Ann Thorac Surg 2000;70:627-632
© 2000 The Society of Thoracic Surgeons
Original articles: cardiovascular
Effects of angiotensin-converting enzyme inhibitor during warm blood cardioplegia
Nobuhiko Hayashida, MDa,
Shingo Chihara, MDa,
Eiki Tayama, MDa,
Shogo Yokose, MDa,
Koji Akasu, MDa,
Eizo Kai, MDa,
Shigeaki Aoyagi, MDa
a Department of Surgery, Kurume University, Fukuoka, Japan
Address reprint requests to Dr Hayashida, Department of Surgery, Kurume University, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
e-mail: nobuhiko{at}med.kurume-u.ac.jp
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Abstract
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Background. Effects of captopril, an angiotensin-converting enzyme inhibitor, during warm blood cardioplegia were assessed in the blood-perfused, isolated rat heart.
Methods. The isolated hearts were arrested for 60 minutes with warm blood cardioplegia given at 20-minute intervals and were reperfused for 60 minutes. The control group ( 
) received standard cardioplegia and the captopril group ( ) received cardioplegia supplemented with captopril (2 mmol/L). Cardiac function, myocardial metabolism, and cardiac release of circulating adhesion molecules were assessed before and after cardioplegic arrest.
Results. Left ventricular end-diastolic pressure and -dp/dt were significantly (p < 0.05) lower and coronary blood flow was significantly (p < 0.05) greater in the captopril group than the control group during reperfusion. The captopril group resulted in significantly (p < 0.05) less cardiac release of lactate, thiobarbituric acid reactive substances during reperfusion. Cardiac release of intercellular adhesion molecule-1 was significantly (p < 0.05) less in the captopril group at 60 minutes of reperfusion.
Conclusions. The results suggest that supplementation of captopril during warm blood cardioplegia provides superior myocardial protection by suppressing lipid peroxidation and leukocyte–endothelial cell interaction during reperfusion.
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Introduction
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Although aortic cross-clamping and cardioplegic arrest are essential techniques for cardiac operations, readmission of coronary flow by aortic declamping has been reported to induce a paradoxical extension of ischemic damage during cardioplegic arrest, the so-called ischemia-reperfusion injury [1]. Reversible and irreversible damage to myocardium and endothelium induced by this phenomenon may be associated with a delayed recovery of myocardial metabolism and cardiac function [1]. To date, a number of therapeutic interventions during ischemia and reperfusion to minimize the injury, including pharmacologic agents or leukocyte depletion, have been investigated in patients undergoing cardiac operation. With regard to the technique of the cardioplegia, warm (30°C to 37°C) blood cardioplegia has been suggested to better preserve myocardial metabolism and cardiac function than cold blood cardioplegia by preventing endothelial dysfunction [2, 3].
Angiotensin-converting enzyme (ACE) inhibitors have been considered as established drugs for the treatment of patients with depressed left ventricular function after acute myocardial infarction [4]. The protective effect of the regimens is considered to be mainly the results of the afterload reduction and favorable ventricular remodeling. In addition to the beneficial effects, it has been suggested that captopril, a sulfhydryl-containing ACE inhibitor, may exert cardioprotective effects during ischemia and reperfusion through its capacity to scavenge oxygen-derived free-radicals [5]. Therefore, it is expected that supplementation of captopril to warm blood cardioplegia provides superior myocardial protection by preventing the ischemia-reperfusion injury. In the present study, we used a blood-perfused, isolated rat heart preparation to investigate the influences of captopril supplementation during warm blood cardioplegia on cardiac function, myocardial metabolism, and leukocyte–endothelial cell interaction during reperfusion.
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Material and methods
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Blood-perfused, isolated rat heart preparation
All animals in this study received human care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institute of Health (National Institutes of Health publication 86-23, revised 1985). A large Wistar rat (450 to 550 g) was anesthetized with sodium pentobarbital (50 mg, intramuscularly) and anticoagulated with heparin (1,000 IU/kg per hour, intravenously). The rat was placed supine on a heating plate (HP-4530; Iuchi, Osaka, Japan) which was maintained at 38°C. Tracheotomy was then performed and the rat was ventilated and oxygenated with a ventilator (SAR-830/A; CWE, Ardomore, PA) to maintain arterial PO2 above 200 mm Hg and PCO2 within 30 to 40 mm Hg. Teflon catheters (Angiocath, 24-gauge, Becton Dickinson Vascular Access, Sandy, UT) were positioned in the left femoral vein (for the administration of fluids and the return of blood collected from the isolated perfused heart) and the left femoral artery (for supplying arterial blood to the isolated heart). The right femoral artery was also cannulated with the same catheter for monitoring systemic pressure of the support rat. During the experiments the support rats’ mean arterial blood pressure was maintained between 60 and 70 mm Hg.
