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Normal heart function depends on the generation and propagation of cardiac action potential. Variety of ion channels in the cardiac myocytes and their delicate behaviors are the physiological basis of cardiac action potential. How drugs affect cardiac ion channels, either their expressions or electrophysiological functions, underlies the pathophysiological mechanism of cardiac arrhythmia caused by the drugs. Recording action potentials firing allows to comprehensively observe drug's action on all of the cardiac ion channels presented in the cardiac myocytes, thus assess the possible risk of cardiac arrhythmia. With different stimulation frequency and drug concentrations during the recording, frequency or/and dose dependency of the drug effect on action potential can be quantified.
Cardiac action potential assay is one of the tests recommended by ICH to evaluate drug's preclinical cardiac safety risk.
Action potential (AP) assay with rabbit heart purkinje fibers or guinea pig heart muscles
|
Assay platform/method |
Intracellular AP recording |
|
Animal tissue used |
Rabbit heart purkinje fibers or guinea pig ventricular papillary muscles or atrial muscles |
|
Measured parameters |
AP: RMP, APA, APD30 (or APD40, APD50), APD60, APD90, VMAX |
|
Test concentrations |
3 doses |
|
Stimulation freqency |
2000ms(0.5Hz),1000ms(1Hz), 600ms(1.7Hz) |
|
Data point repeats |
N = 4 for each concentration |
|
Experiment temperature |
37℃ |
1.Rabbit heart purkinjie fibers
Action potential changes in rabbit heart purkinjie fibers are very sensitive to drug’s effect, hence are excellent models to evaluate drug's cardiac safety risk.
Example1：
Effects of sotalol on the action potential of rabbit heart purkinje fibres at different stimulation frequencies
Percentage bar graph of effects of sotalol on the action potential of rabbit purkinje fibres at different stimulation frequencies
Note：RMP: Resting membrane potential；APA: Action potential amplitude；Vmax，Maximum velocity of AP phase 0；APD50,APD90: Action potential duration at 50% repolarization and 90% repolarization
Example 1 shows that sotalol dose and frequency-dependently increased APD50/90 in rabbit heart purkenjie fibers. mily:"Times New Roman"'>：RMP: Resting membrane potential；APA: Action potential amplitude；Vmax，Maximum velocity of AP phase 0；APD50,APD90: Action potential duration at 50% repolarization and 90% repolarization
Example2：
|
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Haloperidol prolonged APD in rabbit heart purkinje fibres and evokes EAD
