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Ann Thorac Surg 1997;63:1107-1112
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

The Contribution of Na⁺/H⁺ Exchange to Ischemia-Reperfusion Injury After Hypothermic Cardioplegic Arrest

Department of Organ Transplantation and First Department of Surgery, Osaka University Medical School, Osaka, Japan

Accepted for publication November 5, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Background. Na⁺/H⁺ exchange has been reported to be one of the key mechanisms in myocardial ischemia-reperfusion injury. However, the effect of temperature on Na⁺/H⁺ exchange is not fully understood.

Methods. Sodium-propionate-induced cell swelling, an indicator of the function of the Na⁺/H⁺ exchanger, was measured in rat thymic lymphocytes. A Langendorff perfused rat heart model was also employed to investigate the effect of the pharmacologic inhibition of Na⁺/H⁺ exchange on the recovery of cardiac function after hypothermic ischemia. This was done using FR168888, an inhibitor of Na⁺/H⁺ exchange.

Results. In the in vitro study, rat lymphocytes were observed to swell at 17°, 22°, and 27°C, indicating that the Na⁺/H⁺ exchanger remains functional even under hypothermic conditions. FR168888 was found to significantly inhibit Na⁺/H⁺ exchange-induced cell swelling, even at 17°C. In the in vivo study, pretreatment with FR168888 was found to prevent the deterioration of ventricular function, even after 5 hours of hypothermic cardioplegic arrest. This was associated with a decrease in the reperfusion-induced elevation in resting tension.

Conclusions. These results suggest that Na⁺/H⁺ exchange in the heart still occurs, even under hypothermic conditions, and contributes to reperfusion injury, even after hypothermic cardioplegic arrest.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
It has been shown that the inhibition of Na⁺/H⁺ exchange is protective against ischemia-reperfusion injury because it inhibits the sudden restoration of intracellular pH and hence the Na⁺ and Ca²⁺ overload [1–4] mediated by Na⁺/Ca²⁺ exchange. Na⁺/H⁺ exchange can be inhibited either by lowering the extracellular pH during reperfusion or by administering amiloride derivatives. The initial acidic reperfusion theoretically suppresses the Na⁺ influx occurring via Na⁺/H⁺ exchange during reperfusion [5, 6]. It is not, however, practical to apply this method clinically. The pharmacologic inhibition of Na⁺/H⁺ exchange, which may be more practical for clinical use, has been shown to improve postischemic ventricular function after normothermic ischemia [1, 3, 7–10]. The question that needs to be answered, however, is whether this beneficial effect of Na⁺/H⁺ exchange inhibition can be used in the clinical setting to protect the myocardium during cardiac surgical procedures. In the clinical situation, hypothermic cardioplegic arrest is normally used to protect the myocardium during aortic clamping. Therefore it must be determined whether the Na⁺/H⁺ exchanger plays an important role under hypothermic conditions and whether the Na⁺/H⁺ exchanger can reduce the degree of ischemia-reperfusion injury occurring after hypothermic cardioplegic arrest. In the present study the temperature dependency of the Na⁺/H⁺ exchanger and that of an inhibitor, FR168888, were investigated in vitro in rat thymic lymphocytes. Further, the effect of the inhibition of Na⁺/H⁺ exchange on postischemic cardiac function was examined in isolated rat hearts subjected to normothermic or hypothermic arrest.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Detection of Na⁺/H⁺ Exchange-Induced Cell Swelling by Electric Sizing
Thymic lymphocytes were isolated from Male Sprague-Dawley rats (body weight, 250 to 300 g). To do this, the thymus was cut into small fragments in buffer solution (NaCl, 140 mmol/L; KCl, 1 mmol/L; CaCl₂, 1 mmol/L; MgCl₂, 1 mmol/L; glucose, 10 mmol/L; HEPES, 20 mmol/L; pH, 7.3 with NaOH) at room temperature and dissociated. This was then filtered and centrifuged at 1,000 g for 10 minutes at room temperature. The pellet was resuspended in 20 mL of buffer solution and centrifuged at 1,000 g for 10 minutes. The final pellet was resuspended in 10 mL of HEPES-buffered RPMI medium (RPMI 1640; Life Technologies Inc, Grand Island, NY) with 20-mmol/L HEPES (pH, 7.3; nominally HCO₃^- free) and preserved in ice-cold water. The total counts of the cells were adjusted to 1.0 x 10⁷ cells/mL. Na-propionate buffer (Na-propionate, 140 mmol/L; KCl, 1 mmol/L; CaCl₂, 1 mmol/L; MgCl₂, 1 mmol/L; glucose, 10 mmol/L; HEPES, 20 mmol/L; pH, 6.7) was used to induce intracellular acid loading. Using a multichannel particle counter (TA2; Coulter Corp, Miami, FL) equipped with a 50-µm aperture, the cell swelling was measured 1, 2, 3, 4, and 5 minutes after acid loading. FR168888 (C₄H₄NC₆H₃CH₂[OH]CONC(NH₂)₂•CH₃SO₃H; molecular weight, 354.39; Fujisawa Pharmaceutical Company, Tokyo, Japan) was dissolved in dimethysulfoxide solvent.

