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Ann Thorac Surg 1996;61:1400-1406
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Improved Cardiac Function After Prolonged Hypothermic Ischemia With the Na⁺/H⁺ Exchange Inhibitor HOE 694

Departments of Cardiovascular Surgery and Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada

Accepted for publication January 23, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Na⁺/H⁺ exchange represents an important mechanism for pH regulation in the cardiac cell that, however, may paradoxically mediate tissue damage in the reperfused myocardium. We investigated whether inhibition of the exchanger can protect the heart against damage after prolonged hypothermic storage with the use of the selective inhibitor 3-methylsulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694).

Methods. After equilibration, isolated rabbit hearts were arrested with a 3 minute infusion of modified St. Thomas' cardioplegic solution and subsequently maintained in ischemic arrest at 4°C for 12 hours before reperfusion at 37°C for 60 minutes. Left ventricular function and creatine kinase release were measured at intervals throughout reperfusion. High-energy phosphate and adenine nucleotide content were determined in hearts before cardioplegia, at the end of the 12-hour storage period, and at the end of reperfusion. HOE 694 (1 µmol/L) was administered either with cardioplegia and throughout reperfusion (study 1) or selectively with either cardioplegia or reperfusion only (study 2).

Results. In study 1, systolic function in untreated hearts recovered to less than 40% of preischemic values and was associated with a greater than 1,000% percent sustained elevation in left ventricular end-diastolic pressure. In contrast, systolic recovery in HOE 694-treated hearts was significantly accelerated and improved to approximately 80%, whereas left ventricular end-diastolic pressure increased to only 300% of baseline. Significant protection also occurred in those hearts in which HOE 694 was administered only at reperfusion while the drug was less effective if given only during cardioplegia. Creatine kinase release was not significantly affected except in study 2, where it was significantly lower after 60 minutes of reperfusion in hearts where HOE 694 was added at the time of reperfusion. Tissue metabolite content was not affected by drug treatment.

Conclusions. This study shows a marked protective effect of the Na⁺/H⁺ exchange inhibitor HOE 694 in rabbit hearts subjected to 12 hours of hypothermic ischemia and strongly suggests that antiport inhibitors could play an effective role in myocardial preservation.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The myocardial Na⁺/H⁺ exchanger represents a major mechanism for intracellular pH regulation after an acid load by virtue of its ability to extrude H⁺ in exchange for Na⁺ [1, 2]. Although at least five NHE isoforms exist, the sole cardiac isoform thus far identified is NHE-1, a glycoprotein of molecular mass approximately 110 kD, which can be inhibited by amiloride or its derivatives as well as by a number of nonamiloride compounds such as HOE 694. This agent purportedly exhibits greater selectivity and specificity in inhibiting Na⁺/H⁺ exchange than do amiloride and its analogues [3]. Although the Na⁺/H⁺ exchanger can be activated through various mechanisms including phosphorylation processes, the major activation mechanism is the development of a transmembrane H⁺ gradient as occurs with intracellular acidosis. Although H⁺ extrusion and maintenance of intracellular pH homeostasis are critical for cell survival under acidotic conditions as may occur during ischemia, marked activation of Na⁺/H⁺ exchange with reperfusion can contribute to tissue injury because of the sudden large influx of Na. This then results in increased intracellular Ca²⁺ content because of reduced calcium efflux through the Na⁺/Ca²⁺ exchanger [4, 5]. The possible detrimental effect of increased Na⁺/H⁺ exchange to the reperfused myocardium has now been convincingly demonstrated in numerous studies in which inhibition of Na⁺/H⁺ exchange has been shown to exert marked protection against reperfusion injury in terms of improved functional recovery, attenuation of arrhythmias and preservation of cellular ultrastructure [reviewed in reference 5]. Conversely, agents that activate Na⁺/H⁺ exchange, such as the peptide endothelin-1 or ₁ adrenoceptor agonists, can increase cardiac injury through Na⁺/H⁺ exchange-dependent mechanisms [6, 7].

