Eur J Cardiothorac Surg 2002;22:944-950
© 2002 Elsevier Science NL
The role of Na+/H+ exchange in the efficacy of multidose hypothermic cardioplegia in immature rabbit hearts
Toshifumi Murashita*,
Keishu Yasuda
Department of Cardiovascular Surgery, Hokkaido University School of Medicine, Kita-14, Nishi-5, Kita-ku, Sapporo 060-8648, Japan
Received 11 February 2002;
received in revised form 25 July 2002;
accepted 4 September 2002.
* Corresponding author. Tel.: +81-11-716-1161; fax: +81-11-747-0476
e-mail: muratosh{at}med.hokudai.ac.jp
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Abstract
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Objectives: Recent studies have demonstrated that the use of a Na+/H+ exchange inhibitor as an additive can enhance the cardioprotective efficacy of cardioplegia in the adult heart under both normothermic and hypothermic conditions. However, few references are available as to the cardioprotective effect of acidic cardioplegia or Na+/H+ exchange inhibitors in the neonatal heart, particularly under hypothermic conditions. Methods and results: In isolated working hearts from rabbits aged 7–10 days, function was assessed prior to 10 h of ischemia (20 °C) and again after 35 min of reperfusion. All hearts received a pre-ischemic infusion (10 ml) of cardioplegic solution (20 °C) at pH 7.8, followed by nine subsequent infusions (5 ml every 1 h) of cardioplegic solution (20 °C) at pH 6.6, 7.0, 7.4, 7.8 (control) or 8.2 (n=8/group). When the pH was increased to 8.2, post-ischemic recovery of cardiac output was reduced and cumulative creatine kinase (CK) leakage during cardioplegic infusions was increased. In contrast, when the pH of the cardioplegic solution was lowered to 6.6, the post-ischemic recovery of cardiac output was maintained and CK leakage was reduced. Next, the effects of 5-(N,N-dimethyl)amiloride (DMA), an inhibitor of Na+/H+ exchange, were investigated. The inclusion of DMA in the pH 8.2 solution improved the post-ischemic recovery of cardiac output from 12.6±4.1% to 52.0±3.0% (P<0.0001) and reduced cumulative CK leakage during cardioplegic infusions from 38.0±4.0 to 26.1±3.7 IU/45 ml/g dry weight (P=0.044). In contrast, the inclusion of DMA in the pH 6.6 solution provided no added benefit. (Data are expressed as the mean±SEM.) Conclusions: These results suggest that the lesser efficacy of multidose hypothermic cardioplegia in the neonatal rabbit heart may depend on the pH of the cardioplegic solution and is likely to arise, at least in part, from activation of the Na+/H+ exchanger.
Key Words: Multidose cardioplegia • Hypothermia • pH • Na+/H+ exchange • Immature heart
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1. Introduction
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In the past decade, considerable experimental evidence has accumulated to suggest that the use of Na+/H+ exchange inhibitors either as an adjunct or as an additive can significantly enhance the cardioprotective efficacy of cardioplegia in hearts subjected to global ischemia both under normothermic [1–3] and hypothermic [4–7] conditions. However, almost all the studies investigated adult animal hearts, and few references are available as to the cardioprotective effect of Na+/H+ exchange inhibitors against ischemia and reperfusion-induced injury in the neonatal heart [8]. From a clinical perspective, it is important to characterize the protective properties of these agents under both normothermic and hypothermic conditions, since these agents could be of value in warm heart surgery, hypothermic cardioplegic arrest and long-term heart preservation.
In current clinical practice, in contrast to adult cardiac surgery, where warm heart surgery is generally accepted, hypothermic cardioplegic arrest is normally used to protect the myocardium during aortic clamping in neonatal and infant cardiac surgery. However, multidose hypothermic cardioplegia was reported to be less effective in neonatal rabbit hearts [9,10] and its lower efficacy may depend on the frequency of infusions. These findings led us to hypothesize that, in this neonatal heart preparation, multidose cardioplegia may result in cumulative reperfusion injury during the repeated infusions, through Na+/H+ exchange-mediated mechanisms. Therefore, the current study was designed to test this hypothesis by changing the pH of the cardioplegic solution or using a Na+/H+ exchange inhibitor to modify Na+/H+ exchanger activity during multiple cardioplegic infusions under hypothermia.
