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Ann Thorac Surg 1997;63:627-633
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Captopril in Cardioplegia and Reperfusion: Protective Effects on the Ischemic Heart

Department of Thoracic and Cardiovascular Surgery, Elias Sourasky–Tel-Aviv Medical Center, Tel-Aviv University, Tel-Aviv, Israel

Accepted for publication July 31, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Previous studies have shown that long-term treatment with the angiotensin-converting enzyme inhibitor captopril attenuates left ventricular dilatation and improves survival after extensive myocardial infarction. However, there is only sparse evidence of the immediate effects of the drug on hearts undergoing global ischemia and reperfusion. The purpose of this study was to investigate the direct effect of captopril, given in cardioplegia or after ischemia, on the functional recovery of the reperfused myocardium.

Methods. Isolated rat hearts undergoing warm cardioplegic arrest followed by 1 hour of global ischemia and 30 minutes of reperfusion were studied using the modified Langendorff model.

Results. After ischemia, hearts receiving captopril (360 µmol/L) either in the cardioplegic solution (n = 9) or during reperfusion (n = 9) developed higher pressure (p < 0.001), greater first derivative of the rise in left ventricular pressure (p < 0.01 and p < 0.001, respectively), greater first derivative of the fall in left ventricular pressure (p < 0.001 and p < 0.002), higher pressure-time integral (p < 0.001), greater coronary flow (p < 0.001), and higher oxygen consumption values (p < 0.001 and p < 0.003) compared with the control group (n = 9). Hearts receiving captopril both in the cardioplegia and during reperfusion (n = 9) had the best recovery of all three groups and lower levels of creatine kinase (47.8 ± 5.9 U/L versus 73.3 ± 5.6 U/L; p < 0.01) compared with the control group.

Conclusions. Captopril given in cardioplegia and in reperfusion has a favorable, protective, and additive effect on the recovery of isolated rat hearts undergoing global ischemia and reperfusion; hemodynamic performance improves, coronary flow and oxygen consumption increase, and myocardial damage decreases.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Angiotensin-converting enzyme (ACE) inhibitors have beneficial effects in severe heart failure as evidenced by reduced mortality and improved left ventricular (LV) function [1, 2]. The effects of the ACE inhibitor captopril on the myocardium appear to be multifactorial regarding an antiischemic effect and the treatment of heart failure.

Angiotensin-converting enzyme inhibitors have been shown to have an advantageous effect on the remodeling of the myocardium in animal models of experimental myocardial infarction [3, 4] and in clinical studies after myocardial infarction [5, 6]. It has been demonstrated that infarct extension can be impeded and survival improved as a result of ACE inhibition [3–6]. However, even in the experimental studies, the earliest time of drug administration after infarction ranged from 2 hours [4] to 3 weeks [7] postoperatively.

Only sparse and conflicting evidence exists concerning the effect of captopril on the mechanical performance of the myocardium when given immediately after ischemia and reperfusion [4, 7]. Several experimental studies [8, 9] have shown that intravenous administration of captopril exacerbated myocardial injury and had a significant adverse effect on infarct size in the dog. Captopril given before ischemia in the isolated working rat heart provided biochemical and electrophysiologic evidence of myocardial salvage [10], but the influence was insufficient to induce hemodynamic improvement after global ischemia and reperfusion. Other experimental studies [11–13] have demonstrated a reduced reperfusion injury in hearts undergoing segmental ischemia when pretreated with captopril.

For the cardiac surgeon, it seems important to assess the role of cardioplegic pretreatment with captopril on the recovery of the myocardium undergoing global ischemia and reperfusion. The present study, therefore, had three goals: (1) to investigate the effect of captopril on the recovery of the reperfused heart when given in the cardioplegic solution before ischemia; (2) to observe the direct effect of the drug on the functional recovery of the myocardium when given immediately after ischemia during the reperfusion period; and (3) to assess whether the effect of the drug given both in cardioplegia and during reperfusion has an additive or opposing effect on mechanical and functional recovery of the ischemic myocardium. A modified Langendorff isolated rat heart model was used.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Male Wistar rats weighing 335 to 421 g were anesthetized by intraperitoneal injection of sodium pentobarbital (30 mg/kg) and heparinized. Their hearts were rapidly excised, immersed in ice-cold saline solution with heparin sodium, and mounted on the stainless steel cannula of a modified Langendorff perfusion apparatus.

