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): Ralph A. Schmid Joel D. Cooper Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamashita, M. Articles by Patterson, G. A. Search for Related Content PubMed PubMed Citation Articles by Yamashita, M. Articles by Patterson, G. A. Related Collections Related Article

Ann Thorac Surg 1996;62:791-796
© 1996 The Society of Thoracic Surgeons

---

Original Articles: General Thoracic

Nitroprusside Ameliorates Lung Allograft Reperfusion Injury

Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Nitric oxide is believed to play a critical role in the maintenance of vascular integrity through its interaction with neutrophils, platelets, and cellular components of the vessel wall. It has been reported that endogenous nitric oxide level was depressed after ischemia, reperfusion, or both. Furthermore, exogenous as well as endogenous nitric oxide decreases reperfusion-induced vascular dysfunction. We hypothesized that nitroprusside, a potent nitric oxide donor, might enhance lung preservation and reduce posttransplantation lung allograft dysfunction.

Methods. Ten dogs underwent left lung allotransplantation. Donor lungs were flushed with modified Euro-Collins solution and stored for 21 hours at 1°C. Immediately after transplantation, the contralateral right main pulmonary artery and bronchus were ligated to assess isolated allograft function. Hemodynamics and arterial blood gas analysis (inspired oxygen fraction, 1.0) were assessed for 6 hours before sacrifice. Allograft myeloperoxidase activity and wet-to-dry weight ratio were assessed. Group 1 (n = 5) animals received no nitroprusside. In group 2 (n = 5), the donor lung received nitroprusside in the flush solution (10 mg/L) and recipient animals received 0.2 mg/kg just before reperfusion as well as a continuous infusion (0.11 ± 0.01 mg•kg^-1•h^-1) during the assessment period.

Results. Superior gas exchange and hemodynamics were noted in lungs receiving nitroprusside. Although allograft myeloperoxidase activity and the total amount of fluid suctioned from the allograft were significantly reduced in group 2, protein levels in bronchoalveolar lavage fluid were not statistically different.

Conclusions. Nitroprusside administration in the flush solution and during reperfusion improves lung allograft function and blood flow, and reduces pulmonary vascular resistance and myeloperoxidase activity in the transplanted lung. Nitroprusside reduces lung allograft reperfusion injury.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 796.

Early allograft dysfunction remains an unpredictable problem in clinical lung transplantation. Characterized by poor gas exchange, elevated pulmonary vascular resistance, and pulmonary edema, it represents the most frequent cause of early morbidity and mortality after lung transplantation [1]. Although usually reversible with supportive care, in severe cases it usually proves fatal. A variety of strategies have been designed to decrease the severity of early lung allograft dysfunction after prolonged preservation.

