Ann Thorac Surg 2003;75:197-203
© 2003 The Society of Thoracic Surgeons
Original article: cardiovascular
Effect of L-arginine or nitroglycerine during deep hypothermic circulatory arrest in neonatal lambs
Shinichi Hatsuoka, MDa,
Takahiko Sakamoto, MDa,
Ulrich A. Stock, MDa,
Mitsugi Nagashima, MDa,
John E. Mayer, Jr, MDa*
a Department of Cardiovascular Surgery, Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
* Address reprint requests to Dr Mayer, Department of Cardiovascular Surgery, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.
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Abstract
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BACKGROUND: The role of nitric oxide (NO) in ischemia-reperfusion injury remains controversial. This study evaluated the effects of L-arginine (NO precursor) or nitroglycerine (NO donor) on cardiac and lung function after deep hypothermic circulatory arrest in neonatal lambs.
METHODS: Three groups of anesthetized lambs underwent cardiopulmonary bypass, deep hypothermic circulatory arrest (120 minutes at 18°C), and rewarming (40 minutes). During reperfusion, L-arginine (5 mg/kg per minute), nitroglycerine (2 µg/kg per minute), or saline (control group) was infused for 100 minutes. All animals were separated from cardiopulmonary bypass and observed for 3 additional hours. Preload recruitable stroke work, cardiac index, pulmonary vascular resistance, alveolar-arterial oxygen difference, and lung compliance plasma nitrate/nitrite levels (NO metabolites) were measured before and after cardiopulmonary bypass. Malondialdehyde in heart tissue and lung tissue was measured 3 hours after cardiopulmonary bypass.
RESULTS: Recovery of preload recruitable stroke work and cardiac index were significantly higher in the L-arginine and nitroglycerine groups than in the control group (p < 0.05). Pulmonary vascular resistance was significantly lower in the L-arginine and nitroglycerine groups than in the control group (p < 0.05). Levels of NO metabolites and issue malondialdehyde did not differ among groups.
CONCLUSIONS: L-arginine and nitroglycerine improved recovery of left ventricular function and reduced pulmonary vascular resistance after deep hypothermic circulatory arrest. The mechanism of beneficial action could involve increased NO levels, but we did not find higher levels of NO metabolites compared with controls. Tissue malondialdehyde levels were not affected by L-arginine or nitroglycerine. These results show that, at these dosage levels, provision of substrate for NO production or provision of an NO donor were beneficial to the recovery of myocardial and pulmonary vascular function.
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Introduction
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Cardiac surgery for correction of congenital cardiac defects in neonates and infants often requires use of deep hypothermia and circulatory arrest (DHCA). Cardiopulmonary bypass with DHCA can result in myocardial dysfunction and high-permeability pulmonary edema (acute respiratory distress syndrome). Acute respiratory distress syndrome is associated with increased pulmonary vascular resistance and refractory hypoxemia, which are thought to be attributable to the loss of the reflex of hypoxic pulmonary vasoconstriction [1]. Some authors [2, 3] have shown that ischemia and reperfusion cause endothelial damage and that release of nitric oxide (NO) is significantly reduced. Nitric oxide (an endothelium-derived relaxing factor) is synthesized by NO synthase through the conversion of L-arginine to L-citrulline. Nitric oxide is released continuously by the endothelium and plays an important role in the control of vascular tone [4] through the relaxation of vascular smooth muscle [5]. Nitric oxide also inhibits platelet adhesion [6] and aggregation [7], reduces neutrophil interaction with the endothelium [8], and can inactivate superoxide free radicals generated by leukocytes [9]. Several studies suggest that L-arginine is protective against ishemia-reperfusion injury in hearts or lungs [10, 11]. The mechanism for this protective effect may involve the preservation of endothelial cell integrity by a reduction in neutrophil infiltration or through the scavenging capacity of NO for reactive oxygen species. However, other studies have shown a deleterious effect of NO ischemia-reperfusion injury. Increased peroxynitrite (OONO) and hydroxyl radicals (OH·) formation can result from NO production and may be cytotoxic to cardiac myocytes or lung [12, 13].
