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Ann Thorac Surg 2002;73:569-574
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Ischemic preconditioning and Na⁺/H⁺ exchange inhibition improve reperfusion ion homeostasis

^a Department of Surgery, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
^b Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
^c Department of Biostatistics, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

Accepted for publication September 9, 2001.

* Address reprint requests to Dr Holman, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA
e-mail: wholman{at}its.uab.edu

	Abstract

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Background. Intramyocyte sodium (Na⁺) increases during ischemia and reperfusion, which causes myocardial calcium (Ca²⁺) uptake and leads to myocyte injury or death. This study determines if ischemic preconditioning and myocyte sodium-hydrogen ion (Na⁺-H⁺) exchange (NHE) inhibition decreases Na⁺ gain that otherwise occurs with cardioplegic arrest and reperfusion.

Methods. Pigs had 1 hour of cardioplegic arrest followed by reperfusion. Group 1 had no intervention (controls). Group 2 received dimethyl amiloride (DMA, an NHE inhibitor), and group 3 had ischemic preconditioning before cardioplegic arrest. Precardioplegia to postreperfusion change in intramyocyte ion content was measured with atomic absorption spectrometry. The time to initial electrical activity and number of defibrillations needed to establish an organized rhythm postreperfusion were used as electrophysiologic variables to measure ischemia-reperfusion injury.

Results. Intramyocyte Na⁺ content for group 1 increased from 45.9 ± 6.7 to 61.9 ± 22.5 µmol/g (p = 0.02). Group 2 had an insignificant decrease in intramyocyte Na⁺ of 27.7 ± 19.58 µmol/g (p = 0.06), and group 3 had an insignificant decrease of 10.8 ± 46.33 µmol/g (p = 0.48). Interstitial water increased significantly in all groups, but there were no significant increases in intramyocyte water content. Electrophysiologic recovery was similar for all three groups.

Conclusions. The NHE inhibition and ischemic preconditioning each eliminated the increase in intramyocyte Na⁺ content that otherwise occurred with cardioplegic arrest and reperfusion in this porcine model. Because their mechanisms are distinct, it is possible that an additive beneficial effect against ischemia-reperfusion injury can be achieved by using NHE inhibition together with a preconditioning stimulus as prereperfusion therapy.

	Introduction

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This laoratory is currently investigating methods to increase myocardial tolerance to ischemia-reperfusion injury in cardiac operations. Our research focuses on one aspect of myocardial ischemia-reperfusion injury, namely myocyte sodium (Na⁺) influx and consequent loss of ionic homeostasis. An acute increase in cytoplasmic Na⁺ due to increased activity of the myocyte sodium-hydrogen ion (Na⁺-H⁺) exchanger during ischemia and reperfusion is an early step in the sequence of events that leads to myocardial calcium (Ca²⁺) uptake, contractile dysfunction, mitochondrial Ca²⁺ loading, and cell death [1].

To date, we have shown that controlled reperfusion with a period of asystole induced using warm blood cardioplegia solution eliminates the increase in myocyte Na⁺ content that otherwise occurs with cardioplegic arrest and reperfusion [2]. In the present experiment, two other methods for decreasing net myocyte Na⁺ gain due to ischemia-reperfusion injury are tested. These methods are ischemic preconditioning and treatment with the Na⁺-H⁺ exchange inhibitor dimethyl amiloride (DMA).

The mechanism for the beneficial effect of ischemic preconditioning is complex, but probably includes protection of mitochondria within myocytes through protein kinase C (PKC)-modulated opening of adenosine triphosphate (ATP)-dependent potassium (K⁺) channels [3, 4] (Fig 1). We speculate that protection of mitochondria from ischemia-reperfusion injury will improve high energy phosphate production, thereby optimizing the function of ATP-dependent ion exchangers (eg, Na⁺/K⁺ ATPase and ATP-dependent Ca²⁺ transporters) during reperfusion. The mechanism for DMA and other amiloride derivatives is direct inhibition of the Na⁺-H⁺ exchanger [1] (Fig 2).

View larger version (20K): [in this window] [in a new window]   Fig 1. Increased mitochondrial calcium due to acute influx of calcium during ischemia and reperfusion results in opening of mitochondrial transition pores (MTP). Opening of MTP leads to collapse of the inner membrane electrochemical gradient (artwork unavailable), diminished high energy phosphate production and cell death [23]. Opening of K+ATP channels produced by an ischemic preconditioning (IP) stimulus putatively stabilizes the MTP in the closed position. (ATP = adenosine triphosphate; Ca = calcium; K = potassium.)

