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(Circulation. 1999;100:2519.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Inhibition of the Na+/H+ Exchanger Confers Greater Cardioprotection Against 90 Minutes of Myocardial Ischemia Than Ischemic Preconditioning in Dogs
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee (R.J.G., J.M., G.J.G.), and Boehringer Ingelheim Pharma KG, Germany (E.B., C.E., J.D.). Dr Gumina is now at the Mayo Clinic and Foundation, Rochester, Minn.
Correspondence to Garrett J. Gross, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
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Abstract |
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Background—This study compared the efficacy of ischemic preconditioning (IPC) and sodium-hydrogen exchanger (NHE)-1 inhibition to reduce infarct size (IS) induced by a 90-minute ischemic insult and examined the interaction between NHE-1 inhibition and IPC.
Methods and Results—In a canine infarct model, either IPC, produced by 1 or four 5-minute coronary artery occlusions, or the specific NHE-1 inhibitor BIIB 513, 0.75 or 3.0 mg/kg, was administered 15 minutes before either a 60- or 90-minute coronary artery occlusion followed by 3 hours of reperfusion. IS was determined by TTC staining and expressed as a percentage of the area at risk (IS/AAR). Although both IPC and BIIB 513 at 0.75 mg/kg produced comparable and significant reductions in IS/AAR in the 60-minute occlusion model, insignificant reductions in IS/AAR were observed in the 90-minute occlusion model. However, BIIB 513 at 3.0 mg/kg markedly reduced IS in both models (P<0.05). Next, to examine the interaction between NHE-1 blockade and IPC, BIIB 0.75 mg/kg was administered either before IPC or during the washout phase of IPC before 90 minutes of coronary artery occlusion. Both combinations resulted in a greater-than-additive reduction in IS/AAR (P<0.05).
Conclusions—These data demonstrate that although IPC and NHE-1 inhibition provide comparable protection against 60 minutes of myocardial ischemia, NHE-1 inhibition is more efficacious than IPC at protecting against a 90-minute ischemic insult. Furthermore, the combination of NHE-1 inhibition and IPC produces a greater-than-additive reduction in IS/AAR, suggesting either that NHE activity limits the efficacy of IPC or that different mechanisms are involved in the cardioprotective effect of IPC and NHE-1 inhibition.
Key Words: myocardial infarction • ions • ischemia
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ischemic preconditioning (IPC) is a phenomenon in which brief periods of ischemia confer cardioprotection against prolonged ischemia.1 2 Our laboratory first demonstrated that IPC produced cardioprotection via activation of the ATP-sensitive potassium (KATP) channel.3 Pharmacological opening of the channel mimicked IPC, and closing the channel blocked cardioprotection. Interestingly, reexamination of our data indicated that IPC produced a greater and more prolonged cardioprotective effect than that produced by KATP channel openers, suggesting that other factors besides the KATP channel contribute to IPC-induced cardioprotection.
IPC reduces the severity of acidosis during prolonged ischemia,4 5 leading to the suggestion that IPC induces sodium-hydrogen exchanger (NHE) activity, which contributes to the attenuation of intracellular acidosis and the reduction of ischemia-reperfusion injury.6 However, this suggestion contradicts numerous reports demonstrating that NHE inhibition is cardioprotective.7 Furthermore, in isolated hearts, IPC and NHE inhibition are additive.8 9 Thus, enhanced NHE activity may in fact limit the cardioprotection conferred by IPC.