We have previously demonstrated in canine [2] and human [3] lung transplantation that inhaled nitric oxide (NO) decreases lung allograft reperfusion injury. Nitric oxide has a variety of biologic effects that might affect ischemia-reperfusion injury in lung allografts. It is a potent pulmonary vasodilator. In addition, NO has been demonstrated to play a critical role in the maintenance of vascular integrity through its interaction with neutrophils [4, 5], platelets [6], and vascular endothelial cells [7]. Recently it has been reported that endogenously produced NO was depressed after ischemia, reperfusion, or both [7]. Furthermore, exogenous NO, as well as endogenous NO, reduces the reperfusion-induced vascular dysfunction [8, 9]. We hypothesized that nitroprusside (NP), a potent NO donor, administered at the time of harvest and reperfusion, might enhance posttransplantation function of canine left lung allografts.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Weight-matched pairs of 10 adult mongrel dogs were used. All animals 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 Science and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Donor Procedure
Harvest and left lung transplantation were performed as previously described [10]. Briefly, donor animals were anesthetized with thiopental sodium intravenously (10 mg/kg), followed by atropine (0.5 mg) and intubated with a 9F endotracheal tube. The lungs were ventilated (Bennet MA1; Puritan Bennet, Inc, Overland Park, KS) with 100% oxygen at a tidal volume of 550 mL at a rate of 15 breaths/min and 5 cm H₂O of positive end-expiratory pressure. After a median sternotomy, the superior and inferior venae cavae, the ascending aorta, the trunks of the pulmonary artery, and the trachea were isolated. Animals were heparinized (400 U/kg) before insertion of a curved metal-tipped cannula (Sarns, Inc, Ann Arbor, MI) through a pursestring suture in the main pulmonary artery just distal to the pulmonary valve. Before administration of the flush solution, 250 µg of prostaglandin E₁ (Prostin VR Pediatric; The Upjohn Company, Kalamazoo, MI) was injected directly into the pulmonary artery. Cardiac inflow was occluded by ligation of the superior and inferior venae cavae 20 seconds after the infusion of prostaglandin E₁. The proximal inferior vena cava was cut and the left atrial appendage was amputated for decompression of the pulmonary artery flush. The lungs were perfused immediately, at a pressure of 40 cm H₂O, with 1,500 mL of cold (4°C) modified Euro-Collins solution. During the flush the lungs were cooled topically by flooding the thoracic cavity with cold (1°C) saline solution. The flushing pressure was monitored through a transducer between the flushing tube and the pulmonary artery cannula. When the flushing was completed, the trachea was clamped at end-inspiration (tidal volume, 550 mL) and the heart-lung block was excised. The harvested organs were stored in modified Euro-Collins solution (1°C) for 21 hours before implantation.

Recipient Procedure
Left single-lung transplantation was performed as previously described [10]. Recipient animals were anesthetized in the same manner as the donor animals and ventilated with an adjustable-rate Harvard pump respirator (model 613; Harvard Apparatus, South Natick, MA) with 98.5% oxygen and 1.5% halothane. A femoral arterial line and a Swan-Ganz catheter were placed and continuously transduced (Hewlett-Packard 1290A, Andover, MA). After left pneumonectomy, the contralateral main pulmonary artery and upper and intermediate bronchus were mobilized and encircled separately. The donor left lung was separated from the heart-lung block and left single-lung allotransplantation was performed using standard techniques [10]. The allograft was topically cooled with ice slush during implantation. Left atrial anastomosis was performed first using a continuous everting mattress suture. The pulmonary artery and the bronchus were anastomosed by a continuous over-and-over suture. After reperfusion of the allograft, a Millar pressure transducer was placed in the left atrium and two chest tubes were inserted. The contralateral bronchi and pulmonary artery were ligated. At this point ventilation was changed to 15 breaths/min at a tidal volume of 550 mL and 5 cm H₂O positive end-expiratory pressure (Bennet MA1). This ventilator change was required to maintain precise inspired oxygen fraction and positive end-expiratory pressure level during the subsequent assessment period. The chest was closed in layers with absorbable sutures. Animals were turned to the supine position for the 6-hour assessment period.

Study Groups
In group 1, donor lungs were flushed as described above and the NP was not administered. In group 2, NP (10 mg/L) was added to the flush solution described above and recipients were given an NP bolus (2 mg/kg) immediately before reperfusion and a continuous infusion (0.11 ± 0.01 mg•kg^-1•h^-1) with a syringe pump (model 355; Orion Research Inc, Boston, MA) during the 6-hour reperfusion period (Table 1).

Airway edema fluid from the left lung was collected via a fiberoptic bronchoscope 5 minutes before each blood gas assessment, and the total suction volume for the 6-hour assessment period was measured. After the final measurement, the animals were sacrificed by overdose of sodium thiopental and intravenous administration of KCl, 20 mEq. Samples of transplanted lungs were obtained for tissue myeloperoxidase (MPO) assay and bronchoalveolar lavage fluid (BALF) study.

