Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone

Abstract

The electrophysiological effects of amiodarone were studied in guinea pig papillary muscle by means of the single sucrose gap voltage clamp technique. The first time derivative of the upstroke of the action potential was measured as an indicator of the sodium current. The preparations were not voltage clamped during the action potential upstroke. Acute effects of amiodarone (4.4 X 10(-5) M and 8.8 X 10(-5) M; six experiments each) and effects of chronic administration at a single dose level (nine experimental vs. eight control animals) were studied. Results were qualitatively the same for all experimental conditions, and concentration dependent in the acute studies. Amiodarone caused marked use-dependent depression of the first time derivative of the upstroke of the action potential during stimulus trains. For example, at normal resting potential, chronic amiodarone treatment reduced the first time derivative of the upstroke of the action potential of the 16th beat of trains of cycle length 300 msec to 70 +/- 15% (mean +/- SD) of the initial value. This blocking effect was accentuated at more depolarized holding potentials and reduced at hyperpolarized holding potentials. Reduction of the first time derivative of the upstroke of the action potential was found to depend upon sodium channel inactivation. For all experiments, the mean normalized first time derivative of the upstroke of the action potential following a 1-second clamp in the -20 to +20 mV range was 0.92 +/- 0.08 in the control condition and 0.66 +/- 0.20 in the presence of amiodarone (less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)