(Circulation. 1999;100:2260.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Classic Preconditioning Decreases the Harmful Accumulation of Nitric Oxide During Ischemia and Reperfusion in Rat Hearts
From the Departments of Biochemistry (C.C., Z.S., A.T., P.F.) and Pharmaceutical Chemistry (F.F.), Albert Szent-Györgyi University, and the Department of Biophysics (T.P.), Biological Research Center, Szeged, Hungary; the Institute of Molecular Pharmacology (C.C., I.E.B.), Berlin, Germany; and the Departments of Pediatrics and Pharmacology, Cardiovascular Research Group (R.S., P.F.), University of Alberta, Edmonton, Canada.
Correspondence to Peter Ferdinandy, MD, PhD, Cardiovascular Research Group, Department of Biochemistry, Albert Szent-Györgyi University Medical School, PO Box 427, Szeged, H-6701, Hungary. E-mail peter{at}biochem.szote.u-szeged.hu
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Abstract |
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Background—The role of NO in the mechanism of preconditioning is not understood. Therefore, we studied the effect of preconditioning and subsequent ischemia/reperfusion on myocardial NO content in the presence of an NO synthase (NOS) inhibitor.
Methods and Results—Isolated working rat hearts were subjected to preconditioning protocols of 3 intermittent periods of rapid pacing or no-flow ischemia of 5 minutes’ duration each followed by a test 30 minutes of global no-flow ischemia and 15 minutes of reperfusion. Test ischemia/reperfusion resulted in a deterioration of myocardial function and a considerable increase in cardiac NO content as assessed by electron spin resonance. Preconditioning improved postischemic myocardial function and markedly decreased test ischemia/reperfusion-induced NO accumulation. In the presence of 4.6 µmol/L NG-nitro-L-arginine (LNA), basal cardiac NO content decreased significantly, although test ischemia/reperfusion-induced functional deterioration and NO accumulation were not affected in nonpreconditioned hearts. However, the protective effects of preconditioning on both test ischemia/reperfusion-induced functional depression and NO accumulation were abolished. When 4.6 µmol/L LNA was administered after preconditioning, it failed to block the effect of preconditioning. In the presence of 46 µmol/L LNA, ischemia/reperfusion-induced NO accumulation was significantly decreased and postischemic myocardial function was improved in nonpreconditioned hearts.
Conclusions—Our results show that (1) although NO synthesis by the heart is necessary to trigger classic preconditioning, preconditioning in turn attenuates the accumulation of NO during ischemia/reperfusion, and (2) blockade of ischemia/reperfusion-induced accumulation of cardiac NO by preconditioning or by an appropriate concentration of NOS inhibitor alleviates ischemia/reperfusion injury as demonstrated by enhanced postischemic function.
Key Words: nitric oxide • preconditioning • ischemia • reperfusion • electron spin resonance
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Introduction |
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Although the effectiveness of ischemic preconditioning might be attenuated in the heart during some disease states, such as hyperlipidemia and diabetes (see Reference 11 for review), preconditioning confers a remarkable cardioprotection in a variety of species as well as in humans (see References 2 and 32 3 for reviews). The early phase of preconditioning ("classic preconditioning") is manifested within minutes after the ischemic stress and has a duration of <3 hours. The late phase is characterized by a slower onset (
20 hours) and a duration of up to
72 hours. Both phases of preconditioning involve reduction of necrotic
tissue mass, improvement of cardiac performance after
ischemia and reperfusion, and reduction of arrhythmias
(see References 2 and 32 3 for reviews). There is considerable debate
regarding the biochemical mechanism of ischemic
preconditioning. The discrepancies are generally attributed to species
differences, different preconditioning stimuli such as no-flow
ischemia or rapid pacing models,4 and different
study end points, ie, myocardial function, arrhythmias, or
infarct size (see References 3 and 53 5 for reviews). In the normal heart, nitric oxide (NO) is synthesized by Ca2+-dependent NO synthases (NOS) in cardiac myocytes, vascular and endocardial endothelium (NOS III), and specific cardiac neurons (NOS I) and plays an important role in the regulation of coronary circulation and cardiac contractile function.6 Myocardial ischemia leads to increased activity of Ca2+-dependent NOS7 and accumulation of NO,8 which might contribute to ischemia/reperfusion injury.8 9 10
Use of inhibitors of NOS has indicated that NO is involved in both the early11 12 13 and the late phases of preconditioning.14 15 However, no studies have followed changes in myocardial NO content during preconditioning and subsequent ischemia/reperfusion, although this could possibly be key missing information necessary to elucidate the role of NO in the biochemical mechanism of preconditioning.