	Isolated Rat Heart Preparation

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Male Sprague-Dawley rats weighing around 350 g were anesthetized by an intraperitoneal injection of sodium pentobarbital (50 mg/g body weight) and heparin (2 U/g body weight). Hearts were then excised, and a retrograde aortic perfusion was started with Krebs Henseleit buffer (NaCl, 120.0 mmol/L; NaHCO₃ 20.0 mmol/L; KCl, 4.5 mmol/L; MgSO₄, 1.2 mmol/L; KH₂PO₄, 1.2 mmol/L; CaCl₂, 2.5 mmol/L; glucose, 10.0 mmol/L, aerated with 5% carbon dioxide and 95% oxygen to maintain a pH of 7.4) at a pressure of 100 cm H₂O. The temperature of the hearts was kept at 37°C by a temperature-regulated water-jacketed glass chamber.

	Experimental Protocol

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
A left ventricular (LV) balloon was inserted during 30 minutes of stabilization, and the LV systolic pressure at an end-diastolic pressure of 10 mm Hg, coronary flow rate, and heart rate were measured at the end of the stabilization period using a pressure transducer (AP641G; Nihon Koden Co, Tokyo, Japan). St. Thomas' Hospital cardioplegic solution (NaCl, 110.0 mmol/L; KCl, 16.0 mmol/L; MgCl₂, 1.2 mmol/L; CaCl₂, 1.2 mmol/L; NaHCO₃, 10.0 mmol/L, with the pH adjusted to 7.8 with HCl) at each temperature (37° or 17°C) was then infused for 3 minutes at 60 cm H₂O to obtain cardioplegic arrest. The myocardial temperature during ischemia was kept at 37°C for 35 minutes in the normothermic experiment and at 17°C for 4 or 5 hours in the hypothermic experiment. FR168888 was given before (FRpre), during the infusion of St. Thomas' Hospital solution (FRcp), or during reperfusion (FRrep) in the normothermic experiment and before ischemia in the hypothermic experiment. The total amount of FR168888 given was 1 mg (2.82 x 10^-6 mole) in all experimental groups, whereas the control group received only normal saline solution (Fig 1). During the ischemic period the LV balloon was kept inflated to detect the time to the onset and the peak amplitude of the ischemic contracture. The time to the onset of the ischemic contracture was defined to occur when the left ventricular resting tension increased by 1 mm Hg. Hearts were then reperfused for 20 minutes and the hemodynamic indices again measured at the end of reperfusion, with the balloon volume readjusted to keep the end-diastolic pressure at 10 mm Hg. The postischemic hemodynamic recoveries were expressed as a percentage of the preischemic value of each index.

View larger version (34K): [in this window] [in a new window]   Fig 1. . The experimental protocol. The administration of FR168888 is denoted by the black boxes. (CP = the period of the infusion of cardioplegia; FRpre, FRcp, and FRrep = the drug-treated groups during the preischemic period, the infusion of cardioplegic solution, and the reperfusion phase, respectively.)

	Tissue Drug Concentration

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

	Humane Animal Care

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Animals were treated in accordance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1985).

	Data Analysis

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Results are expressed as the mean ± the standard error of the mean. The inhibition constant (K_i) was calculated using the following procedure: The velocity of the change in the cell volume induced by Na-propionate was calculated when FR168888 was added in a concentration of 0, 3.2 x 10^-9, 1.0 x 10^-8, and 3.2 x 10^-8 mol/L at each temperature. By linear regression analysis, data were fitted to the following formula: 1/V = a x S + b, where V is the velocity of the change in the cell volume, S is the concentration of FR168888, and the X intercept was defined as K_i.

The LV static pressure during the early phase of reperfusion after normothermic ischemia was fitted to two exponentials using a personal computer program (Sigma Plot; Jandel Scientific, San Rafael, CA) to evaluate the time constants of the pressure decay occurring during reperfusion, the scaling factors, and the asymptotic pressure. The repeated-measure analysis of variance was used to assess the LV static pressure after hypothermic ischemia. Student's t test was used for the other parameters. A p value of less than 0.05 was defined as significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Temperature Dependency of Na⁺/H⁺ Exchange-Induced Cell Swelling
The activity of Na⁺/H⁺ exchange was gauged by the amount of swelling of thymic lymphocytes induced by the acid load [11]. The diameter of lymphocytes started to increase when they were mixed with propionate buffer. Five minutes after the start of acid loading, the cell diameter increased by approximately 500 nm in normothermia (37°C). Although this swelling was slightly attenuated at lower temperatures (17°, 22°, and 27°C), considerable cell swelling was still detected (Fig 2A). At each temperature, FR168888 (1.0 x 10^-8 nmol/L) caused the percentage of cell swelling to be reduced. The percentage of the inhibition of cell swelling was highest at 17°C. The K_i values were 3.03, 6.42, and 3.23 nmol/L at 17°, 22°, and 27°C, respectively (Fig 2B).

