Inhibition of ion currents in membrane of sensory neuron by the antiarrhythmic drug BK 129 and selected Ca2+ entry blockers.
The inhibitory effects of the prospective antiarrhythmic drug BK 129 on Ca2+ and Na+ inward currents (ICa and INa, respectively) and on fast inactivating and slow noninactivating K+ outward currents (IKf, IKs, respectively) were tested in young rat sensory neurons by modified whole cell voltage clamp technique in vitro. The effects were compared to those of nifedipine, verapamil and local anesthetic carbisocaine. Both BK 129 and carbisocaine are basic carbanilates. At a frequency of test pulses of 0.2 Hz apparent dissociation constants (pD2) of BK 129 to channels conducting ICa, INa, IKf, and IKs were 5.313, 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. In nifedipine only the pD2 for ICa inhibition could be measured (5.624). This drug failed to exert any appreciable effect on the other currents up to the highest concentration used (15 mumol/l). Higher concentrations could not be tested because of the interfering effect of nifedipine solubilizer (ethanol). The inhibiting effect of verapamil on ICa revealed slight potential dependence which however, could not account for the observed low specificity of this drug. Frequency of calcium channel activations might be more important determinant of the verapamil induced ICa inhibition rather than the holding potential. The weak inhibiting effect of omega-conotoxin GVIA (5 mumol/l) and Ni2+ (100 mumol/l) as well as the strong effect of Cd2+, Co2+ (both 5 mmol/l) and nifedipine on ICa indicated that it was mainly the L type Ca2+ channel that conducted this current. The differential effect of Cd2+ and Co2+ (5 mmol/l) compared to tetrodotoxin (3 mumol/l) on ICa and INa disproved the possibility that these currents would pass via identical channels. While nifedipine was shown to be a highly specific inhibitor of ICa in the young rat sensory neurons the other drugs 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 ICa in the neuronal membrane. It is suggested that these properties of BK 129 might participate in its antiarrhythmic effect.
Stolc
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Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava.
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D010880:Piperidines; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D001381:Azepines; D002121:Calcium Channel Blockers; D002219:Carbamates; D010880:Piperidines; C089290:BK 129; C046030:carbizocaine; D014700:Verapamil; D009543:Nifedipine