The heart donor rat was anesthetized with 30 mg of intramuscular sodium pentobarbital and was anticoagulated with heparin (1,000 IU/kg, intravenously). The heart was excised rapidly and was perfused in the Langendorff mode with blood (36°C to 37°C) through a thermostatically controlled delivery line from the support rat by a peristaltic pump (NBM-1000, Mera, Tokyo, Japan). Perfusion was controlled with the aid of a pump speed driver that was designed to adjust the flow rate continuously to maintain a constant aortic pressure of 60 mm Hg. The interval between isolation of the heart and initiation of coronary perfusion was less than 30 seconds in all experiments. The coronary venous blood of the isolated heart was collected and returned to the support rat by means of the pump. The perfusion circuit was primed with 20 mL heparinized blood collected from another same strain rat and 20 mL lactated Ringer’s solution. The donor rat’s blood aspirated from the pericardium through a polypropylene filter by a syringe was also added to the perfusion circuit. Hematocrit of the perfusate was maintained between 25% and 30% and pH of the perfusate was maintained between 7.35 and 7.45 by an administration of sodium bicarbonate. Surfaces of all glass components in contact with blood were siliconized to minimize the activation of platelets and leukocytes.
Experimental protocol
After a 20-minute equilibrium period, the isolated heart was arrested with warm blood cardioplegia (37°C, 20 mL/kg) that was prepared by mixing four parts of oxygenated blood to each part of crystalloid solution (Fremes solution) by means of a syringe pump (CFV-3100, Nihon Kohden, Tokyo, Japan). Second and third dose of cardioplegia were given at 20-minute intervals. After 60 minutes of cardioplegic arrest, reperfusion was began with the 37°C oxygenated blood. The isolated hearts were divided into the following two groups according to the composition of cardioplegia received. In the control group ( ), standard warm blood cardioplegia was given. In the captopril group ( ), captopril, an ACE inhibitor (Sankyo, Tokyo, Japan) was added to the cardioplegia so that the concentration of captopril was 2 mmol/L.
Measurements
A bipolar pacing electrode was placed on the right ventricle and the heart was paced at 320 beats per minute. A latex balloon, inserted into the left ventricle through the left atrium, was connected by a short polyvinyl tube to a pressure transducer (P23XL; Gould-Statham Instruments, Hato Rey, PR). The balloon was large enough that no measurable pressure was generated by the balloon itself over the range of left ventricular volumes used during the experiment. Left ventricular function was evaluated during isovolumic contraction by inflating the intraventricular balloon with 0.01-mL increments of saline until left ventricular end-diastolic pressure (LVEDP) measured 3 mm Hg. Balloon volume was held constant so that an increase in LVEDP signified an increase in diastolic chamber stiffness. Left ventricular developed pressure (LVDP), LVEDP, positive maximum rate of left ventricular pressure rise (dp/dt, mm Hg/s) and negative maximum dp/dt (-dp/dt, mm Hg/s) were measured and recorded (Mingograf 7, Siemens-Elema AG, Solna, Sweden) after a 20-minute equilibrium period, at 30 minutes and 60 minutes of reperfusion. The coronary blood flow was measured by timed collection of the coronary sinus blood.
