HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Niels Bleese Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sawa, Y. Articles by Schaper, W. Search for Related Content PubMed PubMed Citation Articles by Sawa, Y. Articles by Schaper, W.

J Thorac Cardiovasc Surg 1994;108:953-959
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Platelet-activating factor plays an important role in reperfusion injury in myocardiumEfficacy of platelet-activating factor receptor antagonist (CV-3988) as compared with leukocyte-depleted reperfusion

Bad Nauheim, Germany

Received for publication Dec. 17, 1993. Accepted for publication June 2, 1994. Address for reprints: Yoshiki Sawa, MD, First Department of Surgery, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565 Japan.

Abstract

Although platelet-activating factor has been implicated in the pathogenesis of neutrophil-induced reperfusion injury, it has other mechanisms of direct deleterious hemodynamic effect. In this study we evaluated the definitive role of platelet-activating factor in myocardial reperfusion injury. Porcine hearts that underwent 60 minutes of normothermic ischemia with cardioplegia and 60 minutes of reperfusion under cardiopulmonary bypass were divided into three groups according to the methods of 15 minutes of controlled reperfusion: whole blood reperfusion group (n= 6), leukocyte-depleted reperfusion group (n= 6), and platelet-activating factor receptor antagonist (CV-3988) group (n= 6). At 60 minutes of reperfusion, the percentage of recovery of maximum slope of the pressure-volume relationship measured with intraventricular balloon, malondialdehyde value in coronary sinus blood, tissue adenosine triphosphate, and percentage of spontaneous defibrillation were evaluated. The receptor antagonist group showed significantly better recovery of maximum slope of the pressure-volume relationship than did the whole blood reperfusion group. Moreover, the receptor antagonist group showed significantly less release of malondialdehyde in the coronary sinus, higher values of adenosine triphosphate in the myocardium, and a higher percentage of spontaneous defibrillation than did the whole blood reperfusion group. On the other hand, the leukocyte-depleted reperfusion group showed no significant differences of maximum slope of the pressure-volume relationship, malondialdehyde, adenosine triphosphate, or spontaneous defibrillation as compared with the whole blood group. These results suggest that platelet-activating factor receptor antagonist attenuated severe damage in whole blood reperfusion of the myocardium as compared with leukocyte-depleted reperfusion, which also suggests that platelet-activating factor may play a more important role in myocardial reperfusion injury than do neutrophils. (J THORACCARDIOVASCSURG1994;108:953-9)

In spite of the great advances in myocardial protection, intraoperative myocardial reperfusion injury is still a significant problem in neonates with critical conditions or adult patients with compromised hearts or extended aortic crossclamping. ^1-5 Myocardial reperfusion injury is defined as myocardial cell death caused by the re-establishment of coronary perfusion, in contrast to cell death caused by the preceding ischemic episode. ⁶ Several mechanisms have been implicated in reperfusion injury: the generation of oxygen-derived free radicals at the time of reperfusion, the release of vasoactive mediators, and the enhanced degradation of membrane phospholipids. ^6-8

As one of the major sources of oxygen-derived free radicals, neutrophils have been reported to play a significant role in the myocardial reperfusion injury. ^9-11 However, controversies exist about the efficacy of leukocyte-depleted reperfusion with the use of a leukocyte-removal filter as one of the strategies to prevent the neutrophil-induced reperfusion injury. ^12-14 Thus, the evidence implicating the role of neutrophils in reperfusion injury in myocardium is still lacking. ¹²

Platelet-activating factor (PAF), a biologically active phosphoglyceride, has a variety of functions including potent chemotaxis, activation, aggregation, and degradation of neutrophils. ^7,15-18 Recently, a few studies substantiated the involvement of PAF in the injury of myocardial tissue. ^15,16 The release of PAF is detected in the ischemic isolated reperfused rabbit heart, ^16,17 and PAF stimulates hydrogen peroxide production of neutrophils during myocardial reperfusion. ⁷ Moreover, it has also been reported that PAF has direct deleterious hemodynamic effects. ^15,19,20 In this situation, the definitive role of PAF in the pathogenesis of myocardial reperfusion injury needs to be elucidated.

