Abstract
Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure–function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO2)], tested it in vitro, and administered it to hypoxic piglets. ENO2 lowered pulmonary artery pressure and raised the Po2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO2 is less potent than inhaled NO on a dose-equivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency). These results suggest that ENO2 may hold promise as a safe alternative to NO, particularly in hypoxemic conditions characterized by thiol depletion.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- CO:
-
cardiac output
- ENO:
-
ethyl nitrite
- ENO2:
-
ethyl nitrate
- GSH:
-
glutathione
- Fio2:
-
fraction of inspired oxygen
- NMR:
-
nuclear magnetic resonance
- NO:
-
nitric oxide
- NOx:
-
oxides of nitrogen
- Pao2:
-
arterial partial pressure of oxygen
- PAP:
-
pulmonary artery pressure
- PPHN:
-
persistent pulmonary hypertension of the newborn
- PVR:
-
pulmonary vascular resistance
- SNO:
-
S-nitrosothiol
- SVR:
-
systemic vascular resistance
References
Ichiba H, Matsunami S, Itoh F, Ueda T, Ohsasa Y, Yamano T 2003 Three-year follow up of term and near-term infants treated with inhaled nitric oxide. Pediatr Int 45: 290–293
Walsh-Sukys MC, Bauer RE, Cornell DJ, Friedman HG, Stork EK, Hack M 1994 Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes. J Pediatr 125: 104–110
Sadiq HF, Mantych G, Benawra RS, Devaskar UP, Hocker JR 2003 Inhaled nitric oxide in the treatment of moderate persistent pulmonary hypertension of the newborn: a randomized controlled, multicenter trial. J Perinatol 23: 98–103
Roberts JD Jr, Fineman JR, Morin FC 3rd, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM, Gross I, Heymann MA, Zapol WM 1997 Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med 336: 605–610
Finer NN, Barrington KJ 2000 Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev ( 2): CD000399
1997 Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med 336: 597–604
Chen LW, Hwang YC, Chen CJ, Wang JS, Chen JS, Hsu CM 2003 Burn-induced lung damage in rat is mediated by a nitric oxide/cGMP system. Shock 20: 369–74
Millar TM 2004 Peroxynitrite formation from the simultaneous reduction of nitrite and oxygen by xanthine oxidase. FEBS Lett 562: 129–133
Gaston B, Drazen JM, Loscalzo J, Stamler JS 1994 The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 149: 538–551
Zhou JL, Jin GH, Yi YL, Zhang JL, Huang XL 2003 Role of nitric oxide and peroxynitrite anion in lung injury induced by intestinal ischemia-reperfusion in rats. World J Gastroenterol 9: 1318–1322
Lorch SA, Foust R 3rd, Gow A, Arkovitz M, Salzman AL, Szabo C, Vayert B, Geffard M, Ischiropoulos H 2000 Immunohistochemical localization of protein 3-nitrotyrosine and S-nitrosocysteine in a murine model of inhaled nitric oxide therapy. Pediatr Res 47: 798–805
Lamb NJ, Quinlan GJ, Westerman ST, Gutteridge JM, Evans TW 1999 Nitration of proteins in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome receiving inhaled nitric oxide. Am J Respir Crit Care Med 160: 1031–1034
Salguero KL, Cummings JJ 2002 Inhaled nitric oxide and methemoglobin in full-term infants with persistent pulmonary hypertension of the newborn. Pulm Pharmacol Ther 15: 1–5
Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS 1994 Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 90: 2780–2785
Gries A, Herr A, Kirsch S, Gunther C, Weber S, Szabo G, Holzmann A, Bottiger BW, Martin E 2003 Inhaled nitric oxide inhibits platelet-leukocyte interactions in patients with acute respiratory distress syndrome. Crit Care Med 31: 1697–1704
Aranda M, Pearl RG 2000 Inhaled nitric oxide and pulmonary vasoreactivity. J Clin Monit Comput 16: 393–401
Truog WE, Castor CA, Sheffield MJ 2003 Neonatal nitric oxide use: predictors of response and financial implications. J Perinatol 23: 128–132
Moya MP, Gow AJ, McMahon TJ, Toone EJ, Cheifetz IM, Goldberg RN, Stamler JS 2001 S-nitrosothiol repletion by an inhaled gas regulates pulmonary function. Proc Natl Acad Sci USA 98: 5792–5797
Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS 2002 Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 360: 141–143
Langley-Evans SC, Phillips GJ, Jackson AA 1996 Sulphur dioxide: a potent glutathione depleting agent. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 114: 89–98