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2. Materials and methods
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2.1. Experimental preparation
Hearts (approximately 600 mg) were taken from male and female neonatal New Zealand White rabbits, aged 7–10 days. All animals received care in compliance with the ‘Guide for the Care and Use of Laboratory Animals’ prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication No. 85-23, revised 1985).
Animals were anesthetized with sodium pentobarbital (60 mg/kg given intraperitoneally) and were then heparinized (100 units intravenously). The heart was rapidly excised and the aorta was cannulated. The isolated working heart preparation used in this study has been described in detail elsewhere [10]. All hearts were perfused with modified Krebs–Henseleit buffer of the following composition (in mmol/l): NaCl 118.5, NaHCO3 25.0, KCl 4.8, CaCl2 1.8, MgSO4 1.2, KH2PO4 1.2, and glucose 11.0. The buffer was continuously gassed with 95% oxygen+5% carbon dioxide (pH 7.4 at 37.0 °C). All hearts were perfused and maintained in a thermostatically controlled chamber at 37.0 °C during aerobic perfusion or at 20 °C during ischemia.
2.2. Experimental time course
The experimental time course is illustrated in Fig. 1
. Immediately after cannulation of the aorta, Langendorff perfusion was initiated for a 5 min period during which time the left atrium was cannulated. The heart was then aerobically perfused in the working mode for 20 min during which time control values for aortic flow, coronary flow (timed collection of pulmonary artery effluent) and heart rate were recorded. Cardiac output was calculated as the sum of aortic and coronary flow. The aortic and atrial lines were then clamped and the heart was transferred to a storage chamber maintained at 20 °C. The standard cardioplegic solution at pH 7.8 (see Section 2.3) was then infused into the coronary vasculature through a side arm of the aortic cannula (C1, Fig. 1). The cardioplegic solution was maintained at 20 °C, the same temperature as the storage chamber, and 10 ml was infused into each heart at a pressure equivalent to 55 cmH2O. The duration of cardioplegic infusion was measured so that coronary vascular resistance (CVR) could be calculated (see Section 2.4). The infusion line was then clamped and global ischemia was maintained at 20 °C for 10 h. Subsequent infusions (C2–C10, Fig. 1) of required cardioplegic solution (see Section 2.3) were carried out every 1 h at a pressure equivalent to 55 cmH2O. The volume of the cardioplegic solution infused during C2–C10 was kept constant at 5 ml and the duration of each infusion was again measured to evaluate changes in CVR. During each cardioplegic infusion the coronary effluent was collected (total volume 45 ml) and stored at 4 °C until the determination of creatine kinase (CK) activity. Following 10 h of hypothermic ischemia, the hearts were reperfused at 37 °C for 15 min in the non-recirculating Langendorff mode, during which time the coronary effluent was again collected for the determination of CK activity. The total volumes of coronary effluents collected during this Langendorff reperfusion period were recorded, as an indicator of post-ischemic CVR. Hearts were then converted back to the working mode for 20 min during which time the recovery of cardiac function was reassessed.
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Fig. 1. Experiment protocol. Isolated neonatal rabbit hearts were perfused for 5 min in the Langendorff mode before a 20 min control working period. Hearts were then rendered globally ischemic (20 °C) for 10 h with a preceding cardioplegic infusion (C1, 10 ml at pH 7.8) in all groups studied. The subsequent infusions (C2–C10) of the required cardioplegic solution (see Section 2.3) were carried out every 1 h with the volume of each infusion kept constant at 5 ml. Following ischemia, the hearts were reperfused at 37 °C for 15 min in the non-recirculating Langendorff mode before conversion to the working mode and assessment of recovery of function.
