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Eur J Cardiothorac Surg 1998;14:76-81
© 1998 Elsevier Science NL

Effects of adenosine infusion with or without leukocyte depletion on recovery after hypothermic ischemia in neonatal lamb hearts

Fumikazu Nomura, Mitsuru Aoki, Joseph M. Forbess, John E. Mayer, Jr.

The Department of Cardiovascular Surgery, Children's Hospital, Boston, MA, USA

Received 2 February 1998; received in revised form 30 March 1998; accepted 7 April 1998.

Corresponding author. Cardiovascular Surgery, Kure National Hospital, 3-1 Aoyama, Kure, Hiroshima, Japan. Tel.: +81 823 223111; fax: +81 823 210478; e-mail: fnomura@kure-nh.go.jp


   Abstract
Top
 Abstract
Introduction
Results
 Discussion
References
 
Objective: Leukocytes have been shown to have an important role in ischemia/reperfusion injury. Adenosine also reduced this ischemia/reperfusion injury. There is an interaction between adenosine and leukocyte via receptor mediated function. To determine whether beneficial effects of adenosine on reperfusion injury is mediated by changes in leukocyte function, we studied the effects of adenosine with and without leukocyte depletion during reperfusion on the functional recovery of the neonatal myocardium after cold cardioplegic arrest. Materials and methods: We infused adenosine (350 µmol/l) during the first 20 min of reperfusion for adenosine treated group and adenosine-leukocyte treated group. The other two groups were perfused with leukocyte treated blood or untreated blood. All the groups were subjected to 2 h of cold cardioplegic ischemia (n=8 in each group). At 30 min of reperfusion, LV function was measured. Coronary blood flow and oxygen consumption (MVO2) were also measured to evaluate the metabolic recovery. Results: Adenosine treated, adenosine-leukocyte treated, and leukocyte treated groups showed better functional recovery than the control group (maximum developed pressure: control=74.6±5.6%, adenosine treated=97.6±9.5%, adenosine-leukocyte treated=98.5±5.6%, leukocyte treated=82.5±6.0%, P<0.05). Both adenosine treated and adenosine-leukocyte treated groups showed better recovery than leukocyte treated group (P<0.05). Coronary blood flow was higher in adenosine-leukocyte treated group compared to other groups (P<0.05). MVO2/beat was higher in adenosine treated, adenosine-leukocyte treated, and leukocyte treated groups than control group (P<0.05). Conclusion: Adenosine, with or without leukocyte depletion, had similar beneficial effect on recovery of systolic and diastolic functions, which involved other mechanisms in addition to the leukocyte inhibitory effect.

Key Words: Adenosine • Reperfusion • Leukocyte depletion • A2 receptor • Nitric oxide


   Introduction
Top
 Abstract
 Introduction
Results
 Discussion
References
 
Prior work from this laboratory [1] [2] [3] has suggested that vascular events and neutrophil–endothelial interaction play an important role in the recovery of immature hearts after hypothermic cardioplegic ischemia. The effect of leukocyte depletion during reperfusion has been studied to show the amelioration of reperfusion injury [4] [5]. On the other hand, adenosine has been known to have a potent coronary vasodilatory and neutrophil inhibitory effects, and has the effect of blockade of inward calcium currents. Then, adenosine has been shown to reduce reperfusion injury in normothermic ischemia models [6] [7], in rodent hypothermic models [8] [9], and in the model of neonatal lamb heart with cold cardioplegic ischemia [10]. We have demonstrated the receptor mediated beneficial effects of adenosine during reperfusion [10], however, the precise mechanism remains unclear. This study was designed to determine whether previously described beneficial effects of adenosine on reperfusion injury is mediated by changes in leukocyte function.