View larger version (13K): [in this window] [in a new window]   Fig 2. Intracellular acidosis (H+ excess) during ischemia leads to activation of the Na+/H+ exchanger with the subsequent Na+ burden giving rise to Ca++ influx through Na+/Ca2+ exchange and Ca++ overload. (Ca = calcium; H = hydrogen; Na = sodium.)

	Material and methods

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Surgical preparation and experimental interventions
Thirty pigs of both sexes, weighing 25 to 30 kg, were anesthetized, intubated, and mechanically ventilated. A constant infusion of sodium pentobarbital was used to maintain anesthesia. All animals in this study received humane care in compliance with the "Principles of Laboratory Animal Care," formulated by the National Society for Medical Research, and the "Guide for the Care and Use of Laboratory Animals," prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (National Institutes of Health, Publication No. 86–23, revised 1985).

Catheters were placed in the right external jugular vein and right common carotid artery. Systemic blood pressure was measured continuously throughout. Blood samples were assayed for blood gas and electrolyte (Na⁺, K⁺, Ca²⁺) measurements to assure the adequacy of perfusion and electrolyte composition during each experiment. The pigs were given heparin and placed on cardiopulmonary bypass using right atrial and aortic cannulation, and bypass was initiated at a flow of 2.2 L · min · m². The perfusion temperature was initially 37°C and then dropped to 30°C with concomitant decrease in flow to 1.6 L · min · m² for the duration of cardioplegic arrest. Cardioplegia was initiated with a 3-minute infusion of a 4°C hyperkalemic-hypocalcemic blood cardioplegia solution described previously [2], infused at a mean aortic root pressure of 70 mm Hg. Left ventricular venting was accomplished by suction on a pulmonary artery catheter. Supplemental 1-minute infusions of blood cardioplegia were given after 15, 30, and 45 minutes of arrest. After 60 minutes of cardioplegic arrest, reperfusion was initiated with warm blood at a mean aortic root pressure of 70 mm Hg.

The control group (group 1, n = 10 pigs) had no pretreatment before arrest and reperfusion. The DMA group (group 2, n = 10 pigs) was given a bolus dose of 1 mg/kg of 5-(N,N-dimethyl amiloride) (Reasearch Biochemicals Intl, Natick, MA) at the start of cardiopulmonary bypass, followed by a 10-minute loading dose of DMA 5 ug · kg · min, with that same dose continued as a maintenance infusion throughout cardioplegic arrest and into reperfusion. This dose was based on prior published experience with DMA used in an intact porcine heart preparation [5], as well as studies performed in an isolated rat heart model [6].

The preconditioning group (n = 10 pigs) had 5-minutes of global ischemia induced by cross-clamping of the aorta while supported on cardiopulmonary bypass. Ischemia was followed by 15-minutes of reperfusion before cardioplegic arrest. This protocol is similar to protocols used in prior studies of IP [7]. The cardioplegia and reperfusion conditions were the same for all groups, as previously described.

Myocyte electrolyte and water content measurements
Measurements of myocardial water and electrolyte (sodium and potassium) contents were made using atomic absorption spectrometry with cobalt (Co)-ethylenediaminetetraacetic acid (EDTA) as the extracellular marker [8, 9]. Transmural biopsies of left ventricular myocardium were obtained after equilibrating the Co-EDTA in the plasma and interstitial space by 10 minutes of Co-EDTA infusion. The EDTA tightly chelates cobalt ions, so that the complex is nontoxic and has no discernable effect on myocardial contractility (Digerness, SB, unpublished data). Two biopsies were obtained for comparison. The first biopsy was taken before cardioplegic arrest. The second biopsy was taken at 5 minutes of postcardioplegia reperfusion. The tissue samples were analyzed for sodium, potassium, and water content in a manner previously described [2].

Electrophysiologic data acquisition and analysis
Surface electrodes were placed on the extremities to record limb lead electrocardiograms. A single unipolar atrial electrode was sewn to the left atrial appendage, and a multi-electrode recording plaque was sewn to the left ventricular surface. Electrophysiologic data were inspected to determine the time of initial ventricular electrical activity during postcardioplegia reperfusion. If ventricular fibrillation occurred, defibrillation attempts began at 5 minutes after initiating reperfusion. The duration of postcardioplegia reperfusion before defibrillation was chosen based on earlier studies in this laboratory. The number of defibrillation shocks required to terminate ventricular fibrillation was counted.

