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Multiple electrophysiological actions of amiodarone on guinea pig heart
1Department of Physiology, Medical College of Oita, Japan.
Abstract:
The cellular electrophysiologic effects of acute exposure to amiodarone (AM) on guinea pig papillary muscle (PM) and Purkinje fibres (PF) were investigated by means of conventional microelectrode techniques. Superfusion with AM less than 1.1 x 10(-4) mol/l reduced the maximum rate of rise (Vmax) of the action potential (AP) upstroke phase 0 of both PM and PF stimulated at 1 Hz, without changing resting membrane potential (RMP) or action potential duration (APD). AM greater than 1.1 x 10(-4) mol/l decreased APD at all levels, accompanied by decreases in Vmax and RMP. PF AP's were much more sensitive to AM than PM. In contrast, chronic exposure (20 mg/kg/day, 3 1/2 weeks) prolonged PM APD at all levels and decreased Vmax. In addition, acute exposure shifted steady state inactivation of Vmax by 4-7 mV to more negative potentials. The decrease of Vmax was frequency- and concentration-dependent. Half-maximal inhibition (IC50) of Vmax by AM was affected by K+-induced membrane depolarization (in 4 mmol/l K+, IC50 congruent to 2.3 x 10(-4) mol/l; in 8 mmol/l K+, IC50 congruent to 9 x 10(-5) mol/l). Frequency-dependent inhibition of closed Na+ channels by AM was demonstrated and AM increased the time constant for recovery from Na+ channel blockade. Depression of PF plateau by AM was similar to the effects of tetrodotoxin (TTX). Finally, AM depolarized RMP of PM exposed to low K+. The multiplicity of changes suggests that AM exerts inhibitory effects on a number of ionic current components, including at least fast Na+ current, slow inward current, TTX-sensitive plateau and outward K+ currents. Possible implications with respect to the broad spectrum of antiarrhythmic activity exhibited by AM are considered.
Insights
Amiodarone (AM) affects cardiac electrophysiology, altering action potential properties in guinea pig papillary muscles and Purkinje fibers. These cellular effects, particularly on sodium channels, may explain amiodarone's broad antiarrhythmic activity.
Area of Science:
- Cardiac Electrophysiology
- Pharmacology
- Ion Channel Function
Background:
- Amiodarone is a widely used antiarrhythmic drug with a complex mechanism of action.
- Understanding its cellular electrophysiologic effects is crucial for explaining its therapeutic and adverse effects.
Purpose of the Study:
- To investigate the acute and chronic electrophysiologic effects of amiodarone on guinea pig papillary muscle and Purkinje fibers.
- To elucidate the ionic mechanisms underlying amiodarone's actions and relate them to its antiarrhythmic properties.
Main Methods:
- Conventional microelectrode techniques were used to record cellular action potentials.
- Experiments involved superfusion with varying concentrations of amiodarone and different potassium concentrations.
- Studies assessed effects on action potential parameters like Vmax, RMP, and APD under various stimulation frequencies.
Main Results:
- Acute amiodarone exposure reduced Vmax and APD, with Purkinje fibers being more sensitive than papillary muscles.
- Higher amiodarone concentrations decreased RMP and APD, while chronic exposure prolonged APD.
- Amiodarone demonstrated frequency- and concentration-dependent inhibition of sodium channels and affected potassium currents.
Conclusions:
- Amiodarone exerts multiple inhibitory effects on cardiac ionic currents, including fast sodium, slow inward, and potassium currents.
- These diverse electrophysiologic alterations contribute to amiodarone's broad-spectrum antiarrhythmic efficacy.
- The drug's effects on ion channels provide a cellular basis for its clinical use in managing cardiac arrhythmias.