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2.3. Protocols
2.3.1. The effect of altering the pH of the cardioplegic solution
Modified St. Thomas' Hospital cardioplegic solution, which was buffered by 5 mmol/l HEPES instead of bicarbonate, was used (composition in mmol/l: NaCl 110.0, KCl 16.0, MgCl2 16.0, CaCl2 1.2, and HEPES 5.0). The pH was adjusted to 6.6, 7.0, 7.4, 7.8 or 8.2 at 20 °C, by addition of NaOH. The concentration of Na+ was kept constant at 120 mmol/l in each solution by adjusting the NaCl content. During the first infusion (C1, Fig. 1), all hearts received the standard cardioplegic solution at pH 7.8; during the subsequent nine infusions (C2–C10, Fig. 1) hearts in different groups received the cardioplegic solution at pH 6.6, 7.0, 7.4, 7.8 (control) or 8.2.
2.3.2. The effect of 5-(N,N-dimethyl)amiloride
To investigate the possible involvement of altered Na+/H+ exchange activity in the markedly contrasting effects of acidic (pH 6.6) and alkaline (pH 8.2) cardioplegic solutions in the neonatal rabbit heart, 5-(N,N-dimethyl)amiloride (DMA), an inhibitor of Na+/H+ exchange, was added to these solutions. As before, in the first infusion (C1, Fig. 1) all hearts received the pH 7.8 cardioplegic solution without DMA; however, during the subsequent nine infusions (C2–C10, Fig. 1), hearts received the cardioplegic solution at pH 6.6 or pH 8.2, both containing 10 µmol/l of DMA. The post-ischemic recovery of cardiac output and other indices of injury were compared in hearts that received pH 6.6 or pH 8.2 cardioplegic solution, in the presence vs. the absence of DMA.
2.4. Expression of results and statistical analysis
All data are expressed as the mean±the standard error of the mean. Post-ischemic recovery of the various indices of cardiac function is expressed as a percentage of the pre-ischemic control value. Reperfusate volume and myocardial CK leakage during Langendorff reperfusion are expressed relative to heart weight, in units of ml/15 min/g dry weight and IU/15 min/g dry weight, respectively. To evaluate myocardial damage during repeated cardioplegic infusions, cumulative CK leakage during infusions C2–C10 (see Fig. 1) was determined and expressed as IU/45 ml/g dry weight. CVR during each cardioplegic infusion was calculated from the following equation: CVR=PP/CF (where CVR is coronary vascular resistance (cmH2O/ml/min/g dry weight), PP is perfusion pressure (50 cmH2O), and CF is coronary flow (ml/min/g dry weight)). CVR during cardioplegic infusions C2–C10 is expressed relative to that measured during the first cardioplegic infusion (C1). Hearts were allocated to various study groups using a randomization table for each protocol. Data were analyzed using StatView for Macintosh, version 5.01 (SAS Institute, Cary, NC). In the study of altering the pH of cardioplegic solution, one-way ANOVA was used for statistical comparison, while, in the study of DMA, two-way ANOVA was used. Results of CVR in both studies were compared by ANOVA for repeated measurements. When significant F values were detected, multiple comparisons were made by the Bonferroni–Dunn test. Statistical significance was accepted at the P<0.05 level.
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3. Results
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The pre-ischemic control values and the post-ischemic recoveries for aortic flow, coronary flow, cardiac output and heart rate are shown in Table 1. Pre-ischemic cardiac function was comparable in the groups studied, with no statistically significant difference between the groups for any of the functional indices. CVR during the first cardioplegic infusion (C1), during which all hearts received cardioplegic solution at pH 7.8, was also similar in all groups (range 317±13 to 366±16 cmH2O/ml/min/g dry weight).
