Fast sodium influx provides an initial step to trigger contractions
in cat ventricle.
Vites, Ana-Maria, and J. Andrew Wasserstrom.
Reingold ECG Center (Division of Cardiology, Department of
Medicine), Department of Molecular Pharmacology and Biological
Chemistry, Feinberg Cardiovascular Research Institute, Northwestern
University Medical School, Chicago, Illinois, 60611, U.S.A.
APStracts 3:0004H, 1996.
It has been proposed that both fast sodium entry via TTX-sensitive
current (INa) and calcium entry via L-type calcium current (ICa) are
initial steps to trigger the release of calcium from the sarcoplasmic
reticulum during the upstroke of a cardiac action potential. Fast
sodium entry via INa could transiently reverse the Na/Ca-exchanger
and promote calcium entry which triggers Ca2+-induced Ca2+ release
(CICR) and contraction. We examined the possibility that INa may play
a role in excitation-contraction (E-C) coupling in cat ventricular
myocytes. A voltage step from -70mV to -40mV was used to produce a
fast INa, which was followed by a small transient inward current, a
brief loss in voltage control to more positive potentials and a
transient contraction. We established that, under similar conditions,
exposure to nifedipine (10_M) completely blocked ICa but did not
prevent this contraction, causing only a small reduction of approx.
15% in the size of the contraction. This nifedipine-insensitive
contraction was abolished by ryanodine (1-10[mu]M) and by micromolar
concentrations of saxitoxin (STX) and submillimolar concentrations of
Cd2+. The size of these contractions was dependent on the holding
potential, i.e. the more hyperpolarized the VH, the larger the
contraction (_L) triggered by a step to -40mV until a maximum was
achieved at approximately VH=-70mV (_L-VH relation). Anthopleurin-A
(AP-A, 3-10nM), which selectively slows inactivation of INa,
increased the size of the nifedipine-insensitive contraction at all
the VH tested. Thus, producing a shift in the _L-VH relation towards
more positive VH (_V +7mV) and an increase in the maximal _L at VH=
-70mV. The shift produced by AP-A was not prevented by application of
conditioning pulses that replenish the SR with calcium, but the
increase in the maximal _L at VH=-70mV was no longer observed. All
the effects of AP-A could be prevented by preexposure to STX. The
state of the SR calcium stores did not appear to affect the presence
of a nifedipine-insensitive contraction but did determine its
magnitude. Therefore, this contraction was not associated with
calcium overload. Cat ventricular myocytes are like guinea pig
ventricular myocytes in that they both exhibit prominent and distinct
INa-dependent contractions. Whether these contractions are due to a
sudden increase in subsarcolemmal Na+ as a result of fast INa, or due
to the depolarization of the membrane potential and reversal of the
Na/Ca exchange as a result of the large and inward INa, remains
undetermined.
Received 3 October 1994; accepted in final form 19 December 1995.
APS Manuscript Number H889-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 22 January 96