Although numerous studies have examined the cardioprotective effect produced by either IPC or NHE inhibition, only a few reports compare their efficacy or the interaction between these 2 modalities.6 8 9 10 11 12 Furthermore, although the length of the time interval during which the cardioprotective effects of IPC are maintained, ie, the "window of protection," has been elucidated,13 the efficacy of IPC against ischemic insults of increasing duration, ie, the "ceiling of protection," has received little attention. Similarly, the efficacy of NHE inhibition against ischemic insults of >60 minutes has not been examined.14 15 Because the NHE isoform 1 (NHE-1) is predominant in the myocardium,16 the purpose of this study was to compare the efficacy of IPC and NHE-1 inhibition against ischemic insults of either 60 or 90 minutes and to examine the relationship between IPC and NHE-1 inhibition.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Materials
To perform this study, benzamide-N-(aminoiminomethyl)-4-[4-(2-furanylcarbonyl)-1-piperazinyl]-3-(methylsulfonyl)methanesulfonate (BIIB 513) was used (Figure 1
). All
reagents were obtained from Sigma Chemical Co or Gibco BRL unless
otherwise indicated.
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Binding Assays
The experimental conditions for analysis of binding to
each specific channel have been published
previously.17 18 19 20 21 22 23 24 25 BIIB 513 was tested in triplicate in
each assay at 10 µmol/L. The specific radioligand
binding was defined as the difference between total binding and
nonspecific binding determined in the presence of an excess of
unlabeled ligand. Results are expressed as a percentage of inhibition
of specific binding obtained in the presence of BIIB 513.
IC50 values were determined for the reference
compounds by nonlinear regression analysis of their competition
curves.
NHE Assays
An NHE-deficient cell line or cells expressing either NHE
isoform 1 or 3 (PS120 hNHE-1 and PS120 rNHE-3, respectively) were
obtained from Professor J. Pouyssegur (Nice, France) and cultured as
previously described.26 HT-29 cells, a human colon
carcinoma cell line that expresses wild-type hNHE-1, was purchased from
American Type Culture Collection.
The inhibitory effects of the various inhibitors on wild-type NHE-1 were examined via intracellular pH measurements. HT-29 cells, grown to confluence at 37°C with 5% CO2 in DMEM, were incubated with 2.5 µmol/L BCECF-AM at 37°C without CO2. Next, the cells were incubated in acid-loading medium, pH 7.5 (in mmol/L: NH4Cl 50, choline chloride 70, KCl 5, MgCl2 1, CaCl2 1.8, glucose 5, and HEPES 15) for 30 minutes at 37°C without CO2. Cells were rinsed and incubated at 37°C for 4 minutes without CO2 in recovery medium, pH 7.0 (in mmol/L: NaCl 120, KCl 5, MgCl2 1, CaCl2 1.8, glucose 5, and MOPS 15), with or without specific NHE inhibitors. BCECF fluorescence was monitored with a CytoFluor 2350. The cytoplasmic pH was calculated from the ratio of fluorescence at excitation wavelengths of 485 and 440 nm. Dose-response curves were generated from single-cell intracellular pH measurements taken every 10 to 20 seconds for 20 minutes (data not shown).
The selectivity of the various NHE inhibitors for NHE-1 versus NHE-3 was compared by the acute acid load recovery test.26 Cells (PS120 hNHE-1 and PS120 rNHE-3) were incubated for 30 minutes at 37°C without CO2 or Na+ in acid-loading medium. Cells were washed and incubated for 24 hours at 37°C with CO2 in recovery medium containing the specific NHE inhibitors. After the 24-hour incubation, cell viability was determined by fluorescein diacetate staining (excitation 485 nm; emission 530 nm).
Concentrated stock solutions (10-2 mol/L) of NHE-1 inhibitors tested were prepared in DMSO, and aliquots were added to the recovery medium. The final concentration of DMSO was <1%. For generation of concentration-response curves, concentrations of inhibitors ranged from 10-10 to 10-4 mol/L.
