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Ann Thorac Surg 1996;61:1651-1657
© 1996 The Society of Thoracic Surgeons

Original Article: Cardiovascular

Effect of L-Arginine on Metabolic Recovery of the Ischemic Myocardium

Michel Carrier, MD, Ahmad Khalil, MD, Alain Tourigny, Eng, B. Charles Solymoss, MD, L. Conrad Pelletier, MD

Department of Surgery, Montreal Heart Institute, Montreal, Quebec, Canada


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background. The release of nitric oxide is decreased after myocardial ischemia and reperfusion. Whereas the precursor L-arginine can stimulate the release of nitric oxide, its effect on metabolic recovery after myocardial ischemia is unknown.

Methods. To study the effect of L-arginine on metabolic recovery after myocardial ischemia, cardioplegia infusion, and reperfusion, 33 dogs were placed on cardiopulmonary bypass and subjected to a sequence of 30 minutes of normothermic global ischemia, 30 minutes of warm blood cardioplegic arrest, and 30 minutes of reperfusion. A pH probe was inserted in the anterior wall of the left ventricle, and tissue pH was measured throughout the experiment. Coronary blood flow in the left anterior descending coronary artery and the circumflex coronary artery was measured. Blood samples from the coronary sinus were taken to measure blood pH and levels of lactate, creatine kinase, and troponin T.

Results. In the control group of 9 dogs, tissue pH averaged 6.4 ± 0.1, 6.5 ± 0.1, and 6.8 ± 0.1 after the end of global ischemia, cardioplegia, and reperfusion, respectively. Tissue pH averaged 6.4 ± 0.1, 6.6 ± 0.1, and 6.9 ± 0.1, respectively, in the experimental group of 9 animals with 2 mmol/L of L-arginine added to the cardioplegic solution. Tissue pH averaged 6.2 ± 0.1, 6.7 ± 0.1, 7.1 ± 0.1, respectively, in the third group of 9 animals that received an additional infusion of L-arginine (10 mg•kg-1•min-1) during reperfusion. Tissue pH recovered faster in groups with L-arginine (p = 0.00001). A hyperemic response of coronary blood flow was shown at reperfusion in animals in the control group only. In 6 dogs, L-NAME (N-nitro-arginine methyl ester), an inhibitor of nitric oxide synthesis, was injected and resulted in a slower pH recovery on reperfusion compared with that of animals that received L-arginine.

Conclusions. The addition of L-arginine to the cardioplegic solution and the systemic circulation during reperfusion resulted in a significant increase in coronary blood flow during cardioplegia infusion and in a faster recovery of myocardial tissue pH, possibly by increasing coronary blood flow through the release of nitric oxide.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
See also page 1657.

L-Arginine is an amino acid precursor of nitric oxide, which has been identified as the endothelial-derived relaxing factor. The latter causes substantial vasorelaxation [1], inhibits platelet adhesion [2] and aggregation [3], reduces neutrophil interaction with the endothelium [4], and may neutralize superoxide radicals [5]. The former was shown to reduce infarct size, to lower myeloperoxidase activity in the ischemic region, and to preserve endothelial function in an experimental model of ischemia and reperfusion [6].

By promoting endothelial synthesis of nitric oxide, L-arginine may be a simple and effective additive to cardioplegic solution that could be useful in clinical practice. The objective of the present study was to evaluate L-arginine added to warm blood cardioplegia in the metabolic recovery of the myocardium after global myocardial ischemia, cardioplegia infusion, and reperfusion. We hypothesized that adding L-arginine to warm blood cardioplegia may improve metabolic recovery from ischemia by preserving endothelial cell function and by promoting the release of nitric oxide. In addition, the effect of infusing L-arginine during myocardial reperfusion was studied.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
The study was performed in 33 dogs weighing 25 to 30 kg. All animals received human care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

The animals were anesthetized with sodium pentobarbital (30 mg/kg) and ventilated using a Harvard respirator (Harvard Apparatus, South Natick, MA). After a median sternotomy and heparinization (3 mg/kg), the left femoral artery was cannulated for arterial inflow and the right atrium, for venous return. The cannulas were connected to a bubble oxygenator (Baxter Healthcare Corp, Irvine, CA) primed with Ringer's lactate solution. The coronary sinus was cannulated through a transatrial approach for blood sampling, and the left ventricle was vented with a line through the apex. A cannula for cardioplegia delivery was placed in the ascending aorta. The systemic temperature was maintained between 28° and 30°C throughout the procedure.

