Related Experiment Videos
Antiarrhythmic drug carvedilol inhibits HERG potassium channels
C A Karle1, V A Kreye, D Thomas
13rd Department of Internal Medicine (Cardiology), University of Heidelberg Medical School, Bergheimerstrasse 58, D-69115, Heidelberg, Germany.
Insights
Carvedilol blocks human ether-a-go-go related gene (HERG) potassium channels, a key factor in cardiac arrhythmias. This HERG channel blockade by carvedilol may explain its positive clinical outcomes in heart failure patients.
Area of Science:
- Cardiovascular Pharmacology
- Ion Channel Physiology
Background:
- Carvedilol is a multi-action cardiovascular drug used in heart failure.
- Its superiority in clinical trials may stem from specific channel blockade beyond beta-antagonism.
- HERG K(+) channels are critical in cardiac arrhythmias and sudden cardiac death.
Purpose of the Study:
- To investigate the effects of carvedilol on HERG K(+) channels.
- To determine if carvedilol's action on HERG channels contributes to its therapeutic benefits.
Main Methods:
- Utilized double-electrode voltage-clamp experiments.
- Expressed HERG potassium channels heterologously in Xenopus oocytes.
Main Results:
- Carvedilol (10 microM) blocked HERG potassium tail currents by 47%.
- Carvedilol did not affect HERG channel activation, inactivation, or recovery kinetics.
- Evidence suggests a very fast open channel block mechanism by carvedilol.
Conclusions:
- This study is the first to demonstrate carvedilol's blockade of HERG potassium channels.
- The observed HERG channel blockade by carvedilol may possess antiarrhythmic properties.
- These findings could explain the positive clinical outcomes observed in carvedilol trials for heart failure.
Objective:
The aryloxypropanolamine carvedilol is a multiple action cardiovascular drug with blocking effects on alpha-receptors, beta-receptors, Ca(2+)-channels, Na(+)-channels and various native cardiac K(+) channels, thereby prolonging the cardiac action potential. In a number of clinical trials with patients suffering from congestive heart failure, carvedilol appeared to be superior to other beta-blocking agents in reducing total mortality. Given the multiple pharmacological actions of carvedilol, this may be due to specific channel blockade rather than beta-antagonistic activity. Since human ether-a-go-go related gene (HERG) K(+)channels play a critical role in the pathogenesis of cardiac arrhythmias and sudden cardiac death, the effects of carvedilol on HERG K(+)channels were investigated.
Methods:
Double-electrode voltage-clamp experiments were performed on HERG potassium channels which were expressed heterologously in Xenopus oocytes.
Results:
Carvedilol at a concentration of 10 microM blocked HERG potassium tail currents by 47%. The electrophysiological characteristics of HERG, i.e. activation, steady-state inactivation and recovery from inactivation were not affected by carvedilol. Inhibition of current gradually increased from 0% immediately after the test pulse to about 80% at 600 ms with subsequent marginal changes of current kinetics during the resting 29 s, indicating a very fast open channel block by carvedilol as the major blocking mechanism.
Conclusion:
This is the first study demonstrating that carvedilol blocks HERG potassium channels. The biophysical data presented in this study with a potentially antiarrhythmic effect may contribute to the positive outcome of clinical trials with carvedilol.