Bronchoalveolar Lavage Fluid Analysis
Immediately after the 6-hour assessment, the animals were sacrificed and left lingular segments were obtained for use in the BALF study. Fifty milliliters of saline solution were injected slowly and BALF was collected by gravity. This procedure was repeated twice, so that the segment was washed with a total of 100 mL of saline solution. The BALF was centrifuged at 400 g to separate the supernatant and cell pellet. One milliliter of the supernatant was reserved to measure the concentration of protein by the method of Pierce Laboratories [11].

Myeloperoxidase Assay
Recipient lung samples and BALF samples were frozen immediately by immersion in dichlorodifluro methane (CCl₂F₂) that had been precooled to the freezing point and stored at -70°C until assay. Quantitative MPO activity was determined as previously described [10]. Frozen lung tissue (100 mg) was homogenized in 1 mL of 0.5% hexadecyl-trimethyl-ammonium bromide, 5 mmol/L EDTA, and 50 mmol/L potassium phosphate buffer (pH 6.2) with a Broeck tissue grinder (Kontes Glass Co, Vineland, NJ) to release MPO from the primary granules of the neutrophils. The homogenate was centrifuged at 10,000 g for 15 minutes at 4°C. The supernatant was assayed for MPO activity and total soluble protein by the method of Pierce Laboratories [11]. Enzyme activity was measured spectrophotometrically: 10 µL of tenfold dilute supernatant was combined with 0.6 mL of Hanks' bovine serum albumin (0.25% bovine serum albumin added to Hanks' solution), 0.5 mL of 100 mmol/L potassium phosphate buffer (pH 6.2), 0.1 mL of 0.05% H₂O₂, and 0.1 mL of 1.25 mg/ml o-dianisidine. Color development was stopped by addition of 0.1 mL of 1% NaN₃ after 5 minutes and after 20 minutes at room temperature, respectively. The optical density was measured at 460 nm with a spectrophotometer (PMQ II, Carl Zeiss, Germany). The color development from 5 minutes to 20 minutes was linear. Enzyme activity was defined as the amount of MPO that produced an absorbance change of 1.0 optical density unit per minute per milligram of tissue protein at room temperature (OD•min^-1•mg^-1).

Statistical Analysis
All data are presented as the mean ± the standard error of the mean. Comparisons between groups were made by one-way analysis of variance followed by Bonferroni test for multiple comparisons. In addition, analysis of variance with repeated measures was used to compare overall differences of hemodynamics and blood gas data between groups. Differences were considered significant when the p value was less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
There were no significant differences among groups with respect to donor weight, recipient weight, flushing times, preservation time, and warm ischemic time (see Table 1). However flushing pressures in group 2 were significantly lower than those in group 1 (group 1, 18.8 ± 1.1 mm Hg; group 2, 15.1 ± 1.1 mm Hg; p < 0.05). Flushing times in group 1 and 2 were 87 ± 7 and 93 ± 8 seconds, respectively. Preservation time of groups 1 and 2 were 21 hours 7 minutes ± 4 minutes and 20 hours 58 minutes ± 7 minutes, respectively (not statistically significant).

Gas Exchange
Throughout the 6-hour assessment, oxygenation in group 2 animals was superior to that in group 1 (p < 0.02) (Fig 1). During the first 15 minutes of reperfusion, there was no significant difference between the two groups, but gas exchange deteriorated rapidly in group 1. Mean arterial oxygen tension showed significant differences after 30 minutes of assessment. Arterial oxygen tensions in groups 1 and 2 at 360 minutes of assessment were 69.8 ± 6.7 and 307 ± 82.8 mm Hg (p < 0.05), respectively. Arterial carbon dioxide tension was not significantly different between group 1 and group 2. Mean arterial carbon dioxide tensions in groups 1 and 2 at 360 minutes of assessment were 52.3 ± 2.8 and 49.2 ± 4.7 mm Hg, respectively (no significant difference) (see Fig 1).