Experimental preparation
An isolated blood perfused heart model previously described [1] [2] [10] was used for studying 32 hearts from neonatal lambs (2.4–5.9 kg, 2–6 days old). They were anesthetized with intramuscular ketamine (40 mg/kg), intubated, and placed on the respirator with inhalation of 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, Ashland, MA, USA) and oxygenator system (Bio-2; American Bentley, Irvine, CA, USA) before isolation, providing no period of ischemia. After insertion of left ventricular (LV) vent into the apex, the heart was isolated and placed on the temperature controlled water bath. Both superior and inferior cavae were ligated and coronary venous return was drained from the cannula inserted into the right ventricle through the pulmonary artery. A sampling catheter was placed in the coronary sinus via the hemiazygous 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% O2, 5% CO2, and 75% N2 by utilizing bubble oxygenator. The arterial pH was maintained at 7.4 with sodium bicarbonate (corrected to perfusate temperature). Both serum potassium and ionized calcium were maintained at 4–5 mEq/l and 1.0 mEq/l, respectively.

The temperature of perfusate, the water bath and the myocardium were monitored by thermal probes and the perfusate and water bath were controlled at 37°C by a heater-circulator (Model 1252–00; Cole-parmer Instrument, Chicago, IL, USA) except during hypothermic phase which was brought by circulating ice water. Coronary perfusion pressure was maintained constant at 60 mmHg, except during the cooling and reperfusion periods. A latex balloon with pressure transducer (SPC-350; Millar Instruments, Houston, TX, USA) was placed inside the LV through an apex to measure the LV function. A Foley balloon catheter (10 Fr) was inserted in the left atrium and was inflated with 1 ml of saline to prevent the LV balloon from herniating into the left atrium and to vent blood as well as air from the LV.

Measurements
LV function was measured at 30 min after reperfusion during isovolumic contraction by inflating the intraventricular balloon with 0.5 ml increments of saline until a LV end-diastolic pressure (EDP) of 20 mmHg 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 (max DP), positive maximum LV dp/dt. Negative maximum dp/dt and EDP at V10 were measured before and after ischemia to assess the diastolic functional recovery. V10 was defined as the baloon volume to produce an end-diastolic pressure of 10 mmHg during preischemic baseline measurement.

Coronary blood flow (CBF) was measured continuously by an in-line type electromagnetic flow meter (MFV-3100; Nihon Kohden, Tokyo, Japan), which was connected to the venous cannula. This flow was considered to represent total coronary blood flow.

Myocardial oxygen consumption (MVO2) was measured at preischemia, 15, 20 and 30 min after reperfusion. Arterial and venous blood were collected in the beating, but non-working state. The hemoglobin concentration and the oxygen saturation were measured with a blood gas analyzer (Corning Model 280; Ciba-Corning, Medfield, MA, USA) and corrected for temperature and pH by the Severinghaus equation [11]. Oxygen consumption was calculated by these values as the following equation:


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

Experimental protocol
Baseline measurements were made after a 20-min equilibrium period. Then both the perfusate and water bath were cooled down to 15°C. At 10 min after cooling down 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 min followed by topical cooling (myocardial temperature was maintained at 10°C). A second dose of 10 ml/kg was given after 60 min. The composition of cardioplegic solution was 0.45% sodium chloride and 2.5% dextrose solution with 20 mEq/l of potassium chloride and 6 mEq/l of sodium bicarbonate (pH 7.4 at 37°C, osmolarity 360 mOsm/l). After 120 min of cold ischemia, reperfusion was begun with the perfusate at room temperature (25°C) and then rewarmed to the normothermia over 25 min. Mean coronary perfusion pressure was maintained at 20 mmHg during the first 5 min and raised to 40 mmHg during the second 5 min and then kept at 60 mmHg until the end of experiment [2] [3] [10]. During the cooling period and the first 15 min of reperfusion period, the oxygenator was bubbled with high oxygen (95% O2, 5% CO2) in order to imitate the arterial blood gas conditions as clinical cases. Thereafter the gas was changed to 20% O2, 5% CO2, 75% N2.

Experimental groups
The hearts were divided into four groups. In the control group (n=8), blood alone was reperfused without intervention. In adenosine treated group (n=8), adenosine was infused into the side port of arterial cannula during the first 20 min of reperfusion at a rate calculated to achieve a concentration of 350 µmol/l (µM) (10). In adenosine-leukocyte treated group (n=8), adenosine was given in the same manner as adenosine treated group and the hearts were reperfused with leukocyte depleted blood by passing all the blood in the apparatus through a white blood cell removal filter (Sepacell R-500A; Asahi Medical, Japan) while the hearts were arrested. In leukocyte treated group (n=8), the hearts were reperfused with leukocyte depleted blood.

