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Ann Thorac Surg 2001;72:548-553
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

High tissue affinity angiotensin-converting enzyme inhibitors improve endothelial function and reduce infarct size

^a Department of Cardiothoracic Surgery, Boston University School of Medicine, and the Boston Medical Center, Boston, Massachusetts, USA

Accepted for publication April 17, 2001.

Address reprint requests to Dr Lazar, Department of Cardiothoracic Surgery, Boston Medical Center, Suite B404, 88 E Newton St, Boston, MA 02118
e-mail: harold.lazar{at}bmc.org

	Abstract

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Background. Angiotensin-converting enzyme (ACE) inhibitors differ in their ability to inhibit tissue ACE. This study was, therefore, undertaken to determine whether high tissue affinity ACE inhibitors would improve endothelial function and thereby decrease tissue necrosis during ischemia.

Methods. In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. During the period of coronary occlusion, 10 pigs received enalaprilat (low affinity tissue ACE inhibitor), 0.05 mg/kg intravenously, 10 received quinaprilat (high affinity tissue ACE inhibitor), 10 mg intravenously, and 10 others received no ACE inhibitor.

Results. Wall motion scores (4, normal, to -1, dyskinesia) were higher in animals treated with ACE inhibitors (3.20 ± 0.15 SE enalaprilat versus 3.08 ± 0.23 quinaprilat versus 1.52 ± 0.07 no ACE; both p < 0.0001 from no ACE). Endothelial-dependent relaxation to bradykinin was best preserved in the quinaprilat-treated hearts (32.1% ± 7.6% enalaprilat versus 65.8% ± 12.6% quinaprilat versus 30.6% ± 10.7% no ACE; p < 0.0001 from no ACE; p < 0.005 from enalaprilat). This was associated with a greater reduction in infarct size: area necrosis/area risk 24.3% ± 0.8% enalaprilat (p < 0.0001 from no ACE) versus 14.3% ± 3.2% quinaprilat (p < 0.0001 from no ACE; p < 0.005 from enalaprilat) versus 40.0% ± 1.7% no ACE.

Conclusions. ACE inhibitors with higher affinity to tissue ACE result in better preservation of endothelial function and less tissue necrosis during coronary revascularization.

	Introduction

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In a previous experimental study using a porcine model of surgical revascularization of acutely ischemic myocardium, we showed that angiotensin-converting enzyme (ACE) inhibition with enalaprilat improved regional wall motion and limited infarct size [1]. These beneficial effects of ACE inhibition were unrelated to preservation of endothelial function, which remained impaired in the area of ischemic myocardium. Not all ACE inhibitors are alike, however, and they may vary in their potency of plasma and tissue ACE inhibition [2]. Whereas older generation ACE inhibitors such as captopril or enalapril almost exclusively inhibit circulating ACE, newer, more liphopholic compounds such as ramipril and quinapril have a higher affinity to tissue ACE, which represents 90% of all ACE found in the body [2].

Endothelial dysfunction may play an important role in determining the extent of myocardial injury after periods of coronary occlusion and reperfusion, such as that seen during cardioplegic arrest in patients undergoing coronary artery bypass graft (CABG) surgery. Clinical studies have shown that the difference in tissue ACE affinity between ACE inhibitors influences their ability to preserve endothelial function [3–6]. High affinity ACE inhibitors such as quinapril may result in better protection of endothelial function during cardioplegic arrest, and that may translate into more complete myocardial protection after the revascularization of acutely ischemic myocardium.

In this experimental study, we sought to determine whether an ACE inhibitor with high tissue ACE inhibition such as quinaprilat would improve endothelial function compared with enalaprilat, which has low tissue ACE inhibition. Furthermore, we wished to determine whether improvement in endothelial function correlates with increased cardioplegic protection. Finally, we hoped to determine the mechanism for the actions of ACE inhibition during surgical revascularization with cardioplegic arrest on cardiopulmonary bypass.

	Material and methods

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Randomization
Forty-five adult pigs (33 to 38 kg) were entered into the study. Two additional pigs were excluded because of bilateral lobar pneumonia and 2 because of pericarditis. Saline solutions containing enalaprilat, quinaprilat, quinaprilat plus HOE 140, and no ACE inhibitors were prepared in unlabeled infusion bags so that the investigators were blinded to the content of each infusion. All experiments were performed in an alternative, randomized manner, including 10 animals previously reported in the low-dose enalaprilat group.

