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J Thorac Cardiovasc Surg 1995;110:172-179
© 1995 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

Additive effects of L-arginine infusion and leukocyte depletion on recovery after hypothermic ischemia in neonatal lamb hearts

Boston, Mass.

From the Department of Cardiac Surgery, Children's Hospital, and Harvard Medical School, Boston, Mass.

Received for publication Oct. 12, 1994. Accepted for publication Nov. 21, 1994. Address for reprints: John E. Mayer, Jr., MD, Department of Cardiac Surgery, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.

Abstract

Prior experiments on hypothermic ischemia/reperfusion have shown that (1) leukocytes have an important role in the injury resulting from hypothermic ischemia/reperfusion and (2) endothelial dysfunction with reduced release of nitric oxide occurs after hypothermic ischemia/reperfusion. L-Arginine is a nitric oxide precursor, and the effects of nitric oxide released from endothelial cells include vasorelaxation and inhibition of leukocyte adhesion to endothelium. The potential roles of an interaction between endothelial dysfunction and leukocyte-mediated injury were examined in neonatal hearts. Thirty-two isolated, blood-perfused neonatal lamb hearts were subjected to 2 hours of 10° C cardioplegic ischemia. Group L-arginine received a 3 mmol/L dose of L-arginine during the first 20 minutes of reperfusion. In group leukocyte depletion, leukocytes were depleted (Sepacell filter) from the perfusate before reperfusion. In group L-arginine+leukocyte depletion, leukocytes were depleted and a 3 mmol/L dose of L-arginine was infused during early reperfusion. The control group had no intervention during reperfusion. At 30 minutes of reperfusion, left ventricular maximum developed pressure, positive maximum and negative maximum first derivative of left ventricular pressure (dP/dt), developed pressure at V10 (volume that produces a left ventricular end-diastolic pressure of 10 mm Hg at baseline measurement), and dP/dt at V10 were measured. Coronary blood flow was continuously monitored and oxygen consumption was also measured to evaluate the metabolic recovery. In each heart, we also tested coronary vascular resistance response to the endothelium-dependent vasodilator acetylcholine 10^-7mol/L and the endothelium-independent vasodilator trinitroglycerin 3x10^-5mol/L to assess endothelial function. Results are given as mean percent recovery of baseline values ± standard deviation. Group L-arginine+leukocyte depletion showed significantly greater recovery of left ventricular function than the other three groups, and groups L-arginine and leukocyte depletion also showed better recovery than the control group (positive maximum dP/dt: control group = 68.3% ± 8.8%, group L-arginine = 88.8% ± 3.8%, group L-arginine+leukocyte depletion = 100.6% ± 8.7%, group leukocyte depletion = 79.3% ± 8.1%; p< 0.05). Groups L-arginine and L-arginine+leukocyte depletion had higher postischemic coronary blood flow than other groups (control group = 133.0% ± 31.6%, group L-arginine = 203.2% ± 32.1%, group L-arginine+leukocyte depletion = 222.0% ± 30.4%, group leukocyte depletion = 156.3% ± 29.0%; p< 0.05). Group L-arginine+leukocyte depletion showed higher oxygen consumption than the control group (control group = 76.1% ± 19.22.1%, group L-arginine = 96.8% ± 17.6%, group L-arginine+leukocyte depletion = 110.1% ± 19.2%, group leukocyte depletion = 94.4% ± 12.9%, p< 0.05). Groups L-arginine, L-arginine+leukocyte depletion, and leukocyte depletion showed greater recovery of the response to acetylcholine than the control group (control group = 39.9% ± 13.9%, group L-arginine = 61.0% ± 14.8%, group L-arginine+leukocyte depletion = 53.5% ± 14.1%, group leukocyte depletion = 57.9% ± 13.3%), but there were no intergroup differences in the response to trinitroglycerin (control group = 42.4% ± 15.6%, group L-arginine = 36.4% ± 15.4%, group L-arginine+leukocyte depletion = 37.7% ± 10.2%, and group leukocyte depletion = 36.5% ± 11.5%). Conclusion:Reperfusion with leukocyte depletion and L-arginine infusion during reperfusion have additiveeffects on the recovery of mechanical and endothelial function in neonatal lamb hearts. These results suggest that the beneficial effects of L-arginine involve mechanisms beyond leukocyte inhibition, most likely increased endothelial nitric oxide production. (J THORACCARDIOVASCSURG1995;110:172-9)

