Combined class I antiarrhythmic agents have differential effects on tonic and use dependent block of maximum rate of depolarisation of action potentials in guinea pig cardiac muscle

• Published in: Cardiovascular research 1992-05, Vol.26 (5), p.462-469, Article 462
• Main Authors: Nitta, Jun-ichi, Sunami, Akihiko, Furukawa, Tetsushi, Marumo, Fumiaki, Sawanobori, Tohru, Hiraoka, Masayasu
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Anti-Arrhythmia Agents - pharmacology; Antiarythmic agents; Aprindine - pharmacology; Biological and medical sciences; Cardiovascular system; class I antiarrhythmic agents; combination therapy; Disopyramide - pharmacology; Drug Combinations; dV/dtmax of action potentials; Guinea Pigs; Lidocaine - pharmacology; Medical sciences; Mexiletine - pharmacology; Myocardium - metabolism; Pharmacology. Drug treatments; Quinidine - pharmacology; Sodium Channels - drug effects; Sodium Channels - metabolism; tonic block dV/dtmax; use dependent block of dV/dtmax
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/26.5.462

Objective: The aim was to study the difference between tonic and use dependent block of the cardiac sodium channel produced by the combined application of the same subclass of antiarrhythmic agents (class la or lb). Methods: Conventional glass microelectrode technique was used to record the maximum rate of depolarisation (dV/dtmax) of action potentials reflecting sodium channel availability, before and after the combined application of quinidine plus disopyramide, aprindine plus lignocaine, aprindine plus mexiletine, and lignocaine plus mexiletine. Guinea pig papillary muscles (n=4-8 per experiment) were used for the study. Results: All combinations increased tonic block additively compared to use of a single drug. On the other hand, use dependent block was increased by the combination of quinidine 10 μM plus disopyramide 30 μM compared to a single drug, and was not changed by lignocaine 50 μM plus mexiletine 20 μM, whereas it was decreased by aprindine 3 μM plus lignocaine 50 μM or mexiletine 20 μM. When concentrations of mexiletine and lignocaine were increased, both tonic and use dependent block in a single drug were increased dose dependently, whereas the combination produced an additive increase in tonic block but no change in use dependent block compared to a single drug. Conclusions: The results suggested that the binding and unbinding process of the drug to produce tonic block was different from that to produce use dependent block, and that combination of different drugs produced diverse effects on use dependent block even though state dependent affinity of individual drugs seemed similar. These two factors must be born in mind in evaluating the combination therapy.