In the first group of 9 dogs, the cardioplegic solution was made of oxygenated blood diluted 4:1 with a crystalloid solution containing 130 mmol of sodium, 135 mmol of chloride, 3 mmol of calcium, 28 mmol of lactate, 20 g of mannitol, 0.17 g of sodium bicarbonate, and 80 mEq (high concentration) or 34 mEq (low concentration) of KCl per liter. The cardioplegic solution was maintained between 35° and 37°C and was administered at a rate of 150 ml/min. In the second group of 9 animals, 2 mmol of L-arginine was added to 1 L of crystalloid cardioplegic solution. In the third group of 9 dogs, L-arginine was added to the crystalloid solution (2 mmol/L), and an additional infusion of 10 mg•kg-1•min-1 of L-arginine was injected into the systemic circulation during myocardial reperfusion. L-NAME (N-nitro-arginine methyl ester), a powerful inhibitor of nitric oxide synthesis from L-arginine, was added to the cardioplegic solution (2 mmol/L) and injected at 10 µg•kg-1•min-1 during reperfusion in another group of 6 animals.

After the institution of cardiopulmonary bypass, global myocardial ischemia was obtained by clamping the ascending aorta for 30 minutes. After the period of global ischemia, the cardioplegic solution was infused over 30 minutes, after which the aorta was unclamped and the heart reperfused for 30 minutes. Interstitial pH was measured in the anterior myocardial wall throughout the periods of ischemia, cardioplegia infusion, and reperfusion. A tissue pH probe (Vascular Technology Inc, North Chelmsford, MA) was used, and a reference electrode was placed in the mouth of the animal to be in contact with the saliva. Both electrodes were connected to an electronic pH-meter unit. Data were computed and analyzed on a personal computer using an expert database program. A thermoneedle was implanted to monitor myocardial temperature, and that measurement was used to correct myocardial pH for temperature changes on the basis of the Nernst equation. Both pH and thermal probes were positioned in the anterior wall of the left ventricle. The pH electrode was calibrated before each experiment using a standard laboratory buffer solution with a pH of 7 at 35°C. Measures of interstitial pH were recorded every 2 seconds throughout the experiment, and averages were calculated for standardized periods of 100 seconds [7]. Blood flow in the left anterior descending coronary artery and in the circumflex coronary artery was measured with an electronic flowmeter (Transonic, Ithaca, NY).

Blood samples were withdrawn from the coronary sinus for determination of coronary venous pH and levels of lactate, creatine kinase, and troponin T before and after each period of ischemia, cardioplegia, and reperfusion. Lactate production and creatine kinase release were measured using specific enzymatic methods. Troponin T was measured with a newly developed enzymatic-linked immunosorbent assay (Boehringer Mannheim, Mannheim, Germany) [8].

The hemoglobin concentration, hematocrit values, and serum potassium levels in the blood cardioplegic solution were similar between the three groups. The hemoglobin level averaged 4 ± 1 g/L, the hematocrit averaged 13% ± 2%, and the serum potassium concentration averaged 11 ± 2 mEq/L.

The data are presented as the mean ± the standard error. Differences between groups were analyzed using the repeated-measures analysis of variance for a three-factor design (Solo; BMDP Statistical Software Inc, Los Angeles, CA) and the Scheffé test for intergroup comparisons. Differences between the three cardioplegia groups (cardioplegia effect), changes in variables occurring with time during cardioplegia infusion and reperfusion (time effect), and the interaction between cardioplegia effects and time effects were analyzed. The primary hypothesis tested in this study was that a significant interaction exists between the cardioplegia effect and the time effect, ie, changes in studied variables were not similar over time in the three cardioplegia groups [9]. The level of significance was established at 95% (p < 0.05).