Arterial and coronary sinus blood samples were obtained simultaneously and were assayed for the determination of lactate, thiobarbituric acid reactive substances (TBARS), MB isoenzyme of creatinine kinase (CK-MB), circulating intercellular adhesion molecule-1 (ICAM-1), circulating vascular cell adhesion molecule-1 (VCAM-1), and circulating endothelial leukocyte adhesion molecule-1 (E-selectin). Blood samples for the determination of lactate, TBARS, and CK-MB levels were collected after a 20-minute equilibrium period, and then at 1 minute and 15 minutes of reperfusion. Blood samples for the determination of ICAM-1, VCAM-1, and E-selectin levels were collected after a 20-minute equilibrium period, and then at 30 minutes and 60 minutes of reperfusion. Lactate concentration was measured in protein-free supernatant by an enzymatic method (7150 Automatic Analyzer; Hitachi, Tokyo, Japan). CK-MB levels were measured with a chemiluminescent immunoassay (Type II Chemilumi-Analyzer; Ciba Corning, Medfield, MA) and TBARS levels were measured with a thiobarbituric acid reaction (RF-5000; Shimadzu, Tokyo, Japan). Blood samples for the determination of ICAM-1, VCAM-1, and E-selectin levels were drawn in precooled tubes containing EDTA2Na. The samples were immediately centrifuged at 4°C (15 minutes, 600 g) and were stored at -80°C until analysis. Plasma levels of these adhesion molecules were measured with an enzyme-linked immunosorbent assay (Immunoreader E-max; Wako Pure Chemical Industries, Osaka, Japan). These assays were performed with commercially available kits (R & D Systems, Minneapolis, MN) and their sensitivity (minimal detectable dose) for ICAM-1 is less than 0.35 ng/mL, for VCAM-1 less than 2 ng/mL, and for E-selectin less than 1.0 ng/mL. Cardiac release of these measured parameters were calculated as coronary blood flow multiplied by the difference between the coronary arterial and coronary venous content.
Statistical analysis
Statistical analysis was performed with StatView 5.0 software (SAS Institute, Cary, NC). All data are expressed as the mean ± the standard error of the mean. One-way or two-way repeated-measures analysis of variance was used to test the effect of cardioplegia group and time on cardiac function, lactate, CK-MB, TBARS, and adhesion molecules. When analysis of variance indicated a significant effect of cardioplegia group or time (p < 0.05), the differences were specified with Scheffé’s test for within-group comparison and unpaired Student’s t test for between-group comparison. Significance was assumed at a probability level of less than 0.05.
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Results
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Cardiac function
There were no significant differences in the base line cardiac function between the groups (Fig 1). Marked increases in LVEDP were observed in the control group during reperfusion and the levels were significantly (p < 0.05) greater than those in the captopril group at 30 minutes and 60 minutes of reperfusion. Although within-group comparison demonstrated marked decreases in LVDP in both groups at 30 minutes of reperfusion, the decrease was not significant in the captopril group by 60 minutes of reperfusion. No significant difference was found in dp/dt between the groups at any time. The captopril group resulted in significantly (p < 0.05) less -dp/dt than the control group at 60 minutes of reperfusion. The coronary blood flow was significantly (p < 0.05) greater in the captopril group than in the control group at 30 minutes and 60 minutes of reperfusion.
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Fig 1. Cardiac function. LVEDP was significantly (p < 0.05) greater in the control group than those in the captopril group during reperfusion. The captopril group resulted in significantly less -dp/dt than the control group at 60 minutes of reperfusion. The coronary blood flow was significantly greater in the captopril group than in the control group during reperfusion. (Captopril = captopril group; CF = coronary blood flow; Control = control group; LVDP = left ventricular developed pressure; LVEDP = left ventricular end-diastolic pressure; NS = not significant; pre = before ischemia; 30 minutes = 30 minutes of reperfusion; 60 minutes = 60 minutes of reperfusion.)
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Lactate, MB isoenzyme of creatinine kinase, and thiobarbituric acid reactive substances metabolism
There were no significant differences in cardiac release of lactate, CK-MB, and TBARS between the groups during base line measurements (Fig 2). There was no significant difference in cardiac release of CK-MB between the groups at any time. Although a marked myocardial lactate release was found at 1 minute of reperfusion in both groups, the captopril group resulted in significantly less lactate release than the control group did at 1 minute and 15 minutes of reperfusion. A marked cardiac TBARS release was found in the control group at 1 minute of reperfusion, and the levels were significantly (p < 0.05) greater than the captopril group at 1 minute and 15 minutes of reperfusion.
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Fig 2. Cardiac release of lactate, TBARS, and CK-MB. The captopril group resulted in significantly less lactate release than the control group did at 15 minutes of reperfusion. A marked cardiac TBARS release was found in the control group at 1 minute of reperfusion, and the level was significantly (p < n 0.05) greater than the captopril group. (Captopril = captopril group; CK-MB = MB isoenzyme of creatinine kinase; Control = control group; NS = not significant; pre = before ischemia; TBARS = thiobarbituric acid reactive substances; 1 minute = 1 minute of reperfusion; 15 minutes = 15 minutes of reperfusion.)