In this study, the efficacy of a PAF receptor antagonist (CV-3988) versus controlled reperfusion with leukocyte-depleted blood in the porcine heart exposed to 60 minutes of normoxic cardioplegic arrest were compared. The purpose of this study was to test the hypothesis that PAF plays a more important role in myocardial reperfusion injury than do neutrophils.

MATERIALS AND METHODS

Twenty-three German domestic pigs (5 to 6 months of age with a body weight of 20 to 30 kg) were used for these experiments.

Operative procedure
After premedication with intramuscular injections of anesthetic (Azaperon, 2 mg/kg body weight), the pigs were anesthetized with intravenous pentobarbital (30 mg/kg body weight), and the lungs were ventilated through the tracheostomy tube with a ventilator. Anesthesia was maintained with additional doses of intravenous pentobarbital when needed.

Cardiopulmonary bypass
The heart was exposed through a midline sternotomy and cannulated for cardiopulmonary bypass after systemic heparinization. Arterial perfusion was achieved through the ascending aorta with an 18F cannula. Venous return was provided by cannulas placed into the superior and inferior venae cavae. The third cannula was placed into the right atrium to collect coronary sinus effluent. During cardiopulmonary bypass the pulmonary artery and both venae cavae were snared to prevent venous return from entering the right atrium or pulmonary artery. A 14-gauge cannula was inserted into the ascending aorta for administration of the cardioplegic solution and for venting of the left ventricle during the global ischemic period. The bypass circuit was primed with Ringer's lactate solution. Arterial pH was maintained between 7.35 to 7.45, carbon dioxide between 35 and 45 mm Hg, and oxygen tension more than 100 mm Hg by adjusting gas flow and adding sodium bicarbonate as required. Supplement doses of heparin were given to maintain the activating clotting time greater than 500 seconds. The arterial perfusion temperature was maintained at 37° C.

Cardiac arrest and reperfusion
The ascending aorta was crossclamped, and the heart was arrested with a single injection of 300 ml of crystalloid cardioplegic (Hamburger's) solution ²¹ administered at an infusion pressure of 75 mm Hg and a temperature of 37° C. After 60 minutes of cardiac arrest at 37° C, the heart underwent controlled reperfusion for 15 minutes at 1 ml/min per gram of left ventricular mass of constant flow and less than 50 mm Hg of pressure. Thereafter, aortic crossclamping was released, and the heart was reperfused and maintained in the empty beating state on bypass for 45 minutes of reperfusion.

Measurements
Ventricular function was assessed with a compliant left intraventricular balloon inserted through the left ventricular apex. ²² The orifice of the mitral valve was ligated with a purse string suture from outside to prevent herniation of the balloon through the mitral orifice. In all groups, ventricular contractility was quantified by the maximum slope of the pressure-volume relationship (E_max) as described before. ²³ In brief, 3 ml aliquots of normal saline solution were introduced into the intraventricular balloon and peak developed LV systolic and end-diastolic pressures were recorded at every 3 ml of balloon volumes to a maximum volume of 15 ml. E_max was calculated from the maximum value for the instantaneous pressure/volume ratio P(t)/[V(t) -Vo], with P(t) and V(t) being left ventricular instantaneous pressure and volume, respectively, and Vo being the left ventricular volume at which peak pressure was zero. ²³ These measurements were performed just before aortic crossclamping and at 60 minutes of reperfusion and percentage recovery of control values in E_max at 60 minutes of reperfusion were compared among the groups.

The occurrence of spontaneous defibrillation after reperfusion was assessed with the electrocardiogram and defined as percentage of spontaneous defibrillation in each group.

The coronary sinus effluent was collected to measure the number of leukocytes, including the percentage of neutrophils. The malondialdehyde in the coronary sinus effluent during controlled reperfusion was also determined with high-pressure liquid chromatography, ²⁴ and the values were expressed in nanomoles per liter.