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Table 1. Pre-ischemic (basal) cardiac function and post-ischemic recovery for various indices of cardiac functiona
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3.1. The effect of altering the pH of cardioplegic solution
3.1.1. Functional recovery and CK leakage during reperfusion
As shown in Fig. 2
, increasing the pH of the cardioplegic solution infused during C2–C10 from 7.8 to 8.2 resulted in depressed post-ischemic recovery of cardiac output (P<0.0001). Decreasing the pH of the cardioplegic solution to 7.4, 7.0 or 6.6 did not alter post-ischemic functional recovery significantly. As shown in Table 1, the use of pH 8.2 cardioplegic solution also significantly depressed the post-ischemic recoveries for aortic flow and coronary flow, whereas these were not affected significantly by reducing the pH of the solution to 7.4 or lower. The administration of pH 8.2 cardioplegic solution during infusions C2–C10 also decreased the volume of the reperfusate compared to the pH 7.8 group, indicative of increased post-ischemic CVR (Table 2).
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Fig. 2. Post-ischemic recovery of cardiac output in hearts that received cardioplegic solution (20 °C) at pH 6.6, 7.0, 7.4, 7.8 or 8.2 during infusions C2–C10 (see Fig. 1). All data are expressed as the mean±SEM (n=8/group). *P<0.0001 vs. pH 7.8 group.
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3.1.2. CK leakage and CVR during repeated cardioplegic infusions
To evaluate myocardial damage during the repeated cardioplegic infusions (C2–C10), cumulative CK leakage during these infusions was measured. The results are shown in Fig. 3
. Increasing the pH of the cardioplegic solution resulted in increased CK leakage during the repeated infusions. In contrast, reducing the pH of cardioplegic solution tended to decrease CK leakage during the repeated infusions (Fig. 3), with a significant reduction observed at pH 6.6 (P=0.015) and pH 7.0 (P=0.037). The detrimental effect of increasing the pH of the cardioplegic solution was also reflected by increased CVR during the cardioplegic infusions. As shown in Fig. 4
, CVR increased progressively during consecutive infusions in all groups; however, increasing the pH of the cardioplegic solution to pH 8.2 accelerated the rate of this increase in CVR, while decreasing the pH to 6.6 decelerated it. As a consequence, during the tenth cardioplegic infusion (C10), CVR had increased to 491±57% of that during the initial infusion (C1) in the pH 8.2 group, which was significantly greater than the increase observed in the pH 7.8 (control) group (278±31%). In contrast, in the pH 6.6 group the increase in CVR measured only 176±4%, which was not significantly different compared to the increase in the pH 7.8 group.
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Fig. 3. Cumulative CK leakage in the coronary effluent collected during cardioplegic infusions C2–C10 (see Fig. 1) in hearts that received cardioplegic solution (20 °C) at pH 6.6, 7.0, 7.4, 7.8 or 8.2 during these infusions. All data are expressed as the mean±SEM (n=8/group). *P<0.05, **P=0.01 vs. pH 7.8 group.
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Fig. 4. Changes in CVR during cardioplegic infusions C2–C10 (see Fig. 1) in hearts that received cardioplegic solution (20 °C) at pH 6.6, 7.0, 7.4, 7.8 or 8.2 during these infusions. CVR is expressed as a percentage of that obtained during the first cardioplegic infusion (C1). Note that during C1 all hearts received standard cardioplegic solution at pH 7.8. All data are expressed as the mean±SEM (n=8/group). *P<0.0001 vs. pH 7.8 group.
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3.2. The effect of DMA
As shown in Fig. 5
, the inclusion of DMA in the pH 8.2 solution significantly improved the post-ischemic recovery (P<0.0001), and significantly reduced CK leakage during the repeated infusions (P=0.044). In contrast, the inclusion of DMA in the pH 6.6 solution provided no added benefit. Consistent with these findings, in the presence of DMA, the marked differences that were observed in the post-ischemic recoveries of aortic flow and coronary flow between the pH 6.6 and pH 8.2 groups were also attenuated (Table 1).
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Fig. 5. (A) Post-ischemic recovery of cardiac output and (B) cumulative CK leakage in the coronary effluent collected during the repeated infusions (C2–C10) in hearts that received cardioplegic solution without (open columns) or with (closed columns) DMA (10 µmol/l). All data are expressed as the mean±SEM (n=8/group). *P<0.05, **P<0.01, ***P<0.0001 between indicated groups.
