title: 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 (tau(f) = 45 +/- 10; tau(s) = 215 +/- 28 ms), and showed very slow recovery (tau(f) = 1.54 +/- 0.73 s; tau(s) = 7.91 +/- 1.78 s; n = 9; 36 degrees 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(v)4.x, K(v)1.1, -1.2, -1.3, and -3.4 in a highly selective manner as well as H(2)O(2) and tetraethylammonium, did not affect the current. Drugs with K(v)1.5-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) (IC(50) of 132 +/- 47, 17 +/- 10, and 1.25 +/- 0.62 microM, respectively). 4-Aminopyridine suppressed the current and accelerated its decay, reducing charge carriage with an IC(50) of 39 +/- 15 microM. 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(v)1.5 mRNA compared with K(v)1.4, K(v)4.2, and K(v)4.3. 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(v)1.5 expression, and shows a pharmacological profile typical of K(v)1.5-dependent currents.
authors.affiliation: Division of Cardiology, J.W. Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. j.ehrlich@em.uni-frankfurt.de
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Ehrlich
authors.forename: Christin
authors.initials: C
authors.lastname: Hoche
authors.forename: Pierre
authors.initials: P
authors.lastname: Coutu
authors.forename: Christiane
authors.initials: C
authors.lastname: Metz-Weidmann
authors.forename: Werner
authors.initials: W
authors.lastname: Dittrich
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Hohnloser
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Heinz
authors.initials: H
authors.lastname: Gögelein
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002712:Chlorides / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology; D010480:Perhexiline; D011188:Potassium / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013997:Time Factors
chemical_list: D002712:Chlorides; D051666:Kv1.5 Potassium Channel; D009498:Neurotoxins; D015761:4-Aminopyridine; D005424:Flecainide; D010480:Perhexiline; D011188:Potassium