View larger version (39K): [in this window] [in a new window]   Fig 1. . Arterial oxygen tension (PaO2) and arterial dioxide tension (PaCO2) for group 1 (control) and group 2 (nitroprusside administration) through the 6-hour assessment. There was a significant difference in PaO2 (p < 0.02) but there was no significant difference in PaCO2 between the two groups. (NS = not significant.)

View larger version (35K): [in this window] [in a new window]   Fig 2. . Hemodynamic data during the 6-hour assessment. There was no significant difference in mean aortic pressure (AoP) and mean pulmonary artery pressure (PAP) between the two groups over time. Cardiac output (CO) in group 2 was higher than in group 1 (p < 0.05) over time. Pulmonary vascular resistance (PVR) in group 1 was higher than in group 2 (p < 0.05) over time. (NS = not significant.)

View larger version (63K): [in this window] [in a new window]   Fig 3. . Tissue myeloperoxidase (MPO) activity after the 6-hour assessment. Myeloperoxidase activity in group 2 was significantly lower than in group 1 (p < 0.05). (OD = optical density.)

View larger version (51K): [in this window] [in a new window]   Fig 4. . Results of suction fluid volume during the 6-hour assessment period and bronchoalveolar lavage fluid (BALF) protein level after the assessment period. Suction fluid volume from allograft in group 2 was significantly less than in group 1 (p < 0.05). There was no significant difference in BALF protein levels between the two groups. (NS = not significant.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Nitric oxide, identified as an endothelium-derived relaxing factor, has been recently purported to be an important physiologic regulator of microcirculation as well as vascular permeability [4–9, 17]. Nitric oxide released from endothelial cells maintains vascular homeostatic properties by relaxing vascular smooth muscle [7], inhibiting neutrophil adhesion [6, 18] and platelet aggregation [8], and maintaining endothelial barrier properties [4]. Endogenous as well as exogenous NO stimulates guanidine 3`,5`-cyclic monophosphorathiate production as well as regulating vascular tone [8, 19]. Pinsky and colleagues [8] demonstrated that NO level was sharply diminished after preservation and reperfusion, but superoxide dismutase administration during reperfusion increased NO level. Furthermore, continuous production of NO during reperfusion reduced ischemia-reperfusion injury [4]. These results suggested that NO administered at harvest in the flush solution might enhance vascular homeostasis and integrity of the donor lung during ischemia. Furthermore, NO supplementation during the reperfusion period might reduce ischemia-reperfusion injury.

In the present study we administered NP as an exogenous NO donor. It is reasonable to speculate that the observed results are due to a NO donor effect. Nitroprusside improved postpreservation lung allograft function during the reperfusion period. Gas exchange was superior and MPO level was lower in allografts treated with NP. These results are consistent with Payne and Kubes' study [17] that demonstrated that exogenous NO significantly reduced the increased permeability associated with reperfusion of ischemic intestine. Among the various effects of NO, we can speculate as to possible mechanisms whereby lung allograft function would be improved.

First, NO inhibits leukocyte-endothelial adhesive interactions in postcapillary venules, including neutrophil emigration, aggregation and activation [5, 9, 20]. Activated neutrophils produce superoxide, which is known to cause tissue injury and to instantly inactivate the NO produced by vascular endothelium [21]. Kubes and Granger [4] demonstrated in their in vivo model that continuous release of NO played an important role in maintaining an intact endothelial cell barrier largely because NO acted to inhibit leukocyte adherence. However this interference was not due to interference with initial rolling of neutrophils but subsequent CD11b/18-mediated neutrophil adherence [22]. In our present study the MPO level in group 2 was significantly lower than in group 1. It is most probable that NO prevents neutrophil activation by scavenging of superoxide radical [4, 9, 17, 23]. Nitric oxide and superoxide radical react avidly to inactivate their respective biological activities. This is one of the fastest reactions known in biological systems [24]. In an in vivo rat lung transplantation model Pinsky and colleagues [8] demonstrated that the decline of NO level was reversed by superoxide dismutase. Additionally, superoxide enhances NO-dependent relaxation in postischemic vessel [8]. Therefore, the inhibition of leukocyte-endothelial adhesive interactions by NO could be attributed to inactivating superoxide radical generation at preservation and reperfusion [5, 8].