Nuclear Magnetic Resonance Spectra Spectrum 29063M Vol 49. Sadtler Research Laboratories, Philadelphia
Nozik-Grayck E, McMahon TJ, Huang YC, Dieterle CS, Stamler JS, Piantadosi CA 2002 Pulmonary vasoconstriction by serotonin is inhibited by S-nitrosoglutathione. Am J Physiol 282: L1057–L1065
Cheifetz IM, Craig DM, Quick G, McGovern JJ, Cannon ML, Ungerleider RM, Smith PK, Meliones JN 1998 Increasing tidal volumes and pulmonary overdistention adversely affect pulmonary vascular mechanics and cardiac output in a pediatric swine model. Crit Care Med 26: 710–716
Etches PC, Finer NN, Barrington KJ, Graham AJ, Chan WK 1994 Nitric oxide reverses acute hypoxic pulmonary hypertension in the newborn piglet. Pediatr Res 35: 15–19
Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW, Stark AR, Kourembanas S 1997 Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 100: E7
Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, Roy BJ, Keszler M, Kinsella JP 2000 Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med 342: 469–474
Barnes PJ, Belvisi MG 1993 Nitric oxide and lung disease. Thorax 48: 1034–43
Gow AJ, Thom SR, Ischiropoulos H 1998 Nitric oxide and peroxynitrite-mediated pulmonary cell death. Am J Physiol 274: L112–L118
Horvath EP, doPico GA, Barbee RA, Dickie HA 1978 Nitrogen dioxide-induced pulmonary disease: five new cases and a review of the literature. J Occup Med 20: 103–110
Beghetti M, Sparling C, Cox PN, Stephens D, Adatia I 2003 Inhaled NO inhibits platelet aggregation and elevates plasma but not intraplatelet cGMP in healthy human volunteers. Am J Physiol 285: H637–H642
Schreiber MD, Dixit R, Rudinsky B, Hipps R, Morgan SE, Keith RA, Meadow W 2002 Direct comparison of the effects of nebulized nitroprusside versus inhaled nitric oxide on pulmonary and systemic hemodynamics during hypoxia-induced pulmonary hypertension in piglets. Crit Care Med 30: 2560–2565
Schutte H, Grimminger F, Otterbein J, Spriestersbach R, Mayer K, Walmrath D, Seeger W 1997 Efficiency of aerosolized nitric oxide donor drugs to achieve sustained pulmonary vasodilation. J Pharmacol Exp Ther 282: 985–994
Omar HA, Gong F, Sun MY, Einzig S 1999 Nebulized nitroglycerin in children with pulmonary hypertension secondary to congenital heart disease. W V Med J 95: 74–75
Jacobs BR, Brilli RJ, Ballard ET, Passerini DJ, Smith DJ 1998 Aerosolized soluble nitric oxide donor improves oxygenation and pulmonary hypertension in acute lung injury. Am J Respir Crit Care Med 158: 1536–1542
Wieslander G, Norback D, Lindgren T 2001 Experimental exposure to propylene glycol mist in aviation emergency training: acute ocular and respiratory effects. Occup Environ Med 58: 649–655
Cohen BM, Crandall C 1964 Physiologic benefits of “thermo fog” as a bronchodilator vehicle: acute ventilation responses of 93 patients. Am J Med Sci 247: 57–61
LaKind JS, McKenna EA, Hubner RP, Tardiff RG 1999 A review of the comparative mammalian toxicity of ethylene glycol and propylene glycol. Crit Rev Toxicol 29: 331–365
McMullan DM, Bekker JM, Johengen MJ, Hendricks-Munoz K, Gerrets R, Black SM, Fineman JR 2001 Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1. Am J Physiol 280: H777–H785
Chen L, He H, Mondejar EF, Hedenstierna G 2003 Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model. Am J Physiol 284: H290–H298
Boesgaard S 1995 Thiol compounds and organic nitrates. Dan Med Bull 42: 473–484
Lawson DL, Nichols WW, Mehta P, Mehta JL 1991 Captopril-induced reversal of nitroglycerin tolerance: role of sulfhydryl group vs. ACE-inhibitory activity. J Cardiovasc Pharmacol 17: 411–418
Fung HL, Chong S, Kowaluk E, Hough K, Kakemi M 1988 Mechanisms for the pharmacologic interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcysteine. J Pharmacol Exp Ther 245: 524–530
Acknowledgements
We gratefully thank Michael Gentile for technical assistance and David Tanaka for help with data analysis.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by a Duke Translational Medicine Award.
Rights and permissions
About this article
Cite this article
Brandler, M., Powell, S., Craig, D. et al. A Novel Inhaled Organic Nitrate That Affects Pulmonary Vascular Tone in a Piglet Model of Hypoxia-Induced Pulmonary Hypertension. Pediatr Res 58, 531–536 (2005). https://doi.org/10.1203/01.PDR.0000179399.64025.37
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000179399.64025.37