View larger version (18K): [in this window] [in a new window]   Fig 2. . Temperature dependency of Na+/H+ exchange and its inhibitor. (A) The acid load induced swelling of rat thymic lymphocytes for 5 minutes. (B) Percentage of inhibition of cell swelling by FR168888. The drug concentration was 10 x 10-8 mol/L. The Ki values were 3.03, 6.42, and 3.23 nmol/L at 17°, 22°, and 27°C, respectively.

	Isolated Rat Heart Experiment

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

During the very early stage of reperfusion, the resting tension increased and peaked within 15 seconds, which then decreased with time (Fig 3). This change in the LV static pressure during the early reperfusion period was fit to two exponentials (e), as follows:

View larger version (23K): [in this window] [in a new window]   Fig 3. . The raw trace of a representative pressure recording during early reperfusion. At the onset of reperfusion in the normothermic experiment, the resting tension started to increase. After peaking, it gradually decreased. The trace was from the control group (e = exponential.)

where ± is the time from the onset of reperfusion, T1 and T2 are the time constants of each exponential component, A and B are the scaling factors, and C is the asymptotic pressure. There was no significant difference in A, B, T1, or T2 between groups. However, the asymptotic pressure was significantly lower in the FRcp group than in the other groups (Table 1).

View larger version (21K): [in this window] [in a new window]   Fig 4. . Percentage of recovery of left ventricular systolic pressure in the normothermic (A) and hypothermic (B) experiments. It was significantly higher in the FR168888-treated groups (FR) than in the control group at both temperatures. (FRpre, FRcp, and FRrep = the drug-treated groups during the preischemic period, the infusion of cardioplegic solution, and the reperfusion phase, respectively; *p < 0.01; **p < 0.001.)

During hypothermic ischemia with cardioplegia, no significant difference was seen in the time to the onset or peak amplitude of the ischemic contracture between the control and drug-treated groups at each duration of ischemia (86.6 ± 2.1 minutes versus 95.5 ± 0.5 minutes, 11.2 ± 2.3 mm Hg versus 12.0 ± 2.4 mm Hg and 99.0 ± 5.7 minutes versus 101.6 ± 9.6 minutes, 10.7 ± 2.4 mm Hg versus 6.6 ± 2.0 mm Hg in the control versus the FR168888-treated group at 4 and 5 hours, respectively).

Upon reperfusion, the myocardial temperature was not fully restored for 2 minutes. The resting tension increased and peaked in about 10 seconds, then stayed at this level or decreased for about 1 minute. In the 4-hour experiment, no significant difference was observed in the profile of the resting tension. In the 5-hour experiment, the resting tension was significantly lower in the FR168888-treated group than in the control group (Fig 5). There was a significant difference in the percentages of the recovery of LV systolic pressure after 4 hours of ischemia between the control and the FR168888-treated groups (72.2% ± 4.3% and 98.1% ± 4.0%, respectively; p < 0.01). However, the difference was more prominent in the 5-hour experiment (38.4% ± 2.5% and 74.7% ± 5.4%, respectively; p < 0.001) (see Fig 4B). FR168888 also improved the percentage of the recovery of coronary flow by 16.3% after 4 hours and by 12.9% after 5 hours of ischemia and decreased the incidence of ventricular fibrillation (3/5 versus 0/5 in the 4-hour groups and 3/5 versus 1/5 in the 5-hour groups).

View larger version (20K): [in this window] [in a new window]   Fig 5. . The change in the resting tension during early reperfusion after hypothermic arrest for 5 hours. The resting tension started to increase and peaked at about 10 seconds. After this it remained at this level in the control group and decreased in the FR168888-treated group (FR). (*p < 0.05.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
The present study showed that Na⁺/H⁺ exchange occurs even under hypothermic conditions and can be inhibited by FR168888, a newly synthesized inhibitor of Na⁺/H⁺ exchange [12]. This inhibition of Na⁺/H⁺ exchange with FR168888 improved the postischemic functional recovery in isolated rat heart after both normothermic and prolonged hypothermic cardioplegic arrest.