Preparation
Animals were premedicated with ketamine (15 mg/kg intramuscularly [IM]) and xylazine (0.5 mg/kg IM), anesthetized with -chloralose (75 mg/kg), and placed on positive-pressure endotracheal ventilation. After a median sternotomy and systemic heparinization (3 mg/kg), the second and third diagonal branches just distal to the take-off of the left anterior descending artery were occluded with snares for 90 minutes. Pigs were then placed on cardiopulmonary bypass (CPB), followed by 45 minutes of multidose, antegrade/retrograde, cold blood cardioplegic arrest (potassium 25 mEq/L, hematocrit 20%, pH 7.6, temperature 4°C), supplemented with topical hypothermia. After the aortic cross clamp was removed, the coronary snares were released, and all hearts were reperfused for 180 minutes on CPB at 37°C.

Treatment groups
During the 90-minute period of coronary occlusion, animals were divided into the following groups:

No ACE group
In 10 animals, no ACE inhibitors were given. These animals received only a 50-mL saline infusion for the first 30 minutes during the period of coronary occlusion.

Low-dose enalaprilat group
In 10 animals, an intravenous infusion of enalaprilat (0.05 mg/kg in 50 mL saline) was begun 5 minutes after the coronary vessels were snared and continued for 30 minutes. We reported our findings with these 10 animals in our earlier study [1].

High-dose enalaprilat group
In 5 animals, a higher dose of enalaprilat (0.3 mg/kg in 50 mL saline) was intravenously infused 5 minutes after the coronary vessels were snared and continued for 30 minutes to determine the effects of higher doses of a low affinity tissue ACE inhibitor.

Quinaprilat group
In 10 animals, we infused quinaprilat (10 mg in 50 mL saline) intravenously 5 minutes after the coronary vessels were snared and continued for 30 minutes. We used doses of quinaprilat that clinical studies have shown reduce ACE and angiotensin II activity [7].

Quinaprilat plus HOE 140
In 10 animals, the bradykinin antagonist HOE 140 (1 µg/kg in 50 mL saline) was intravenously infused together with quinaprilat (10 mg) 5 minutes after the coronary vessels were snared and continued for 30 minutes. Previous studies have shown that HOE effectively blocks bradykinin at this dosage [8].

Measurements and statistical analyses
Electrocardiographic leads were placed to measure heart rate and to monitor electrical activity during arrest. Left ventricular end-diastolic pressure (LVEDP) was recorded with a piezoelectric Mikro-Tip catheter pressure transducer (Millar Instruments Inc, Houston TX) inserted through a stab wound in the left ventricular apex. Intravenous lidocaine was used to treat ventricular arrhythmias. Electrical cardioversion was used for ventricular fibrillation and ventricular tachycardia, which was either unresponsive to intravenous lidocaine or resulted in a substantial (> 20 mm Hg from base line) decrease in systolic blood pressure.

Echocardiographic short and long-axis sections obtained from transthoracic echocardiograms were used to define wall motion changes in the area of risk as previously described [9]. A wall motion score was derived (4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, 1 = severe hypokinesis, 0 = akinesis, -1 = dyskinesia) to indicate changes in wall motion. The sections were interpreted by an experienced echocardiographer (S.A.B.) in a blinded fashion, and the scores were averaged for the coronary occlusion and reperfusion periods for all experimental groups.

Infarct size was assessed by determining the areas of necrosis to areas of risk using histochemical staining techniques with triphenyltetrazolium chloride as previously described [9]. Stained myocardial slices were planimetered to obtain the area of risk compared with the total left ventricular mass and the percent area of infarct in that area of risk.

Epicardial vascular relaxation was assessed using standard organ chamber methodology. A segment of the second or third diagonal vessel in the area at risk was dissected, cut into rings and suspended in organ chambers with oxygenated Krebs buffer at 37°C. Ring tension was determined using a force displacement transducer (Grass Instruments, Inc, West Warwich, RI) attached to each tensiometer apparatus and recorded on MacLab recording software. The rings were allowed to equilibrate at a passive tension of 2 g to 3 g for 60 minutes and then contracted with 1 µmol/L prostaglandin (PG) F₂ and allowed to stabilize. Once a stable contraction was obtained, coronary vasomotor function was assessed by generating dose-response curves to cumulative concentrations of nitroglycerin (10^-9 to 10^-5 mol/L), an endothelial-independent coronary vasodilator, and the calcium ionophore A23187 and bradykinin, endothelial-dependent coronary vasodilators. Relaxation in response to each concentraton of the agonist was calculated as the percent reduction in isometric tension from the tension produced by 1 µmol/L PGF₂. Values were calculated for each experiment and mean values were computed for the various treatment groups.

We report all findings as mean ± standard error. Differences in measurements between the various groups and across time were assessed by repeated measurements analysis of variance. We used Stat View 4.5 (Abacus Concepts Inc, Berkeley, CA) to conduct these analyses. Findings with p values less than 0.05 were considered statistically significant.

All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council and published by the National Academy Press (revised 1996).