Retrograde aortic perfusion was initiated at a perfusion pressure of 85 mm Hg with an oxygenated modified Krebs-Henseleit buffer solution with the following composition (in millimoles): NaCl, 118; KCl, 4.7; CaCl, 2.0; MgSO₄7H₂O, 1.2; KH₂PO₄, 1.2; glucose, 11.1; and NaHCO₃, 25. The perfusate was bubbled continuously with 95% oxygen and 5% carbon dioxide, maintaining a pH of 7.4 to 7.5. The oxygen tension and the carbon dioxide tension in the perfusion solution were 450 to 550 mm Hg and 25 to 30 mm Hg, respectively.

The heart temperature was monitored by a thermistor implanted in the right ventricular wall and carefully maintained at 37°C or 31°C (at ischemia) by means of a water jacket around the perfusate reservoir and the isolated heart. The right atrium was removed, and the heart was paced to 300 beats/min at 4 V using an external pacemaker (type E4162; Devices Limited, Implants Division), thus ensuring identical heart rates for all hearts. A water-filled latex balloon was placed in the LV cavity through a small incision in the left atrium and was connected to a Mennen Medical PI 32284 pressure transducer. The balloon was tied and inflated to a volume that produced 0 mm Hg diastolic pressure. Zero calibration of the pressure transducer was maintained throughout the experiment.

All animals received humane care as described in "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and "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 85-23, revised 1985).

Hemodynamic Measurements
Left ventricular pressure, time-to-peak systolic pressure, relaxation time, first derivative of the rise and the fall in LV pressure (dP/dt max and dP/dt min, respectively), the area calculated under the LV developed pressure curve (pressure–time integral), which correlates with oxygen consumption [14], and coronary flow were measured. The variables were continuously recorded, and measurements were taken at 10-minute intervals.

Protocol
Thirty-six rats were randomly divided into four groups of 9 animals each: controls (group 1); isolated hearts receiving captopril (360 µmol/L) in the cardioplegic solution (group 2); hearts receiving captopril (360 µmol/L) during the reperfusion period (group 3); and isolated hearts receiving captopril (360 µmol/L) both in the cardioplegic solution and during the reperfusion period (group 4).

Control measurements were recorded after a 15-minute period of stabilization, and each heart was thereafter perfused for a 30-minute period. Warm (37°C) cardioplegia (KCl, 16 mEq/L in Krebs-Henseleit solution with or without captopril) was administered for 2 minutes (perfusion pressure, 73 mm Hg), and the arrested heart then underwent a 60-minute period of global ischemia at 31°C. Creatine kinase (CK) activity was measured spectrophotometrically in the effluent at the first minute of reperfusion after ischemia. Thereafter, measurements of LV function were taken every 10 minutes during the 30-minute reperfusion period. Throughout the study, the experiments were alternated between the control and the experimental limbs to avoid bias or differences in results.

Oxygen Consumption
Perfusate afferent and efferent gases were measured after 15 minutes of stabilization, 1 minute before cardioplegia, at 10 minutes of reperfusion, and at the end of reperfusion. Samples were withdrawn from the Langendorff perfusion apparatus and from the right ventricle using a tiny polyethylene catheter inserted through a pulmonary artery incision. Oxygen consumption was calculated using the following formula [15]:

(1)

Wet-to-Dry Ratio
Finally, the hearts were dried at 90°C for 24 hours to achieve a constant weight. Wet-to-dry weight ratio was calculated for each heart.

Statistical Analysis
Results are presented as the mean ± the standard error. To avoid differences in baseline values, the value for the first 15 minutes of contraction of each heart was used as its control. All control values for LV function, coronary effluent, and oxygen consumption were considered to be 100%. Coronary effluent was normalized to gram of dry heart weight. Because of differences in effluent flow during the first postischemic minute, CK values were normalized to units per milliliter of flow per minute per gram of dry heart weight. Between-group baseline data and CK levels were analyzed by Student's paired or unpaired t test. Two-way analysis of variance (ANOVA) for time and drug effect was performed for all variables before and after ischemia. Significance was established at a p value of less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All variables measured after 15 minutes of stabilization were identical for all four groups of hearts (Table 1). Moreover, the four groups maintained similar measurements for all variables during the 30-minute perfusion period preceding ischemia.

View larger version (44K): [in this window] [in a new window]   Fig 1. . Hemodynamic performance: peak systolic pressure. Results are shown as the percentage of baseline measurements after 15 minutes of stabilization. Before ischemia, all four groups demonstrated similar peak-systolic pressures. After ischemia, however, the control group had a significant deterioration in myocardial hemodynamics, whereas hearts given captopril either immediately before ischemia in the cardioplegic solution ( Cardioplegia) or immediately after ischemia (Reperfusion) exhibited improved recovery. When captopril was given both in cardioplegia and during reperfusion (Card & Rep), peak systolic pressure was significantly better than in all three other groups (p < 0.001), and left ventricular hemodynamic deterioration was minimal.

