Effects of Class III Antiarrhythmic Drugs on Transient Outward and Ultra-rapid Delayed Rectifier Currents in Human Atrial Myocytes1
- 1Department of Medicine (J.F., Z.W., G.-R.L., S.N.), 2Montreal Heart Institute and University of Montreal, and Department of Pharmacology and Therapeutics (S.N.), McGill University, Montreal, Quebec, Canada
Abstract
A variety of class III antiarrhythmic agents have been shown to block the delayed rectifier current, but their effects on other K+ currents, particularly in human tissues, are less clear. We studied the concentration-dependent actions of the class III compounds d -sotalol, E-4031 and ambasilide on the transient outward current (Ito) and the ultra-rapid delayed rectifier current (IKur) in human atrial myocytes. d -Sotalol and E-4031 failed to alter Ito or IKur at concentrations up to 500 and 50 μM, respectively. In contrast, ambasilide produced a concentration-dependent inhibition of Ito and IKur, with statistically significant effects at 10 μM and maximum effects at 100 μM. The 50% inhibitory concentration of ambasilide averaged 23 ± 2 μM and 34 ± 3 μM for Ito and IKur respectively. Ambasilide did not alter the voltage-dependence of activation or inactivation of Ito, or the voltage-dependence of IKur, and it did not affect Ito recovery from inactivation. On the other hand, ambasilide accelerated Ito inactivation, by introducing a more rapid component that accelerated with increasing drug concentration. Furthermore, block of both Ito and IKur developed over time after the onset of depolarization, with time constants of 5.8 ± 0.8 msec and 2.5 ± 0.4 msec at concentrations of 10 and 50 μM for Ito and 6.1 ± 0.8 msec and 2.1 ± 0.3 msec at 10 and 50 μM for IKur. We conclude that neither d -sotalol nor E-4031 affects Ito or IKur, whereas ambasilide produces efficacious open-channel block of both currents, in human atrial myocytes.
Footnotes
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Send reprint requests to: Dr. Stanley Nattel, Montreal Heart Institute, 5000 Belanger St. East, Montreal, Quebec, Canada H1T 1C8.
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↵1 This study was supported by the Medical Research Council of Canada, the Québec Heart Foundation, and the Fonds de Recherche de l’Institut de Cardiologie de Montréal.
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↵2 Supported by a Medical Research Council of Canada Postdoctoral Fellowship.
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↵3 Supported by a Fonds de la Recherche en Santé du Québec Research Scholarship.
- Abbreviations:
- AF
- atrial fibrillation
- ANOVA
- analysis of variance
- 4AP
- 4-aminopyridine
- CP
- conditioning pulse
- E-4031
- investigational class III drug
- EGTA
- ethylene glycol-bis (β-aminoethylether)-N,N,N′, N′-tetraacetic acid
- I
- Itoamplitude
- IC
- current under control conditions
- ICa
- calcium current
- ID
- current under drug conditions
- IK
- delayed rectifier K+ current
- IK,ACh
- ACh-induced K+ current
- IK1
- inward rectifier current
- IKr
- rapid component of delayed rectifier K+ current
- IKs
- slow component of delayed rectifier K+ current
- IKur
- ultra-rapid delayed rectifier K+ current
- IMax
- maximum current
- INa
- sodium current
- Ito
- transient outward current
- Kv1.5
- potassium channel clone of Shaker family
- nS
- nanosiemens
- NS
- nonsignificant
- O.D.
- outside diameter
- P1
- first pulse of a paired-pulse protocol
- P2
- second pulse
- Rs
- series resistance
- t
- time
- τ1
- rapid-phase time constant
- τ2
- slow-phase time constant
- τc
- capacitive time constant
- TP
- test potential
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- Received June 17, 1996.
- Accepted December 30, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
