and 4.154, of carbisocaine 5.428, 5.896, 3.992, and 4 .091, and of verapamil 4.249, 4.093, 3.839, and 4.453, respectively. I n nifedipine only the pD(2) for I-Ca inhibition could be measured (5.6 24). This drug failed to exert any appreciable effect on the other cur rents up to the highest concentration used (15 mu mol/l). Higher conce ntrations could not be tested because of the interfering effect of nif edipine solubilizer (ethanol). 3) The inhibiting effect of verapamil o n I-Ca, revealed slight potential dependence which however, could not account for the observed low specificity of this drug. Frequency of ca lcium channel activations might be more important determinant of the v erapamil induced I-Ca inhibition rather than the holding potential. 4) The weak inhibiting effect of w-conotoxin GVIA (5 mu mol/l) and Ni2(100 mu mol/l) as well as the strong effect of Cd2+, Co2+ (both 5 mmol /l) and nifedipine on I-Ca indicated that it was mainly the L type Ca2 + channel that conducted this current. 5) The differential effect of C d2+ and Co2+ (5 mmol/l) compared to tetrodotoxin (3 mu mol/l) on I-Ca, and I-Na disproved the possibility that these currents would pass via identical channels. 6) While nifedipine was shown to be a highly spec ific inhibitor of I-Ca in the young rat sensory neurons the other drug s tested inhibited the currents with a much smaller selectivity, with verapamil being the least specific at low stimulus rates (0.2 Hz). BK 129 is a powerful although nonspecific blocker of the inward I-Ca in t he neuronal membrane. It is suggested that these properties of BK 129 might participate in its antiarrhythmic effect.