Ischemia-Reperfusion Protocol
A standard canine myocardial ischemia-reperfusion
protocol was used (Figure 2).15 The in vivo doses of
BIIB 513 were based on the t1/2 and plasma
levels. The t1/2 for BIIB 513 is 
60 minutes
with a maximum plasma level of 10 µmol/L after dosing with 7.5
mg/kg. Thus, doses to provide 0.3 µmol/L and 1 µmol/L
concentrations were used. Dogs were randomly assigned to 1 of 11
groups. All dogs were subjected to either 60 or 90 minutes of left
anterior descending coronary artery (LAD) occlusion and 3 hours
of reperfusion. In groups 1 to 3, either saline (control group) or 1 of
2 doses of BIIB 513 (0.75 or 3.0 mg/kg) was infused
intravenously for 15 minutes before 60 minutes of LAD
occlusion. In group 4, IPC was achieved by 5 minutes of LAD occlusion
followed by 10 minutes of reperfusion before 60 minutes of LAD
occlusion (1x5' IPC). In groups 5 to 7, either saline or 1 of 2 doses
of BIIB 513 (0.75 or 3.0 mg/kg) was infused intravenously
for 15 minutes before 90 minutes of LAD occlusion. In group 8, IPC, 5
minutes of LAD occlusion followed by 10 minutes of reperfusion, was
conducted before 90 minutes of LAD occlusion (1x5' IPC). In group 9,
IPC, four 5-minute periods of LAD occlusion followed by 5 minutes of
reperfusion, was conducted before 90 minutes of LAD occlusion (4x5'
IPC). In group 10, 0.75 mg/kg of BIIB 513 was infused 10 minutes before
1x5' IPC. In group 11, 1x5' IPC was followed by 10 minutes of
reperfusion, during which time 0.75 mg/kg of BIIB 513 was infused
before 90 minutes of LAD occlusion. In all groups,
hemodynamics and blood gas analyses were
measured before LAD occlusion, at 30 minutes during LAD occlusion, and
every hour after reperfusion. Regional myocardial blood flows were
determined at 30 minutes during the LAD occlusion period and at the end
of the experiment.
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At the end of the 3-hour reperfusion period, the anatomic area at risk (AAR) and the nonischemic area were differentiated, and the hearts were processed and stained with 2,3,5-triphenyl tetrazolium chloride (TTC) to differentiate the infarcted myocardium.15 Infarct size (IS) was expressed as a percentage of the AAR. Regional myocardial blood flow was measured by the radioactive microsphere technique.27
Dogs were excluded if (1) heartworms were found, (2) transmural collateral blood flow was >0.20 mL · min-1 · g-1, (3) heart rate was >180 bpm at the beginning of the experiment, or (4) >3 consecutive attempts were needed to convert ventricular fibrillation.
Statistical Analysis
All values are expressed as mean±SEM. Differences between
groups in hemodynamics and blood gases were compared by
use of a 2-way ANOVA with repeated measures. Differences between groups
in tissue blood flows, AAR, and IS were compared by 1-way ANOVA,
and comparisons between individual groups were made with a 2-tailed
t test. ANCOVA was used to determine whether the
relationship between transmural collateral blood flow and IS differed
between the control and treated groups. For all experiments,
differences between groups were considered significant if the
probability value was P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Selectivity of BIIB 513
To determine the selectivity of BIIB 513 for NHE isoforms, the recovery from an acute acid load in cells expressing either NHE-1 or NHE-3 was compared. The IC50 for inhibition of recovery from acid load in cells expressing wild-type NHE-1 was 27 nmol/L (Table 1
). This is 8
times more potent than that obtained for HOE 642 (210
nmol/L).28 The IC50 determined from
cells expressing recombinant human NHE-1 is 10-fold greater than
that obtained from cells expressing wild-type NHE-1; however, this is
due to an 15-fold overexpression of recombinant human NHE-1 in the
transfected PS120 cells due to gene amplification.29
Finally, the IC50 for BIIB 513 in cells
expressing recombinant rat NHE-3 was >1000 µmol/L. On the basis
of these data, BIIB 513 is 37 000 times more selective toward
NHE-1.
