Electrophysiologic effects of amiloride in canine Purkinje fibers: Evidence for a delayed effect on repolarization

Amiloride, a potassium-sparing diuretic, inhibits Na⁺ transport, Na⁺-H⁺ exchange and possibly Na⁺-Ca⁺⁺ exchange in a variety of cellular and epithelial tissues. Similar membrane ion transport mechanisms exist in cardiac tissue, yet there are little data on possible interference by amiloride with ion transport in the heart. Given recent evidence for a delay in amiloride uptake into erythroid cells, we studied the electrophysiologic effects of amiloride after polonged drug exposure in canine Purkinje fibers using standard microelectrode techniques. Amiloride (1-10 μM) led to a progressive lengthening of action potential duration with a τ of 1.8± 0.5 hr (n = 15). At long cycle lengths (≥ 2000 msec) early afterdepolarizations and oscillations around the plateau were seen. To determine the etiology of the afterdepolarizations, Purkinje fibers treated for 2 hr with 10 μM amiloride were then exposed to tetrodotoxin, manganese and nisoldipine. Tetrodotoxin (7.8 x 10^-7 M) reversed completely all amiloride effects rapidly and reversibly. MnCl₂ (4 mM) increased the afterdepolarizations, and arrest occurred at the plateau potential routinely. Nisoldipine (10^-6 M), a more selective blocker of slow inward current, shortened action potential duration somewhat but did not reverse fully the effects of amiloride. We conclude that amiloride has a pronounced effect on repolarization in the canine Purkinje fiber and this effect is manifest only aftr prolonged exposure to the drug.