Myocardial biopsy specimens obtained from the left ventricular apex after 60 minutes of reperfusion were rapidly frozen by contact with forceps cooled in liquid nitrogen and stored at -70° C. Adenosine triphosphate was determined by high-pressure liquid chromatography.

Pilot experiment to determine the dose response curve
Several doses (0, 0.75, 1.5, 3.0, and 6.0 mg/kg) of PAF receptor antagonist (CV-3988; Takeda Pharmaceutical Co., Osaka Japan) ²⁵ were given to five pigs in the blood of cardiopulmonary bypass before reperfusion, and the relation between the dose of CV-3988 and the recovery of ventricular contractility was determined.

Study groups
Eighteen pigs were divided into three groups according to the methods of controlled reperfusion for 15 minutes. Six pigs underwent whole blood reperfusion (WB group), and six pigs (LD group) were reperfused with leukocyte-depleted blood with the use of a leukocyte removal filter (Sepacell; Asahi, Tokyo, Japan). ²⁶ Another six pigs were reperfused with whole blood and received CV-3988 (3 mg/kg) in the blood of cardiopulmonary bypass before reperfusion (PA group).

Statistics
Results were expressed as mean ± standard deviation. Newman-Keuls multiple comparison were used to compare all data. For the percentage rate of spontaneous defibrillation, the ² test was used. Significant differences were defined as probabilities for each test of p < 0.05.

RESULTS

Dose response of CV-3988
The relation between the percentage recoveries of E_max and the doses of CV-3988 at 0, 0.75, 1.5, 3.0, and 6.0 mg/kg showed the half-bell shaped curve. A dosage of 3 mg/kg body weight were chosen from this curve for the following experiments (Fig. 1).

View larger version (24K): [in this window] [in a new window]   Fig. 1. Relation between the percentage recoveries of Emax and the doses of CV-3988. The half-bell shaped curve was shown in this relation. A dosage of 3 mg/kg body weight was chosen from this curve for the following experiments.

View larger version (30K): [in this window] [in a new window]   Fig. 2. Comparison of percentage of recovery of Emax among the WB, LD, and PA groups. The PA group showed significantly higher recovery of Emax than did the WB group, although no significant difference of Emax between the LD and the WB groups or the LD and the PA groups was found.

View larger version (22K): [in this window] [in a new window]   Fig. 3. Comparison of the percentage of spontaneous defibrillation among the WB, LD, and PA groups. The PA group showed significantly higher occurrence of spontaneous defibrillation than did the WB group, whereas the LD group showed no differences compared with the WB and PA groups.

View larger version (24K): [in this window] [in a new window]   Fig. 4. Comparison of malondialdehyde in coronary sinus effluent among WB, LD and PA groups. The PA group showed a significantly lower value of malondialdehyde in coronary sinus effluent than did the WB group, whereas the LD group showed no significant difference compared with the WB and PA groups.

View larger version (25K): [in this window] [in a new window]   Fig. 5. Comparison of adenosine triphosphate in the myocardium among the WB, LD, and PA groups. The PA group showed a significantly higher value of adenosine triphosphate in the myocardium than did the WB group. However, no significant differences in tissue adenosine triphosphate between the LD and WB groups, or between the LD and PA groups were found.

Earlier studies have shown that most of the myocardial damage occurs during the period of ischemia and that the effect of reperfusion on ischemic myocardium generally depends on the severity of the preceding ischemic injury. ⁶ Reperfusion of reversibly injured myocardium generally leads to structural improvement and reorganization in contrast to that of irreversibly injured myocardium, which shows further deterioration of tissue. ⁶ However, neutrophils contribute to the extension of the myocardial damage after re-establishment of coronary circulation, which is similar to the inflammatory process. ^9-12 In this situation, PAF has been proposed to play a significant role in neutrophil-induced reperfusion injury. ^15-17