All animals in this study received humane care in compliance with the European Convention on animal care, and the study was approved by the institutional ethics committee.

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


   Results
Top
 Abstract
 Introduction
Results
Discussion
References
 
Baseline measurement (Table 1)
There were no significant differences among the four groups in baseline data.


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  		Table 1. Baseline measurement

 
White blood cell counts
WBC counts before ischemia were similar in the four groups. Adenosine treated group (2558±435/mm3), Adenosine-leukocyte treated group (2880±608/mm3), leukocyte treated group (3293±500/mm3), and the control group (2505±738/mm3). Leukocyte depletion effectively removed over 96% of the leukocytes prior to reperfusion. In adenosine-leukocyte treated group and leukocyte treated group, white blood cell counts decreased to 92±20/mm3 and 126±48/mm3 at reperfusion, respectively. In adenosine treated and control group, white blood cell count at reperfusion were 85–88% of preischemic levels: adenosine treated group (2033±416/mm3), control group (2202±653/mm3).

Left ventricular function (Table 2)
Adenosine-treated and adenosine-leukocyte treated groups achieved a significantly greater recovery of systolic function indices than both control group and leukocyte treated group, including max DP, max LV dp/dt at 30 min of reperfusion. Leukocyte depletion group also showed greater improvement in the recovery of max DP than control group. The effects on recovery of diastolic function were greater in adenosine treated, adenosine-leukocyte treated groups compared to control and leukocyte treated groups.


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  		Table 2. Recovery of left ventricular function at 30 minutes of reperfusion (percent baseline)

 
Changes in heart rate (Table 3)
Adenosine treated and adenosine-leukocyte treated groups had lower heart rates than control group at 15 and 20 min of reperfusion, but there were no statistical differences compared to control at 30 min of reperfusion.


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  		Table 3. Changes in heart rate (beats/min)

 
Coronary blood flow (CBF) (Table 4)
Adenosine-leukocyte treated groups had significantly higher CBF than any other groups. Both adenosine treated and leukocyte treated groups had higher postischemic CBF than the controls, but these differences were not statistically significant.


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  		Table 4. Percent recovery of coronary blood flow

 
Oxygen consumption (MVO2/beat) (Table 5)
At 15, 20, and 30 min of reperfusion, adenosine-leukocyte treated group showed significantly higher recovery of MVO2 than control group. Adenosine treated and leukocyte treated groups demonstrated higher MVO2 than control group at 30 min of reperfusion.


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  		Table 5. Percent baseline of myocardial oxygen consumption

 

   Discussion
Top
 Abstract
 Introduction
Results
 Discussion
References
 
These studies demonstrate that either adenosine administration or leukocyte depletion during reperfusion improved functional recovery of neonatal lamb hearts after hypothermic cardioplegic ischemia. However, adenosine infusion combined with leukocyte depletion during reperfusion resulted in the similar recovery of mechanical function compared to adenosine treated alone reperfusion.

Previous experiments from our laboratory using an isolated blood perfused neonatal lamb heart model have shown that an infusion of adenosine given only during reperfusion after 2 h of cold ischemia resulted in a significant improvement in the post-ischemic recovery of mechanical function in these hearts [10]. In earlier experiments we also found that removal of leukocytes from the blood during reperfusion resulted in improved post-ischemic recovery [2].

The coronary endothelium plays a significant role in cardiophysiology and pathophysiology [1] [12]. The beneficial actions of adenosine in these experiments have resulted in part from its effects on the coronary vasculature. The potent coronary vasodilator effects of adenosine are well described, and are thought to result from stimulation of A2 receptors on the endothelium [13] and of A1 and/or A2 receptors on the vascular smooth muscle [14] [15]. Adenosine has been recently reported to enhance nitric oxide production by vascular endothelial cell [16]. We have previously found a positive correlation between recovery of endothelial function and the recovery of mechanical ventricular function [2], and have also found that vasodilatation with nitroglycerin would provide a better recovery of mechanical function in the postischemic period [17]. Increase in coronary blood flow may potentially lead to improved ventricular function through the `garden hose' effect [18], but we have shown that post ischemic infusion of theophylline (which is an adenosine receptor antagonist) caused increased coronary flow and lowered coronary resistance, but was associated with worse recovery of ventricular function [10], leading us to conclude that coronary vasodilatation alone during reperfusion is not sufficient to improve recovery of contractile function after hypothermic ischemia. In this experiment, leukocyte depletion increased coronary blood flow as well as oxygen consumption (which are not statistically significant). Moreover, combination of adenosine with leukocyte depletion during reperfusion resulted in the highest coronary blood flow as well as myocardial oxygen consumption, possibly involving the mechanism of prevention of vascular stunning.