Second, NO maintains endothelial viability [4] and has antiatherogenetic properties [18]. Caterina and associates [18] demonstrated that NO donors reduce cytokine-induced endothelial activation. Nitric oxide donors inhibited cytokine (tumor necrosis factor- and interleukin-1)-stimulated expression of vascular cell adhesion molecule-1, E-selectin, and intercelluar adhesion molecule-1. Inhibition of endogenous NO synthesis induced vascular cell adhesion molecule-1 expression and rapid increase in microvascular permeability. Nitric oxide donors including NP completely reversed the increase in microvascular permeability. Although there was no significant difference in BALF protein level between group 1 and group 2, the volume of suction fluid in group 1 was more than that in group 2. Nitric oxide has been reported to inhibit platelet aggregetion [25]. Yao and associates [26] demonstrated that NP inhibited platelet aggregation and prolonged thrombosis time. Platelet function was not assessed in this current study. Nonetheless we might speculate that the beneficial effect of exogenous NO on preserved lung allografts may be similar to that noted with platelet-activating factor antagonist, which has previously been shown to reduce lung allograft reperfusion injury [15].

Finally, NO has a vasodilating effect. Nitroprusside is a potent endothelium-independent vasodilator [27]. When NP interacts with plasma, NP releases NO directly, causing vasodilatation and subsequent increased blood flow [28]. In this study, donor lung flush pressure was significantly lower in NP-treated lungs. Allograft blood flow in group 2 was significantly greater than in group 1. Group 2 cardiac output was significantly greater and pulmonary vascular resistance in group 2 was significantly less than group 1. Although it is possible that some of the effects observed in the nitroprusside group may be due to vasodilatation, we believe other effects (eg, decreased neutrophil sequestration) are not due to vasodilatory effects of nitroprusside.

We do not know whether the observed NP effects were due to its administration in the flush solution or during reperfusion or both. In an in vitro model we have previously shown that superoxide-induced permeability injury occurs during the ischemic phase [29]. We therefore thought that exogenous NP administered in the flush solution may have a beneficial effect through its O₂ radical scavenging properties. There is also solid rationale for administration of NP during reperfusion. The Columbia University group [8, 30] have demonstrated that nitroglycerin or guanidine 3`,5`-cyclic monophosphorathiate analogue maintained graft vascular homeostasis and enhanced preservation in a rat lung transplantation model. They also demonstrated NO levels after reperfusion were depressed in the face of stable NO synthetase activity after 6 hours of preservation. However, Kimblad and colleagues [31] demonstrated that endothelial-dependent pulmonary artery function was impaired after 12 hours of preservation. Fullerton and associates [27] also showed that endothelium-dependent vasodilation function was impaired by 1 hour of reperfusion.

In conclusion, NP administration in the flush solution and the reperfusion period significantly improves posttransplantation function of canine lung allografts preserved in modified Euro-Collins solution. Our data suggest that NP will preserve graft vasomotor function and integrity, prevent neutrophil sequestration, and consequently reduce ischemia-reperfusion injury.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported by National Institutes of Health grant 1 R01 HL41281.

We thank Jill Manchester for assisting with the myeloperoxidase and protein assay; Dennis Gordon, Donna Marquart, Timothy Morris, Duane Probst, and Steve Labarbera for their expert technical assistance; and Mary Ann Kelly and Dawn Schuessler for secretarial support. Statistical advice was obtained from Richard B. Schuessler, PhD.

Nitroprusside was kindly supplied by Abbott Laboratories, St. Louis, MO.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL., Jan 29-31, 1996.

