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ATP and the role of IK.ATP during acute myocardial ischemia: controversies revive
Wilde, A.A.M.
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Cardiovascular research
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Citation for published version (APA):
Wilde, A. A. M. (1997). ATP and the role of IK.ATP during acute myocardial ischemia: controversies revive.
Cardiovascular research, 35, 181-183.
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Download date: 17 Jun 2017
Cardiovascular Research 35 Ž1997. 181–183
Editorial
ATP and the role of I K.ATP during acute myocardial ischemia:
controversies revive
Arthur A.M. Wilde
),1
Academic Medical Center, Department of Clinical and Experimental Cardiology, Amsterdam, and the Heart-Lung Institute, UniÕersity of Utrecht, Utrecht,
Netherlands
Received 23 May 1997
Keywords: Myocardial ischemia; Potassium channel, ATP sensitive; Ionic currents
Detailed insight into the electrophysiology of ischemia
is of utmost importance in understanding the arrhythmogenic nature of myocardial ischemia. The players in the
field—the ionic currents—are known, but their respective
roles are disputed. Direct recordings of ionic currents are
best obtained in isolated cells, but the impossibility of
exposing isolated cells to ischemia seriously complicates
the issue. Even elegant solutions like the mineral oil
droplet technique w1x do not meet all criteria. Hitherto,
recordings of ionic currents have usually been obtained
from tissue or cells in simulated ‘ischemia’, that is exposure to a variable combination of ischemic factors including hypoxia or metabolic deprivation by metabolic inhibitors, high extracellular potassium ŽwKqx o ., acidosis and
catecholamines. In this respect, the theoretical studies by
Shaw and Rudy w2,3x may offer a new dimension to the
long-lasting discussion on the mechanism underlying the
most essential events.
In the simulation study, published in this issue of
CardioÕascular Research w3x, the focus is on the three
components of ischemia which are generally accepted as
the most essential: i.e., anoxia, acidosis and elevated wKqx o .
The results are not very surprising: elevated wKqx o by
depolarizing the resting membrane reduces Naq channel
availability and thus affects cell excitability, and anoxia
underlies the action potential shortening by activating
ATP-sensitive Kq current Ž I K.ATP . w3x. The role of acidosis
seems modifying in nature but of importance, in particular
)
Address for correspondence: PO Box 22700, 1100 DE Amsterdam,
Netherlands. Tel.: q31 Ž20. 5663265; fax: q31 Ž20. 6975458.
1
Dr. Wilde is a clinical investigator for the Dutch Heart Foundation
ŽNHS, grant D95r014..
0008-6363r97r$17.00 q 1997 Elsevier Science B.V. All rights reserved.
PII S 0 0 0 8 - 6 3 6 3 Ž 9 7 . 0 0 1 3 5 - 1
where it concerns the transition from the Naq-currentdominated to the Ca2q-current-dominated action potential
upstroke.
Shaw and Rudy only studied these three elements of
ischemia and one may argue that this study is similar to
experiments in which isolated cells are exposed to Žonly.
these ischemic factors. However, the detailed quantitative
evaluation of the electrophysiological changes is unique
and particularly helpful in the analysis of indirect changes
in other currents by the changes in action potential configuration w3x. As indicated by the authors, pharmacological
assessment of ischemic arrhythmias should take these significant indirect changes into account. In addition, by
including more ischemia-related variables, this theoretical
exercise has strong potential to resolve many controversial
issues on the role of other potentially contributing currents
andror contributing ischemic conditions. Some of them
are mentioned in the article, others include the potential
role of chloride currents and of the transient outward
current I TO which may also be involved in modulation of
action potential duration w4,5x. Other issues which might be
addressed are the electrophysiological background of the
initial prolongation which is observed in many experimental models Žfor review. see Ref. w6x. and the secondary
improvement in upstroke velocity Žand transient lengthening of the action potential. observed after 10–15 min of
ischemia. The absence of the initial prolongation in the
present simulations is compatible with experimental data
suggesting that inhibition of I TO underlies the initial increase in action potential duration w5x. Because the model
used is based on guinea-pig ventricular cells, I TO is not
included.
