Nitric oxide (NO) is a gas naturally produced by the human body that plays an important physiological role. Specifically, it binds guanylyl cyclase to induce smooth muscle relaxation. NO’s other protective functions have been well documented, particularly its protective endothelial functions, effects on decreasing pulmonary vascular resistance, antiplatelet, and anticoagulation properties. The use of nitric oxide donors as vasodilators has been known since 1876. Inhaled nitric oxide has been used as a pulmonary vasodilator and to improve ventilation perfusion matching since the 1990s. It is currently approved by the United States Food and Drug Administration for neonates with hypoxic respiratory failure, however, it is used off-label for acute respiratory distress syndrome, acute bronchiolitis, and COVID-19.
Purpose
In this article we review the currently understood biological action and therapeutic uses of NO through nitric oxide donors such as inhaled nitric oxide. We will then explore recent studies describing use of NO in cardiopulmonary bypass and extracorporeal membrane oxygenation and speculate on NO’s future uses.
GoldbartAGolan-TriptoIPillarG, et al.Inhaled nitric oxide therapy in acute bronchiolitis: a multicenter randomized clinical trial. Sci Rep2020; 10(1): 9605. DOI: 10.1038/s41598-020-66433-8.
7.
BagateFTuffetSMasiP, et al.Rescue therapy with inhaled nitric oxide and almitrine in COVID-19 patients with severe acute respiratory distress syndrome. Ann Intensive Care2020; 10(1): 151. DOI: 10.1186/s13613-020-00769-2.
8.
RobertsBWMitchellJKilgannonJH, et al.Nitric oxide donor agents for the treatment of ischemia/reperfusion injury in human subjects: a systematic review. Shock Augusta Ga2013; 39(3): 229–239. DOI: 10.1097/SHK.0b013e31827f565b.
9.
TousoulisDKampoliAMTentolourisC, et al.The role of nitric oxide on endothelial function. Curr Vasc Pharmacol2012; 10(1): 4–18. DOI: 10.2174/157016112798829760.
10.
ZimmetJMHareJM. Nitroso-redox interactions in the cardiovascular system. Circulation2006; 114(14): 1531–1544. DOI: 10.1161/CIRCULATIONAHA.105.605519.
11.
LevineABPunihaoleDLevineTB. Characterization of the role of nitric oxide and its clinical applications. Cardiology2012; 122(1): 55–68. DOI: 10.1159/000338150.
12.
KlingerJRAbmanSHGladwinMT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med2013; 188(6): 639–646. DOI: 10.1164/rccm.201304-0686PP.
13.
NapoliCPaolissoGCasamassimiA, et al.Effects of nitric oxide on cell proliferation: novel insights. J Am Coll Cardiol2013; 62(2): 89–95. DOI: 10.1016/j.jacc.2013.03.070.
14.
SunJMurphyE. Protein S-nitrosylation and cardioprotection. Circ Res2010; 106(2): 285–296. DOI: 10.1161/CIRCRESAHA.109.209452.
15.
HareJMStamlerJS. NO/redox disequilibrium in the failing heart and cardiovascular system. J Clin Invest2005; 115(3): 509–517. DOI: 10.1172/JCI24459.
16.
BurwellLSNadtochiySMTompkinsAJ, et al.Direct evidence for S-nitrosation of mitochondrial complex I. Biochem J2006; 394(Pt 3): 627–634. DOI: 10.1042/BJ20051435.
17.
GodoyLCMorettiAIJuradoMC, et al.Loss of CD40 endogenous S-nitrosylation during inflammatory response in endotoxemic mice and patients with sepsis. Shock Augusta Ga2010; 33(6): 626–633. DOI: 10.1097/SHK.0b013e3181cb88e6.
18.
KubesPSuzukiMGrangerDN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A1991; 88(11): 4651–4655. DOI: 10.1073/pnas.88.11.4651.
19.
KhanRKirschenbaumLALaRowC, et al.Augmentation of platelet and endothelial cell eNOS activity decreases sepsis-related neutrophil-endothelial cell interactions. Shock Augusta Ga2010; 33(3): 242–246. DOI: 10.1097/SHK.0b013e3181b0f96f.
20.
FörstermannUXiaNLiH. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res2017; 120(4): 713–735. DOI: 10.1161/CIRCRESAHA.116.309326.
21.
TheofilisPSagrisMOikonomouE, et al.Inflammatory mechanisms contributing to endothelial dysfunction. Biomedicines2021; 9(7): 781. DOI: 10.3390/biomedicines9070781.
22.
BlitzerMLLohERoddyMA, et al.Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans. J Am Coll Cardiol1996; 28(3): 591–596. DOI: 10.1016/0735-1097(96)00218-5.
23.
SemigranMJCockrillBAKacmarekR, et al.Hemodynamic effects of inhaled nitric oxide in heart failure. J Am Coll Cardiol1994; 24(4): 982–988. DOI: 10.1016/0735-1097(94)90859-1.
24.
Kieler-JensenNRickstenSEStenqvistO, et al.Inhaled nitric oxide in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance. J Heart Lung Transplant Off Publ Int Soc Heart Transplant1994; 13(3): 366–375.
25.
JournoisDPouardPMauriatP, et al.Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects. J Thorac Cardiovasc Surg1994; 107(4): 1129–1135.
26.
SinghYLakshminrusimhaS. Pathophysiology and management of persistent pulmonary hypertension of the newborn. Clin Perinatol2021; 48(3): 595–618. DOI: 10.1016/j.clp.2021.05.009.
27.
