Multiple electrophysiological actions of amiodarone on guinea pig heart

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 < 1.1 × 10⁻⁴ mol/l reduced the maximum rate of rise ( \(\dot V\) _max) 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 > 1.1 × 10⁻⁴ mol/l decreased APD at all levels, accompanied by decreases in \(\dot V\) _max and RMP. PF AP's were much more sensitive to AM than PM. In contrast, chronic exposure (20 mg/kg/day, 3/12 weeks) prolonged PM APD at all levels and decreased V _max. In addition, acute exposure shifted steady state inactivation of V _max by 4–7 mV to more negative potentials. The decrease of V _max was frequency- and concentration-dependent. Halfmaximal inhibition (IC₅₀) of V _max by AM was affected by K⁺-induced membrane depolarization (in 4 mmol/1 K⁺,IC₅₀ ≌ 2.3 x 10⁻⁴ mol/l; in 8 mmol/1 K⁺, IC₅₀ ≌ 9 x 10⁻⁵ mol/1). Frequency-dependentinhibitionof 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.