The role of I K.ATP in action potential shortening is
disputed. In this theoretical study application of the theo-
182
A.A.M. Wilde r CardioÕascular Research 35 (1997) 181–183
retical presumptions for I K.ATP activation, which are based
on sound experimental evidence, provides compelling evidence that I K.ATP is the main current involved in the
shortening of action potential w3x. The experimental evidence, however, is less convincing and almost exclusively
based on the observation that sulfonylureas inhibit or even
abolish the shortening w6,7x. As indicated previously, sulfonylureas affect several other ionic currents and affect
cell metabolism with potential consequences for the action
potential duration. In addition, I K.ATP in isolated cells is
activated with a fairly long time delay after exposure to
hypoxia w8x or simulated ischemia w1x. The latter observations are particularly difficult to reconcile with a dominant
role for I K.ATP in early action potential shortening. In the
absence of more specific I K.ATP blockers, further theoretical studies with an even more extensive model Žincorporating more ionic currents. can be very helpful. Shaw and
Rudy argued that elimination of other factors that can
explain action potential shortening ‘‘supports I K.ATP as the
dominant factor in ischemic action potential shortening’’
w3x. This argument cannot be considered a very strong one
since only those factors included can be eliminated. As
indicated above, at least two potentially involved ionic
currents have not been included. Nevertheless, I tend to
agree with the outcome of the model with regard to the
pivotal role of I K.ATP . An eventual role for I K.ATP may
have clinical impact because Žinhomogeneous. action potential shortening determines, at least in part, the degree of
ST-segment elevation. Indeed, in dogs glibenclamide has
been shown to attenuate the ST segment changes in acute
myocardial ischemia w9x. Extrapolation of these findings to
diabetic patients on sulfonylureas potentially masks the
early electrocardiographic signs of an acute myocardial
infarct w10x.
Regulation of I K.ATP during myocardial ischemia is
another issue of controversy. At what level of intracellular
ATP ŽwATPx i . is I K.ATP activated in myocardial ischemia?
It is known that metabolic factors such as ADP, intracellular pH and lactate decrease I K.ATP sensitivity to
wATPx i-based inactivation. By including this in their model
Shaw and Rudy calculated that wATPx i s 3.0 mM led to
0.8% I K.ATP activation. At this level of I K.ATP activation
the impact on the action potential duration is already
significant and as such the ‘spare channel hypothesis’ has
been adopted by these authors. Alternatively, it has been
suggested that ATP may be compartmentalized and that
ATP produced by anaerobic glycolysis preferentially regulates the activity of the channel w11x. This seems to contrast
the experimental fact that selective inhibition of oxidative
phosphorylation Žby 2,4-dinitrophenol wDNPx or cyanide.
also activates I K.ATP . Shigematsu and Arita addressed this
controversy and designed experiments to answer the question whether I K.ATP is regulated primarily by ATP derived
from glycolysis, oxidative phosphorylation or from a combination of the two w12x. Their conclusion that the major
part of regulation of I K.ATP under conditions of quiescence
and anoxia is by ATP produced by oxidative phosphorylation is of interest and contrasts with earlier findings w11x.
There are at least two theoretical arguments which favor
this conclusion. The first has been mentioned above and
simply relates to the fact that selective inhibition of oxidative phosphorylation activates I K.ATP . In this respect the
use of DNP should, however, be re-evaluated since preliminary data suggest that DNP directly affects the gating
characteristics of the channel w13x. Secondly, if glycolytically produced ATP were to control I K.ATP , activation in
early ischemia might be prevented because of the reported
enhancement of anaerobic glycolysis in this phase.
Are the experimental data of Shigematsu and Arita
sufficient to demonstrate that primarily ATP produced by
oxidative phosphorylation regulates I K.ATP activity? Three
arguments are given: Ž1. omission of glucose from the
perfusate does not affect action potential duration Žover 2
hours. and Ž2. the presence of glucose exerted only a
limited effect on the anoxia-induced shortening. It may,
however, be argued that utilization of intracellular glycogen stores is sufficient to maintain adequate ATP levels
and to prevent I K.ATP activation. Under anoxic conditions
anaerobic glycolysis might become inhibited after prolonged anoxia and thus no longer contribute to ATP
production. Hence, the presence of glucose would be of no
significance. The third argument—the complete restoration
of the action potential duration and complete inhibition of
I K.ATP by oxygen alone—is addressed by the authors.
Indeed, glycolytically produced ATP Žby ‘aerobic’ glycolysis. might be sufficient to inactivate I K.ATP .
In my view the authors are to be complimented that
they tried to resolve a controversy that has gone apparently
unnoticed over so many years. However, it is questionable
whether their data do permit the conclusion that glycolytically produced ATP can be excluded as important in the
regulation of I K.ATP under anoxic Žand ischemic. conditions. It seems that further investigation is needed to
conclude that ATP produced by oxidative phosphorylation
and not ATP produced by anaerobic glycolysis regulates
K.ATP channels. It is highly conceivable that the gap
between theory and experiment can similarly be bridged
by computer model studies.
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