The purpose of the present study was to evaluate the effects of L-arginine and an NO donor (nitroglycerin), which were administered during reperfusion, on the recovery of cardiac and lung functions after DHCA.
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Material and methods
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Eighteen neonatal lambs (aged 3 to 6 days, weight 3.5 to 5.9 kg) were premedicated with ketamine (50 mg/kg) intramuscularly. Orotracheal intubation was performed, and mechanical ventilation was commenced (Servo ventilator 900C; Siemens-Elena, Danvers, MA) with a tidal volume of 20 mL/kg and 4 cm H2O positive end expiratory pressure (PEEP) less than 100% of inspired oxygen fraction (FiO2) during the experiment. The animals were anesthetized with a bolus infusion of fentanyl (200 µg/kg) followed by continuous infusion of ketamine (5 mg · kg-1 · h-1), midazolam (0.2 mg · kg-1 · h-1), fentanyl (50 µg · kg-1 · h-1), and pancuronium (0.2 mg · kg-1 · h-1) throughout the experiment. A 19-G catheter was inserted into the femoral artery and passed into the thoracic aorta to measure systemic arterial pressure and to sample blood gases. The heart was exposed through a median sternotomy. A 5-F side-hole catheter (Berman angiographic catheter; Arrow International Inc., Reading, PA) was inserted to measure pulmonary arterial pressure.
An electromagnetic flow probe (FR-100T, Nihon Kohden, Tokyo, Japan) was placed on the main pulmonary artery for the measurement of cardiac output. The ductus arteriosus was ligated. After systemic heparinization, a 5-F polyurethane sheath was inserted into left atrium for pressure measurement and blood sampling. A 19-G catheter (SPC-330; Millar Instruments Inc, Houston, TX) was placed into the left ventricular [LV]) cavity through the apex to measure LV pressure. Two pairs of ultrasonic transducers were implanted in the LV midmyocardium to measure the length of the long and short axis. Animals received 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 Institute of Laboratory Animal Resources and published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985).
Measurements
Cardiac function
Indices were measured using a digital ultrasonic measurement system (Sonometrics Corporation, Ontario, Canada). Left ventricular volume was calculated using the following ellipsoidal model: LV volume = 
(DL) (DS)2, where DL is long axis length and DS is short axis length obtained by ultrasonic tranducers.
Stroke work (SW) was calculated as the integral of LV pressure and LV volume over each cardiac cycle by the following formula:
where LVp is left ventricular pressure. Preload recruitable stroke work (PRSW) was calculated from the slope of the relation between SW and end-diastolic LV volume.
Lung function
Pulmonary vascular resistance (PVR) was calculated using the formula:
where PAP is mean pulmonary artery pressure, LAP is mean left arterial pressure, and CO is cardiac output.
Pulmonary dynamic compliance (Cdyn) was calculated with the lung mechanics calculator (Servo 940, Siemens-Elema, Sweden) according to the formula Cdyn (mL/cm H2O) = expiratory tidal volume (mL)/[pause pressure (cm H2O) - end expiratory lung pressure (cm H2O). Alveolar - arterial oxygen tension difference (A–aDO2) was calculated using the following equation: A–aDO2 (mm Hg) = 1 x (760 - 47) - PACO2 / R - measured PaO2, where PACO2 is alveolar carbon dioxide tension, R is the respiratory exchange ratio, and PaO2 is arterial oxygen tension. It is assumed that R = 0.85 and PACO2 is the same as arterial carbon dioxide tension.
Experimental protocol
After surgical instrumentation, animals were stabilized for 10 minutes. Then baseline cardiac and lung function were measured.