It has been established that reperfusion injury caused by Na⁺ overload resulting from Na⁺/H⁺ exchange occurs after normothermic ischemia in the very early stage of reperfusion [6, 13] and can be inhibited by suppressing this exchanger [4, 7, 9]. However, it is still unclear whether Na⁺/H⁺ exchange plays an important role during reperfusion after hypothermic ischemia in which the myocardial temperature is not fully restored. The study in which Na⁺/H⁺ exchange was assessed in lymphocytes showed that Na⁺/H⁺ exchange is still considerably functional, even at low temperatures, which implies that inhibition of the Na⁺/H⁺ exchanger protects against myocardial reperfusion injury, even at low temperatures.

In the isolated rat heart perfusion study, the inhibition of Na⁺/H⁺ exchange did not change the development of ischemic contracture in either the normothermic or the hypothermic experiment. In the early stage of reperfusion, the LV static pressure increased as the consequence of the change in the intracellular Ca²⁺ concentration, which may be affected by the intracellular pH and Na⁺ activity. After normothermic ischemia, the inhibition of Na⁺/H⁺ exchange with FR168888 did not cause the peak amplitude or the exponential time constant of the decay in the LV static pressure to be altered during early reperfusion but did cause the asymptotic pressure to be changed. This parallel and downward shift of the LV static pressure indicates that FR168888 may cause a decrease in the intracellular Ca²⁺ activity but does not affect the speed of the Ca²⁺-extruding mechanism, such as Na⁺/Ca²⁺ exchange or Ca²⁺ sequestration by sarcoplasmic reticulum [14–17]. This is compatible with the conventional concept that the inhibition of Na⁺/H⁺ exchange shows its beneficial effect mainly in the early stage of reperfusion [18]. The improvement in functional recovery coincided well with the tissue drug concentration during the early reperfusion phase. In the hypothermic experiments, the better functional recovery and the downward shift in the profile of the resting tension in the early stage of reperfusion were observed in the FR168888-treated group in the 5-hour experiment, indicating that FR168888 may cause the reperfusion injury to be reduced, even in the setting of low myocardial temperature. In the 4-hour experiment the downward shift of the resting tension during early reperfusion was not observed in the FR168888-treated group, whereas the postischemic functional recovery was significantly greater in the FR168888-treated group than in the control group. It can be assumed that the beneficial effect of the inhibition of Na⁺/H⁺ exchange on the change in the resting tension appears only when ischemia-reperfusion injury is severe.

The protective effect of FR168888 became prominent when the ischemic insult was severe as the result of prolonged arrest, indicating that the Na⁺/H⁺ exchanger may play an important role in the pathogenesis of severe myocardial ischemia-reperfusion injury. It is possible that the severe intracellular acidification induced during extended ischemia causes the Na⁺ overload occurring as the result of Na⁺/H⁺ exchange to be exaggerated, and hence Ca²⁺ overload in myocytes. A better functional recovery was associated with a lower incidence of ventricular fibrillation after hypothermic arrest, which is consistent with reports that various inhibitors of Na⁺/H⁺ exchange protect myocardium against reperfusion-induced arrhythmia after normothermic ischemia [19].

In cardiac surgical procedures, hypothermic, multidose cardioplegic infusion is widely employed to obtain a better oxygen supply and washout of the metabolites. However, such multidose cardioplegia necessitates multitime reperfusion [20, 21] to alter the pH gradient between the inside and outside of the cells and at the same time causes ions to move through the Na⁺/H⁺ exchanger during every infusion. It has also been reported that multidose cardioplegia is harmful to neonatal myocardium because of the Na⁺/H⁺ exchange-related mechanism triggered [22, 23]. Therefore a single-dose cardioplegic infusion was employed in this series of experiment to enable the simple interpretation of the data.

Although the present study has its limitations because of its experimental nature, the results did show the importance of inhibiting Na⁺/H⁺ exchange after hypothermic ischemia, which implies the possibility of its future use in cardiovascular surgical procedures.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
We thank the Fujisawa Pharmaceutical Company for the supply of FR168888.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 
Address reprint requests to Dr Ichikawa, Pediatric Cardiovascular Surgery, Michigan Congenital Heart Center, F7830 Mott Children's Hospital, 1500 East Medical Center Dr, Ann Arbor, MI 48105-0223.

	References

Top Footnotes Abstract Introduction Material and Methods Isolated Rat Heart Preparation Experimental Protocol Tissue Drug Concentration Humane Animal Care Data Analysis Results Isolated Rat Heart Experiment Comment Acknowledgments References

 

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This Article Abstract 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): Hajime Ichikawa Norihide Fukushima Hikaru Matsuda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamauchi, T. Articles by Shirakura, R. Search for Related Content PubMed PubMed Citation Articles by Yamauchi, T. Articles by Shirakura, R.