Therefore, the aim of the present study was to determine the effects of classic preconditioning in the presence and absence of the NOS inhibitor NG-nitro-L-arginine (LNA) on changes in cardiac NO content both during preconditioning and after subsequent test ischemia and reperfusion.
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Methods |
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The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1985).
Isolated Heart Preparation
Hearts of male Wistar rats (300 to 360 g,
anesthetized with diethylether and given 500 U/kg heparin) were
isolated and perfused at constant pressure (9.8 kPa) in Langendorff
mode or in working mode at 37°C with Krebs-Henseleit bicarbonate
buffer at a constant preload (1.7 kPa) and afterload (9.8 kPa) as
described.12 16 Heart rate, left ventricular
developed pressure (LVDP), +dP/dtmax,
-dP/dtmax, and left ventricular
end-diastolic pressure (LVEDP) were derived from the
online-digitized left intraventricular pressure
recording as described.12 Coronary flow
was measured by collection of effluent from the right atrium for a
timed period, and aortic flow was measured by rotameter (KDG
Flowmeters).4 12
Experimental Groups
A time-matched nonpreconditioning protocol (C,
control), pacing-induced preconditioning protocol (C-VOP,
control–ventricular overdrive pacing), and no-flow
ischemia–induced preconditioning protocol (C-NFlow,
control–no-flow ischemia) were applied before induction of
test ischemia/reperfusion (Figure 1
). The same protocols were applied in
the presence of 4.6 µmol/L LNA (Sigma) to test whether NO is
necessary to trigger preconditioning (LNA-C, LNA-VOP, and LNA-NFlow
groups). This concentration of LNA was selected for these groups
because according to our previous results,12 17 it did not
significantly affect coronary flow or any of the myocardial
functional parameters during preconditioning protocols and
test ischemia/reperfusion, except for an 80% increase in
preischemic LVEDP. However, it decreased basal cardiac NO
content near the detection limit (0.05 nmol NO/g wet tissue
weight)18 as assessed by electron spin resonance (ESR)
spectroscopy.12 13 To test whether NO is a mediator of
preconditioning, in 2 separate groups, LNA was added to the perfusion
medium immediately after the preconditioning protocols, ie, late
treatment (LNA-Late-VOP, LNA-Late-NFlow). In these groups, test
ischemia was applied 20 minutes after termination of the
pacing/no-flow periods to allow for LNA to exert its
inhibitory effect on NO synthesis in the
heart.12 17 According to our preliminary experiments (data
not shown) and our previous studies,12 this 15-minute
extension of the perfusion protocol did not affect protection by
preconditioning. A higher concentration of LNA (46 µmol/L) that
was able to decrease NO accumulation during ischemia and
reperfusion (see Results) was also tested in
nonpreconditioning (LNA46-C), pacing-induced
preconditioning (LNA46-VOP), and no-flow ischemia-induced
preconditioning (LNA46-NFlow) protocols (n=7 in each group).
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Preconditioning Protocols
After 10 minutes of aerobic perfusion as working hearts, the
hearts were subjected to either 3 intermittent periods (4.75 minutes
each) of Langendorff-mode perfusion without pacing
(nonpreconditioning protocol) or with rapid pacing at
10 Hz, or to no-flow ischemia, each separated by 0.5 minute of
Langendorff perfusion followed by 4.75 minutes of aerobic working
perfusion as described4 12 (Figure 1
). The 0.5
minute of Langendorff perfusion allowed for the spontaneous restoration
of sinus rhythm before switching to working-mode perfusion between
pacing or no-flow periods. Pacing and no-flow were performed as
described.4 12 According to our previous
studies4 12 13 as well as this study, all cardiac
functional parameters recovered within 3 minutes after the
termination of pacing or no-flow ischemia, indicating that they
induced a completely reversible ischemia (data not shown).
Test Ischemia/Reperfusion
After nonpreconditioning and preconditioning
protocols, test ischemia/reperfusion was induced by 30 minutes
of global no-flow ischemia followed by 15 minutes of
reperfusion. In the first 5 minutes of reperfusion, Langendorff
perfusion was applied to allow spontaneous recovery of sinus rhythm
before switching to the working perfusion for another 10 minutes. In
the first minute of reperfusion, the incidence of
ventricular fibrillation (VF) was determined by
ECG,4 and the hearts were mechanically defibrillated when
necessary to avoid VF-induced free radical release, which might
interfere with the ischemia/reperfusion-induced depression of
myocardial function.19 Hearts with unsuccessful
defibrillation were excluded from the measurement of cardiac function
and LDH release. Functional parameters were recorded
before and after preconditioning and after 15 minutes of reperfusion.