Cardiopulmonary bypass and postoperative management
The circuit for CPB consisted of a roller pump and a membrane oxygenator (VPCML; COBE Laboratories, Arvada, CO). The pump prime consisted of 50 mL/kg of Normosol R (Abbott Laboratories, North Chicago, IL) and 100 mL/kg of homologous heparanized donor blood to achieve a hematocrit of 20%. An 8-F arterial cannula and a 24-F venous cannula were placed into the left femoral artery and right atrium, respectively. The animals were cooled to 18°C for 30 minutes using a pH stat strategy. Cardiopulmonary bypass flow was maintained at 150 mL · kg-1 · min-1. The esophageal temperature was kept between 16 and 18°C using a temperature-controlled blanket during the 120 minutes of DHCA. The patent foramen ovale was closed using autologous pericardium through a right atriotomy during DHCA. The animal was rewarmed to achieve an esophageal temperature of 38°C. The heart was defibrillated if necessary at a temperature of 30°C. L-arginine was infused intravenously just before the onset of reperfusion as a continuous infusion of 5 mg · kg-1 · min-1 for 100 minutes. In controls, normal saline solution was infused at a rate of 1 mL/minute. Nitroglycerin infusion at 2 µg/kg per minute was started just before reperfusion and continued for 100 minutes. The animals were weaned from bypass and observed for 3 hours after reperfusion in both groups. The esophageal temperature was kept between 37 and 38°C.
Measurements
Preload recruitable stroke work and CI were measured before CPB and 30, 60, 120, and 180 minutes after CPB. Lung function, including AaDO2, lung compliance, PVR, systemic pulmonary pressure/systemic arterial pressure ratio (PAP/SAP) were measured before CPB and 15, 30, 60, 120, and 180 minutes after CPB. Blood samples were collected from the systemic coronary sinus artery, left atrium, and pulmonary artery before CPB and 15, 30, 60, 120, and 180 minutes after CPB. Myocardial oxygen extraction was determined as 2 [arterial - O2 content (coronary sinus)]/O2 content (arterial). Nitrate and nitrite were measured to assess NO production by modified Griess reaction [nitrate/nitrite colorimetric assay kit; Cayman Chemical, Ann Arbor, MI]. Heart and lung tissue samples were collected at the end of the experiment. Tissue malondialdehyde was measured using a spectrophotometric method [14]. Mitochondrial respiratory chain complexes were measured as follows: Cytochrome c oxidase (complex IV) was measured as described by Glerum and associates [15]. Succinate cytochromic c reductase (complexes II + III) by following the reduction of cytochrome e was measured as described by Fischer and colleagues [16]. Rotenone sensitive nicotine amide dinucleotide (reduced)-cytochrome c reductase activity (complex I + III) was measured by the method of Moreadith and associates [17].
Total body water was estimated by bioelectrical impedance [18]. If it is assumed that the animals have a relatively constant conduction configuration, the relationship between total body water and impedance is given by the following formula: Total body water 
height2/impedance, where impedance is calculated as (reactance2 + resistance2)0.5. The animals were placed in the supine position. The right forearm, upper arm, and lower leg were shaved and cleaned with ethyl alcohol to position the electrodes. The impedance readings were obtained using the Weight Manager Analyzer (BIA-I0IQ; RJL System, Clinton Township, MI), in which the current-transmitting clips were connected to the electrodes.
Statistics
All values are expressed as mean ± standard error of the mean (SEM). Cardiac index, PRSW, PVR, Cdyn, and bioimpedance were normalized by comparison to baseline values and expressed as a percentage of the baseline values. The paired Student’s t test and one-way analysis of variance were used for comparison of variables among experimental groups. If the analysis of variance revealed a significant interaction, pairwise tests of individual group means were compared by means of multiple comparisons (Tukey test) using a level of significance of p less than 0.05.
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Results
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There was no significant difference between groups for baseline values of CI, PRSW, PVR, PAP/SAP ratio, or other biochemistry data. There were no significant differences among the groups in systemic perfusion pressures after resumption of CPB.
