Received for publication June 29, 2006.
Revised August 15, 2006.
Accepted for publication August 15, 2006.

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 anti-arrhythmic 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 (termed 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 (_f=45±10, _s=215±28 ms) and showed very slow recovery (_f=1.54±0.73 sec; _s=7.91±1.78 sec, n=9, 36° C). Activation and inactivation were voltage-dependent and current properties were consistent with predominant K⁺-conductance. Neurotoxins (heteropodatoxin, hongatoxin, BDS) that block Kv4.x, Kv1.1, 1.2, 1.3 and 3.4 in a highly-selective manner, as well as H₂O₂ and TEA, did not affect the current. Drugs with Kv1.5-blocking properties (flecainide, perhexiline and the novel atrial-selective anti-arrhythmic AVE0118) inhibited I_K,PO (IC₅₀ 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 Kv channel-subunit sequences were cloned to permit real-time quantitative RT-PCR on RNA extracted from isolated cardiomyocytes, which showed much greater abundance of Kv1.5 mRNA compared to Kv1.4, Kv4.2 and Kv4.3. Action potential recordings showed that I_K,PO-inhibition with 0.1 mM 4-AP delayed repolarization (e.g., APD 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 classical I_to, is associated with strong Kv1.5 expression and shows a pharmacological profile typical of Kv1.5-dependent currents.

Key words: AVE0118, IKur, action potential, atrial fibrillation, cardiomyocyte, potassium current

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