Statistical analysis
Times until electrical activation were analyzed by means of a likelihood ratio test based on an exponential survival time model (SAS, Cary, NC). A mixed model repeated measures of analysis of variance (SAS, Cary, NC) was used to compare the average number of defibrillation attempts for the three groups.

The biochemical data were analyzed using the SAS General Linear Models procedure (SAS, Cary, NC). It was noted that there was a strong linear relationship between the base line value and the size and sign of the change precardioplegia to postcardioplegia. Thus for analysis of the change scores, analysis of covariance was used with group (controls vs preconditioning or DMA) as the fixed effect and the base line score treated as a covariate. The means that were compared were the least squares means, which are the predicted means at the average base line score across all participants. In addition, standard multivariate analysis and mixed models analysis with suitably specified contrasts were used. The results were the same in all cases.

	Results

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Biochemical analysis
Precardioplegia and postreperfusion values for intramyocyte sodium and potassium content are shown in Table 1. Initially there were 10 animals per group, however 2 animals in the control group and 2 animals in the DMA group were excluded because of values for intramyocyte Na⁺ content that were negative, despite repeated atomic absorption spectrometry measurements of the biopsy material. Negative values are impossible and reflect the derived nature of atomic absorption spectrometry measurements of intramyocyte Na⁺; this is described in greater detail in the "Comment" section.

View larger version (34K): [in this window] [in a new window]   Fig 3. Precardioplegia (Pre) and postcardioplegia (Post) measurements of intramyocyte sodium for individual animals, according to experimental group. (A) Control group. (B) Dimethyl amiloride group. (C) Ischemic preconditioning group. (SD = standard deviation.) ( = individual animal values; • = group mean.)

	Comment

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Our goal in the present study was to examine the change in intracellular Na⁺ content during postcardioplegia reperfusion in three groups of animals: (1) a control group, (2) a group subjected to cardioplegic arrest and reperfusion in the presence of 5-(N,N-dimethyl amiloride) (DMA), a potent and selective inhibitor of NHE, and (3) a group subjected to cardioplegic arrest and reperfusion after a preconditioning stimulus. Atomic absorption spectrometry was used to determine intracellular ion content. Atomic absorption spectrometry measures total ion content in a tissue sample. Intracellular ion content is calculated by subtracting extracellular ion content, which is determined using the extracellular marker Co-EDTA, from the total ion content [2]. Hence the value for intracellular ion content is derived from other measurements and is subject to variability, particularly when measuring an ion that exists predominantly in the extracellular rather than the intracellular space (eg, Na⁺). One consequence of this variability is that atomic absorption spectrometry calculated a negative value for intramyocyte Na⁺ content in four hearts (2 controls and 2 DMAs). These hearts were excluded from the analysis. Alternative methods to measure intramyocyte Na⁺, including fluorescent dyes and nuclear magnetic resonance spectroscopy, were considered for this study. However, these alternative methods have important limitations of their own that made them less desirable than atomic absorption spectrometry for an intact porcine model utilizing cardiopulmonary bypass.

Statistical analysis that accounted for variation in the precardioplegia measurements of intramyocyte ion content showed that DMA and ischemic preconditioning each prevented the net postcardioplegia gain in intracellular Na⁺ that was seen in the control group. An acute increase in intracellular Na⁺ is one of the earliest and most critical steps in ischemia-reperfusion injury.

Analysis of myocardial water content demonstrated that, in this experimental model, interstitial rather than intracellular edema accounted for the gain in total myocardial water content that occurred after cardioplegic arrest and reperfusion. The water content data serve as a way to estimate ion concentration from the ion content data and confirm that intracellular Na⁺ content was not altered by excess Na⁺ pulled passively into myocytes by intracellular edema formation during postcardioplegia reperfusion.