The results of this study show that the PAF receptor antagonist CV-3988 attenuated reperfusion injury occurring in severely damaged porcine heart, whereas controlled reperfusion with leukocyte-depleted blood contributed less to recovery from this reperfusion injury. These results suggests a superior protective effect of PAF receptor antagonist on the myocardium as compared with the situation of leukocyte-depleted reperfusion, which means that PAF-induced reperfusion injury by means of both neutrophil activation and direct negative inotropic action may be more deleterious for the myocardium than neutrophil-induced reperfusion injury. Our hypothesis that PAF has a more important role in myocardial reperfusion injury than do neutrophils was thus confirmed. However, Black and associates ²⁷ reported that inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage in canine heart models in which the left circumflex artery is ligated. Only this report is inconsistent with our study. In their study, they used regional ischemic models in canine heart, which is more tolerant than global ischemic models in porcine heart. They evaluated the recoveries of hemodynamics without suitable parameters, such as E_max, for comparison of cardiac performance. The opposite results may be provided as a result of the differences of the animals with different degrees of ischemic insult and different parameters for cardiac performance as compared with other reports. ²⁸

Experimental model of ischemia
In this model, 60 minutes of normothermic ischemia in the porcine heart arrested with cardioplegia under cardiopulmonary bypass were used. The ischemic hearts reperfused with whole blood showed a significantly lower recovery of ventricular contractility and adenosine triphosphate contents and a significant release of malondialdehyde. They also showed a low percentage of spontaneous defibrillation. These results show that the degree of myocardial damage in this model may be at the turning points between reversibility and irreversibility. ⁶ In this regard, this model appears to simulate the high-risk situation of patients with severely damaged hearts during cardiac operation.

Controlled reperfusion with leukocyte-depleted blood
The first 15 minutes of reperfusion is the critical period for reperfusion injury. ^6,7,29 The conditions of reperfusion during this period possibly determine the fate of the myocardium; therefore controlled reperfusion has been proposed and used in the clinical situation. ²⁹ However, this procedure still has limitations for the severely damaged myocardium, and further modifications are needed. ²² In this regard, we assessed the efficacy of leukocyte-depleted reperfusion during the first 15 minutes. Leukocyte depletion for 15 minutes seems to be long enough to improve the first critical stage of reperfusion injury, and it is a suitable duration for controlled reperfusion under clinical conditions. ³⁰ This procedure, however, failed to attenuate severe myocardial damage associated with a burst of free radicals as compared with the effect of CV-3988. This comparison suggests that a burst of free radicals may be derived not only from neutrophils but also other origins in the reperfused myocardium as described before ^12-14; further investigations seem to be required.

Potential role of PAF in reperfusion injury
It has been postulated that several mechanisms of PAF contribute to the propagation of severe myocardial damage. ¹⁵ PAF is a directly negative isotropic agent, ¹⁹ and PAF-induced increase in coronary vascular resistance can result in cardiac depression. ²⁰ Moreover, PAF is also known to cause an increase in myocardial vascular permeability. ¹⁵ These mechanisms provide an impairment of myocardial performance directly and indirectly in association with the mechanism of neutrophil activation, which may explain the superior efficacy of the PAF receptor antagonist to that of controlled reperfusion with leukocyte-depleted blood.

It has been reported that PAF can produce arrhythmia in the isolated perfused guinea pig heart. ¹⁹ In our experiments, all hearts in which CV-3988 was administered showed spontaneous defibrillation without arrhythmia when reperfused. Thus, CV-3988 may exert some degree of antiarrhythmic activity, although we did not perform any definitive electrophysiologic studies.

The biologic activities of PAF for aggregation and degranulation of platelets are also important mechanisms. ³¹ However, a relatively low percentage of platelet accumulation in ischemic and reperfused hearts was reported. ¹⁶ Conversely, the increased accumulation of platelets in the lung microvasculature and its significant reduction by a PAF antagonist suggest that the platelets activated by generation of cardiac PAF are mainly trapped in the lung and result in the "reperfusion lung." ¹⁶ Moreover, the rat is insensitive to PAF-induced platelet aggregation as compared with the cat, whose platelets aggregate in the presence of PAF. ³² Thus, the inhibition of PAF-induced platelet aggregation is not the mechanism for the protection of CV-3988.