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Effect of Global Ischemia on Interstitial pH and Myocardial Metabolic Markers
After 30 minutes of global myocardial ischemia created by cross-clamping the ascending aorta, interstitial myocardial pH was similar in all experimental groups. It averaged 6.4 ± 0.1 in the control group, 6.4 ± 0.1 in the group with L-arginine added to the cardioplegic solution, 6.2 ± 0.1 in animals treated with L-arginine during cardioplegia and reperfusion, and 6.2 ± 0.1 in animals with L-NAME infusion, differences that were not significant. Venous pH and lactate, troponin T, and creatine kinase levels in the coronary sinus blood were similar in all groups at the end of the period of global ischemia (Table 1Go).


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  		Table 1. . Metabolic Markers During Ischemia, Cardioplegia, and Reperfusiona
 
Effect of L-Arginine on Coronary Blood Flow
There was no significant difference in absolute value of coronary blood flow in the left anterior descending coronary artery between the control group and the two groups treated with L-arginine (cardioplegia effect, p = 0.06), although changes in blood flow with time throughout the periods of cardioplegia infusion and reperfusion were significant (time effect, p = 0.04). There was also a significant difference in the interaction between cardioplegia effect and time effect (p = 0.00001) between groups. The analysis suggests that changes in blood flow occurred during cardioplegia infusion and reperfusion and that these changes were different for the three cardioplegia groups. Whereas a hyperemic response of coronary blood flow was shown at reperfusion in the control group, blood flow remained stable during reperfusion in animals treated with L-arginine (Fig 1Go).



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  		Fig 1. . Changes in blood flow in left anterior descending coronary artery. A significant hyperemic response was shown at reperfusion in the control group. (Control = control animals; L-Arginine (cardio) = animals treated with L-arginine during cardioplegia infusion; L-Arginine (cardio + rep) = animals treated with L-arginine during cardioplegia and reperfusion; arrow = myocardial reperfusion.)

 
There were no significant differences in absolute values of coronary blood flow (cardioplegia effect, p = 0.17) or in flow changes with time (time effect, p = 0.37) in the circumflex coronary artery throughout cardioplegia infusion and reperfusion. The interaction between the three cardioplegia groups was significant (interaction between cardioplegia effect and time effect, p = 0.00001), indicating that the changes in coronary blood flow were different in each group during cardioplegia infusion and reperfusion (Fig 2Go). Coronary blood flow during cardioplegia infusion was higher in animals treated with L-arginine. However, control animals displayed a hyperemic response on reperfusion.



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  		Fig 2. . Changes in blood flow in circumflex coronary artery. A significant hyperemic response was shown at reperfusion in the control group. Blood flow was higher during cardioplegia infusion in groups with L-arginine. (arrow = myocardial reperfusion; abbreviations are the same as in Fig 1Go.)

 
Effect of L-Arginine on Myocardial Tissue pH
Changes in tissue pH with time were significant (time effect, p = 0.00001), as was the interaction between the control group and the two groups treated with L-arginine (interaction between cardioplegia effect and time effect, p = 0.00001), although the absolute pH values were not different in the three groups throughout the various periods of ischemia, cardioplegia infusion, and reperfusion (cardioplegia effect, p = 0.8). This indicates that interstitial tissue pH decreased significantly during ischemia but recovered faster during reperfusion in animals treated with L-arginine compared with the control group (Fig 3Go).



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  		Fig 3. . Changes in myocardial tissue pH. Changes were similar between the three groups during ischemia and infusion of cardioplegic solution. The pH recovered faster on reperfusion in L-arginine-treated groups (p = 0.00001). (arrow = beginning of cardioplegia infusion; double arrow = myocardial reperfusion; abbreviations are the same as in Fig 1Go.)