LDH release was assayed from coronary effluents collected in
the first 3 minutes of reperfusion as described.16
Design of ESR Studies
The spin-trap for NO, the complex of
N-methylglucamine dithiocarbamate (MGD, synthesized
as described)20 with ferrous ion
[Fe2+(MGD)3], was
prepared fresh before each experiment. MGD 175 mg and
FeSO4 50 mg dissolved in distilled water (pH 7.4,
volume 6 mL) was infused into the aortic cannula under Langendorff
perfusion for 5 minutes at a rate of 1 mL/min before the
preconditioning protocol was begun to measure basal myocardial NO
content. In separate experiments, the infusion of the spin trap
commenced immediately after the preconditioning protocol and was
maintained for 5 minutes to assess the effect of preconditioning on
cardiac NO content. A tissue sample from the apex of the heart (
150
mg) was collected at the end of the infusion of
Fe2+(MGD)3, placed into a
quartz ESR tube, and frozen in liquid nitrogen. To measure the
accumulation of NO during the test ischemia, in separate
studies, Fe2+(MGD)3
infusion was started 5 minutes before the induction of test
ischemia to load the heart with the spin-trap before the
perfusion line was clamped, and tissue samples were collected at the
end of ischemia. To assess the generation of NO during early
reperfusion, the spin trap was infused for 5 minutes starting at the
onset of reperfusion, and tissue samples were collected at the end of
the infusion. ESR spectra of the
NO-Fe2+(MGD)2 adduct were
recorded with a Bruker ECS106 spectrometer (parameters:
X band; modulation frequency, 100 kHz; temperature, 160 K; microwave
power, 10 mW; modulation amplitude, 2.85 G; central field, 3356 G) and
analyzed for NO signal intensity as
described.13 18 21
Statistics
Data were expressed as mean±SEM. All groups were
analyzed with Fischer’s exact test or 1-way ANOVA followed by
Bonferroni test. Significant difference was established when
P<0.05.
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Results |
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Preconditioning in the Absence of LNA
In control (C) hearts, test ischemia/reperfusion resulted in a marked decrease in coronary flow (Figure 2A
), aortic flow (Figure 2B), LVDP
(Figure 3A), and both
+dP/dtmax and -dP/dtmax
(Table), a considerable increase in LVEDP
(Figure 3B) and LDH release (Figure 4A), and 100% incidence of VF (Figure 4B). When test ischemia was preceded by preconditioning
elicited by ventricular overdrive pacing (C-VOP) or no-flow
ischemia (C-NFlow), coronary flow, aortic flow, LVDP,
+dP/dtmax, and -dP/dtmax
improved and LVEDP, LDH release, and the incidence of VF decreased,
showing the protective effect of preconditioning against acute
ischemia/reperfusion injury (Table; Figures 2 to 4).
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In the control (C) hearts, NO content was not changed when measured
before or after preconditioning (Figure 5A). However, test ischemia
induced a marked increase in cardiac NO signal intensity (Figure 5B). On reperfusion, NO content was significantly lower than
that measured at the end of ischemia, but it was still
significantly higher than the basal cardiac NO content (Figure 5B). Both preconditioning protocols significantly attenuated the
ischemia/reperfusion-induced increase in cardiac NO signal
(Figure 5B).
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Preconditioning in the Presence of 4.6 µmol/L LNA
When LNA treatment (4.6 µmol/L) was commenced before
preconditioning, cardiac functional parameters (Figures 2 and 3; Table), LDH release (Figure 4A),
and VF (Figure 4B) were not influenced before or after test
ischemia, but LVEDP (Figure 3B) increased before test
ischemia in the LNA-C group. The protective effect of
preconditioning induced by either pacing or no-flow ischemia
was prevented by LNA, because neither cardiac function, LDH release,
nor the incidence of VF was improved by preconditioning. When LNA
treatment was applied after preconditioning (in LNA-Late-VOP and
LNA-Late-NFlow groups), the preconditioning phenomenon was not
affected, because cardiac function improved and both LDH release and
the occurrence of VF decreased after test
ischemia/reperfusion.