In this study, the level of PAF was not measured. CV-3988 is a potent receptor antagonist of PAF and does not decrease the level of PAF such that measurements of PAF appeared to be meaningless as means to evaluate the efficacy of this antagonist. Recently, Hoshikawa-Fujimura and colleagues ³³ reported the significant increase of PAF in patients with cardiac operations, suggesting a role of PAF in ischemia reperfusion injury even under hypothermic conditions. Consequently, a significant release of PAF in this study can be easily assured from the significant efficacy of CV-3988 and from these current reports that PAF is detected in the coronary sinus effluent early after reperfusion. ^16,17,33

Potential clinical application of CV-3988
The potent PAF receptor antagonist CV-3988 appears to be effective in the prevention of myocardial reperfusion injury with attenuation of the PAF-induced negative inotropic action, ¹⁹ reperfusion arrhythmias, ¹⁹ increased vascular resistance ²⁰ and permeability, ¹⁵ and neutrophil activation. ^15-18 This drug, therefore, may be useful as an additive for myocardial protection of the severely damaged heart.

In summary, reperfusion with whole blood caused severe myocardial injury in the porcine hearts exposed to 60 minutes of normothermic ischemia. PAF receptor antagonist significantly attenuated this reperfusion injury as compared with controlled reperfusion with leukocyte-depleted blood. This finding suggests that PAF may play a more important role in myocardial reperfusion injury than do neutrophils.

Footnotes

From the Department of Experimental Cardiology, Max Planck Institute of Cardiovascular Surgery ^a and KerckoffClinic, ^b Bad Nauheim, Germany.

References

1. Flameng W, Vusse GJV, Meyere RD, Borgers M. Intermittent aortic cross-clamping versus St. Thomas' Hospital cardioplegia in extensive aorta-coronary bypass grafting. J THORAC CARDIOVASC SURG 1984;88:164-73.[Abstract]
   
2. Sawa Y, Matsuda H, Shimazaki Y, et al. Ultrastructural assessment of the infant myocardium receiving crystalloid cardioplegia. Circulation 1987;76(Suppl):V141-5.
   
3. Wechsler AS. Deficiencies of cardioplegia: the hypertrophied ventricle. In: Engelman RM, Levitsky S, eds. A textbook of clinical cardioplegia. New York, Futura Publishing Co., 1982:381-90.
   
4. Mundth ED, Goel IP, Morgan RJ. Effect of potassium cardioplegia and hypothermia on left ventricular function in hypertrophied and non-hypertrophied heart. Surg Forum 1975;7:550.
   
5. Matsuda H, Maeda S, Nakano S. Optimum dose of cold potassium cardioplegia for patients with chronic aortic valve disease: determination by left ventricular mass. Ann Thorac Surg 1986;41:22-6.[Abstract]
   
6. Schaper J, Schaper W. Reperfusion of ischemic myocardium: ultrastructural and histochemical aspects. J Am Coll Cardiol 1983;1:1037-46.[Abstract]
   
7. Ko W, Hawes AS, Lazenby WD, et al. Myocardial reperfusion injury: platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion. J THORAC CARDIOVASC SURG 1991;102:297-308.[Abstract]
   
8. Hearse DJ. Reperfusion of the ischemic myocardium. J Mol Cell Cardiol 1977;9:605-16.[Medline]
   
9. Engler RL, Schmid-Schoenbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol 1983;111:98-111.[Abstract]
   
10. Forman MB, Puett DW, Virmani R. Endothelial and myocardial injury during ischemia and reperfusion: pathogenesis and therapeutic implications. J Am Coll Cardiol; 13:450-9.
    