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Although DMA tended to reduce the progressive increase in CVR that was induced during repeated infusions of the pH 8.2 cardioplegic solution (Fig. 6)
, this does not reach statistical significance. However, reperfusate volume was significantly increased (P<0.0001) when DMA was included in the pH 8.2 solution (Table 2), suggesting the reduced CVR in the presence of DMA.
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Fig. 6. Changes in CVR during the repeated infusions (C2–C10) in hearts that received cardioplegic solution at pH 6.6 or pH 8.2 containing DMA (10 µmol/l) during these infusions. CVR is expressed as a percentage of that obtained during the first cardioplegic infusion (C1). Note that during C1 all hearts received standard cardioplegic solution at pH 7.8. All data are expressed as the mean±SEM (n=8/group). No statistical significance was detected by ANOVA for repeated measurements.
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4. Discussion
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4.1. Different responses to multidose cardioplegia in immature hearts
The cellular effects of warm cardioplegia may differ greatly from those of cold cardioplegia and the cellular effects of the first cardioplegic infusion may differ from those of subsequent infusions. The roles of the initial infusion in both warm and cold cardioplegia are the induction of rapid diastolic arrest and the subsequent conservation of the energy state. Under normothermia the major beneficial effects of subsequent cardioplegic infusions is the maintenance of arrest, the washout of accumulated toxic intermediates, and the resupply of components such as oxygen and substrates. In contrast, with hypothermic cardioplegia, the hypothermia itself would maintain arrest and slow the cellular metabolism, thus limiting the beneficial effects of cardioplegic reinfusions. On the other hand, hypothermic reinfusion of cardioplegic solution would continue to supply potentially detrimental components. This scenario, however, would also apply to the adult heart which, unlike the neonatal heart, responds well to multidose hypothermic cardioplegia. Thus, it appears that the balance of beneficial vs. detrimental effects of repeated cardioplegic infusions may be altered unfavorably in the neonate.
4.2. Possible underlying mechanisms
In the past decade, considerable experimental evidence has accumulated to indicate that activation of sarcolemmal Na+/H+ exchange is an important factor in the development of myocardial injury during ischemia and reperfusion [11–13]. Thus, intracellular acidosis (H+ excess) during ischemia leads to activation of the Na+/H+ exchanger with the subsequent Na+ burden giving rise to Ca2+ influx through Na+/Ca2+ overload. Blocking Na+/H+ exchange reduces the intracellular Na+ and Ca2+ load after ischemia and hence improves functional recovery. Because the transsarcolemmal H+ gradient serves as a strong stimulator of Na+/H+ exchange, acidic reperfusion may result in less stimulation of Na+/H+ exchange during the early stage of reperfusion, leading to less sodium entry and, subsequently, less Ca overload. In the present studies using the various pH solutions, cardioplegic solutions below pH 7.8 provided better post-ischemic functional recovery than pH 8.2 solution, while cumulative CK leakage and CVR during repeated infusions were increased when the pH of the cardioplegic solution was increased. These results indicated that increasing pH in the repeated cardioplegic infusions exacerbated myocardial damage and at some point, pH 8.2 in this study protocol, the post-ischemic recovery was significantly impaired. In the presence of DMA, the difference between the pH 6.6 and pH 8.2 groups in post-ischemic recovery of cardiac output was abolished while that in CK leakage during the repeated infusions was much reduced. These results suggested that a Na+/H+-mediated mechanism was involved, at least in part, in the lower efficacy of hypothermic multidose cardioplegia in neonates. Since the neonatal heart has a greater capacity for anaerobic glycosis than the adult heart [14], which leads to greater accumulation of protons and lactate during ischemia, even under hypothermic condition [15], the greater acidosis during ischemia could accelerate Na+/H+ exchange during repeated infusions. In addition, Meno et al. [16] reported that Na+/H+ exchanger activity was higher in the neonatal rabbit heart than in the adult rabbit heart, and recently Chen et al. [17] reported that the Na+/H+ exchanger-1 mRNA level in the newborn rabbit heart was greater than in the adult heart. These findings would suggest that multidose hypothermic cardioplegia may be less protective for neonatal hearts, whereas for adult hearts multidose hypothermic cardioplegia remains highly efficacious.