Address reprint requests to Dr Patterson, Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes Hospital Plaza, Suite 3108 Queeny Tower, St. Louis, MO 63110.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Patterson GA, Cooper JD, eds. Lung transplantation. Chest surgery clinics of North America. Philadelphia: Saunders, 1993:3.
2. Okabayashi K, Triantafillou AN, Yamashita M, et al. Effects of inhaled nitric oxide on lung allograft in early postoperative period. J Thorac Cardiovasc Surg (in press).
3. Date H, Triantafillou AN, Trulock EP, Pohl MS, Cooper JD, Patterson GA. Inhaled nitric oxide reduces human lung allograft dysfunction. J Thorac Cardiovasc Surg 1996;111:913–9.[Abstract/Free Full Text]
4. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992;262:H611–5.[Abstract/Free Full Text]
5. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:323–6.
6. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109–42.[Medline]
7. Pinsky DJ, Oz MC, Koga S, et al. Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway. J Clin Invest 1994;93:2291–7.
8. Pinsky DJ, Naka Y, Chowdhury NC, et al. The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation. Proc Natl Acad Sci USA 1994;91:12086–90.[Abstract/Free Full Text]
9. Andrews FJ, Malcontenti-Wilson C, O'Brien PE. Protection against gastric ischemia-reperfusion injury by nitric oxide generators. Dig Dis Sci 1994;39:366–73.[Medline]
10. Okabayashi K, Aoe M, DeMeester SR, Cooper JD, Patterson GA. Pentoxifylline reduces lung allograft reperfusion injury. Ann Thorac Surg 1994;58:50–6.[Abstract]
11. Smith PK, Krohn RI, Hemanson GT, et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985;150:768–85.
12. Gaboury J, Woodman RC, Granger DN, Reinhardt P, Kubes P. Nitric oxide prevents leukocyte adherence: role of superoxide. Am J Physiol 1993;265:H862–7.[Abstract/Free Full Text]
13. McCord JM. Oxygen-derived free radicals in post ischemic tissue injury. N Engl J Med 1985;312:159–63.[Abstract]
14. Egan TM, Ulicny KS, Lambert CJ, Wilcox BR. Effect of a free radical scavenger on cadaver lung transplantation. Ann Thorac Surg 1993;55:1453–9.[Abstract]
15. Qayumi AK, Jamieson WRE, Poostizadeh A. Effects of platelet-activating factor antagonist CV-3988 in preservation of heart and lung for transplantation. Ann Thorac Surg 1991;52:1026–32.[Abstract]
16. Mandfil G. ARDS, neutrophils, and pentoxifylline. Am Rev Respir Dis 1988;138:1344–50.
17. Payne D, Kubes P. Nitric oxide donors reduce the rise in reperfusion-induced intestinal mucosal permeability. Am J Physiol 1993;265:G189–95.[Abstract/Free Full Text]
18. Caterina RD, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60–8.
19. Ignarro LJ, Harbison RG, Wood KS, Kadowitz PJ. Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetyl choline, bradykinin, and arachidonic acid. J Pharmacol Exp Ther 1986;237:893–900.[Abstract/Free Full Text]
20. Gauthier TW, Davenpeck KL, Lefer AM. Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. Am J Physiol 1994;267:562–8.
21. Gryglewski RJ, Palmer RMJ, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 1986;3228:454–6.
22. Kubes P, Kurose I, Granger N. Nitric oxide donors prevent integrin-induced leukocyte adhesion, but not P-selectin-independent rolling in postischemic venules. Am J Physiol 1994;267:M931–7.
23. Gaboury J, Woodman RC, Granger DN, Reinhardt P, Kubes P. Nitric oxide prevents leukocyte adherence: role of superoxide. Am J Physiol 1993;265:H862–7.
24. Huie RE, Padmaja S. Reaction of nitric oxide with superoxide anion. Free radical. Res Commun 1993;18:195–200.
25. Garg UC, Hasid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774–7.
26. Yao SK, Akhtar S, Scott-Burden T, et al. Endogenous and exogenous nitric oxide protect against intracoronary thrombosis and reocclusion after thrombolysis. Circulation 1995;92:1005–10.[Abstract/Free Full Text]
27. Fullerton DV, Mitchell MB, McIntyre RC, et al. Cold ischemia and reperfusion each produce pulmonary vasomotor dysfunction in the transplanted lung. J Thorac Cardiovasc Surg 1993;106:1213–7.[Abstract]
28. Feelisch M, Noack E. Correlation between nitric oxide formation during degeneration of organic nitrate and activation of guanylate cyclase. Eur J Pharmacol 1987;139:19–30.[Medline]
29. Hanuida M, Dresler CM, Mizuta T, Cooper JD, Patterson GA. Free radical-mediated vascular injury in lungs preserved at moderate hypothermia. Ann Thorac Surg 1995;60:1376–81.[Abstract/Free Full Text]
30. Naka Y, Chowdhury NC, Oz MC, et al. Nitroglycerin maintains graft vascular homeostasis and enhances preservation in an orthotopic rat lung transplantation model. J Thorac Cardiovasc Surg 1995;109:206–11.[Abstract/Free Full Text]
31. Kimblad PO, Massa G, Sjöberg T, Steen S. Endothelium-dependent relaxation in pulmonary arteries after lung preservation and transplantation. Ann Thorac Surg 1993;56:1329–34.[Abstract]

