(Circulation. 2000;102:1977.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Na+/H+ Exchange Inhibitor Cariporide Attenuates Cell Injury Predominantly During Ischemia and Not at Onset of Reperfusion in Porcine Hearts With Low Residual Blood Flow
From the Division of Cardiology, Städt Krankenanstalten Idar-Oberstein GmbH (H.H.K., S.P), the Department of Experimental Animal Research, University of Göttingen (S.L.-H., K.N.), and the Department of Pathology, University of Giessen (R.M.B.), Germany.
Correspondence to Prof Dr H.H. Klein, Städt Krankenanstalten Idar-Oberstein GmbH, Dr Ottmar-Kohler-Str 2, 55743 Idar-Oberstein, FRG.
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Abstract |
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Background—This study investigated whether myocardial protection by inhibition of Na+/H+ exchange (NHE) occurs during ischemia and/or during reperfusion.
Methods and Results—The left anterior descending coronary artery was occluded in 32 pigs for 60 minutes and then reperfused for 24 hours. Infarct sizes (nitroblue tetrazolium [NBT] stain, histology) were determined at the end of the experiments. An extracorporeal bypass was used to achieve a constant residual blood flow of 3 mL/min in the myocardium at risk during ischemia. The NHE-1 inhibitor cariporide or distilled water was infused into the extracorporeal bypass system. In group 1, active treatment was administered from the onset of ischemia until 10 minutes of reperfusion (n=8). In group 2, active treatment was infused during the first 30 minutes of ischemia only (n=8). The group 3 animals (n=8) received intracoronary cariporide after 45 minutes of ischemia until 10 minutes of reperfusion. The control animals (group 4, n=7) were treated similarly to group 1 animals, with the cariporide solution being replaced by distilled water. Infarct sizes of group 1 (NBT stain, 41.5±20%; histology, 44.6±12%) and group 2 (NBT stain, 33.5±14%; histology 34.9±15%) differed significantly (at least P=0.012) from infarct sizes of group 3 (NBT stain, 71.6±15%; histology, 69.2±12%) and the control group (NBT stain, 76±9%; histology 72.4±12%). Cariporide treatment in group 1 and group 2 significantly improved functional recovery after 24 hours of reperfusion.
Conclusions—Myocardial protection by cariporide is predominantly achieved by NHE inhibition during ischemia and not during early reperfusion.
Key Words: infarction • ischemia • reperfusion • ions
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Na+/H+ exchange (NHE) inhibition has been shown to substantially protect the ischemic, reperfused myocardium in different species and in a great variety of preparations (summarized in Reference 1 ). It is still a matter of controversy whether myocardial protection by Na+/H+ exchange inhibition takes place during ischemia and/or during reperfusion. Preischemic intravenous treatment with the NHE-1 inhibitors HOE694,2 3 cariporide4 5 6 and EMD 851317 in regionally ischemic, reperfused pig, rabbit, and dog hearts reduced infarct size to a highly significant extent.2 3 4 5 6 7 Three of these 6 studies did not find a significant decrease in infarct size by an intravenous treatment at the time of reperfusion,2 4 5 whereas the other 3 studies5 6 7 reported a significant reduction in infarct size under these circumstances. Although these results favor myocardial protection by NHE-1 inhibition during ischemia, it cannot not be ruled out that the positive effects of preischemic treatment were achieved at the time of reperfusion and that NHE-1 inhibition induced by a treatment at the time of reperfusion does not occur fast enough to counteract the rapid changes in Na+/H+ exchange on reperfusion. This study in regionally ischemic, reperfused porcine hearts with low residual blood flow was designed to clarify whether myocardial protection by cariporide (HOE642, 4-isopropyl-3 methylsulphonylbenzoyl-guanedine methanesulphonate) takes place during ischemia or at the onset of reperfusion.
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Methods |
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The experiments were approved by the government of Lower Saxony, Germany, and in accordance with institutional guidelines.
General Experimental Setup
Anesthesia, medication, and the general experimental
setup have been described in previous studies.2 8
Thirty-seven farm pigs (37 to 51 kg) were used in this study. Each was
premedicated with azaperon, metomidate hydrochloride, and atropine.