The NHE inhibition and ischemic preconditioning are believed to exert their beneficial effects through independent mechanisms [10, 11], although this remains somewhat controversial [12, 13]. The precise mechanism for the attenuating effect of ischemic preconditioning on postischemic Na⁺ gain is not currently known; however, it may involve the preservation of mitochondrial capacity for ATP synthesis through the protection of mitochondria from Ca²⁺ overload injury (Fig 1). Recent evidence suggests that Ca²⁺ overload in mitochondria results in opening of the mitochondrial permeability transition pore [14]. This results in collapse of the proton electrochemical gradient and loss of mitochondrial function, predisposing the cell to necrosis or apoptosis. Opening mitochondrial ATP-sensitive K⁺ channels decreases mitochondrial Ca²⁺ uptake and promotes Ca²⁺ release [15], thus decreasing the likelihood for opening of the permeability transition pore. Protection of mitochondrial synthetic capability will, in theory, allow rapid postischemic restoration of intramyocyte ion homeostasis through ATP-dependent transport mechanisms (eg, sarcolemmal Na⁺-K⁺ ATPase).

The mechanism for preservation of intramyocyte ion homeostasis by DMA is blockade of Na⁺-H⁺ exchange (Fig 2). In the treated heart, Na⁺-H⁺ exchange inhibition results in slower normalization of intracellular pH during reperfusion, and diminishes intramyocyte Ca²⁺ uptake through the Na⁺/Ca²⁺ exchanger. The attenuation of net myocyte Ca²⁺ gain during ischemia and particularly during reperfusion protects the myocyte and its mitochondria from ischemia-reperfusion injury. An association between ion homeostasis and superior recovery of high energy phosphate charge has previously been demonstrated with interleaved nuclear magnetic resonance spectroscopy measurements obtained in an isolated heart model of global ischemia and reperfusion [16]. This study showed that NHE inhibition with another amiloride derivative (ethyl-isopropyl-amiloride) decreases the uptake of sodium during ischemia and reperfusion in association with more rapid return of high energy phosphate content during reperfusion as compared with controls.

Two electrophysiologic variables were analyzed in this experiment: (1) the time to onset of earliest electrical activity, and (2) the number of defibrillations needed to convert postreperfusion ventricular fibrillation to a nonfibrillating rhythm. Prior studies in animals [2, 17] and humans [18] have shown that controlled reperfusion techniques decrease postcardioplegia reperfusion arrhythmias, which are generally accepted as a marker for reperfusion injury [19]. We postulated that an improvement in myocyte ion homeostasis due to ischemic preconditioning or DMA treatment would similarly decrease postcardioplegia arrhythmias. However, in the present experiment there was no evidence that this was the case. Our finding is somewhat surprising because NHE inhibition and ischemic preconditioning suppress reperfusion arrhythmias in most experimental models of regional ischemia-reperfusion injury that do not involve cardioplegic arrest [20–22], although NHE inhibition failed to suppress reperfusion arrhythmias in at least one study [5]. The absence of antiarrhythmic effects for NHE inhibition and IP in our study may be due to the return of cardiac electrical activity at a time when the myocardium had residual regional heterogeneity of temperature and interstitial electrolyte concentrations. This heterogeneity may have overwhelmed any antiarrhythmic effect of the interventions.

In summary, NHE inhibition and preconditioning were each shown to eliminate the increase in intramyocyte Na⁺ content that otherwise occurred with cardioplegic arrest and reperfusion in a porcine model. Given the fact that their mechanisms are independent, it is possible that an additive beneficial effect mediated by superior protection of mitochondrial function and intramyocyte ion homeostasis can be achieved by using NHE inhibition together with a preconditioning stimulus as prereperfusion therapy. The addition of controlled reperfusion, another intervention that preserves intramyocyte ion homeostasis, may even further improve cardiac tolerance to ischemia-reperfusion injury, thereby providing a clinically useful technique that combines the three aforementioned methods (Na⁺/H⁺ exchange inhibition, preconditioning, and controlled reperfusion) to decrease the mortality and morbidity resulting from severe ischemia-reperfusion injury in patients undergoing cardiac operations.

	Acknowledgments

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This work was partially funded by American Heart Association Grant-In-Aid No. 96006390 (William L. Holman), National Institutes of Health RO1 HL66015 (William L. Holman), and National Institutes of Health National Research Service Award HL-09493 (Jonathan L. Skinner).

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): William L. Holman Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldberg, S. P. Articles by Holman, W. L. Search for Related Content PubMed PubMed Citation Articles by Goldberg, S. P. Articles by Holman, W. L. Related Collections Myocardial protection