Cardiac function
The percentage recovery of PRSW of 60 minutes after CPB was significantly higher in the L-arginine and nitroglycerine groups than in the control group. The percentage recovery of PRSW of 30 and 180 minutes after CPB remained significantly higher in the L-arginine group than in the control group (Fig 1A).
The percentage of recoveries of cardiac index at 30 and 60 minutes after CPB was significantly higher in the L-arginine and nitroglycerine groups than in the control group (Fig 1B).
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Fig 1. (A) Percentage recovery of preload recruitable stroke work before and after cardiopulmonary bypass (CPB). *p < 0.05 compared with nitroglycerine (TNG) and L-arginine group. #p < 0.05 compared with L-arginine group. (B) Percentage recovery of cardiac index before and after cardiopulmonary bypass *p < 0.05 compared with nitroglycerine and L-arginine groups.
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Lung function
The percentage of recoveries of PVR at 30 and 60 minutes after CPB were significantly better (lower) in the L-arginine and nitroglycerine groups than in the control group. The percentage of recoveries of PVR at 15, 120, and 180 minutes after CPB remained significantly better (lower) in nitroglycerine group than in the control group (Fig 2A).
The PAP/SAP ratios at 15 and 60 minutes after CPB were significantly lower in the L-arginine and nitroglycerine groups than in the control group (Fig 2B). There was no significant difference between groups for SAP at any time point. There was no significant difference among the three groups in AaDO2 (Fig 3A).
The percentage recovery of Cdyn at 60 minutes after CPB was significantly higher in the L-arginine group than in the control group (Fig 3B). There were no differences in percentage change of bioimpedance (Fig 4).
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Fig 2. (A) Percentage recovery of pulmonary vascular resistance before and after cardiopulmonary bypass (CPB). *p < 0.05 compared with nitroglycerine (TNG), L-arginine group; #p < 0.05 compared with nitroglycerine group. (B) Recovery of systemic pulmonary pressure/systemic arterial pressure ratio (PAP/SAP) before and after cardiopulmonary bypass. *p < 0.05 compared with nitroglycerine, L-arginine group; #p < 0.05 compared with nitroglycerine group.
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Fig 3. (A) Percentage recovery of alveolar-arterial oxygen tension difference before and after cardiopulmonary bypass (CPB). (N.S. = not significant.) (B) Percentage recovery of lung compliance. *p < 0.05 compared with L-arginine group.
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Fig 4. Percentage recovery of bioelectric impedance. (CPB = cardiopulmonary bypass; N.S. = not significant; TNG = nitroglycerine.)
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Biochemical studies
There were no significant differences among the three groups in nitrate/nitrite (Fig 5A),
heart malondialdehyde, and lung malondialdehyde (Fig 5A). Nitric oxide metabolites at 30 and 60 minutes after CPB were significantly higher than at baseline in both L-arginine and nitroglycerine groups. However, there were no significant differences between groups for NO metabolites (Figure 5B). There were no significant differences in mitochondrial respiratory function between groups (Fig 6A).
However, the myocardial oxygen extraction ratio at 60 minutes after CPB was significantly lower in the L-arginine group than in the control group (Fig 6B).
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Fig 5. (A) Nitric oxide metabolites in the coronary sinus plasma before and after cardiopulmonary bypass. (B) Malondialdehyde (MDA) in heart and lung tissue. (CPB = cardiopulmonary bypass; N.S. = not significant; TNG = nitroglycerine.)
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Fig 6. (A) Mitochondrial respiratory chain complex activities. (B) Percentage recovery of oxygen extraction ratio before and after cardiopulmonary bypass (CPB). *p < 0.05 control group vs. L–arginine and vs. TNG. (COX = cytochrome c oxidase; N.S. = not significant; TNG = nitroglycerine.)