Other possible mechanisms include a salutary effect of intracellular acidosis on preserving high-energy phosphate nucleotides due to inhibition of 5'-nucleotidase. Thus, resynthesis of ATP during the first few minutes of reperfusion occurs only by rephosphorylation of the remaining pool of cytosolic adenine nucleotides, mainly AMP. Therefore, preservation of the adenosine nucleotide pool, especially the AMP pool, during ischemic episodes is essential for maintaining cell function and viability, and the inhibition of 5'-nucleotidase activity by H+ determines the size of the AMP pool and hence the capacity for ATP resynthesis in the intact heart [18,19]. The greater tolerance of the neonate vs. mature myocardium to ischemia-reperfusion injury has been attributed to a lower concentration of 5'-nucleotidase [20] and presumably lower capacity to hydrolyze AMP. Grosso et al. [20] indicated that 5'-nucleotidase activity was lower in the neonatal than in adult rabbit myocardium and Lofland's human nucleotide data [21] suggested a relative deficiency of 5'-nucleotidase during the neonatal period. Therefore, the inhibition of 5'-nucleotidase activity by H+ (acidic reperfusion) may be less effective in neonatal than in adult myocardium. Hence multidose cardioplegia with acidic solution may supply potentially detrimental components such as sodium, calcium and water, promoting cellular injury and edema.
4.3. Clinical implications and limitations of this study
In contrast to adult cardiac surgery where warm heart surgery is generally accepted, hypothermic cardioplegic arrest is normally used to protect the myocardium during aortic clamping in pediatric cardiac surgery. In addition, multidose cardioplegia is universally used in neonatal cardiac surgery. Therefore, in the present study, the role of the pH of the cardioplegic solution and the efficacy of a Na+/H+ exchange inhibitor were tested using multidose cardioplegia under hypothermia. The results in the present study showed that increasing the pH of cardioplegic solution seemed to be detrimental in terms of cumulative CK leakage and CVR during repeated cardioplegic infusions, but post-ischemic cardiac function was comparable when the pH of the cardioplegic solution was controlled between 7.8 and 6.6. These findings would suggest that an acidic solution is safer than an alkaline solution for the neonatal heart when multidose hypothermic cardioplegia is used. Considering the greater activity of Na+/H+ exchange in neonates than in adults, manipulation of Na+/H+ exchange may be an important strategy to attenuate ischemia-reperfusion injury in the neonatal heart.
The present study has limitations because of its experimental model, as our preparation was asanguineous and used isolated rabbit hearts obtained from healthy animals. The neonatal rabbit hearts are exceptionally resistant to ischemia and therefore hearts had to be subjected to long periods (10 h) of ischemia. Such times are not normally encountered clinically. The role of Na+/H+ exchange in blood cardioplegia or blood perfusion may greatly differ because of not only the pH of the blood but also because of the much greater buffering capacity of blood. In addition to cardiac cells, an additional salutary effect of Na+/H+ exchange inhibition may also involve attenuation of activation of both platelets and neutrophils [22], which are important mediators of cardiac injury. Furthermore, some studies [23] have reported that cardiac hypertrophy activates Na+/H+ exchange and gene expression, suggesting that the role of Na+/H+ exchange in the normal cardiovascular systems may differ from that in the diseased state. Indeed, disease states such as ventricular hypertrophy and cyanosis, observed with many congenital heart defects, might also alter the response of the immature heart to multidose hypothermic cardioplegia. Clearly, the potential efficacy of Na+/H+ exchange inhibitors during neonatal cardiac surgery warrants further investigation.
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Acknowledgments
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We gratefully acknowledge the help of Professors D.J. Hearse (The Rayne Institute, St. Thomas' Hospital London) and Metin Avkiran (Centre for Cardiovascular Biology and Medicine, King's College London) for their suggestions and critical review of the manuscript.
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References
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Abstract
1. Introduction