General anesthesia was maintained with metomidate
hydrochloride and intravenous piritramide. Artificial
ventilation was performed with nitrous oxide and oxygen. All animals
were anticoagulated with intravenous heparin (10 000 IU)
before the first arterial catheter was introduced. Another
10 000 IU heparin was given intravenously before the
extracorporeal bypass system was introduced.
After median thoracotomy, the left anterior descending coronary artery (LAD) was dissected free distal to the first diagonal branch. Left ventricular (LV) pressure and its first derivative (dP/dt) were measured with a 5F Millar catheter-tipped manometer. A 5F catheter was placed into the ostium of the great cardiac vein. The LAD was occluded at the prepared site for 60 minutes and then reperfused for 24 hours. Forty-five minutes after the onset of reperfusion, the chest was closed in layers and the animal was allowed to recover. On the following day, the pig was reanesthetized and the thoracotomy was repeated.
Measurement of Global Hemodynamics, Regional
Systolic Shortening, and LAD Blood Flow
Global hemodynamic variables, including LV
peak pressure (LVPP), LV end-diastolic pressure (LVEDP),
dP/dt max, and heart rate were monitored continuously and recorded
before coronary artery occlusion, at 5 minutes intervals during
ischemia, during the first 45 minutes of reperfusion, and at
the end of the experiment.
One pair of ultrasonic crystals was implanted in the midmyocardial layer of the risk region. The end-diastolic distance of the crystals (EDD) was determined at the onset of ventricular systole. The end-systolic distance (ESD) was defined by peak negative dP/dt. Relative systolic shortening (SS%) was assessed as the difference of EDD minus ESD over EDDx100. SS% was recorded before treatment, immediately before coronary artery occlusion, immediately before reperfusion, after 45 minutes of reperfusion, and at the end of the experiment after thoracotomy had been repeated. EDD was additionally recorded after 10 minutes of reperfusion. EDD values were normalized to 100% before ischemia.
The LAD blood flow (mL/min) was recorded with a 1- or 2-mm ultrasonic flow probe (T-106 Flowmeter, Transonic Systems Inc) at the same time intervals as global hemodynamic parameters. The flow probe was placed around the coronary artery distal to the site of occlusion.
Plasma Concentrations of Cariporide
Coronary venous plasma concentrations of cariporide were
determined after 30 minutes of ischemia (groups 1 and 2),
immediately before reperfusion, and after 1 minute of reperfusion. In
addition, venous plasma concentrations of cariporide were assessed
immediately before reperfusion. Measurements were performed by Aventis,
with a high-performance liquid chromatography
method.
Histochemical Measurement of Infarct Size
After 24 hours of reperfusion, the heart was excised after
occlusion of the coronary artery at exactly the same site and
after administration of a central venous injection of 10 mL 10%
fluorescein sodium solution. The heart was cut into slices
of 
5-mm width parallel to the atrioventricular
groove. All slices containing reperfused myocardium were
weighed and photographed under ultraviolet light. The slices proximal
to the inserted crystals (in general, 5) were stained with nitroblue
tetrazolium (NBT) solution to assess the infarcted tissue and
photographed once more, always at the same magnification. Infarct size
was calculated as the ratio of infarcted myocardium to risk
regionx100.
Micromorphometric Evaluation of Infarct Size
Histological evaluation of infarct size has been described in
detail previously.2 8 The area at risk of necrosis was cut
out from the second proximal slice toward the apex under
fluorescent illumination. The tissue was routinely
paraffin-embedded, serially sectioned, stained with hematoxylin and
eosin (HE), and quantitatively analyzed by light microscopy.
Infarct size was calculated as the sum of necrotic fields in relation
to the entire risk region and expressed as a percentage of the risk
region.