In view of the extensive evidence supporting an important role for Na⁺/H⁺ exchange activation in myocardial reperfusion injury, it is hypothesized that Na⁺/H⁺ exchange inhibition may be potentially of importance in myocardial preservation strategies used in cardiac transplantation. Accordingly, we investigated the effects of HOE 694 with respect to its ability to influence function of rabbit hearts after reperfusion after 12 hours of hypothermic (4°C) storage. We report a marked ability of HOE 694 to improve contractile recovery that was dependent on its presence during the reperfusion period irrespective of pretreatment before hypothermic storage.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Animals
Studies were carried out in male New Zealand rabbits weighing 2.0 to 2.5 kg. The rabbits were housed in the animal care facility at Victoria Hospital with free access to food and water and received humane care in compliance with the guidelines of the Canadian Council on Animal Care and the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Isolated Heart Preparation
Rabbits were anticoagulated with 500 units of heparin and anesthetized with sodium pentobarbitone (50 mg/kg) administered through the marginal ear vein. After median sternotomy, the hearts were rapidly excised, mounted on a nonrecirculating Langendorff apparatus, and perfused with oxygenated (95% O₂–5% CO₂) Krebs-Henseleit solution (composition in mmol/L: NaCl, 118.3; KCl, 4.7; KH₂PO₄, 1.2; CaCl₂, 2.5; NaHCO₃, 25.0; MgSO₄, 1.2; glucose, 10.0) at 37°C at a constant flow rate of 30 mL/min. Pacing electrodes were inserted in the right ventricle and pacing commenced with a Medtronic (Minneapolis, MN) pulse generator to maintain a heart rate of 180 beats/minute. Perfusion pressure, which reflects coronary vascular resistance in this constant flow model, was monitored through a branch of the aortic cannula by means of a fluid-filled catheter connected to a pressure transducer. Left ventricular function was assessed by means of a latex balloon inserted through the mitral valve into the left ventricle. Distilled water was injected into the balloon to achieve a left ventricular end-diastolic pressure of 5 mm Hg and this was subsequently left unadjusted for the duration of the protocol. The rates of left ventricular pressure development (+dP/dt) and relaxation (-dP/dt) were determined electronically with a differentiator amplifier.

Experimental Protocol
Two studies were carried out to more clearly characterize the potential protective effect of HOE 694. There were two randomized groups in study 1: control and HOE 694 added to both the cardioplegia solution and to the reperfusate. Study 2 consisted of three randomized groups: control, HOE 694 in the cardioplegic solution only, and HOE 694 in the reperfusate only. Three hearts in the study 2 control group fibrillated throughout reperfusion and these hearts were not included in the analysis. Each study group consisted of six hearts. HOE 694 was dissolved in room temperature distilled water and added to the cardioplegic solution or reperfusate, or both, for a final concentration of 1 µmol/L. This concentration was based on a previous report showing that it exerted maximal beneficial effect in a rabbit heart normothermic ischemia/reperfusion model [8]. HOE 694 was a generous gift from Dr Wolfgang Scholz of Hoeschst AG, Frankfurt/Main, Germany.

After a 35-minute equilibration period, baseline hemodynamic readings were obtained. The hearts were then arrested with a 3-minute infusion of modified St. Thomas' cardioplegic solution (composition in mmol/L: NaCl, 91.6; KCl, 25.0; KH₂PO₄, 1.2; NaHCO₃, 25.0; CaCl₂, 0.6; MgSO₄, 1.2; MgCl₂, 15.0; glucose, 11.0) delivered at 4°C at an infusion rate of 30 mL/min for 3 minutes. Pacing was discontinued at the onset of cardioplegia administration. Hearts were then maintained in ischemic arrest immersed in cardioplegic solution at 4°C for 12 hours. Initial reperfusion after ischemia was at 37°C at 15 mL/min for the initial 2 minutes before increasing to the preischemic rate of 30 mL/min. Pacing was commenced after the first 4 minutes of reperfusion. Hemodynamic data were obtained every 5 minutes for 1 hour.

Creatine Kinase Levels
Samples of coronary effluent were obtained before ischemia and at 1, 5, 20, and 60 minutes of reperfusion for determination of creatine kinase (CK) levels. Samples were assayed immediately spectrophotometrically according to the procedure described by Rosalki [9] using commercially available kits (catalog no. 45-5; Sigma, St. Louis, MO).

High-Energy Phosphate and Adenine Nucleotide Levels
At the end of the reperfusion period, all hearts in each study group were clamped while on the cannula using Wollenberger tongs precooled in liquid nitrogen. A separate group perfused for the equilibration period but not subjected to hypothermic storage (n = 5) was analyzed to determine baseline levels. Two additional groups of hearts underwent hypothermic storage but were freeze-clamped without reperfusion: one group served as a control (n = 5) and the other received HOE 694 in the cardioplegia (n = 4). Hearts were stored in liquid nitrogen for subsequent assay of high-energy phosphates and adenine nucleotides. Hearts were homogenized and metabolite levels in 6% perchloric acid extracts were determined spectrophotometrically according to Bergmeyer [10]. Adenosine triphosphate (ATP) and creatine phosphate contents were determined by measuring changes in extinction at 340 nm, indicative of an increase in reduced nicotinamide adenine dinucleotide phosphate formation after addition of hexokinase and CK, respectively. Adenosine diphosphate and adenosine monophosphate contents were assessed by monitoring reduction in reduced nicotinamide adenine dinucleotide after the addition of pyruvate kinase and myokinase, respectively. All chemicals used for the metabolite determination were purchases from Sigma.