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Circulating adhesion molecules
Cardiac release of VCAM-1 and E-selectin increased significantly (VCAM-1, p = 0.02 by one-way analysis of variance, p < 0.05 by Sheffé’s test; E-selectin, p = 0.03 by one-way analysis of variance, p < 0.05 by Sheffé’s test) at 60 minutes of reperfusion in both groups; however, no significant differences were found between the groups at any time (Fig 3). Cardiac release of ICAM-1 increased significantly (p = 0.01 by one-way analysis of variance, p < 0.05 by Sheffé’s test) in the control group at 60 minutes of reperfusion and the level was significantly (p = 0.02 by unpaired Student’s t test) greater than that in the captopril group.
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Fig 3. Cardiac release of adhesion molecules. No significant differences were found in the levels of cardiac release of VCAM-1 and E-selectin between the groups at any time. The level of cardiac ICAM-1 release was significantly lower in the captopril group at 60 minutes of reperfusion. (Captopril = captopril group; Control = control group; ICAM-1 = intercellular adhesion molecule-1; pre = before ischemia; VCAM-1 = vascular cell adhesion molecule-1; 30 minutes = 30 minute of reperfusion; 60 minutes = 60 minutes of reperfusion.)
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Comment
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It has been well documented for many years that myocardial ischemia and reperfusion impairs the endothelial function to release vasoactive substances such as endothelium-derived relaxing factor [6, 7]. This impairment of endothelium-dependent relaxation has been suggested to be attributable to oxygen-derived free radicals produced rapidly on reperfusion [7]. In cardiac surgical field, likewise, cardioplegic arrest and reperfusion may induce endothelial dysfunction mediated by the generation of oxygen-derived free radicals [8]. To date, a number of therapeutic interventions during ischemia and reperfusion to minimize the injury, including pharmacologic agents or leukocyte depletion, have been investigated in vitro and in vivo. With regard to the cardioplegic temperature, we demonstrated previously that coronary vascular resistance during infusion of cardioplegia was lower in either tepid or warm blood cardioplegia than that in cold blood cardioplegia, suggesting the preservation of endothelial function [2]. A recent report has also suggested that warm blood cardioplegia preserved endothelium-derived relaxation and ultrastructure of coronary endothelium, whereas cold crystalloid cardioplegia could not [3]. Because of these beneficial effects, warm blood cardioplegia was used in the present study.
It is well established that long-term treatment with ACE inhibitors has salutary effects on hemodynamics, neuroendocrine activation, and ventricular structure and function, and thus leads to a reduction in mortality in patients with myocardial infarction [4, 9, 10]. In addition to these long-term effects, early ACE inhibition during ischemia and reperfusion has also been suggested to be beneficial because it may act as a potent scavenger of free radicals [5, 11, 12]. In particular, thior- or sulfhydryl- (-SH) containing ACE inhibitors, such as captopril, zofenopril, and fentiapril, have been shown to be effective scavengers of nonsuperoxide free radicals whereas non-SH ACE inhibitors were not [12]. Captopril has also been shown to scavenge hydrogen peroxide and singlet oxygen and inhibit microsomal lipid peroxidation [12]. Moreover, because angiotensin II may cause a marked increase in superoxide anion levels in vascular smooth muscle [13], it is expected that ACE inhibition may prevent this phenomenon. In the present study, a marked release of TBARS (as a marker of lipid peroxidation) was observed in the control group immediately after reperfusion, whereas the levels were significantly less in the captopril group, a finding suggesting a reduction in lipid peroxidation by the captopril treatment. Because a primary site of free radical attack is believed to be membrane phospholipids in which the chain reaction of lipid peroxidation may be initiated, a reduced lipid peroxidation in the captopril group suggests free radical scavenging effect by the regimen. However, because the specific antioxidant effect of captopril was not investigated in detail in the present study and moreover, effects of captopril on free radical and oxidant scavenging are still controversial [14], further studies are required for firm conclusions.
