Amiodarone blocks the inward rectifier potassium channel in isolated guinea pig ventricular cells

We examined the effects of amiodarone (5-20 μM) on both whole cell inward rectifier potassium current (I(K1)) and single I(K1) channel activity in isolated guinea pig ventricular myocytes using patch-clamp techniques. In whole-cell voltage-clamp experiments (n = 8), amiodarone (10-20 μM) caused only a small reduction of outward current at -50 mV (12 ± 6%, no significant difference, N.S.). However, inward current was significantly reduced at -120 mV (21 ± 7%; P < .05). When CdCl₂ (100 μM) and tetrodotoxin (10 μM) were used to block inward Ca⁺⁺ and Na⁺ current, respectively, amiodarone significantly reduced I(K1) in both the inward (14 ± 5% at -120 mV; P < .02) and outward (12 ± 5% at -50 mV; P < .05; n = 11) directions. However, block required high drug concentrations (10-20 μM) and was slow in onset. In contrast, amiodarone did not affect membrane current when I(K1) had been previously blocked by Ba⁺⁺ (5 mM), in inside-out patch-clamp experiments, amiodarone (5 μM) reduced single I(K1) channel open probability by increasing interburst interval (from 0.6 ± 0.03 to 3.1 ± 0.9 sec; n = 5; P < .05) with no significant difference in the duration of mean open and closed times or the number of shut events within a burst. The net result was that there was only a small change in both burst duration and single-channel kinetics within a burst. Complete channel block occurred after the increase in interburst interval (n = 6 of six cells). In cell-attached patches, amiodarone exerted similar effects on single-channel behavior except that, as for whole-cell experiments, the onset of block was slow and required higher drug concentrations (≥5 μM). We conclude that amiodarone 1) reduces whole- cell I(K1) by virtue of a direct blocking action. 2) inhibits single I(K1) channel activity by prolonging interburst interval and 3) interacts either with a hydrophobic site within the membrane and/or a hydrophilic site accessible only from within the cell.