Comparative mechanisms of 4-aminopyridine-resistant transient
outward current in human and rabbit atrial myocytes.
Li, Gui-Rong, Jianlin Feng, Zhiguo Wang, Bernard Fermini, and Stanley
Nattel.
Department of Medicine, Montreal Heart Institute, University of
Montreal (G-RL, JF, BF, SN), and Department of Pharmacology and
Therapeutics, McGill University (ZW, SN), Montreal, Quebec, H1T 1C8,
Canada
APStracts 2:0129H, 1995.
The cardiac transient outward current (Ito) has been shown in several
species to consist of two components _ a 4-aminopyridine (4AP)
-sensitive component (Ito1) and a 4AP-resistant component (Ito2). In
rabbits, Ito2 is a Ca2+-dependent Cl- current (ICl.Ca), and similar
mechanisms have been suggested to underlie Ito2 in human atrium. We
used whole-cell patch-clamp techniques to define the mechanism of
Ito2 (defined as the component resistant to 5 mM 4AP) in human atrial
myocytes, with parallel experiments performed in rabbit atrial cells.
In rabbit atrium, Ito2 activated more slowly than Ito1 and had a
bell-shaped current-voltage relation. Ryanodine suppressed a
component of Ito in the rabbit with properties similar to Ito2, and a
similar component recorded with pipette K+ replaced by Cs+ was
suppressed by the substitution of methanesulfonate for Cl- in the
superfusate. In human cells, a 4AP-resistant Ito2 was recorded at a
depolarizing pulse frequency of 1 Hz, but not at 0.1 Hz. Ito2
activated rapidly and inactivated earlier than Ito1, while its
current-voltage relation was linear like that of Ito1. Ryanodine had
no effect on human atrial Ito. When K+-free pipette solutions were
used no Ito was recorded in 30 human atrial myocytes, and external
Cl- replacement with methanesulfonate failed to reveal an Ito. In 13
human myocytes, isoproterenol increased ICa, but failed to activate a
transient outward current compatible with ICl.Ca. While caffeine
suppressed human atrial Ito, it also suppressed Ito1 (in the presence
of 200 [mu]M Cd2+ to block ICa and 5 mM intracellular EGTA to buffer
[Ca2+]i) in both human and rabbit atrium, indicating an action
unrelated to Ca2+-triggered Ca2+ release. In conclusion, we were
unable to demonstrate the presence of ICl.Ca in human atrial
myocytes, and the 4AP-resistant component of Ito appeared to be due
to 4AP unblocking.
Received 3 June 1994; accepted in final form 1 March 1995.
APS Manuscript Number H485-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 April 1995.