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Comment
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The results of this study suggest that the addition of L-arginine or nitroglycerine during reperfusion appears to have a beneficial effect on the recovery of cardiac and lung function after DHCA. Possible mechanisms for the beneficial effects of NO are scavenging oxygen-derived free radicals [9], blocking both neutrophil aggregation and neutrophil adhesion [8], direct coronary vasodilation [4], and decreasing oxygen demands through vasodilation-induced hypotension.
Nitric oxide and cardiac function
We found that when the NO precursor L-arginine or the NO donor nitroglycerine is administered during reperfusion after DHCA, both the percentage recovery of PRSW and percentage recovery of cardiac index were improved without increasing the heart tissue malondialdehyde and without decreasing the activities of mitochrondrial respiratory chain complexes. These results suggest that the administration of L-arginine or nitroglycerine during reperfusion might be a useful therapeutic maneuver and that provision of either increased amounts of NO substrate or a NO donor did not result in increased malondialdehyde (free radical) production. Contrary to the results of this study, administration of a NO synthase inhibitor has been shown to decrease postischemic injury in some studies in rabbits. Radi and associates [19] reported that peroxynitrite, formed as a result of the interaction between superoxide anions and NO, exerts cytotoxic effects. Beckman and colleagues [20] suggested that generation of hydroxyl radical (OH·) by the Haber-Weiss pathway might be limited in vivo and proposed that during the decompensation of ONOO, the highly reactive oxygen species, OH· can be formed by the following mechanism:
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However, the present study demonstrates that in this experimental model, NO supplemention did not increase the production of malondialdehyde, which is an indicator of free-radical production and oxidative stress. Recently, endogenous peroxynitrite (ONOO) formation derived from NO and superoxide (O2) has been suggested to be responsible for the cardiac contractile dysfunction and the inhibiton of mitochondrial respiration during postischemic reperfusion [21]. Although our results showed that the oxygen extraction ratio of the heart was lower in the L-arginine group than in the control group, neither L-arginine nor nitroglycerine decreased the activities of mitochondrial respiratory chain complexes. It is possible that the oxygen extraction ratio decreased in the L-arginine group because of an increase in coronary blood flow, but coronary blood flow was not measured in this study. One possible explanation for this discrepancy between the various studies could be the differences in the types of perfusate (blood versus crystalloid) and the time at which L-arginine or nitroglycerine was infused. In the blood-perfused model which we used, the action of L-arginine or nitroglycerine on platelets and neutrophils might have had a greater magnitude of effect than any direct free radical–promoting effect. In our experiments, NO metabolites at 30 and 60 minutes after CPB were significantly higher than baseline in both the L-arginine and nitroglycerine groups. However, there were no significant differences between the experimental groups for nitric oxide release. This finding suggests that NO was not overproduced in this model. Kronon and associates [22] reported that the beneficial effect of L-arginine is dose dependent and that high-dose L-arginine increased oxygen free radical production resulting in vascular and myocardial dysfunction. Several studies have investigated the effect of L-arginine or nitroglycerine administered during ischemia as a cardioplegia additive on the recovery of cardiac function. The results of cardioplegic experiments are not consistent. Recently, Nonami and colleagues [23] demonstrated that L-arginine administered to human ventricular myocytes during reoxygenation was more effective than preischemic L-arginine treatment. The variable results of these studies suggest that dosages or timing of L-arginine or NO donors may be responsible for the variable effects. Further studies are required to determine the optimal dose and timing of L-arginine or NO donor administration.