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Exclusions to Canine Ischemia-Reperfusion Studies
One hundred ten dogs were used in this study. Four were excluded
because transmural collateral blood flow was >0.2 mL ·
min-1 · g-1 (1 in
the 60-minute control group, 1 in the 60-minute low-dose BIIB
513–treated group, 1 in the 60-minute high-dose BIIB 513–treated
group, and 1 in the 90-minute high-dose BIIB 513–treated group). One
dog in the 60-minute control group and 1 in the 60-minute group treated
with 3.0 mg/kg of BIIB 513 were excluded because of intractable
ventricular fibrillation. Thus, 104 dogs successfully
completed the protocol.
Hemodynamic and Blood Gas Data
Table 2 summarizes the
hemodynamic data from all groups. There were no
significant differences within or between groups.
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IS Measurements
Figure 3 and Table 3 demonstrate the effect of IPC, NHE-1
inhibition, or the combination on the AAR and IS expressed as a
percentage of the AAR (IS/AAR) and left ventricle (IS/LV). In the
60-minute model, both IPC and administration of 0.75 or 3.0 mg/kg of
BIIB 513 produced comparable reductions in IS/AAR (Figure 3).
However, in the 90-minute occlusion model, no statistically significant
reduction in IS/AAR was observed with either IPC (1x5') or 0.75 mg/kg
of BIIB 513 (Figure 3, Table 3). In contrast, 3.0 mg/kg
of BIIB 513 significantly reduced IS/AAR (P<0.05) against
90 minutes of ischemia. Furthermore, comparison of the efficacy
of IPC and NHE-1 inhibition against 60 and 90 minutes of occlusion
revealed that NHE-1 inhibition with 3.0 mg/kg of BIIB 513 produced
marked cardioprotection in both models, whereas the cardioprotection
from IPC or 0.75 mg/kg of BIIB 513 was limited to the 60-minute model
(Figure 3).
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Increasing the number of brief occlusions before the sustained
coronary artery occlusion has been reported to significantly
reduce IS/AAR against 90 minutes of ischemia.30
However, as shown in Figure 3
, no greater cardioprotection was
conferred with multiple periods of IPC (4x5') compared with the single
period of IPC (1x5').
Next, we used IPC and 0.75 mg/kg of BIIB 513 to determine whether the
combination of these modalities was antagonistic, additive,
or synergistic. Administration of 0.75 mg/kg of BIIB 513 during the
interval surrounding IPC should be sufficient to inhibit NHE-1 activity
while providing minimal cardioprotection against 90 minutes of
ischemia. As shown in Figure 3, administration of BIIB
513 either before IPC or during the washout phase of IPC resulted in a
greater-than-additive reduction in IS.
There were no significant differences in LV weight, AAR, AAR/LV, or
transmural collateral blood flow between groups (Table 3).
Against 60 minutes of ischemia, the regression lines describing
the relationship between transmural collateral blood flows and IS/AAR
were shifted down in BIIB 513– and IPC-treated animals compared with
the control group (Figure 4A). In
contrast, the regression lines describing this relationship between
groups treated with 0.75 mg/kg of BIIB 513, (1x5') IPC, and (4x5')
IPC were not different from that of the control group after 90 minutes
of ischemia (Figure 4B). However, in animals treated
with 3.0 mg/kg BIIB 513 or the combinations of IPC and 0.75 mg/kg, the
regression lines describing this relationship were shifted down
compared with the 90-minute control group (Figure 4C).
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indicates
control, y=-72.5x+29.8; 
, 0.75 mg/kg
BIIB 513, y=-73.4x+15.4; •, 3.0 mg/kg
BIIB 513, y=-22.2x+5.1; 
, IPC (1x5'),
y=-11.6x+6.8. B, 90 minutes of
ischemia. IPC (1x5' or 4x5') and 0.75 mg/mg BIIB 513–treated
groups did not have regression lines that were significantly shifted
downward by ANCOVA. 
