Properties of a time-dependent potassium current in pig atrium: evidence for a role of kv1.5 in repolarization.
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.
Ehrlich
Joachim R
JR
Division of Cardiology, J.W. Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt, Germany. j.ehrlich@em.uni-frankfurt.de
Hoche
Christin
C
Coutu
Pierre
P
Metz-Weidmann
Christiane
C
Dittrich
Werner
W
Hohnloser
Stefan H
SH
Nattel
Stanley
S
Gögelein
Heinz
H
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
D002712:Chlorides; D051666:Kv1.5 Potassium Channel; D009498:Neurotoxins; D015761:4-Aminopyridine; D005424:Flecainide; D010480:Perhexiline; D011188:Potassium