Prior experiments from our laboratories on hypothermic ischemia/reperfusion have shown that (1) leukocytes have an important role in the injury resulting from hypothermic ischemia/reperfusion ^1,2 and (2) endothelial dysfunction with reduced release of nitric oxide (NO) occurs after hypothermic ischemia/reperfusion. ³ NO is produced from the semiessential amino acid L-arginine as it is converted to L-citrulline by NO synthase in endothelial cells. ^4,5 In the vascular system, NO release from endothelial cells causes vasorelaxation ^6,7 in vessels, as well as inhibition of leukocyte aggregation. ⁸

We found that L-arginine infusion during early reperfusion improves functional recovery of neonatal lamb hearts after cold cardioplegic ischemia, ⁹ although others have reported that augmentation of NO production by L-arginine increases postischemic injury. ^10,11 However, the precise mechanism for the beneficial effects of NO in our experiments remain unclear. This study was designed to investigate the interactions between the endothelial dysfunction and leukocyte-mediated injury by examining the effects of L-arginine infusion with or without leukocyte depletion during reperfusion on functional recovery after cold cardioplegic ischemia.

MATERIALS AND METHODS

Experimental preparation
An isolated blood-perfused heart model previously described ^1,2,3,9 was used to study 32 hearts from neonatal lambs (2.3 to 5.9 kg, 2 to 7 days old). Animals were anesthetized with intramuscular ketamine (40 mg/kg), intubated, and supported by a respirator with inhalation of a 1:1 mixture of oxygen and nitrous oxide and 0.5% halothane. Through a median sternotomy, an arterial cannula with a blood pressure monitoring port was inserted into the brachiocephalic artery after systemic heparinization (2000 units). Coronary perfusion was established with a roller pump (Coronary Perfusion Pump, Olson Medical Products Inc., Ashland, Mass.) and oxygenator system (Bio-2, American Bentley, Irvine, Calif.) before isolation of the heart, providing no period of ischemia. After insertion of the left ventricular (LV) vent into the apex, the heart was isolated and placed on the temperature-controlled water bath. Both superior and inferior venae cavae were ligated and coronary venous return was drained with a cannula inserted into the right ventricle through the pulmonary artery. A sampling catheter was placed in the coronary sinus via the hemiazygos vein for coronary venous blood gas analysis. Heparinized fresh homologous blood was used as the perfusate, and it was oxygenated with a mixture of 20% oxygen, 5% carbon dioxide, and 75% nitrogen by use of a bubble oxygenator. Arterial pH was maintained at 7.4 (corrected to perfusate temperature) with sodium bicarbonate. Serum potassium and ionized calcium concentrations were maintained at 4 to 5 mEq/L and 1.0 mEq/L, respectively.

The temperatures of the perfusate, the water bath, and the myocardium were monitored with thermal probes. The perfusate and water bath were controlled at 37° C by a heater-circulator (model 1252-00, Cole-Parmer Instrument Co., Chicago, Ill.) except during the hypothermic phase, which was produced by circulating ice water. Coronary perfusion pressure was maintained constant at 60 mm Hg except during the hypothermic and reperfusion phases. A pressure transducer containing a latex balloon (SPC-350, Millar Instruments, Inc., Houston, Tex.) was placed inside the LV through the apex to measure the LV function. A Foley balloon catheter (10F) was inserted in the left atrium to prevent the LV balloon from herniating into the left atrium and to vent blood and air from the LV.