 
Effect of Inhibition of Nitric Oxide Synthesis With L-NAME
The effect of inhibiting the synthesis of nitric oxide with L-NAME (6 animals) was compared with nitric oxide stimulation with L-arginine (9 animals) during cardioplegia injection and reperfusion. Changes in tissue pH with time were significant (p = 0.00001), as was the interaction between the two groups (interaction between cardioplegia effect and time effect, p = 0.01), although average pH values were not different between the two groups throughout the various periods of ischemia, cardioplegia, and reperfusion (cardioplegia effect, p = 0.63). This analysis and the data shown in Figure 4Go suggest that changes in myocardial tissue pH were similar during the period of cardioplegia infusion but that tissue pH recovered faster during reperfusion in the group with L-arginine compared with animals receiving L-NAME.



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  		Fig 4. . Changes in myocardial tissue pH in hearts treated with L-arginine and L-NAME (N-nitro-arginine methyl ester) during cardioplegia infusion and reperfusion. Tissue pH recovered faster on reperfusion in the group treated with L-arginine than in that treated with L-NAME.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Several authors [10–12] have shown that endothelial dysfunction occurs after myocardial ischemia and reperfusion and that the release of nitric oxide is significantly reduced in both in vitro and in vivo experimental models. Pearson and associates [13] reported that global myocardial ischemia and reperfusion impairs the endothelium-dependent relaxation response to aggregating platelets and that G proteins, which normally regulate intracellular endothelial-derived relaxing factor synthesis, are damaged and therefore are probably responsible for the decrease in nitric oxide release [14].

According to Nakanishi and co-workers [15], reperfusion with cold blood cardioplegia after normothermic ischemia impairs endothelium-dependent coronary relaxation and is associated with anatomic damage to the endothelium. Thus, blood cardioplegia does not prevent reperfusion injury to the endothelium, a finding suggesting that adjunct therapy may be necessary to prevent damage and dysfunction. L-Arginine, the physiologic precursor of nitric oxide, and donors of nitric oxide were suggested as potential adjuncts to blood cardioplegia.

Several studies [10–16] have shown that no or minimal damage to and dysfunction of the endothelium occur during cold and warm ischemic periods but that reperfusion is mainly responsible for structural and functional changes in the coronary endothelium [17]. Sellke and colleagues [18] found that cold potassium cardioplegia impairs endothelium-dependent microvascular relaxation. On the other hand, Evora and coauthors [19] suggested that the cardioplegic solution itself is not responsible for endothelial damage because relaxation responses of the coronary arteries to acetylcholine remained normal in epicardial coronary arteries. Moreover, G proteins responded normally to stimulation by promoting endothelial-derived relaxing factor release and coronary vasorelaxation. Finally, decreased microvascular blood flow and increased neutrophil accumulation in tissues after perfusion with hypothermic hyperkalemic crystalloid cardioplegic solutions and blood reperfusion were observed by Keller and associates [20].

Several groups have investigated the ability of L-arginine to protect the coronary endothelium from ischemic and reperfusion damage. L-Arginine administered during ischemia and reperfusion decreased the area of myocardial necrosis and myeloperoxidase activity in the ischemic region, with preservation of the endothelium-dependent relaxation to acetylcholine, in a model of ischemia and myocardial reperfusion in the cat [6]. In the neonatal lamb, L-arginine-supplemented hearts had better recovery of left ventricular function and coronary flow after hypothermic ischemia [1]. In the dog, Sato and co-workers [21] showed that L-arginine used as an adjunct to blood cardioplegia reduced infarct size, restored postischemic systolic and diastolic function in the ischemic and reperfused segment, and may act by recruiting endogenous nitric oxide from the vascular endothelium. Nitric oxide donor agent SPM-5185 improves coronary endothelial and ventricular function after global ischemia, cardioplegia and reperfusion [22]. On the other hand, Matheis [23], Naseem [24], and their colleagues suggested that inhibition of nitric oxide synthesis may protect against myocardial reoxygenation injury.

