Use-dependent block of atrial sodium current by ethylisopropylamiloride

Ethylisopropylamiloride (EIPA) is a potent inhibitor of Na(+)-H+ exchange in many tissues and is frequently used to study cellular regulation of pH, but the electrophysiologic effects of EIPA on cardiac cells have not been studied previously. The use-dependent effects of EIPA on the sodium current (INa) of cultured embryonic chick atrial myocytes were investigated using standard whole-cell patch-clamp techniques. With 150-ms depolarizations from -140 to 0 mV, applied at 1-3 Hz in the presence of 10 microM EIPA, a decrement in INa was observed. This use-dependent reduction equaled 31 +/- 6% of control INa at steady state during 1-Hz stimulation. Inhibition increased with stimulation rate and with depolarization of the holding potential to -100 mV, but there was no effect of pulse duration on the EIPA-induced inhibition over the range of 20-500 ms. Moreover, repetitive depolarizations to potentials that did not activate macroscopic current but that did yield pronounced channel inactivation did not result in a decrement in INa. The effect of EIPA increased over the concentration range of 1-30 microM so that with 3-Hz stimuli steady-state inhibition increased from 3 +/- 1 to 85 +/- 5%. Amiloride, which slows repolarization of the cardiac action potential, was at least 100-fold less potent than EIPA in reducing INa. We conclude that EIPA is an "open-channel" blocker of the cardiac sodium current at concentrations comparable to those of many type I antiarrhythmic agents.