Extracorporeal Bypass System
An extracorporeal bypass was used to achieve a constant residual
blood flow of 3 mL/min during ischemia. A 5F catheter was
introduced into the femoral artery and connected through the silicone
tubing of a laboratory pump with a 4F end-hole catheter that was
advanced into the LAD 0.3 cm distal to the planned site of
occlusion.9 A 3-way stop cock was placed between the
femoral catheter and the pump tubing to allow a continuous infusion of
heparin (500 IU/h). An in-line ultrasonic flow probe (T-106 Flowmeter,
Transonic Systems Inc) was positioned between the pump tubing and the
coronary catheter to constantly adjust the pump delivered blood
into the LAD to exactly 2.8 mL/min during ischemia. Two 3-way
stop cocks were positioned distal to the flowmeter for infusions of
cariporide or distilled water. Residual blood flow together with the
treatment solution or distilled water was administered into the
proximal part of the LAD distal to the site of occlusion.
Experimental Protocol
Cariporide (0.22 mg/kg body wt) was dissolved in 100 mL
distilled water. Four groups with 8 animals each were formed. The
animals of group 1 were treated with an intracoronary infusion
of 0.2 mL/min of the cariporide solution and 2.8 mL/min of
arterial blood during the whole ischemic period
(cariporide dose: 44 ng/kg per minute). At the onset of reperfusion,
the coronary catheter was withdrawn into the ostium of the LAD,
the extracorporeal bypass system was stopped, and the cariporide
solution was infused into the proximal LAD at an infusion speed of 2
mL/min for another 10 minutes. The pigs in group 2 were treated in the
same way as in group 1 for the first 30 minutes of ischemia. At
that time, active treatment was replaced by distilled water. In group
3, active treatment with cariporide was started after 45 minutes of
ischemia and was then identical to group 1. In the control
group (group 4), which was treated according to the protocol of group
1, cariporide solution was replaced by distilled water.
Relation Between Cariporide Blood Levels and Infarct Size
Reduction
The effective plasma concentration of cariporide to reduce
infarct size was studied in another 5 pigs subjected to 45 minutes of
distal LAD occlusion and 24 hours of reperfusion. Five minutes before
ischemia, 1 pig each was treated intravenously with
cariporide doses of 0.5 mg/kg, 0.25 mg/kg, 0.1 mg/kg, 0.05 mg/kg, and
placebo. Venous plasma concentrations of cariporide were determined at
the onset of ischemia and infarct sizes at the end of the
experiments.
Statistics
All data are presented as mean±SD. Weights of the left
ventricles and ischemic regions, residual blood flows, and
infarct sizes among the 4 groups were compared with the Kruskal-Wallis
H test followed by a Mann-Whitney U test.
Hemodynamic data and parameters of regional
myocardial function were analyzed among the groups with 2-way
repeated-measures ANOVA. When ANOVA indicated a significant difference,
the Student-Newman-Keuls post hoc test was applied to further compare
the data. Statistical significance was accepted at the 5% level and in
case of multiple comparisons (Mann-Whitney U test) at the
0.017 (3 comparisons) and 0.0125 level (4 comparisons).
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Results |
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General Results
One animal of group 4 died in the postoperative night. Thus, the analyses of the control group are based on 7 experiments. Ventricular fibrillation occurred in 4 pigs (group 1, 2 pigs; group 3, 2 pigs) during ischemia and in 1 animal of group 2 during reperfusion. It was immediately terminated by electrical countershocks.
Plasma Concentrations of Cariporide
In the treated groups, venous plasma concentrations of
cariporide were 30 to 40 nmol/L at the time of reperfusion.
Coronary venous (cv) plasma levels of cariporide were similar
in group 1 (0.92±0.18 µmol/L) and group 2 (0.97±0.29
µmol/L) after 30 minutes of ischemia. Immediately before
reperfusion, cv cariporide concentrations of group 1 (0.91±0.21
µmol/L) and group 3 (0.82± 0.07 µmol/L) did not differ and
were significantly higher than in group 2 (0.24±0.1 µmol/L,
P<0.004). After 1 minute of reperfusion, cv cariporide
levels were significantly higher (P<0.004) in group 1
(1.82±0.56 µmol/L) and group 3 (1.97±0.81 µmol/L)
compared with group 2 (0.31±0.06 µmol/L).
Global Hemodynamic Variables
There was no significant difference among the 4 groups during the
experiments (Table
). Initiation of
ischemia resulted in a decrease in LVPP and dP/dt max and an
increase in heart rate and LVEDP. Except for LAD blood flow and LVEDP,
global hemodynamics remained depressed until 24 hours
of reperfusion.