LNA 4.6 µmol/L decreased basal NO content to a nondetectable
level; however, it did not decrease the NO signal during test
ischemia or reperfusion in nonpreconditioned
(LNA-C) groups (Figure 5). However, unlike in the C-VOP and
C-NFlow groups, the NO signal intensity during test ischemia
and reperfusion was not decreased by either mode of preconditioning (in
LNA-VOP and LNA-NFlow groups). When LNA was applied after
preconditioning, the NO signal intensity during test ischemia
and reperfusion was decreased by both preconditioning protocols.
Preconditioning in the Presence of 46 µmol/L LNA
LNA 46 µmol/L decreased coronary flow (Figure 2A) and increased LVEDP (Figure 3B) before test
ischemia/reperfusion and significantly improved functional
parameters (Figures 2 and 3; Table),
decreased LDH release (Figure 4A), and reduced the incidence of
VF (Figure 4B) after test ischemia/reperfusion (LNA46-C
group). In the presence of 46 µmol/L LNA, preconditioning
protocols did not significantly affect the protective effect of 46
µmol/L LNA itself on test ischemia/reperfusion.
LNA 46 µmol/L significantly decreased basal NO content as well
as the NO signal during test ischemia and reperfusion (LNA46-C
group) compared with the control group (C). Similar changes of NO
content were seen in the LNA46-VOP and LNA46-NFlow groups (Figure 5).
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Discussion |
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This is the first demonstration that classic preconditioning inhibits ischemia- and reperfusion-induced accumulation of cardiac NO, resulting in an improvement of postischemic myocardial function and reduction of arrhythmias. Furthermore, our results strongly suggest that NO biosynthesis during preconditioning is necessary to trigger preconditioning but that NO itself does not mediate the protective effect of classic preconditioning.
NO and Ischemia/Reperfusion
Using ESR, we have shown here that there is a marked increase in
the cardiac NO signal after 30 minutes of ischemia in the
working rat heart. This finding confirms the results of Zweier et
al,8 22 who showed by the same technique that the
myocardial NO signal increased substantially after 30 minutes of
ischemia in Langendorff-perfused rat hearts. Depre et
al7 23 demonstrated that global ischemia in
perfused rabbit hearts increased cardiac NOS activity and cGMP content.
Ischemia-induced increase in NO synthesis was previously
suggested by others on the basis of indirect pharmacological
evidence.24 25 Although LNA 4.6 µmol/L decreased
basal NO content similar to that seen in our previous
studies,12 13 it was not able to prevent the accumulation
of NO by ischemia/reperfusion and did not improve
postischemic myocardial function. In contrast, LNA at the
10-fold higher concentration (46 µmol/L) was able to reduce the
NO signal during ischemia and reperfusion significantly. This
was accompanied by an improved postischemic cardiac
performance, decreased LDH release, and reduced incidence of
VF. These results show that accumulation of NO during ischemia
and reperfusion contributes to ischemia/reperfusion injury.
Numerous earlier studies that used different concentrations of NOS inhibitors or NO donors, without attempting to measure actual changes in myocardial NO content, led to contradictory conclusions about endogenous NO being either protective, neutral, or a destructive player in ischemia/reperfusion.9 16 26 27 28 29 30 Recent studies suggest that the harmful effects of NO in the heart and in the vasculature are not due to NO itself but rather to peroxynitrite, a reaction product of NO and superoxide10 31 (see Reference 3232 for review). A seminal study addressing this controversy by Yasmin et al10 demonstrated that the NO-dependent ischemia/reperfusion injury is mediated by peroxynitrite in the heart. NG-monomethyl-L-arginine 10 µmol/L abolished peroxynitrite generation and was cardioprotective at this concentration, whereas this beneficial effect was lost at 100 µmol/L as a result of a marked decrease in coronary flow.10 The NO donor S-nitroso-N-acetyl-penicillamine (0.2 µmol/L) was also cardioprotective in their model,10 because NO in itself is an antioxidant that interferes with peroxynitrite-mediated radical chain propagation reactions.33 Wang and Zweier31 reported that NOS inhibitors at concentrations that decreased cardiac NO during ischemia/reperfusion alleviate peroxynitrite generation and ischemia/reperfusion injury. These results, including our present data, suggest that to draw valid conclusions from studies using NOS inhibitors during ischemia/reperfusion, the selection of an appropriate concentration of an NOS inhibitor to reduce the excessive generation of NO during ischemia/reperfusion and protect the heart from subsequent injury requires the measurement of myocardial NO content.