Nitric oxide and lung function
Cardiopulmonary bypass and DHCA often cause lung dysfunction, with increased pulmonary resistance, pulmonary edema, and impaired gas exchange. That dysfunction remains a significant cause of morbidity in patients with impaired right ventricular function. Pulmonary vasomotor tone is modulated by the vascular endothelium, which maintains a balance between vasodilators and vasoconstrictors. Cardiopulmonary bypass with DHCA may alter the balance by impairing endothelium-dependent vasodilation and increasing production of vasoconstrictors. Our results show that L-arginine or nitroglycerine decreased PVR and PAP/SAP after DHCA. The inflammatory response resulted in an increase in vascular fluid and protein leakage as well as leukocyte activation and adhesion in postcapillary venules. Our bioimpedance results show the possibility that NO is an important mediator of fluid accumulation during cardiopulmonary bypass with DHCA. This finding also suggests that NO might modulate microvascular permeability and minimize pulmonary edema. The results are in agreement with recent studies showing that inhaled NO reduces microvascular injury produced by an oxygen radical generation system [24]. However, the protective mechanism of NO donors against ischemia-reperfusion–induced microvascular injury is still not known. It is possible that NO donors prevent microvascular damage by increasing cyclic guanosine monophosphate levels in leukocytes and by reducing leukocyte-endothelial cell interactions and neutrophil reaction in the lung [25]. Nitric oxide is also known to decrease platelet aggregation [7]. This decrease in platelet aggregation may improve the microcirculation in the pulmonary vascular bed. However, the impairments in gas exchange function were only partially reversed by L-arginine.
In contrast with our results, some studies have shown that oxidative lung injury could be induced by L-arginine infusion. They indicate that NO has the ability to form the toxic reactive oxygen species peroxynitrite in the presence of superoxide [13]. As in the case of cardiac function, these discrepancies may result from model differences.
In conclusion, the addition of a NO precursor or a NO donor during reperfusion had beneficial effects on cardiac and lung function. The toxic reaction mediated by peroxynitrite production in ischemia-reperfusion injury did not appear to be present in our model. Although the exact mechanism of the protective or toxic effects still remains unclear, NO appears to be a potentially important component in the recovery of myocardial and lung function from ischemia-reperfusion injury. Further studies are required to determine the optimal dose and timing of L-arginine or NO donor administration.
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Discussion
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DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): That was a very nice presentation, a very nice study.
One comment on nitric oxide versus peroxynitrite, because many people do look at nitric oxide as having two sides. Really, you only see damaging effects if you have very, very high doses or concentrations of nitric oxide, or if you are using nitric oxide in crystalloid solutions where there is no detoxifying agent such as glutathione or other thiol agents. So, it is not very surprising, and it is actually gratifying to see, that you found beneficial effects with nitric oxide in your in vivo model.
And one question: Did you use a different donor than nitroglycerine, maybe a more spontaneous donor than nitroglycerine? And what is your mechanism of action?
DR HATSUOKA: I thank you very much for your question.
Certainly nitric oxide has been found to have both good and bad effects in various studies. In the blood-perfused model, the action of L-arginine or nitroglycerine on platelets and neutrophils may have a confounding effect and make it difficult to determine the actual effect of L-arginine or nitroglycerine on the myocardium or lung. Our results did show that there was no significant difference in malondialdehyde between groups. We think that the possible explanation for the discrepancy of many nitric oxide studies may be due to difference in the perfusate, and therefore further studies would be required to solve the problem of the optimal dose or optimal time at the infusion.
DR JOHN W. BROWN (Indianapolis, IN): I guess I like to take the privilege of the podium to ask the senior author, John Mayer, to make a comment as to whether or not the use of L-arginine or nitroglycerine has crept into their clinical practice and whether it has affected their use of nitric oxide in the pre- and postoperative management of children with congenital heart disease.
DR MAYER: Well, I would say that I routinely administer nitroglycerine beginning 5 or 10 minutes before we take the aortic cross-clamp off as part of a routine clinical practice. So to that extent I guess you can say this has more than crept into our clinical practice.
When we initially got involved in the studies around nitric oxide, one of the thoughts that I had was to infuse L-arginine; maybe that would be an interesting study to do. But since nitroglycerine is so available and does not have demonstrably different effects, at least in these kinds of studies, and is much less expensive than trying to make up drips containing L-arginine, we chose to go with the nitroglycerine.
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Abstract
Introduction