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Regional Myocardial Function
The EDD of the implanted crystals did not differ among the groups
before ischemia and before reperfusion. EDD amounted to
10.5±2.6 mm (group 1), 10.4±2.8 mm (group 2),
10.4±1.6 mm (group 3), and 10.7±1.6 mm (group 4) before
ischemia. After 10 minutes of reperfusion, the alterations in
end-diastolic distance of the reperfused
myocardium of groups 1 and 2 indicated no contracture
(group 1, 102±14%; group 2, 106±10%) compared with baseline values.
In contrast, EDD was reduced in group 3 to 85±11% and in the control
group to 66±10%. Groups 1 and 2 differed significantly from groups 3
and 4. Contracture of EDD in group 3 was significantly less compared
with the control group. A similar result was observed after 45 minutes
of reperfusion, except for the insignificant difference between groups
3 and 4. This result indicates that treatment of groups 1 and 2
exhibited the same protection from myocardial contracture during early
reperfusion, which was less pronounced when treatment was started
shortly before reperfusion (group 3).
SS% did not differ among the groups before ischemia, before
reperfusion, and after 45 minutes of reperfusion. Recovery of regional
systolic shortening was significantly better in groups 1 and 2
compared with both other groups at the end of the experiments (Figures 1 and 2).
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Histochemical and Micromorphometric Infarct Sizes
Left ventricular weights (group 1, 1336±14.5 g; group
2, 1223±16.8 g, group 3, 124.4±6.2 g; group 4, 119.3±11.4 g) and
risk regions (group 1, 32.0±7.9 g; group 2, 28.3±3.2 g; group 3,
29.2±4.7 g; group 4, 29.7±3.6 g) did not differ significantly among
the groups. Histochemical infarct sizes amounted to 41.5±20% (group
1), 33.5±14% (group 2), 71.6±15% (group 3), and 76±9% (group 4).
Micromorphometric infarct sizes were 44.6±12% (group 1), 34.9±15%
(group 2), 69.2±12% (group 3), and 72.4±12% (group 4). Salvage of
jeopardized myocardium was mainly observed in the
midmyocardial and subepicardial layers. The continuous
intracoronary treatment during ischemia and early
reperfusion (group 1) as well as the active treatment during the first
30 of minutes ischemia (group 2) reduced histochemical and
micromorphometric infarct sizes highly significantly compared with
groups 3 and 4 (group 1 versus group 3, P=0.012 [NBT
stain], P=0.003 [histology]; group 1 versus group 4,
P=0.0026 [NBT stain], P=0.008 [histology];
group 2 versus group 3, P=0.0008 [NBT stain],
P=0.002 [histology]; group 2 versus group 4,
P=0.0012 [NBT stain], P=0.0012 [histology]).
The differences between groups 1 and 2 as well as between groups 3 and
4 were not significant. These results demonstrate that continuous
treatment during ischemia and during early reperfusion was not
more effective than therapy with cariporide during the first half of
ischemia. Of particular note is that cariporide administration
during late ischemia and early reperfusion did not result in a
significant protection from cell death compared with the control group.
The mean infarct size of group 3 was 6% (NBT stain) or 4% (histology)
smaller than in the control group. These findings show that cariporide
predominantly attenuates cell death caused by ischemia and
reperfusion by NHE inhibition during ischemia and not at the
onset of reperfusion (Figure 3).