11. Mehta JL, Nichols WW, Mehta P. Neutrophils as potential participants in acute myocardial ischemia: relevance to reperfusion. J Am Coll Cardiol 1988;11:1309-16.[Abstract]
    
12. Reimer KA, Murry CE, Richard VJ. The role of neutrophils and free radicals in the ischemic-reperfused heart: Why the confusion and controversy? J Mol Cell Cardiol 1989;21:1225-39.[Medline]
    
13. Jeremy RW, Becker LC. Neutrophil depletion does not prevent myocardial dysfunction after brief coronary occlusion. J Am Coll Cardiol 1989;13:1155-63.[Abstract]
    
14. Carlson RE, Schott RJ, Buda AJ. Neutrophil depletion fails to modify myocardial no reflow and functional recovery after coronary reperfusion. J Am Coll Cardiol 1989;14:1803-13.[Abstract]
    
15. Stahl GL, Terashita G, Lefer AM. Role of platelet activating factor in propagation of cardiac damage during myocardial ischemia. J Pharmacol Exp Ther 1988;244:898-904.[Abstract/Free Full Text]
    
16. Montrucchio G, Alloatti G, Tetta C, De Luca R, Cordis GA, Das DK. Release of platelet-activating factor from ischemic-reperfusion rabbit heart. Am J Physiol 1989;256:H1236-46.[Abstract/Free Full Text]
    
17. Montrucchio G, Alloatti G, Mariano F, et al. Role of platelet-activating factor in the reperfusion injury of rabbit ischemic heart. Am J Pathol 1990;137:71-83.[Abstract]
    
18. Cabellos C, MacIntyre DE, Forrest M, Burroughs M, Prasad S, Toumanen E. Differing role of platelet-activating factor during inflammation of the lung and subarachnoid space. J Clin Invest 1992;90:612-8.
    
19. Levi R, Burke JA, Zhao-Gui G, et al. Acetyl glyceryl ether phosphorylcholine, a putative mediator of cardiac anaphylaxis in the guinea pig. Circ Res 1984;54:117-24.[Abstract/Free Full Text]
    
20. Stahl GL, Leffer AM. Heterogeneity of vascular smooth muscle responsiveness to lipid vasoactive mediator. Blood Vessels 1989;24:24-30.
    
21. Bleese N, Doering V, Kalmar P, et al. Intraoperative myocardial protection by cardioplegia in hypothermia: clinical findings. J THORAC CARDIOVASC SURG 1978;75:405-13.[Medline]
    
22. Lazar HL, Buckberg GD, Manganaro AM, Becker H. Myocardial energy replenishment and reversal of ischemic damage by substrate enhancement of secondary blood cardioplegia with amino acids during reperfusion. J THORAC CARDIOVASC SURG 1980;80:350-9.[Medline]
    
23. Yaku H, Goto Y, Futaki S, Ohgoshi Y, Kawaguchi O, Suga H. Ventricular fibrillation does not depress postfibrillatory contractility in blood perfused dog hearts. J THORAC CARDIOVASC SURG 1992;103:514-20.[Abstract]
    
24. Bull AW, Marnett LJ. Determination of malondialdehyde by ionpairing high-performance liquid chromatography. Analyt Biochem 1985;149:284-90.
    
25. Terashita Z, Tsushima S, Yoshioka Y, Nomura H, Inada Y, Nishikawa K. CV-3988: a specific antagonist of platelet activating factor (PAF). Life Sci 1983;32:1975-82.[Medline]
    
26. Sirchia G, Parravicini A, Carnell V, Gianotti A, Bertolini F. Leukocyte depletion of red cell units at the bedside by transfusion through a new filter. Transfusion 1987;27:402-5.[Medline]
    
27. Black SC, Driscoll EM, Lucchesi BR. Inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage. J Cardiovasc Pharmacol 1992;20:997-1005.[Medline]
    
28. Ko W, Lang D, Hawes AS, Zelano JA, Isom OW, Krieger KH. Platelet-activating factor antagonism attenuates platelet and neutrophil activation and reduces myocardial injury during coronary reperfusion. J Surg Res 1993;55:504-15.[Medline]
    
29. Buckberg GD. Studies of controlled reperfusion after ischemia. I. When is cardiac muscle damaged irreversibly? J THORAC CARDIOVASC SURG 1986;92:483-7.
    
