Properties of a Time-Dependent Potassium Current in Pig Atrium: Evidence for a Role of Kv1.5 in Repolarization

Abstract

Cardiac electrical activity is modulated by potassium currents. Pigs have been used for antiarrhythmic drug testing, but only sparse data exist regarding porcine atrial ionic electrophysiology. Here, we used electrophysiological, molecular, and pharmacological tools to characterize a prominent porcine outward K⁺ current (I_K,PO) in atrial cardiomyocytes isolated from adult pigs. I_K,PO activated rapidly (time to peak at +60 mV; 2.1 ± 0.2 ms), inactivated slowly (τ_f = 45 ± 10; τ_s = 215 ± 28 ms), and showed very slow recovery (τ_f = 1.54 ± 0.73 s; τ_s = 7.91 ± 1.78 s; n = 9; 36°C). Activation and inactivation were voltage-dependent, and current properties were consistent with predominant K⁺ conductance. Neurotoxins (heteropodatoxin, hongatoxin, and blood depressing substance) that block K_v4.x, K_v1.1, -1.2, -1.3, and -3.4 in a highly selective manner as well as H₂O₂ and tetraethylammonium, did not affect the current. Drugs with K_v1.5-blocking properties (flecainide, perhexiline, and the novel atrial-selective antiarrhythmic 2′-{2-(4-methoxyphenyl)-acetylamino-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide; AVE0118) inhibited I_K,PO (IC₅₀ of 132 ± 47, 17 ± 10, and 1.25 ± 0.62 μM, respectively). 4-Aminopyridine suppressed the current and accelerated its decay, reducing charge carriage with an IC₅₀ of 39 ± 15 μM. Porcine-specific K_v channel subunit sequences were cloned to permit real-time quantitative reverse transcription-polymerase chain reaction on RNA extracted from isolated cardiomyocytes, which showed much greater abundance of K_v1.5 mRNA compared with K_v1.4, K_v4.2, and K_v4.3. Action potential recordings showed that I_K,PO inhibition with 0.1 mM 4-AP delayed repolarization (e.g., action potential duration at –50 mV increased from 45 ± 9 to 69 ± 5 ms at 3 Hz; P < 0.05). In conclusion, porcine atrium displays a current that is involved in repolarization, inactivates more slowly than classic transient outward current, is associated with strong K_v1.5 expression, and shows a pharmacological profile typical of K_v1.5-dependent currents.