Statistical Analysis
All values are expressed as mean ± standard error. Data were analyzed using analysis of variance with a post-hoc Student's-Newman-Keuls test where applicable. Differences were considered significant at p less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
As shown in Table 1, there were no significant differences between the control and drug treatment groups in the two studies with respect to baseline hemodynamic function after the initial 35-minute equilibration period.

View larger version (34K): [in this window] [in a new window]   Fig 1. . Study 1. Recovery of left ventricular developed pressure and end-diastolic pressure (as a percentage of baseline value) during 60 minutes of reperfusion after 60 minutes of hypothermic ischemic arrest in the control group (black circles) or with HOE 694 (1 µmol/L) (white circles) present in cardioplegia as well as throughout reperfusion. Each point represents mean ± standard error (n = 6). (*p < 0.05 between groups.)

View larger version (30K): [in this window] [in a new window]   Fig 2. . Study 1. Recovery of rates of left ventricular pressure development (+dP/dt) and relaxation (-dP/dt) (as a percentage of baseline value) during 60 minutes of reperfusion after 60 minutes of hypothermic ischemic arrest in the control group (black circles) or with HOE 694 (1 µmol/L) (white circles) present in cardioplegia as well as throughout reperfusion. Each point represents mean ± standard error (n = 6). (*p < 0.05 between groups.)

View larger version (35K): [in this window] [in a new window]   Fig 3. . Study 2. Recovery of left ventricular developed pressure and end-diastolic pressure (as a percentage of baseline value) during 60 minutes of reperfusion after 60 minutes of hypothermic ischemic arrest in the control group (black circles) or with HOE 694 (1 µmol/L) present either during cardioplegia only (white squares) or reperfusion only (white circles). Each point represents mean ± standard error (n = 6). (*p < 0.05 from control group.)

View larger version (27K): [in this window] [in a new window]   Fig 4. . Study 2. Recovery of rates of left ventricular pressure development (+dP/dt) and relaxation (-dP/dt) (as a percentage of baseline value) during 60 minutes of reperfusion after 60 minutes of hypothermic ischemic arrest in the control group (black circles) or with HOE 694 (1 µmol/L) present either during cardioplegia only (white squares) or reperfusion only (white circles). Each point represents mean ± standard error (n = 6). (*p < 0.05 from control group.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Extensive experimental evidence has strongly supported the above hypothesis. A number of studies have demonstrated that pharmacologic inhibition of the Na⁺/H⁺ exchanger exerts a marked cardioprotective influence on the reperfused myocardium as manifested by improved functional recovery [8, 11–17], reduced contracture [11, 12, 14–16], diminished incidence of arrhythmias [12, 18, 19], and ultrastructural preservation [12]. The salutary effects of Na⁺/H⁺ exchange inhibition have been demonstrated convincingly in studies using relatively brief periods of ischemia; this report demonstrates such protection in a model of prolonged hypothermic storage. We chose to use HOE 694 to assess the role of Na⁺/H⁺ exchange because this drug lacks most of the nonspecific actions that have been observed with higher concentrations of amiloride or its analogues with respect to other ion-regulatory processes.

The protective effects of HOE 694 were characterized primarily by improved functional indices in terms of systolic recovery coupled with significantly diminished elevation in LVEDP. This protection was not associated with improved metabolic status particularly in terms of residual high-energy phosphate content at the end of the storage period or after reperfusion suggesting that, at least in this model, improved high-energy phosphate repletion does not dictate functional recovery after reflow. This lack of relationship between recovery and high-energy phosphate content differs from studies using HOE 694 in a normothermic rabbit isolated heart model in which reperfusion with the antiport inhibitor did show significant preservation of high-energy phosphate levels [8]. However, previously we have reported improved functional recovery with the use of amiloride derivatives that was similarly not associated with preservation of high-energy phosphate content [20]. Moreover, it has also been demonstrated that improved postischemic recovery of amiloride-treated hearts occurs independently of improved mitochondrial oxidative phosphorylation rates [12]. Thus, the precise relationship between energy metabolites and functional recovery after treatment with Na⁺/H⁺ exchange inhibitors requires further investigation. Neely and Grotyohann [21] have proposed that ATP content represents an important determinant of recovery only under conditions of severe depletion. Thus, although ATP levels as determined in this study declined by approximately 60%, the residual ATP content was apparently adequate to permit recovery of function with restored perfusion.