This article has been cited by other articles:

				K. Kaya, M. Oguz, A. R. Akar, S. Durdu, A. Aslan, S. Erturk, R. Tasoz, and U. Ozyurda The effect of sodium nitroprusside infusion on renal function during reperfusion period in patients undergoing coronary artery bypass grafting: a prospective randomized clinical trial Eur. J. Cardiothorac. Surg., February 1, 2007; 31(2): 290 - 297. [Abstract] [Full Text] [PDF]

				S. Takashima, G. Koukoulis, H. Inokawa, M. Sevala, and T. M. Egan Inhaled nitric oxide reduces ischemia-reperfusion injury in rat lungs from non-heart-beating donors J. Thorac. Cardiovasc. Surg., July 1, 2006; 132(1): 132 - 139. [Abstract] [Full Text] [PDF]

				C. L. Lau, G. A. Patterson, and S. M. Palmer Critical Care Aspects of Lung Transplantation J Intensive Care Med, March 1, 2004; 19(2): 83 - 104. [Abstract] [PDF]

				C.L. Lau and G.A. Patterson Current status of lung transplantation Eur. Respir. J., November 16, 2003; 22(47_suppl): 57s - 64s. [Abstract] [Full Text] [PDF]

				O. Cakir, A. Oruc, S. Eren, H. Buyukbayram, L. Erdinc, and N. Eren Does sodium nitroprusside reduce lung injury under cardiopulmonary bypass? Eur. J. Cardiothorac. Surg., June 1, 2003; 23(6): 1040 - 1045. [Abstract] [Full Text] [PDF]

				M. O. Meade, J. T. Granton, A. Matte-Martyn, K. McRae, B. Weaver, P. Cripps, and S. H. Keshavjee A Randomized Trial of Inhaled Nitric Oxide to Prevent Ischemia-Reperfusion Injury after Lung Transplantation Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1483 - 1489. [Abstract] [Full Text] [PDF]

				M. de Perrot, M. Liu, T. K. Waddell, and S. Keshavjee Ischemia-Reperfusion-induced Lung Injury Am. J. Respir. Crit. Care Med., February 15, 2003; 167(4): 490 - 511. [Abstract] [Full Text] [PDF]

				K. Minamoto, D. J. Pinsky, T. Fujita, and Y. Naka Timing of Nitric Oxide Donor Supplementation Determines Endothelin-1 Regulation and Quality of Lung Preservation for Transplantation Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 14 - 21. [Abstract] [Full Text] [PDF]