Measurements
LV function was measured during isovolumic contraction by inflating the intraventricular balloon as described previously ^1,2,3,9 with 0.5 ml increments of saline solution until an LV end-diastolic pressure of 20 mm Hg was reached. LV pressure and its first derivative (dP/dt) were recorded at each volume. The recovery of systolic function was evaluated by measuring the maximum developed pressure, positive maximum LV dP/dt, peak developed pressure at a constant balloon volume (V10), and peak dP/dt at V10. V10 was defined as the balloon volume to produce an end-diastolic pressure of 10 mm Hg during preischemic baseline measurement. Negative maximum dP/dt was measured before and after ischemia to assess the diastolic functional recovery. Coronary blood flow was assessed continuously by an in-line electromagnetic flowmeter (MFV-3100, Nihon Kohden, Tokyo, Japan), which was connected to the venous cannula. This flow was considered to represent total coronary blood flow. Coronary endothelial function was assessed by the coronary vascular resistance response to acetylcholine infusion as described previously. ^1,2,3,9 A vasodilator response to acetylcholine is dependent on the release of endothelium-derived relaxing factor. Acetylcholine was infused for 30 seconds into the side port of the arterial cannula at rates calculated to achieve an arterial concentration of 10^-7 mol/L. Maximum decrease in coronary vascular resistance during the acetylcholine infusion, divided by baseline coronary vascular resistance, was defined as the coronary vascular resistance response. Trinitroglycerin (3 x 10^-5 mol/L) was infused in the same way and the response of the coronary vascular resistance to infusion of trinitroglycerin was used to assess nonendothelium-dependent vasodilator capacity. The pump perfusion flow was not changed during these infusions. Both LV function and coronary endothelial function were measured before ischemia and 30 minutes after reperfusion. Myocardial oxygen consumption (MVO₂ ) was measured before ischemia and 5, 15, 20, and 30 minutes after reperfusion as described previously. ^1,2,3,9 Arterial and venous blood was collected with the heart in the beating nonworking state. The hemoglobin concentration and the oxygen saturation were measured with a blood gas analyzer (Stat Profile 5, NOVA Biomedical, Waltham, Mass.) and corrected for temperature and pH. MVO₂ was calculated by these values as the following equation:

MVO₂(ml/min per 100 gm tissue)

= (Arterial O₂ content – Coronary sinus O₂ content)

x CBF/myocardial wet weight

O₂ content (ml/dl)

= 1.39 x Hb x O₂ saturation/100 + 0.0031 x PO₂

where CBF is coronary blood flow, Hb is hemoglobin, and Po₂ is oxygen tension

Circulating white blood cell counts were measured with an automated counter (Technicon H-1, Miles Laboratories, Tarrytown, NY.).

Experimental protocol
Baseline measurements were made after a 20-minute equilibrium period. Then both the perfusate and water bath were cooled to 15° C. At 10 minutes after the start of cooling, when the myocardial temperature reached 15° C, the heart was subjected to cold cardioplegic ischemic arrest by infusion of 20 ml/kg body weight of cardioplegic solution over 2 minutes followed by topical cooling (myocardial temperature was maintained at 10° C). A second dose of cardioplegic solution (10 ml/kg) was given after 60 minutes. The composition of cardioplegic solution was 0.45% sodium chloride and 2.5% dextrose solution with a 20 mEq/L concentration of potassium chloride and a 6 mEq/L concentration of sodium bicarbonate (pH 7.4 at 37° C, osmolarity 360 mOsm/L). Reperfusion was begun with the perfusate at room temperature (25° C) and then rewarming to normothermia was carried out over 25 minutes. Mean coronary perfusion pressure was maintained at 20 mm Hg during the first 5 minutes, raised to 40 mm Hg during the second 5 minutes, and then kept at 60 mm Hg until the end of the experiment. During the cooling period and the first 15 minutes of reperfusion, the oxygenator was bubbled with a high concentration of oxygen (95% oxygen and 5% carbon dioxide) to imitate the arterial blood gas conditions as clinical cases. Thereafter the gas was changed to 20% oxygen, 5% carbon dioxide, and 75% nitrogen.

Experimental groups
The hearts were divided into four groups: In the control group (n = 8), blood alone was reperfused without intervention. In group L-arginine (n = 8), L-arginine was infused into the side port of the arterial cannula during the first 20 minutes of reperfusion at a rate calculated to achieve a concentration of 3 mmol/L⁹ in the coronary blood. In group leukocyte depletion (n = 8), the hearts were reperfused with blood depleted of leukocyte by passing all of the blood in the apparatus through a white blood cell removal filter (Sepacell R-500A, Asahi Medical Co., Tokyo, Japan) while the hearts were arrested. In group L-arginine + leukocyte depletion (n = 8), the hearts were reperfused with leukocyte-depleted blood and L-arginine was infused as in group L-arginine.