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Cariporide Plasma Concentration and Infarct Size Reduction
In the pigs subjected to 45 minutes of ischemia and 24
hours of reperfusion, infarct size was reduced from 64% (control) to
4% (cariporide concentration 1.21 µmol/L) and to 18%
(cariporide concentration 0.7 µmol/L). Lower plasma
concentrations (0.4 and 0.16 µmol/L) were associated with
infarct sizes of 60% and 65%
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Discussion |
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Limitations of the Study
This investigation was performed to clarify to what extent cariporide protects the myocardium during ischemia and/or during reperfusion. Because an intravenous treatment before ischemia can be expected also to be active at the onset of reperfusion and because an intravenous treatment before reperfusion may not be fast enough to immediately block the NHE system at the onset of reperfusion, cariporide was infused into the myocardium at risk of necrosis at different time intervals. It is known from earlier experiments that a residual blood flow of 3 mL/min results in a distinct transmural perfusion gradient with the level of subendocardial flow only being 30 to 40% of subepicardial flow.9
The dose of cariporide was chosen to achieve a coronary venous
level of 1 µmol/L during the specified ischemic
intervals and a higher level at the onset of reperfusion. A
concentration of 1 µmol/L has been shown to almost completely
block the amiloride-sensitive sodium influx in rabbit erythrocytes and
the NHE system in human platelets.10 This
concentration was also effective in reducing infarct size in the
dose-response evaluation in this study. Thus, it can be expected that
the myocardial concentration of cariporide in our experiments was high
enough to effectively block the myocardial NHE system at the time of
active treatment. Although the intracoronary infusion of
cariporide in group 2 was restricted to the first 30 minutes of
ischemia, the low residual blood flow prevented a complete
myocardial washout of the compound during the second half of
ischemia. It cannot be ruled out that this lower myocardial
concentration of cariporide still offered some protection from
ischemia-reperfusion injury. In contrast to almost all other
groups who have investigated the effect of NHE inhibition on
experimental infarct size, this study used a reperfusion long enough to
delineate the necrotic myocardium by histochemical as well
as histological means.
Myocardial Protection by Na+/H+
Exchange Inhibition
Five or even 6 isoforms of the
Na+/H+ exchanger have been
described. NHE-1 has been found in every tissue examined and
represents the isoform involved in myocardial cytoplasmic pH
and volume regulation.11 12
Characteristic features of myocardial ischemia include increased intracellular proton generation resulting in intracellular acidosis and accumulation of intracellular sodium accompanied by an increase of intracellular free calcium.13 14 Reperfusion is associated with an initially further increase followed by a decrease in intracellular sodium and an additional accumulation of intracellular calcium. It is generally accepted that intracellular calcium overload can induce cell death in myocardial ischemia and reperfusion.15 As early as 1985 it was hypothesized that intracellular calcium overload during reperfusion is the consequence of intracellular sodium accumulation. During myocardial ischemia, the intracellular and extracellular pH drop to low levels, rendering the NHE system inactive. At the onset of reperfusion, the pH gradient across the cell membrane results in the maximum activation of the NHE system. Intracellular protons are exchanged with extracellular sodium, with the consequence of intracellular sodium overload. Intracellular sodium is cycled with extracellular calcium by the Na+-Ca2+ exchanger, leading to calcium overload and cell death during reperfusion.13
Revised Concept of Myocardial Protection From
Ischemia-Reperfusion Injury by NHE Inhibition in Intact
Animals
The results of this and of previous studies of our
laboratory2 8 16 that used the specific NHE
inhibitors HOE 694 and cariporide form the basis for a
revised concept of myocardial protection by NHE inhibition in regional
ischemia and reperfusion in intact animals. The best protection
by NHE inhibition is clearly achieved by a treatment before
ischemia and in the case of a low residual blood flow, also
during early ischemia. This protection cannot be ascribed to
NHE inhibition at the onset of reperfusion because NHE inhibition
during late ischemia8 and at the onset of
reperfusion, group 3 in this study, did not reduce infarct size
significantly in this preparation. The high coronary venous
levels of cariporide in group 3 immediately before and after
