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Electrophysiological effects of Ro 22–9194, a new antiarrhythmic agent, on guinea‐pig ventricular cells
Author(s) -
Maruyama Kazuyasu,
Kodama Itsuo,
Anno Takafumi,
Suzuki Ryouko,
Toyama Junji
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb14900.x
Subject(s) - electrophysiology , chemistry , patch clamp , voltage clamp , membrane potential , guinea pig , inward rectifier potassium ion channel , medicine , biophysics , ion channel , biology , biochemistry , receptor
1 Cardiac effects of Ro 22–9194 were examined in papillary muscles and single ventricular myocytes isolated from guinea‐pigs and compared with those of moricizine. 2 In papillary muscles, both Ro 22–9194 (≥ μ m ) and moricizine (≥ μ m ) caused a significant dose‐dependent decrease in the maximum upstroke velocity (V̇ max ) and a shortening of the action potential duration. 3 In the presence of either drug, trains of stimuli at rates ≥ 0.2 Hz led to an exponential decline in V̇ max . This use‐dependent block was enhanced at higher stimulation frequencies. A time constant (τR) for V̇ max recovery from the use‐dependent block was 9.3 s for Ro 22–9194 and 26.4 s for moricizine. 4 The curves relating membrane potential and V̇ max in single myocytes were shifted by Ro 22–9194 (30 μ m ) or by moricizine (3 μ m ) in a hyperpolarizing direction by 8.4 mV and 8.0 mV respectively. 5 In myocytes treated with Ro 22–9194 (30 μ m ), a 10 ms conditioning clamp to 0 mV caused a significant decrease in V̇ max of the subsequent test action potential; further prolongation of the clamp pulse duration resulted in a modest enhancement of the V̇ max inhibition. In the presence of moricizine (3 μ m ), a similar conditioning clamp > 200 ms caused a significant V̇ max reduction; the longer the clamp pulse duration, the greater the V̇ max reduction. 6 Ro 22–9194 ≥ 30 μm caused a slight decrease of calcium inward current ( I Ca ) of myocytes without affecting the delayed rectifier potassium current ( I K ). 7 These findings suggest that the primary electrophysiological effect of Ro 22–9194 as an antiarrhythmic agent is, like moricizine, a use‐ and voltage‐dependent inhibition of sodium channels. From the onset and offset kinetics of the use‐dependent block, Ro 22–9194 belongs to the intermediate kinetic Class I drugs, while moricizine is a slow kinetic drug. From the state‐dependence of sodium channel block, Ro 22–9194 may belong to activated channel blockers, while moricizine belongs to inactivated channel blockers.