All animals in this study received humane 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 Institutes of Health (NIH Publication No. 80-23, revised 1978).

Statistics
All values were expressed as mean ± standard deviation and analyzed by a statistical analysis system (SPSS, SPSS Inc., Chicago, Ill.). The one-way analysis of variance and repeated-measures two-way analysis of variance were used to compare the differences in recovery between groups. Data were further compared by the Student-Newman-Keuls test if analysis of variance was significant. A p value less than 0.05 was considered to be significant.

RESULTS

Baseline measurement
There were no significant differences among the four groups in baseline data. (Table I).

LV function (Table II).
Groups L-arginine, L-arginine + leukocyte depletion, and leukocyte depletion achieved significantly greater recovery of all systolic function indices than the control group, including maximum developed pressure, positive maximum dP/dt, developed pressure at V10, and dP/dt at V10 at 30 minutes of reperfusion. Group L-arginine + leukocyte depletion also showed greater improvement in the recovery of maximum dP/dt and dP/dt at V10 than groups L-arginine and leukocyte depletion. Group L-arginine also showed better recovery of maximum developed pressure and maximum dP/dt than group leukocyte depletion. The effects on recovery of diastolic function were greatest in group L-arginine + leukocyte depletion, which had greater recovery of maximum negative dP/dt than the other three groups. Group L-arginine also showed better recovery than the control group.

Coronary blood flow (Table III).

MVO2(Table IV).

Coronary endothelial function (coronary vascular resistance response)(Table V).

These results demonstrate that either L-arginine administration or leukocyte depletion during reperfusion improved recovery of both systolic and diastolic ventricular function and endothelial function in neonatal lamb hearts after hypothermic cardioplegic ischemia. Moreover, L-arginine infusion combined with leukocyte depletion during reperfusion resulted in greater recovery of mechanical function and coronary blood flow than leukocyte depletion alone. This combination resulted in greater MVO₂ than in the control group.

Recent investigations have characterized endothelium-derived relaxing factor as NO. ^12,13 In the vascular system, NO release from endothelial cells accounts for vasorelaxation ^6,7 in vessels, as well as inhibition of platelet ¹⁴ and neutrophil aggregation. ⁸ Moreover, NO is a primary radical species and is inactivated by superoxide radicals ^15,16 ; but, conversely, NO may also neutralize superoxide radicals. ¹⁷ NO is produced from the semiessential amino acid L-arginine as it is converted to L-citrulline by NO synthase in endothelial cells. ^4,5 Because ischemia/reperfusion results in diminished NO release from endothelial cells, ¹⁸ attempts have been made to supplement the reduced NO to attenuate myocardial injury associated with ischemia/reperfusion injury. In normothermic ischemic models in cats or dogs, the administration of NO donors, ¹⁹ NO itself, ²⁰ or a precursor of NO L-arginine ^21,22 has been reported to ameliorate reperfusion injury. We ⁹ have previously demonstrated that infusion of L-arginine at 3 mmol/L during the early phase of reperfusion significantly improved endothelial dysfunction and functional recovery of the LV after hypothermic ischemia/reperfusion in neonatal lamb hearts.

The exact mechanisms by which L-arginine is beneficial remain unclear, but if NO release is maintained close to the site of injury, it could have cytoprotective effects by inhibiting neutrophil aggregation and adherence. Recently, NO has been shown to be an endogenous inhibitor of leukocyte chemotaxis, ²³ adherence, ²⁴ and activation. ²⁵ Normal endothelial cells release NO basally, and this NO may prevent leukocytes from adhering to endothelial cells. In contrast, decreased basal release of NO after myocardial ischemia/reperfusion will favor adherence of leukocytes to the coronary endothelium, which is likely involved in leukocyte-induced myocardial injury. ²⁶ In a report by Kubes, Suzuki, and Granger, ²⁴ inhibition of basal release of NO with N-nitro-L-arginine methyl ester (L-NAME) increased neutrophil adherence to postcapillary venular endothelium by fifteenfold. This increased neutrophil adherence was completely reversed with exogenous L-arginine, suggesting that endothelium-derived NO is an important intrinsic modulator of leukocyte adherence. ²⁴ However, the present study showed that the combination of L-arginine with leukocyte depletion during reperfusion resulted in the highest coronary blood flow and MVO₂ and functional recovery, which indicated that L-arginine appeared to have beneficial effects beyond leukocyte inhibitory effect to prevent "vascular stunning." ²⁷