View larger version (45K): [in this window] [in a new window]   Fig 2. . Hemodynamic performance: first derivative of rise in left ventricular pressure. Details and abbreviations are the same as in Figure 1.

View larger version (45K): [in this window] [in a new window]   Fig 3. . Hemodynamic performance: pressure–time integral. Details and abbreviations are the same as in Figure 1.

View larger version (47K): [in this window] [in a new window]   Fig 4. . Coronary flow before and after ischemia. Results are shown as the percentage of baseline measurements after 15 minutes of stabilization. Before ischemia, all four groups performed similarly. After ischemia, hearts treated with captopril had a significantly better recovery and viability compared with the control group in terms of coronary flow ( p < 0.001). Hearts treated with captopril both before and after ischemia (Card & Rep) had the best results, and when this group was compared with the control group, analysis of variance for drug effect was most prominent (p < 0.001). (Cardioplegia = hearts given captopril in cardioplegic solution; Reperfusion = hearts given captopril during reperfusion.)

View larger version (37K): [in this window] [in a new window]   Fig 5. . Oxygen consumption before and after ischemia. Details and abbreviations are the same as in Figure 4.

Captopril Given Both in Cardioplegia and After Ischemia
Hearts receiving captopril (360 µmol/L) both in the cardioplegic solution and during reperfusion (group 4) had the best recovery of all three captopril-treated groups after 1 hour of ischemia. All postischemic hemodynamic measurements (peak systolic pressure, dP/dt max, dP/dt min, and pressure–time integral) were significantly better (p < 0.001) (see Figs 1–3) than those of group 1. In addition, coronary flow (p < 0.001) (see Fig 4) and oxygen consumption (p < 0.001) (see Fig 5) were higher, and CK levels were lower (p < 0.01) (see Table 2).

The protective effect of captopril against ischemia-reperfusion injury was additive. The recovery of group 4 hearts was significantly better than that in group 2 (captopril in cardioplegia only) in terms of higher dP/dt max (p < 0.03) and pressure–time integral (p < 0.003) values. The recovery was also better than that of group 3. Group 4 had significantly higher values for peak systolic pressure (p < 0.05), dP/dt max (p < 0.05), pressure–time integral (p < 0.05), and coronary flow (p < 0.05) compared with group 3 hearts.

Oxygen Consumption
Ischemia had no significant influence on the oxygen consumption of hearts receiving captopril. After 1 hour of ischemia and then 30 minutes of reperfusion, groups 2, 3, and 4 had values similar to those measured before ischemia (95.1%, 76.2%, and 96.7% of baseline, respectively). However, in the control group, prolonged ischemia decreased the oxygen consumption dramatically to 58.2% ± 6.4% of baseline (p < 0.001).

Wet-to-Dry Ratios and CK Levels
Differences in CK levels between groups are summarized in Table 2. No differences in wet-to-dry heart weight ratio were observed between groups.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Late Initiation of Captopril
Long-term administration of the ACE inhibitor captopril attenuates LV dilation after myocardial infarction [3–6]. Nevertheless, early initiation of captopril therapy several days or even a few hours after coronary artery ligation in rats did not appear to produce a greater effect than treatment started 3 weeks after the experimental infarction [3, 4]. Moreover, in one experimental study [7], captopril given 3 to 5 weeks after infarction improved cardiac function, and when given early (within 1 to 21 days after infarction), captopril treatment led to increased tachycardia and decreased stroke volume, results suggesting deterioration of rather than improvement in cardiac function.

Our Findings
Our study examined the immediate effect of captopril on the isolated heart undergoing global ischemia, and our results were unequivocal. Hearts treated with captopril either in the cardioplegia or after global ischemia during the reperfusion period had a significant improvement in mechanical performance and myocardial recovery compared with the control group. This was reflected by higher peak systolic pressure, dP/dt max, dP/dt min, pressure–time integral, and coronary flow values, greater oxygen consumption, and lower CK levels. Best results were achieved when the drug was given both in cardioplegia and during reperfusion. The improved oxygen consumption and the lower CK release were evidence of greater viability and decreased rates of cellular injury, which correlated well with the improvement in myocardial hemodynamics. Neely and colleagues [15] had already confirmed this correlation between peak systolic pressure and pressure–time integral and between oxygen consumption both in the isolated working heart and in the Langendorff apparatus.