In the present study, blood cardioplegic solution with L-arginine administered after normothermic global ischemia resulted in a higher blood flow in the circumflex coronary artery during cardioplegia infusion and caused a loss of the initial hyperemic response on reperfusion. Myocardial tissue pH recovered faster during reperfusion in L-arginine-treated animals than in the control group and the animals treated with L-NAME. Although troponin T and serum creatine kinase levels were similar in all groups during ischemia, cardioplegia injection, and reperfusion, serum lactate levels in the coronary sinus were significantly higher in control animals than in those treated with L-arginine.

The beneficial effect of L-arginine supplementation and nitric oxide stimulation during cardioplegia infusion and myocardial reperfusion remains controversial. Although blood flow in the circumflex artery was higher in L-arginine-treated animals during cardioplegia infusion, a finding suggesting a higher local release of nitric oxide, blood flow in the left anterior descending coronary artery was not significantly altered. In the dog, basal coronary blood flow is lower in the left anterior descending coronary artery than in the circumflex coronary artery, and small changes may be more difficult to measure accurately. The initial hyperemic response on reperfusion found in control animals suggests that coronary endothelium still released nitric oxide and adenosine, a response that was absent in L-arginine-treated animals [25–28]. Successful repayment of blood flow debt during infusion of cardioplegic solution with L-arginine could explain the absence of a hyperemic reaction in these hearts. Because recovery of myocardial tissue pH was similar in all groups during cardioplegia infusion but faster during reperfusion in hearts supplemented with L-arginine, mechanisms other than increase in coronary blood flow could be involved in the response. It is known that nitric oxide inhibits platelet and neutrophil aggregation and adhesion to subendothelial extracellular matrix and postcapillary veins and that endothelium-derived nitric oxide decreases neutrophil interaction with the endothelium under whole-blood arterial flow conditions [4]. Thus, by synthesizing nitric oxide from the amino-acid precursor L-arginine, vascular endothelial cells play an important role not only in the relaxation of the underlying vascular smooth muscle but also in the modulation of circulating blood cell interaction with the vessel wall [2, 4]. Reperfusion with neutrophil-depleted blood is associated with improved postischemic function after cardioplegic arrest [29, 30], and a decrease in basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adhesion to the coronary endothelium [31]. Adding L-arginine to coronary artery blood significantly attenuates the increase in neutrophil adherence in these experiments [32].

Several other possible mechanisms, including depletion of L-arginine, blockade of recycling of L-citrulline to L-arginine, decreased enzyme activity in nitric oxide synthase, and inhibition of nitric oxide synthesis by oxygen-derived free radicals, can explain the decrease in nitric oxide release with ischemia and reperfusion [31]. Although several questions remain unanswered, L-arginine appears to improve both coronary blood flow during cardioplegia infusion without a hyperemic response at reperfusion and recovery of interstitial tissue pH on reperfusion compared with the results in hearts without L-arginine or supplemented with the inhibitor of nitric oxide synthesis L-NAME.

In conclusion, nitric oxide plays a major role in the regulation of coronary endothelial function and vessel wall function under normal conditions, a regulatory mechanism that is lost after ischemia and reperfusion. Our data suggest that warm blood cardioplegic solution with L-arginine and systemic blood reperfusion supplemented with L-arginine improves metabolic recovery of the heart monitored by interstitial tissue pH after global myocardial ischemia.


   Footnotes
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Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 
Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29-31, 1996.

Address reprint requests to Dr Carrier, Montreal Heart Institute, 5000 Belanger St, Montreal, PQ H1T 1C8, Canada.


   References
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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M. Carrier, M. Pellerin, P. L. Page, N. R. Searle, R. Martineau, C. Caron, B. C. Solymoss, and L. C. Pelletier
Can L-arginine improve myocardial protection during cardioplegic arrest? Results of a phase I pilot study
Ann. Thorac. Surg., July 1, 1998; 66(1): 108 - 112.
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