There are two potent endogenously produced autacoids such as adenosine [10] [14] and NO [12] which have several cardioprotective actions in the similar way and have an interaction [17]. Vinten-Johansen et al. [19] reported that an important mechanism in cardioprotective effect of adenosine and NO is the attenuation of neutrophil-mediated damage. A focused effect of adenosine in this study is the inhibition of neutrophil function. The effects of adenosine on neutrophils include inhibition of oxygen radical formation [20] [21] [22] and inhibition of neutrophil adhesion to the endothelium [7] [23] [24]. Olafsson et al. [6] reported reduced neutrophil accumulation in the myocardium with adenosine infusion after normothermic ischemia. These inhibitory effects on neutrophil function are generally thought to occur via stimulation of A2 receptors and do not depend on neutrophil uptake of adenosine. We have previously shown that neutrophil depletion or the inhibition of neutrophil function with a PAF antagonist or with an antibody to the leukocyte adhesion molecule CD18 improved the recovery of the neonatal heart after hypothermic ischemia [2] [3]. As adenosine has been investigated to have new A3 receptor which opens the adenosine triphosphate-sensitive potassium channels and may relate to preconditioning [25], the other potential mechanism of leukocyte-independent adenosine-mediated protection is opening of potassium channels [26].

There are several limitations to the current studies. First, the model which was utilized is an isolated, blood perfused heart system. The advantages and disadvantages of this model for the assessment of cardiac function after ischemia have been previously discussed [1] [2] [3], and 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 adenosine when administered following hypothermic ischemia seem to involve mechanisms beyond leukocyte inhibition such as opening of potassium channel, the precise mechanism still remains unclear.

The current study clearly shows that reperfusion with leukocyte-depleted blood did not have additional effect on the benefits of adenosine on the functional recovery after cardioplegic ischemia. Thus, the beneficial effect of adenosine after ischemia/reperfusion seem to involve mechanisms in addition to leukocyte inhibition, possibly another receptor mediated effects of opening of potassium channel and enhanced endothelial production of NO as well.


   Acknowledgments
 
I sincerely thank Mark A. Cioffi, M.A.T. for his technical assistance.


   References
Top
 Abstract
 Introduction
Results
 Discussion
References
 

  1. Sawatari K., Kadoba K., Bergner K.A., Mayer J.E. Influence of initial reperfusion pressure after hypothermic cardioplegic ischemia on endothelial modulation of coronary tone in neonatal lambs. J Thorac Cardiovasc Surg 1991;101:777-782.[Abstract]
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  11. Severinghaus J.W. Oxyhemoglobin dissociation curve correction of temperature and pH variation in human blood. J Appl Physiol 1958;12:485-486.[Free Full Text]
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  13. Newman W.H., Becker B.F., Heier M., Nees S., Gerlach E. Endothelium-mediated coronary dilatation by adenosine does not depend on endothelial adenylate cyclase activation: studies in isolated guinea pig hearts. Pflugers Arch 1988;413:1-7.[Medline]
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  17. Kawata H., Aoki M., Mayer J.E., Jr. Nitroglycerin improves functional recovery of neonatal lamb hearts after 2 hours of cold ischemia. Circulation 1993;88(Suppl.II):366-371.
  18. Marcho P., Vatner S.F. Effect of nitroglycerin and nitroprusside on large and small coronary vessels in conscious dogs. Circulation 1981;64:1101-1107.[Abstract/Free Full Text]
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  20. Cronstein B.N., Daguma L., Nicholls D., Hutchison A.J., Williams M. The adenosine neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit superoxide generation respectively. J Clin Invest 1990;80:1150-1157.
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