				S. Hillinger, P. Sandera, G. L. Carboni, U. Stammberger, M. Zalunardo, G. Schoedon, and R. A. Schmid Survival and graft function in a large animal lung transplant model after 30 h preservation and substitution of the nitric oxide pathway Eur. J. Cardiothorac. Surg., September 1, 2001; 20(3): 508 - 513. [Abstract] [Full Text] [PDF]

				S. Erkasap and E. Ates L-Arginine-enriched preservation solution decreases ischaemia/reperfusion injury in canine kidneys after long-term cold storage Nephrol. Dial. Transplant., August 1, 2000; 15(8): 1224 - 1227. [Abstract] [Full Text] [PDF]

				J. S. Young, C. S. Rayhrer, T. D. Edmisten, G. A. Cephas, C. G. Tribble, and I. L. Kron Sodium nitroprusside mitigates oleic acid-induced acute lung injury Ann. Thorac. Surg., January 1, 2000; 69(1): 224 - 227. [Abstract] [Full Text] [PDF]

				R. A. Schmid, S. Hillinger, R. Walter, A. Zollinger, U. Stammberger, R. Speich, A. Schaffner, W. Weder, and G. Schoedon THE NITRIC OXIDE SYNTHASE COFACTOR TETRAHYDROBIOPTERIN REDUCES ALLOGRAFT ISCHEMIA-REPERFUSION INJURY AFTER LUNG TRANSPLANTATION J. Thorac. Cardiovasc. Surg., October 1, 1999; 118(4): 726 - 732. [Abstract] [Full Text] [PDF]

				S. Hillinger, R. A. Schmid, P. Sandera, U. Stammberger, D. Schneiter, G. Schoedon, and W. Weder 8-Br-cGMP is superior to prostaglandin e1 for lung preservation Ann. Thorac. Surg., October 1, 1999; 68(4): 1138 - 1142. [Abstract] [Full Text] [PDF]

				S. C. Clark, C. Sudarshan, J. Roughan, P. A. Flecknell, and J. H. Dark MODULATION OF REPERFUSION INJURY AFTER SINGLE LUNG TRANSPLANTATION BY PENTOXIFYLLINE, INOSITOL POLYANIONS, AND SIN-1 J. Thorac. Cardiovasc. Surg., March 1, 1999; 117(3): 556 - 564. [Abstract] [Full Text] [PDF]

				R. C. King, V. E. Laubach, R. C. Kanithanon, A. M. Kron, P. E. Parrino, K. S. Shockey, C. G. Tribble, and I. L. Kron Preservation with 8-bromo-cyclic GMP improves pulmonary function after prolonged ischemia Ann. Thorac. Surg., November 1, 1998; 66(5): 1732 - 1738. [Abstract] [Full Text] [PDF]

				S. C. Body and S. K. Shernan The Utility of Nitric Oxide in the Postoperative Period Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 1998; 2(1): 4 - 30. [Abstract] [PDF]

				M. Yano, C. H. R. Boasquevisque, R. K. Scheule, M. D. Botney, J. D. Cooper, and G. A. Patterson SUCCESSFUL IN VIVO AND EX VIVO TRANSFECTION OF PULMONARY ARTERY SEGMENTS IN LUNG ISOGRAFTS J. Thorac. Cardiovasc. Surg., November 1, 1997; 114(5): 793 - 802. [Abstract] [Full Text]

				S. Fujino, I. Nagahiro, A. N. Triantafillou, C. H. R. Boasquevisque, M. Yano, J. D. Cooper, and G. A. Patterson Inhaled Nitric Oxide at the Time of Harvest Improves Early Lung Allograft Function Ann. Thorac. Surg., May 1, 1997; 63(5): 1383 - 1389. [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): Ralph A. Schmid Joel D. Cooper Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamashita, M. Articles by Patterson, G. A. Search for Related Content PubMed PubMed Citation Articles by Yamashita, M. Articles by Patterson, G. A. Related Collections Related Article