NO and Preconditioning
Our results show that although preconditioning with rapid pacing
or no-flow ischemia did not significantly change basal cardiac
NO content, it markedly decreased NO accumulation during test
ischemia and reperfusion, improved postischemic
myocardial function, and decreased the release of LDH and the incidence
of VF. In the presence of 4.6 µmol/L LNA, which reduced basal NO
synthesis, preconditioning failed to protect against
ischemia/reperfusion and failed to attenuate test
ischemia/reperfusion-induced NO accumulation. When LNA was
applied after the preconditioning protocol, the effect of
preconditioning on myocardial function and NO content was not affected.
When preconditioning was applied in the presence of the higher
concentration of LNA (46 µmol/L), which protected
nonpreconditioned hearts, no further improvement of
postischemic myocardial function and LDH release was seen,
nor did it further decrease the NO signal during ischemia and
reperfusion. These results show that intact NO synthesis is required to
elicit preconditioning but that NO is not a mediator of the
cardioprotective effect of classic preconditioning. On the contrary, it
suggests that the cardioprotection provided by preconditioning induced
by either pacing or no-flow ischemia involves a mechanism that
decreases the accumulation of NO in the myocardium during
ischemia and reperfusion. The nature of this mechanism is not
known. Preconditioning may decrease the rate of enzymatic6
or nonenzymatic22 NO production during
ischemia/reperfusion by altering pH and the availability of
cofactors and/or substrate for NO synthesis, or it may possibly
stimulate the formation of endogenous NOS
inhibitors.34
Our present results support those of Vegh at al,11 who demonstrated that 10 mg/kg LNA methyl ester abolished the antiarrhythmic effect of preconditioning in a coronary occlusion model in anesthetized dogs. However, studies by Lu et al35 using 10 mg/kg NG-monomethyl-L-arginine or LNA methyl ester in anesthetized rats with coronary occlusion/reperfusion and by Weselcouch et al30 using 30 µmol/L LNA methyl ester in isolated rat hearts showed, surprisingly, that the different NOS inhibitors did not interfere with the outcome of ischemia/reperfusion with or without preceding preconditioning as assessed by postischemic myocardial function, LDH release,30 and arrhythmias.35 Because NO generation was not determined and only a single dose of NOS inhibitor was used in these studies, it is difficult to interpret these negative results.
Limitations of the Study
Although the present results clearly demonstrate marked
changes in the ESR signal of NO during ischemia/reperfusion
with or without a previous period of preconditioning, the cellular
sources of cardiac NO are not demonstrated, because ESR
analysis of total cardiac tissue was performed. Absolute
quantification of NO concentration by ESR detection in tissue samples
is not possible12 18 21 ; therefore, we expressed NO signal
intensity in arbitrary units, which allowed us to demonstrate relative
changes in cardiac NO.12 13 21 The isolated rat heart with
test global ischemia and reperfusion used in this study is a
convenient model to follow changes in cardiac NO content by ESR;
however, this model does not allow direct measurement of necrotic
tissue mass, the traditional marker of preconditioning. Therefore, we
assessed the cardioprotective effect of preconditioning by measuring
postischemic myocardial function, arrhythmias, and
LDH release as an indirect indicator of tissue damage. Nevertheless,
this study is the first attempt to follow changes in cardiac NO content
during preconditioning and subsequent test
ischemia/reperfusion.
Conclusions
This is the first demonstration that preconditioning protocols do
not change basal cardiac NO content but effectively reduce the
accumulation of NO during subsequent ischemia and reperfusion,
resulting in an improvement of postischemic myocardial
function. Furthermore, our results suggest that cardiac NO biosynthesis
is necessary to trigger preconditioning but that NO itself does not
mediate the protective effect of classic preconditioning. In terms of
the role of NO, it appears that there is no difference between the
mechanism of pacing-induced or no-flow ischemia–induced
classic preconditioning. Finally, we suggest that pharmacological
inhibition of cardiac NO biosynthesis, although it may confer
protection to the ischemic heart, may also abolish the
development of endogenous cardioprotective mechanisms.
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Acknowledgments |
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This work was supported by grants from the Hungarian Scientific Research Fund (F19946, T029843), the Hungarian Technical Development Committee (05201950616), the Ministries of Education (FKFP1284/1997) and of Health (ETT 047/98), the Hungarian Space Research Office, the Volkswagen Stiftung (I/71-193), and the Alberta Heart and Stroke Foundation. Dr Schultz is a Senior Scholar of the Alberta Heritage Foundation for Medical Research. Dr Ferdinandy is a Fellow of the Medical Research Council of Canada and the Alberta Heritage Foundation for Medical Research.
Received March 26, 1999; revision received July 6, 1999; accepted July 13, 1999.
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