	Results

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Heart rate, MAP, and LVEDP during coronary occlusion before CPB
Table 1 summarizes changes in heart rate, mean arterial pressure (MAP), and LVEDP during the 90-minute period of coronary occlusion before CPB. Heart rates were similar in all groups before coronary occlusion and decreased significantly in each group during the period of coronary occlusion. However, there was no difference between the groups after 90 minutes. Mean arterial pressure was also similar between groups before coronary occlusion. Although each group showed a small but significant decrease in MAP after 90 minutes of coronary occlusion, there was no difference in MAP between groups. All hearts also showed a small but statistically significant increase in LVEDP from preocclusion values. However, there was no difference in LVEDP among the groups after 90 minutes of occlusion.

Coronary vasomotor function
Vasodilator responses to endothelium-independent and endothelium-dependent relaxation in the diagonal coronary arteries are shown in Figure 1. Endothelium-independent relaxation to nitroglycerin resulted in no significant difference in dose response curves among the groups. In contrast, endothelium-dependent relaxation was markedly impaired in both the enalaprilat and no ACE treated hearts when both the calcium ionophore A23187 and bradykinin were used. Increasing the dose of enalaprilat from 0.05 mg/kg to 0.3 mg/kg failed to improve relaxation. In contrast, quinaprilat resulted in significantly higher percent relaxation in response to both A23187 (84% ± 9%) and bradykinin (66% ± 12%). Adding the bradykinin antagonist HOE 140 completely reversed the relaxation seen with quinaprilat in vessels exposed to bradykinin (66% ± 12% quinaprilat versus 35% ± 8% quinaprilat + HOE 140; p < 0.0001) and partially reversed the relaxation in quinaprilat treated hearts with A23187 (84% ± 9%) quinaprilat versus 58% ± 14% quinaprilat + HOE 140; p < 0.0001).

View larger version (25K): [in this window] [in a new window]   Fig 1. Vascular relaxation. (A) Endothelium-independent nitroglycerin. (B) Endothelium-dependent A23187. (C) Endothelium-dependent bradykinin. All values represent the mean ± standard error. *p < 0.001 from no ACE, enalaprilat 0.05 mg/kg, enalaprilat 0.3 mg/kg; p < 0.001 from quinaprilat plus HOE 140. (ACE = angiotensin-converting enzyme.)

	Comment

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Our results in a model of ischemia-reperfusion in cardioplegic treated hearts are consistent with results from other clinical and experimental studies in beating hearts that show that quinapril and other ACE inhibitors with high tissue ACE affinity improve endothelial function by a bradykinin-mediated mechanism. Koh and coworkers [10] found that in males with coronary artery disease who received quinapril (20 mg to 40 mg daily) for 8 weeks, endothelial-dependent vasodilation as measured by brachial ultrasonography was significantly increased. Serum nitrogen oxide levels were decreased, suggesting that quinapril may increase the availability of nitric oxide (NO) in vascular smooth muscle cells. Hornig and coworkers [5] studied radial artery diameter and blood flow in patients without evidence of coronary arteriosclerosis using high-resolution ultrasound and Doppler techniques. Quinaprilat increased flow-dependent dilatation by 46%. This increase was abolished when the bradykinin antagonist icatibant (HOE 140) was added to the quinaprilat. Further insight into the role of bradykinin and NO in the cardioprotective action of ACE inhibition was shown by Hartman in a rabbit model of 30 minutes of ischemia followed by 120 minutes of reperfusion [8]. ACE inhibition with ramiprilat significantly reduced infarct size; but pretreatment with HOE 140 abolished this protective effect. When NO was inhibited with NG nitro-L-arginine methylester, the cardioprotective effect of ramiprilat was also abolished. Ramiprilat and bradykinin also improved cell viability in isolated cardiomyocytes exposed to hypoxia. This suggests that the protective effect of ACE inhibitors occurs at the local tissue level and further supports the concept that alterations in local tissue rather than systemic ACE activity is responsible for the beneficial actions of ACE inhibitors.

Similar findings were noted by Matoba and coworkers [11] who looked at the effects of the ACE inhibitor cilazaprilat in neonatal rat cardiomyocytes exposed to hypoxia. Cilazaprilat and bradykinin preserved myocyte function whereas CV-11974, an angiotensin II receptor antagonist, did not. Cilazaprilat significantly enhanced bradykinin production in the culture media and increased the content of cGMP. The protective effects of cilazaprilat were abolished by HOE 140, the NO synthase inhibitor NG-monomethyl-L-arginine monoacetate (L-NMMA) and the guanylate cyclase inhibitor methylene blue. This study demonstrates that myocardial bradykinin levels can be increased by ACE inhibition during ischemia and that the protective effects of bradykinin appear to be mediated by NO, which modulates guanylate cyclase and cGMP synthesis.

