Differential Electrophysiologic Effects of Chronically Administered Amiodarone on Canine Purkinje Fibers versus Ventricular Muscle

Abstract

BACKGROUND: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 µM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. METHODS AND RESULTS: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) from 227.8 +/- 6.3 ms (n = 20) to 262.3 +/- 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 +/- 9.2 (n = 21) to 308.3 +/- 7.1 (n = 19; P <.05). Acute superfusion of 5 µM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 +/- 13.6 ms to 281.9 +/- 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 µM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 µM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 µM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 µM dofetilide + 20 µM BaCl(2) + 2 mM CsCl) in 5 of 6 experiments and caused strong use-dependent V(max) block with relatively fast onset kinetics (rate constant = 1.23 +/- 0.13 AP(-1), n = 5) and offset (time constant = 364 +/- 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 µM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. CONCLUSIONS: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone

“…Later it became evident that amiodarone has multiple actions, including use‐dependent block of the inward sodium ( Mason et al ., 1984 ; Varró et al ., 1985 ; Follmer et al ., 1987 ) and calcium ( Nishimura et al ., 1989 ) currents, block of the α and β adrenoceptors ( Polster & Broekhuysen, 1976 ) and it may also have some other yet less well explored properties. Amiodarone, in contrast with pure Class III drugs, decreased dispersion of repolarization between ventricular epicardial, endocardial M cells ( Sicouri et al ., 1997 ) and Purkinje fibres ( Papp et al ., 1996 ). These features of amiodarone may, at least partly, explain the low proarrhythmic potential of the drug ( Lazzara, 1989 ).…”

Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs

“…In addition, the larger concentration of SZV-270 prolonged APD 90 in a lesser degree and significantly shortened APD 50 (depressed the plateau phase) in dog Purkinje fibers (Table 4). These effects can decrease repolarization heterogeneity in the ventricle, resembling a similar effect of amiodarone (Papp et al, 1996). Even high concentrations of SZV-270 did not affect I K1 , I to and I Ca,L in rabbit right ventricular cardiomyocytes (Figs.…”

5,7,8-Trimethyl-benzopyran and 5,7,8-Trimethyl-1,4-benzoxazine Aminoamide Derivatives as Novel Antiarrhythmics against Ischemia−Reperfusion Injury

“…Both analogues decreased V max and increased CT more at fast stimulation frequencies corresponding to cycle lengths of less than 2000 ms than at normal or slow ones, but they delayed repolarization reflected as increase of APD 90 somewhat more at slow than at fast stimulation frequencies. This combination of class IB and class III antiarrhythmic properties resembles to that of amiodarone 49 and suggests combined or multichannel drug action.…”