, IPC (4x5'),
y=-146.5x+37.8. C, 90 minutes of
ischemia. Groups treated with 3.0 mg/kg BIIB 513, IPC/0.75
mg/kg BIIB 513, or 0.75 mg/kg BIIB 513/IPC had regression lines that
were significantly shifted (P<0.05) downward by ANCOVA.
, IPC (1x5')/0.75 mg/kg BIIB 513,
y=-60.2x+14.0; 
, 0.75 mg/kg BIIB
513/IPC (1x5'), y=-78.9x+12.9. |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates that IPC and NHE-1 inhibition do not antagonize one another but rather produce greater-than-additive myocardial protection against prolonged ischemia-reperfusion injury in vivo. Furthermore, this study demonstrates that although IPC and NHE-1 inhibition provide comparable cardioprotection against 60 minutes of myocardial ischemia, NHE-1 inhibition provides significantly greater protection against 90 minutes of ischemia in vivo.
Efficacy of IPC Versus NHE-1 Inhibition Against Prolonged
Myocardial Ischemia
Because the interval from onset of symptoms of myocardial
infarction to treatment is often delayed, any clinically efficacious
treatment must be effective against prolonged ischemic injury.
Although the cardioprotective effect of IPC and NHE inhibition has been
demonstrated consistently in a number of animal
species,7 until now, no studies have compared the efficacy
of these treatments in an in vivo model of prolonged
ischemia-reperfusion injury. This study demonstrates that
although IPC and NHE-1 inhibition conferred comparable cardioprotection
against 60 minutes of ischemia, the efficacy of IPC and 0.75
mg/kg of BIIB 513 was greatly diminished against 90 minutes of
ischemia. Interestingly, no greater cardioprotection was
conferred by a 4x5' IPC protocol, confirming that the cardioprotection
induced by the 1x5' IPC protocol was optimal. This contrasts with
previous work showing that against a 90-minute ischemic insult,
4x5' IPC reduces IS to a degree comparable to that generally observed
in a 60-minute occlusion model in dogs.30 However, NHE-1
inhibition with 3.0 mg/kg of BIIB 513 still afforded significant
cardioprotection against 90 minutes of ischemia. Interestingly,
in a model of canine myocardial ischemia-reperfusion injury
that used 90 minutes of ischemia, a significant proportion of
myocytes within the infarct region were shown to be viable at the time
of reperfusion and to subsequently lose viability during reperfusion,
suggesting cell death due to reperfusion injury.31 NHE-1
activity increases in cardiomyocytes not only during
ischemia32 but also during the first few minutes
of reperfusion,33 resulting in an accumulation of
Ca2+, which contributes to cellular damage. Thus,
in contrast to IPC, NHE-1 inhibition may prevent both
ischemia-induced and reperfusion-induced myocardial injury
against prolonged ischemia.
The fact that the efficacy of IPC is significantly diminished as the duration of ischemia is increased is intriguing. Although much attention has been focused on defining the window of protection induced by IPC, ie, the time interval between episodes of brief coronary artery occlusions and the final sustained ischemia during which cardioprotection is still observed, no studies have examined the efficacy of IPC against myocardial ischemia of increasing duration. Similarly, no studies have examined the efficacy of NHE inhibition against ischemic insults >60 minutes.14 15 Thus, the results of this study demonstrate that just as a window of protection for IPC exists, a ceiling of cardioprotection also exists, ie, IPC is cardioprotective only against ischemia of a defined duration. However, the same ceiling does not appear to be present for NHE-1 inhibition.