Both enalaprilat and quinaprilat contain a phenophylpropyl moiety in place of the sulfhydryl group seen in first generation ACE inhibitors such as captopril. The distinctive tetrahydroiso-quinolone moiety of quinaprilat is thought to increase its interaction at a second hydrophobic site. This additional biochemical interaction is characteristic of "high-affinity" ACE inhibition and may be responsible for the improved endothelial function seen clinically with quinapril [3–6]. Hornig and coworkers [12] studied the effects of quinaprilat and enalaprilat on radial artery diameter and blood flow in patients with congestive heart failure. Quinaprilat but not enalaprilat increased flow-dependent dilatation. Similar to our own results, increasing the dosage of enalaprilat failed to increase flow-dependent dilatation. Lyons and coworkers [6] measured brachial artery flow using strain-gauge plethysmography in healthy males. Similar doses of quinapril and enalapril each produced the same degree of plasma ACE inhibition; however, quinapril resulted in significantly more reduction in angiotensin II induced vasoconstriction than did enalapril. Similar results were seen in the TREND (Trial on Reversing Endothelial Dysfunction) study, which showed that quinapril therapy for 6 months decreased the epicardial coronary artery constriction response to acetylcholine in angiographically normal or minimally diseased coronary arteries [4]. In the BANFF (Brachial Artery Normalization of Forearm Function) study, only quinapril had a significant effect on flow-mediated vasodilation; enalapril, amlodipine, and losartan did not [3].

In our study, the improved endothelial function with quinaprilat was associated with a significant reduction in infarct size. A possible mechanism for the reduction in infarct size is provided by Hoshida and coworkers [13] who pretreated cholesterol fed rabbits with quinapril followed by a period of coronary occlusion and reperfusion. Animals not receiving quinapril had a significant increase in ACE activity in both normal and ischemic myocardium. This was associated with decreased myocardial cGMP content and increased expression of P-selectin, an adhesive molecule that is involved in interactions between leukocytes and the coronary endothelium and has been shown to be suppressed by NO [14]. P-selectin contributes to ischemic necrosis by increasing leukocyte adhesiveness to the endothelium. Quinapril decreased tissue ACE, increased cGMP content, and decreased expression of P-selectin. By reducing P-selectin expression, leukocyte adhesiveness is decreased and blood flow is increased to the ischemic myocardium. This resulted in a significant decrease in infarct size. These beneficial effects were blocked by HOE 140 and the competitive NO-synthase inhibitor L-NAME. As in our study, the beneficial effects of quinapril were achieved in doses that had no effects on MAP. This reduction in infarct size did not correlate with further improvement in wall motion compared with enalaprilat treated hearts. However, these measurements were made early in the reperfusion period. It is conceivable that significant improvements in wall motion could have been detected after several days.

Our experimental findings demonstrating the beneficial effects of ACE inhibitors during surgical revascularization were observed in two clinical trials involving CABG patients [15, 16]. In the QUO VADIS (Effects of Quinapril on Vascular ACE and Determinants of Ischemia) trial, 149 patients scheduled for elective CABG were randomized to receive quinapril 40 mg per day or placebo for 3 to 4 weeks before CABG and for 1 year after surgery [15]. Patients receiving quinapril had an 80% reduction in ischemic events after 1 year from 18% to 4% (p = 0.02). Sirivella and coworkers [16] studied the effects of administering ACE inhibitors to postcardiotomy patients with low cardiac output syndrome requiring an intraaortic balloon pump and inotropic support. Patients treated with ACE inhibitors had lower hospital mortality (31% versus 14.5%), less morbidity (37% versus 20%), and shorter hospital length of stay (22 days versus 17 days).

In conclusion, our experimental findings suggest that ACE inhibition during surgical revascularization of acutely ischemic myocardium reduces ventricular irritability, improves regional wall motion, and limits ischemic necrosis. Our data confirm the results of previous work which show that not all ACE inhibitors are equally effective in preserving endothelial function. ACE inhibitors with higher tissue affinity to tissue ACE, such as quinapril result in better preservation of endothelial function during ischemia. This enhances cardioplegic protection and results in less ischemic necrosis. Our data also suggest that this improvement in endothelial function during surgical revascularization on cardiopulmonary bypass is bradykinin mediated. High affinity tissue ACE inhibitors such as quinaprilat may play an important role in enhancing cardioplegic protection during the surgical revascularization of acutely ischemic myocardium.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This work was supported in part by a grant from Parke-Davis Pharmaceuticals Inc, Morris Plains, NJ. The secretarial support of Ellie LaBombard is appreciated.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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