reperfusion can almost rule out that cariporide was not available in
the myocardium at risk of necrosis at an effective
concentration. Thus, attenuation of cell death is predominantly
achieved by NHE inhibition during ischemia and not at the onset
of reperfusion. Although extracellular-intracellular ionic shifts were
not determined in our studies, the consistency of our
results allows the formulation of a revised concept of myocardial
protection by NHE inhibition. From the onset of ischemia,
intracellular acidosis activates the NHE system, which results
in acid extrusion and an increase in intracellular sodium. The rise in
intracellular sodium is accompanied by an increase of intracellular
free calcium.17 18 When ischemia continues, the
decrease in extracellular pH attenuates the activity of the NHE system,
reducing the sodium influx. Studies of cardiac Purkinje fibers suggest
that acid efflux by the NHE system can still occur even when the
chemical gradient for protons is reversed from an outward to an inward
gradient.19 Thus, the activity of the NHE system will
decrease during ischemia; however, a complete inactivation of
NHE is not likely to occur. This view is supported by the results of
our study,8 which demonstrated that the
intravenous use of cariporide 15 minutes after the onset of
ischemia reduced infarct size in a preparation with low
residual blood flow. The kinetics of intracellular sodium gain in the
presence of NHE inhibition in ischemia of longer duration have
not been reported. The attenuation of intracellular sodium accumulation
by NHE inhibition is substantial during 30 minutes of
ischemia.20 It is very likely that NHE inhibition
is able to delay the increase in intracellular sodium and probably
intracellular free calcium only a limited time because infarct sizes
after 45 minutes of ischemia without NHE inhibition were
similar to those after 70 minutes of ischemia in the presence
of NHE inhibition in regionally ischemic, reperfused porcine
hearts.16 Although reperfusion immediately establishes a
large transmembrane pH gradient that activates the NHE system,
recovery of intracellular pH is mainly mediated by lactate and
CO2 washout and the gain in intracellular sodium
is more likely caused by
Na+-HCO3-
coinflux than sodium coupled acid extrusion.21 Because NHE
inhibition at the time of reperfusion (group 3) attenuated myocardial
contracture after 10 minutes of reperfusion but did not reduce infarct
size significantly, it is speculated that intracellular free calcium
accumulation during early reperfusion might have been reduced to some
extent. However, this favorable action prevented cell death in only an
insignificant amount of myocardium (4% to 6% of infarct
size) in this study. Although the contribution of many details of NHE
inhibition on attenuation of cell death in ischemia and
reperfusion cannot be quantified, for example, delayed recovery of
intracellular pH during reperfusion,20 22 the delay of the
increase in intracellular sodium during ischemia associated
with a reduced intracellular free calcium accumulation during
ischemia and to some extent during early reperfusion appears to
be the key mechanism for myocardial protection by NHE inhibition.
Conclusions
This study in regionally ischemic, reperfused porcine
hearts with low residual blood flow suggests that NHE inhibition by
cariporide protects the myocardium predominantly during
ischemia and not at the time of reperfusion. It is assumed that
myocardial injury is mainly attenuated by a delayed increase in
intracellular sodium and free calcium during ischemia and to a
much lesser extent by a reduced calcium accumulation during
reperfusion.
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Acknowledgments |
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Cariporide (HOE642) was kindly provided by Aventis Pharma, Frankfurt/Main, Germany.
Received March 21, 2000; revision received May 19, 2000; accepted May 22, 2000.
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References |
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 A. Toth, J. R. Jeffers, P. Nickson, J.-Y. Min, J. P. Morgan, G. P. Zambetti, and P. Erhardt Targeted deletion of Puma attenuates cardiomyocyte death and improves cardiac function during ischemia-reperfusion Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H52 - H60. [Abstract] [Full Text] [PDF]
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M. Ten Hove and C. J.A Van Echteld Limited effects of post-ischemic NHE blockade on [Na+]i and pHi in rat hearts explain its lack of cardioprotection Cardiovasc Res, February 15, 2004; 61(3): 522 - 529. [Abstract] [Full Text] [PDF]