Setting Study Protocol
Our study protocol was used previously with a different agent, aprotinin [16]. However, 45 minutes of ischemia in that study did not cause sufficient deterioration of myocardial performance in the control group to show significant differences between treatment and control groups. We therefore decided to lengthen the ischemic period to 60 minutes. The temperature of 31°C during ischemia was chosen, as previous results illustrated a sharp decline in protection when the temperature rose higher than 30°C [14]. Because captopril affects myocardial performance in a dose-dependent manner [7, 17, 18], our captopril dose of 360 µmol/L was set in correlation with the maximal dose in other studies [7, 17].

Conflicting Evidence in the Literature
Our results were at variance with those in other experimental studies showing that intravenous administration of captopril was associated with exacerbation of myocardial injury after 1 hour of coronary artery occlusion [8] or balloon angioplasty occlusion [9]. The deleterious effects in the dog were linked particularly to the high collateral flow [8]. Favorable studies of local ischemia and reperfusion suggesting that treatment with high doses of captopril reduced myocardial injury (assessed by plasma CK levels) in a porcine model have been reported [18]. Westlin and Mullane [11] observed that when administered either before occlusion or 2 minutes prior to reflow, captopril significantly enhanced postischemic contractile function in dogs subjected to 15 minutes of transient coronary artery occlusion. Cosin and co-workers [13] demonstrated similar results.

Insights
This study contributes several insights into the effect of captopril. First and foremost, it proves the drug's favorable efficacy on the recovery of the myocardium after global ischemia, whereas other studies showed this only in cases of local ischemia performed by segmental occlusion [13] or ligation [11]. Second, our study demonstrates that immediate postischemic instillation of the drug, and not necessarily delayed therapy as suggested by other studies, has beneficial effects [7]. Third, it demonstrates the additive effect of the drug when given in cardioplegia before ischemia and during reperfusion.

Limitations Bear Advantages
The limitations of such an experimental study (for example, animal model, isolated heart, and blood-free environment) require caution regarding clinical extrapolations but seem to have one major advantage. The ACE inhibitors were thought to exert their function primarily through systemic mechanisms such as afterload reduction. It appeared that the major benefit from ACE inhibition was due to improvement in organ function resulting from changes in loading conditions, whereas muscle function remained compromised [19]. By examining the isolated heart, we have demonstrated here that captopril given in conjunction with ischemia acts both favorably and through local myocardial mechanisms.

Possible Mechanisms
The mechanisms responsible for the cardioprotective effect of captopril were not clarified in our study. They might be partially explained as follows:

INCREASE IN CORONARY FLOW.
Given before ischemia in the cardioplegic solution or after ischemia in the reperfusion period or at both times, captopril significantly increased the coronary flow almost to preischemic levels in our study. The mechanism is probably mediated by the effect of captopril on the myocardial autocrine function of the angiotensin system, the inhibition of the local vasoconstrictor effect of angiotensin II, or the potentiation of bradykinin because the ACE is identical to the kinase II enzyme, which degrades bradykinin [20]. This vasodilator effect could even be caused by the direct action of captopril demonstrated in vitro and is probably due to interference in the metabolism of arachidonic acid [21]. Recent investigations [22] attribute the increase in coronary flow to local release of endothelium-derived relaxing factor by captopril.

INHIBITION OF SYMPATHETIC STIMULATION.
Angiotensin II potentiates response to sympathetic stimulation, and this increase in adrenergic response can be prevented by an angiotensin II receptor blocker and by ACE inhibition [23, 24].

FREE RADICAL SCAVENGER.
The production of free radicals plays an important role in the pathogenesis of reperfusion damage [25]. Captopril possesses a sulfhydryl group, which probably serves as a free radical trapper [17]. In at least two previous studies [12, 17] of experimental infarction, it was suggested that captopril exerted myocardial preservation primarily as a result of its free radical–scavenging activity, particularly of the potent free radicals ^-OH and OCl^-.

Future Research
Our results call for further experimental and clinical studies. Captopril might be administered in the cardioplegic solution during open heart operations as well as immediately after operations and in other settings of acute ischemia.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All data were statistically analyzed by Mrs Yael Villa, MSc, School of Mathematics, Tel-Aviv University. We thank Mrs Lynda Hemi for help in editing the manuscript.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Gurevitch, Department of Thoracic and Cardiovascular Surgery, Ichilov Hospital, Elias Sourasky–Tel-Aviv Medical Center, 6 Weizman St, Tel-Aviv 64239, Israel.

	References

Top Footnotes Abstract Introduction Material and Methods Results 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): Jacob Gurevitch Rephael Mohr Vladimir Yakirevich Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gurevitch, J. Articles by Yakirevich, V. Search for Related Content PubMed PubMed Citation Articles by Gurevitch, J. Articles by Yakirevich, V.