Another possible mechanism of the cardioprotective effect of L-arginine is through direct coronary vasodilation. ^6,7 Our laboratory found that nitroglycerin administration would offset the deleterious effects of high-pressure reperfusion. ²⁸ We ²⁹ also found that vasodilation with nitroglycerin would provide better recovery of mechanical function in the postischemic period after cold cardioplegic ischemia. Increases in coronary blood flow may potentially lead to improved ventricular function through the Gregg or "garden hose" effect, ³⁰ but we ⁹ have shown that an infusion of L-arginine without ischemia does not improve ventricular function. Recent experiments from our laboratory have also shown that postischemic infusions of theophylline (which is an adenosine receptor antagonist) caused increased coronary blood flow and lowered coronary resistance, but was associated with worse recovery of ventricular function, leading us to conclude that coronary vasodilation alone during reperfusion is not sufficient to improve recovery of contractile function after hypothermic ischemia. ³¹

Increased endothelial production of NO with L-arginine infusion also may be cardioprotective through the action of directly quenching superoxide free radicals. NO is a primary radical species and is inactivated by superoxide radicals, ^15,16 but NO may also neutralize superoxide radicals. ¹⁷ Conditions associated with enhanced production of superoxide have been shown to increase neutrophil adherence. Thus administration of NO could prevent endothelial injury resulting from toxic substances such as superoxide radicals.

Others have reported that augmentation of NO by L-arginine increases postischemic injury or that blockade of NO synthase with an arginine analog decreases postischemic injury. ^10,11 The mechanism by which NO expresses deleterious effects is suggested to be cytotoxic peroxynitrite and hydroxyl radical formation from NO. ³² However, these observed deleterious effects may be model dependent. Takeuchi and associates ¹⁰ reported a negative inotropic effect of L-arginine in isolated rabbit hearts, but they used crystalloid perfusion, which may induce maximum vasodilation from the baseline measurement, and in that model the beneficial vasodilatory effect of L-arginine will be offset after reperfusion compared with our blood-perfused model. Despite the cytotoxic effects of NO observed in the in vitro study, NO has other tissue-sparing effects based on antineutrophil, antiplatelet, direct quenching of superoxide free radicals, and vasodilator actions within ischemic tissue. These may play much more important roles, especially in the in vivo environment.

The current studies have several limitations. First, the model that was used is an isolated, blood-perfused heart system. The advantages and disadvantages of this model for the assessment of cardiac function after ischemia have previously been discussed. ^1-3 We have continued to use this model because of the elimination of the influence of adrenergic, neural, and anesthetic variations and the ability to provide coronary blood flow independent of mechanical function of the heart.

Although the current experiments strongly suggest that the beneficial effects of L-arginine when administered after hypothermic ischemia seem to involve mechanisms beyond leukocyte inhibition, the precise mechanisms still remain unclear. The current experiments do clearly show that reperfusion with leukocyte-depleted blood and infusion of L-arginine at 3 mmol/L during reperfusion have additive effects on the functional recovery of neonatal lamb hearts after cold cardioplegic ischemia. Thus the beneficial effects of L-arginine after ischemia/reperfusion seem to involve mechanisms in addition to leukocyte inhibition, most likely enhanced endothelial production of NO. Additional studies in the whole animal will help to define the potential clinical value of postischemic infusion of L-arginine.

Acknowledgments

We thank Mark A. Cioffi, MAT, for his technical assistance.

Footnotes

J THORAC CARDIOVASC SURG 1995;110:172-9

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