Because ACE, also named kininase II, degradates bradykinin, which promotes synthesis of prostacyclin (PGI2) as well as nitric oxide, ACE inhibition may potentiate the vasodilation and attenuate reperfusion injury through the bradykinin-stimulated nitric oxide production [15, 16]. Therefore, as suggested by Linz and colleagues [15], the greater coronary flow and earlier resumption of lactate metabolism during reperfusion in the captopril group can potentially be explained by the augmented nitric oxide production by ACE inhibition. Although cardioprotective effects of nitric oxide is still unclear, recent reports have indicated that nitric oxide inhibits neutrophil superoxide anion production via direct effects on membrane components of the nicotinamide adenine dinucleotide phosphate oxidase [17] and inhibition of nitric oxide synthesis with L-nitro-arginine methyl ester (L-NAME) increases adherence of polymorphonuclear leukocytes to coronary endothelium [18]. We also have shown that L-arginine, a nitric oxide precursor, added to cardioplegic solution reduced endothelial inflammation during early reperfusion as assessed by cardiac release of circulating adhesion molecules [19]. Therefore, it seems likely that nitric oxide has cardioprotective effect during ischemia and reperfusion. In cultured endothelial cells, angiotensin II has been shown to stimulate the expression of adhesion molecule, and thus modulates the interaction of leukocytes with endothelial cells [20]. Thus, it is expected that both the augmentation of nitric oxide production and the decrease of angiotensin II synthesis by ACE inhibition attenuate endothelial injury as a results of ischemia and reperfusion. Among a number of adhesion molecules, ICAM-1, VCAM-1, and E-selectin are constitutively present on endothelial cells and are readily expressed on endothelium by ischemic insult [21]. ICAM-1 and VCAM-1 are important mediators in the firm adhesion of neutrophils to the vascular endothelium and E-selectin serves both as an adhesion and as a trigger that recruits the participation of additional adhesion molecules [21]. Therefore, to test the hypothesis that ACE inhibition attenuates endothelial injury during ischemia and reperfusion, cardiac release of these circulating adhesion molecules were measured in the present study. Our study has clearly shown that marked increases in the adhesion molecules were found in the control group, whereas the increase in ICAM-1 level was suppressed by the captopril treatment significantly. ICAM-1 has been reported to be the major counter-receptor on endothelial cells for CD11/CD18, which is the major form responsible for firm adhesion of neutrophils to the vascular endothelium. It has also been suggested that monoclonal antibody against ICAM-1, but not against E-selectin, leads to a marked preservation of coronary endothelium in myocardial ischemia and reperfusion [22, 23]. Thus, the lesser levels of circulating ICAM-1 after captopril cardioplegia in the present study indicated the inhibitory effect of ACE inhibition on leukocyte–endothelial cell interaction. However, histologic examination or myeloperoxidase assays, to determine quantitative changes in neutrophil infiltration, would be required for this conclusion. The mechanism of the action, as stated above, appears to be mediated by either an augmentation of nitric oxide production or a decrease of angiotensin II synthesis by ACE inhibition. Although physiologic significance of circulating adhesion molecules are still unclear, it has been shown that adhesion molecules are readily released by endothelial cells and the amount of soluble form released is directly correlated with cell surface expression in vitro [24, 25]. Therefore, we believe that the levels may be taken as an indirect but substantially relevant measure of the endothelial inflammatory response after ischemia and reperfusion.
Very recently, Ma and colleagues showed that a large amount of myocardial ischemia-reperfusion injury is programmed cell death [26]. It has also been demonstrated that captopril, as an oxygen-derived free radical scavenger, may provide cardioprotection by inhibiting oxygen-derived free radical-induced cardiomyocyte apoptosis [27]. Therefore, although it remains to be elucidated, the inhibitory effects of captopril on apoptosis might have contributed to the present results.
In summary, supplementation of captopril during warm blood cardioplegia preserved left ventricular diastolic compliance and coronary flow, and provided early recovery of lactate metabolism after cardioplegic arrest. The technique also reduced the cardiac release of TBARS and circulating ICAM during reperfusion. The results suggest that supplementation of captopril during warm blood cardioplegia may provide superior myocardial protection by suppressing lipid peroxidation and leukocyte–endothelial cell interaction during ischemia and reperfusion. The technique can be a novel cardioprotective strategy in patients undergoing cardiac operation.
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Acknowledgments
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This work was supported in part by the Grant-in-Aid for Encouragement of Young Scientists, Japan Society for the Promotion of Science, Japan (grant A-11770751 and grant A-11770753).
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Accepted for publication March 13, 2000.
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Ann. Thorac. Surg.,
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Abstract
Introduction