30. Sawa Y, Matsuda H, Kaneko M, et al. Evaluation of leukocyte-depleted terminal blood cardioplegia in patients undergoing elective and emergency coronary artery bypass grafting. J THORAC CARDIOVASC SURG (In press).
    
31. Benveniste J, Henson PM, Cochrance CG. Leukocyte-dependent histamine release from rabbit platelets: the role of IgE, basophils and platelet-activating factor. J Exp Med 1972;136:1356-77.[Abstract]
    
32. Namm DH, Tadepalli AS, High JA. Species specificity of the platelet responses to 1-0-alkyl-2-acetyl-sn-glycero-phosphocoline. Thromb Res 1982;25:341-50.[Medline]
    
33. Hoshikawa-Fujimura AY, Auler JO Jr, Da Rocha TR, et al. PAF-acether, superoxide anion and beta-glucuronidase as parameters of polymophonuclear cell activation associated with cardiac surgery and cardiopulmonary bypass. Braz J Med Biol Res 1989;22:1077-82.[Medline]
    

This article has been cited by other articles:

				V. Stangl, G. Baumann, K. Stangl, and S. B Felix Negative inotropic mediators released from the heart after myocardial ischaemia-reperfusion Cardiovasc Res, January 1, 2002; 53(1): 12 - 30. [Abstract] [Full Text] [PDF]

				H. A. Hennein Inflammation After Cardiopulmonary Bypass: Therapy for the Postpump Syndrome Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 236 - 255. [Abstract] [PDF]

				G Matheis, M Scholz, A Simon, O. Dzemali, and A Moritz Leukocyte filtration in cardiac surgery: a review Perfusion, September 1, 2001; 16(5): 361 - 370. [Abstract] [PDF]

				D. P. Taggart Biochemical assessment of myocardial injury after cardiac surgery: Effects of a platelet activating factor antagonist, bilateral internal thoracic artery grafts, and coronary endarterectomy J. Thorac. Cardiovasc. Surg., October 1, 2000; 120(4): 651 - 659. [Abstract] [Full Text] [PDF]

				E. N. Morgan, E. M. Boyle Jr, W. Yun, J. C. Kovacich, T. G. Canty Jr, E. Chi, T. H. Pohlman, and E. D. Verrier Platelet-Activating Factor Acetylhydrolase Prevents Myocardial Ischemia-Reperfusion Injury Circulation, November 9, 1999; 100(90002): II-365 - 368. [Abstract] [Full Text] [PDF]

				J. Zhang, W.R. E. Jamieson, H. Sadeghi, K. Gillespie, J. R. Marier, H. Mickleson, and R. McGibbon Strategies of myocardial protection for operation in chronic model of cyanotic heart disease Ann. Thorac. Surg., November 1, 1998; 66(5): 1507 - 1513. [Abstract] [Full Text] [PDF]

				Q. Huang, M. Wu, C. Meininger, K. Kelly, and Y. Yuan Neutrophil-dependent augmentation of PAF-induced vasoconstriction and albumin flux in coronary arterioles Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1138 - H1147. [Abstract] [Full Text] [PDF]

				A. K. Qayumi, J. C. English, D. V. Godin, D. M. Ansley, E. B. Loucks, J. U. Lee, and C.-W. Kim The Role of Platelet-Activating Factor in Regional Myocardial Ischemia-Reperfusion Injury Ann. Thorac. Surg., June 1, 1998; 65(6): 1690 - 1697. [Abstract] [Full Text] [PDF]

				F. C. Faes, Y. Sawa, H. Ichikawa, Y. Shimazaki, T. Ohashi, H. Fukuda, R. Shirakura, and H. Matsuda Inhibition of Na+/H+ Exchanger Attenuates Neutrophil-Mediated Reperfusion Injury Ann. Thorac. Surg., August 1, 1995; 60(2): 377 - 381. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Niels Bleese Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sawa, Y. Articles by Schaper, W. Search for Related Content PubMed PubMed Citation Articles by Sawa, Y. Articles by Schaper, W.