Tomoaki Tokuno (1), Katsuhiko Muraki (2), Minoru Watanabe (2) and Yuji
Imaizumi (1,*)
(1) Department of Pharmacology & Therapeutics and (2) Department
of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Nagoya City
University, Nagoya 467-8603, Japan
(*) To whom correspondence should be addressed.
Abstract: Effects of K+ channel modulators, cromakalim
and E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulfonylaminobenzoyl)
piperidine], on the relationship between the action potential duration (APD)
and Ca2+ transients were examined in single myocytes isolated
from guinea pig cardiac left ventricle. Application of cromakalim decreased
APD at 90% repolarization (APD90) and Ca2+ transient
elicited at 0.5 Hz (IC50s=0.6 and 3 microM, respectively). Application
of 0.3 microM E4031 increased these parameters by 110% and 45%, respectively.
Under voltage-clamp, the relation between the duration of depolarization
to 0 mV and Ca2+ transients could be described by the sum of
two exponential components; the time constants were approximately 5 and
280 msec, respectively. The first component was abolished by 10 microM ryanodine,
suggesting the involvement of Ca2+-induced Ca2+ release
(CICR). Neither cromakalim nor E4031 directly affected Ca2+ current
and Ca2+ transients under voltage clamp. When APD was changed
by K+ channel modulators, the relation between APD90
and Ca2+-transients was almost similar to that obtained by
changing the depolarization duration under voltage-clamp. CICR was changed
significantly only when APD90 was markedly shortened by cromakalim.
The extensively prolonged AP and Ca2+ transient in the presence
of E4031 were reduced by an addition of cromakalim. It is concluded that
these two K+ channel modulators can significantly alter the AP-induced
Ca2+ transient mainly by changing APD, which regulates both Ca2+
influx and extrusion.
Keywords: Heart, K+ channel, Cromakalim, E4031, Ca2+
transient