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C. Kupatt, R. Hinkel, J. Horstkotte, M. Deiss, M.-L. von Bruhl, M. Bilzer, and P. Boekstegers Selective retroinfusion of GSH and cariporide attenuates myocardial ischemia-reperfusion injury in a preclinical pig model Cardiovasc Res, February 15, 2004; 61(3): 530 - 537. [Abstract] [Full Text] [PDF]
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W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. W. Hendrick, J. A. Sample, K. B. Dowdy, J. E. McLean, J. T. Mingoia, F. A. Crawford Jr, and F. G. Spinale Modulation of calcium transport improves myocardial contractility and enzyme profiles after prolonged ischemia-reperfusion Ann. Thorac. Surg., December 1, 2003; 76(6): 2054 - 2061. [Abstract] [Full Text] [PDF]
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J. S. Corvera, Z.-Q. Zhao, L. S. Schmarkey, S. L. Katzmark, J. M. Budde, C. D. Morris, T. Ehring, R. A. Guyton, and J. Vinten-Johansen Optimal dose and mode of delivery of Na+/H+ exchange-1 inhibitor are critical for reducing postsurgical ischemia-reperfusion injury Ann. Thorac. Surg., November 1, 2003; 76(5): 1614 - 1622. [Abstract] [Full Text] [PDF]
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 W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. T. Mingoia, J. A. Sample, J. W. Hendrick, K. B. Dowdy, J. E. McLean, R. E. Stroud, and F. G. Spinale Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1489 - 1497. [Abstract] [Full Text] [PDF]
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M. Ruiz-Meana, D. Garcia-Dorado, P. Pina, J. Inserte, L. Agullo, and J. Soler-Soler Cariporide preserves mitochondrial proton gradient and delays ATP depletion in cardiomyocytes during ischemic conditions Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H999 - H1006. [Abstract] [Full Text] [PDF]
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S. B. Digerness, P. S. Brookes, S. P. Goldberg, C. R. Katholi, and W. L. Holman Modulation of mitochondrial adenosine triphosphate-sensitive potassium channels and sodium-hydrogen exchange provide additive protection from severe ischemia-reperfusion injury J. Thorac. Cardiovasc. Surg., April 1, 2003; 125(4): 863 - 871. [Abstract] [Full Text] [PDF]
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A. Rodriguez-Sinovas, D. Garcia-Dorado, F. Padilla, J. Inserte, J. A. Barrabes, M. Ruiz-Meana, L. Agullo, and J. Soler-Soler Pre-treatment with the Na+/H+ exchange inhibitor cariporide delays cell-to-cell electrical uncoupling during myocardial ischemia Cardiovasc Res, April 1, 2003; 58(1): 109 - 117. [Abstract] [Full Text] [PDF]
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D. G Allen and X.-H. Xiao Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion Cardiovasc Res, March 15, 2003; 57(4): 934 - 941. [Abstract] [Full Text] [PDF]
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R. M. Mentzer Jr, R. D. Lasley, A. Jessel, and M. Karmazyn Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection Ann. Thorac. Surg., February 1, 2003; 75(2): S700 - 708. [Abstract] [Full Text] [PDF]
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S. Muraki, C. D. Morris, J. M. Budde, Z.-Q. Zhao, R. A. Guyton, and J. Vinten-Johansen Blood cardioplegia supplementation with the sodium-hydrogen ion exchange inhibitor cariporide to attenuate infarct size and coronary artery endothelial dysfunction after severe regional ischemia in a canine model J. Thorac. Cardiovasc. Surg., January 1, 2003; 125(1): 155 - 164. [Abstract] [Full Text] [PDF]
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D. Garcia-Dorado, M. Ruiz-Meana, F. Padilla, A. Rodriguez-Sinovas, and M. Mirabet Gap junction-mediated intercellular communication in ischemic preconditioning Cardiovasc Res, August 15, 2002; 55(3): 456 - 465. [Abstract] [Full Text] [PDF]
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Q.-D. Wang, J. Pernow, P.-O. Sjoquist, and L. Ryden Pharmacological possibilities for protection against myocardial reperfusion injury Cardiovasc Res, July 1, 2002; 55(1): 25 - 37. [Abstract] [Full Text] [PDF]
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 M. Avkiran and M. S. Marber Na+/h+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects J. Am. Coll. Cardiol., March 6, 2002; 39(5): 747 - 753. [Abstract] [Full Text] [PDF]
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U. Zeymer, H. Suryapranata, J. P. Monassier, G. Opolski, J. Davies, G. Rasmanis, G. Linssen, U. Tebbe, R. Schroder, R. Tiemann, et al. The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial J. Am. Coll. Cardiol., November 15, 2001; 38(6): 1644 - 1650. [Abstract] [Full Text] [PDF]
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M. Avkiran, G. Gross, M. Karmazyn, H. Klein, E. Murphy, and K. Ytrehus Na+/H+ exchange in ischemia, reperfusion and preconditioning Cardiovasc Res, April 1, 2001; 50(1): 162 - 163. [Full Text] [PDF]
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