Interaction Between NHE Activity and IPC
As stated earlier, there is contradictory evidence on the
interaction between IPC and NHE activity.6 8 9 10 11 12 During
the brief periods of coronary artery occlusion of IPC,
intracellular pH decreases and intracellular Na+
increases.5 6 Because the primary activator of
NHE is acidosis,33 it would be expected that NHE activity
would increase with IPC. The observation that ischemic
preconditioned rat hearts recover more rapidly from ammonium chloride
pulse–induced acidosis has been used as evidence for increased NHE
activity during IPC.6 Studies that used isolated heart
preparations demonstrate an additive effect between IPC and NHE-1
inhibition and suggest either that IPC and NHE inhibition confer
cardioprotection by different mechanisms or that NHE activity is a
detrimental consequence of IPC that limits its cardioprotective
effect.8 9 In isolated rat hearts, NHE inhibition with
1 µmol/L HOE 642 provided additive cardioprotection to IPC, as
measured by creatine kinase leakage and LV developed pressure
recovery.9 In a separate study, the combination of
EIPA and IPC produced a greater-than-additive reduction in IS in
isolated rat hearts.8 However, other studies suggest that
NHE activity is necessary for IPC-induced cardioprotection and that NHE
inhibition reduces the IPC-induced cardioprotection.6 12
In isolated rat hearts, 3 µmol/L of ethylisopropylamiloride
(EIPA) inhibited IPC-induced cardioprotection as measured by creatine
kinase leakage and LV developed pressure recovery.6
However, in the rabbit heart, administration of 1 µmol/L of EIPA
provided no additive cardioprotection to IPC, although no antagonism
was observed.11 Finally, in an in vivo canine model of
ischemia-reperfusion injury, intramyocardial injections of
dimethylamiloride (DMA) antagonized cardioprotection induced by
IPC.12 Although the in vivo concentration of drug (30
injectionsx0.15 mL of 400 µmol/L DMA) is difficult to
ascertain, estimating myocardial interstitial volume to be
0.5 L results in a concentration of 3.6 µmol/L, a
concentration comparable to that used in isolated rat hearts in which
antagonism with IPC was observed.6 Because amiloride and
its analogues have numerous nonspecific effects at higher
doses,34 35 the discrepancies observed at high
doses of EIPA and DMA in the experiments reviewed above may not be due
to specific inhibition of NHE-1 but rather to nonspecific effects. Such
an interpretation is consistent with the overwhelming evidence
that NHE inhibition is cardioprotective.7 8 9 14 15 36
This study demonstrates that in vivo, NHE-1 inhibition either before IPC or during the washout phase of IPC results in a greater-than-additive reduction in myocardial IS. Several possible explanations might account for the greater-than-additive cardioprotection observed. An increase in NHE activity actually may represent a detrimental side effect of IPC, and the true cardioprotective potential of IPC may be unmasked only by concomitant inhibition of NHE. Alternatively, IPC and NHE-1 inhibition may act via separate complementary mechanisms to confer cardioprotection. In fact, preliminary results from our laboratory have previously demonstrated that glibenclamide and PD 115199, inhibitors of IPC, do not attenuate NHE inhibitor–mediated cardioprotection. Furthermore, although this was not examined in the present study, if NHE activity is a detrimental factor induced by IPC, then one might speculate that the combination of BIIB and IPC might also increase the window of protection as well as the ceiling of protection.
Conclusions
The present study demonstrates that NHE-1 inhibition is
significantly more efficacious against prolonged myocardial
ischemia than IPC. Furthermore, IPC and NHE-1 inhibition do not
antagonize one another but rather produce greater-than-additive
cardioprotection, suggesting either that NHE activity limits the
efficacy of IPC or that different mechanisms may be involved in the
cardioprotective effect of IPC and NHE-1 inhibition. On the basis of
the data reported, NHE-1 inhibition would be predicted to have
beneficial effects in patients with unstable angina, which is purported
to be the clinical correlate to IPC. Thus, NHE-1 inhibitors
may have wide clinical applicability in scenarios such as preventive
therapy in patients at high risk for myocardial infarction.
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Acknowledgments |
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This study was supported by NIH grant HL-08311 and a grant from Boehringer Ingelheim Pharma KG. The authors thank Anna Hsu for her excellent technical assistance.
Received April 12, 1999; revision received July 9, 1999; accepted July 21, 1999.
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