The CK efflux during the reperfusion period was also assessed as an indirect determinant of cell necrosis and whether this could be modified by drug treatment. The amount of CK release was variable such that significant modulation of this parameter was generally not observed, although a significant reduction in CK release was seen in HOE 694-treated hearts when the drug was present only in the reperfusate. A trend toward diminished enzyme release was apparent in those hearts in which HOE 694 administration resulted in improved functional recovery. Recently, we have found similar results in rabbit hearts subjected to 60 minutes of normothermic ischemia in which the Na⁺/H⁺ exchange inhibitors amiloride or methylisobutyl amiloride improved ventricular recovery but only tended to decrease CK release [20]. At present it is difficult to place the present results in perspective with other reports as the effects of Na⁺/H⁺ exchange inhibitors have not been investigated previously with respect to protection in the setting of prolonged hypothermic ischemia. In studies involving acute ischemia, discrepant results have been reported with both an attenuation of CK efflux [11, 14, 15] or no effect [16, 22] of exchange inhibitors. In the present study, the consistent, albeit variable, trend toward diminution in CK release is suggestive of at least some preservation of cellular integrity with HOE 694.

To further characterize the protective effect of HOE 694 a second series of experiments was undertaken during which the drug was administered with either cardioplegia or reperfusion only. Our study shows that the presence of HOE 694 only during reperfusion bestows marked protection as manifested by 100% restoration of contractile function and a markedly reduced elevation in LVEDP. In contrast, exposure to HOE 694 only with cardioplegia before prolonged hypothermic storage resulted in less marked improvement in functional recovery. These results suggest that antiport activation during reperfusion represents a major contributory mechanism to impaired functional recovery.

In studies using models of normothermic myocardial ischemia and reperfusion, discrepant results have been reported in studies in which Na⁺/H⁺ inhibitors were added only during reperfusion: these include a lack of protection [11, 20], reduced protection [8, 13, 16], as well as marked protection [14, 15] comparable to that observed in the present study. Some investigators have suggested that drug treatment before ischemia is a prerequisite for maximum cardioprotection. Indeed, some studies have demonstrated that Na⁺/H⁺ inhibitors attenuate the rise in both intracellular Ca²⁺ and Na⁺ concentrations during ischemia, suggesting that at least under some conditions activation of the antiporter during ischemia per se may contribute to tissue damage [22].

Administration of HOE 694 at the time of reperfusion in a rat heart model of myocardial stunning showed a beneficial effect not obtained with amiloride in the same model, suggesting greater efficacy of the newer agent [23]. HOE 694 was less effective in isolated blood-perfused rabbit hearts [8] or in porcine hearts [17] when administered solely at reperfusion. Although it is difficult to compare our study with those using short periods of normothermic ischemia, our results support the concept that drug pretreatment is not required for a beneficial effect, at least with this highly specific and potent inhibitor in a model of prolonged hypothermic ischemia. An important factor in this study is the potentially altered cellular response under profound hypothermic conditions as opposed to normothermic ischemia as has been used in virtually all other studies involving Na⁺/H⁺ exchange inhibition. Thus, it is possible that hypothermia renders the myocardium more amenable to the protective effect of Na⁺/H⁺ exchange inhibitors administered only at reperfusion. Although to our knowledge HOE 694 is a specific Na⁺/H⁺ exchange inhibitor devoid of effects unrelated to Na⁺/H⁺ exchange inhibition, it would be of interest to assess the effects of other agents such as amiloride analogues to determine whether they exert similar protective actions when selectively administered only during reperfusion.

In conclusion, our study shows a marked cardioprotective influence of the potent and highly selective Na⁺/H⁺ exchange inhibitor HOE 694 in hearts subjected to prolonged hypothermic ischemia. In view of the marked ability of HOE 694 to enhance recovery when administered only during reperfusion, it is likely that in this model the protection is mediated primarily by inhibition of antiport activation at the time of reperfusion. Emerging evidence supports a potentially important role of Na⁺/H⁺ exchange inhibitors in cardiovascular therapeutics [24]. Although extrapolation of the findings of the present study to clinical application must be done with great caution, the salutary effect of Na⁺/H⁺ exchange inhibition may ultimately prove beneficial in cardiac surgery where controlled ischemia and reperfusion is used routinely. Moreover, in view of the present limitations with hypothermic storage [25], the use of antiport inhibitors may be of particular benefit in extending current techniques of myocardial preservation for transplantation.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by the Heart and Stroke Foundation of Ontario (HSFO grant A2400) and the Medical Research Council of Canada (grant MT-10284). Dr Karmazyn is a Career Investigator of the HSFO.

We thank Drs Guang-Hue Li and Parviz Fahrangkhoee for technical assistance. We thank Dr Wolfgang Scholz of Hoechst AG (Frankfurt, Germany) for generously supplying us with HOE 694.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Myers, Victoria Hospital, 370 South St, #C101, London, Ontario N6B 1B8 Canada.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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