Ataei AtaabadiEGolshiriKJüttnerA, et al.Nitric oxide-cGMP signaling in hypertension: current and future options for pharmacotherapy. Hypertens Dallas Tex 19792020; 76(4): 1055–1068. DOI:10.1161/HYPERTENSIONAHA.120.15856.
28.
HottingerDGBeebeDSKozhimannilT, et al.Sodium nitroprusside in 2014: a clinical concepts review. J Anaesthesiol Clin Pharmacol2014; 30(4): 462–471. DOI: 10.4103/0970-9185.142799.
29.
HeidenreichPABozkurtBAguilarD, et al.2022 ACC/AHA/HFSA guideline for the management of heart failure. J Card Fail2022; 28(5): e1–e167. DOI: 10.1016/j.cardfail.2022.02.010.
30.
DivakaranSLoscalzoJ. The role of nitroglycerin and other nitrogen oxides in cardiovascular therapeutics. J Am Coll Cardiol2017; 70(19): 2393–2410. DOI: 10.1016/j.jacc.2017.09.1064.
31.
RuoppNFCockrillBA. Diagnosis and treatment of pulmonary arterial hypertension: a review. JAMA2022; 327(14): 1379–1391. DOI: 10.1001/jama.2022.4402.
SherlockLGWrightCJKinsellaJP, et al.Inhaled nitric oxide use in neonates: balancing what is evidence-based and what is physiologically sound. Nitric Oxide Biol Chem2020; 95: 12–16. DOI: 10.1016/j.niox.2019.12.001.
34.
The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. The neonatal inhaled nitric oxide study group (NINOS). Pediatrics. 1997; 99(6): 838–845. DOI:10.1542/peds.99.6.838.
35.
TomaiuoloMBrassLFStalkerTJ. Regulation of platelet activation and coagulation and its role in vascular injury and arterial thrombosis. Interv Cardiol Clin2017; 6(1): 1–12. DOI: 10.1016/j.iccl.2016.08.001.
36.
MakhoulSWalterEPagelO, et al.Effects of the NO/soluble guanylate cyclase/cGMP system on the functions of human platelets. Nitric Oxide Biol Chem2018; 76: 71–80. DOI: 10.1016/j.niox.2018.03.008.
37.
GolebiewskaEMPooleAW. Platelet secretion: from haemostasis to wound healing and beyond. Blood Rev2015; 29(3): 153–162. DOI: 10.1016/j.blre.2014.10.003.
38.
PagelOWalterEJurkK, et al.Taking the stock of granule cargo: platelet releasate proteomics. Platelets2017; 28(2): 119–128. DOI: 10.1080/09537104.2016.1254762.
39.
TutejaNChandraMTutejaR, et al.Nitric oxide as a unique bioactive signaling messenger in physiology and pathophysiology. J Biomed Biotechnol2004; 2004(4): 227–237. DOI: 10.1155/S1110724304402034.
40.
MellionBTIgnarroLJOhlsteinEH, et al.Evidence for the inhibitory role of guanosine 3’, 5’-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood1981; 57(5): 946–955.
41.
MellionBTIgnarroLJMyersCB, et al.Inhibition of human platelet aggregation by S-nitrosothiols. Heme-dependent activation of soluble guanylate cyclase and stimulation of cyclic GMP accumulation. Mol Pharmacol1983; 23(3): 653–664.
42.
ArnoldWPMittalCKKatsukiS, et al.Nitric oxide activates guanylate cyclase and increases guanosine 3’:5’-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A1977; 74(8): 3203–3207. DOI: 10.1073/pnas.74.8.3203.
43.
SchultzKSchultzKSchultzG. Sodium nitroprusside and other smooth muscle-relaxants increase cyclic GMP levels in rat ductus deferens. Nature1977; 265(5596): 750–751. DOI: 10.1038/265750a0.
44.
EvgenovOVPacherPSchmidtPM, et al.NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov2006; 5(9): 755–768. DOI: 10.1038/nrd2038.
45.
SuchytaDJHandaHMeyerhoffME. A nitric oxide-releasing heparin conjugate for delivery of a combined antiplatelet/anticoagulant agent. Mol Pharm2014; 11(2): 645–650. DOI: 10.1021/mp400501c.
46.
KehDThiemeAKürerI, et al.Inactivation of platelet glycoprotein IIb/IIIa receptor by nitric oxide donor 3-morpholino-sydnonimine. Blood Coagul Fibrinolysis Int J Haemost Thromb2003; 14(4): 327–334. DOI: 10.1097/00001721-200306000-00002.
GambaryanSGeigerJSchwarzUR, et al.Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase. Blood2004; 103(7): 2593–2600. DOI: 10.1182/blood-2003-09-3349.
49.
CraneMSRossiAGMegsonIL. A potential role for extracellular nitric oxide generation in cGMP-independent inhibition of human platelet aggregation: biochemical and pharmacological considerations. Br J Pharmacol2005; 144(6): 849–859. DOI: 10.1038/sj.bjp.0706110.
50.
BeghettiMSparlingCCoxPN, et al.Inhaled NO inhibits platelet aggregation and elevates plasma but not intraplatelet cGMP in healthy human volunteers. Am J Physiol Heart Circ Physiol2003; 285(2): H637–642. DOI: 10.1152/ajpheart.00622.2002.
51.
IgnarroLJBugaGMWoodKS, et al.Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A1987; 84(24): 9265–9269. DOI: 10.1073/pnas.84.24.9265.
52.
HuangPLHuangZMashimoH, et al.Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature1995; 377(6546): 239–242. DOI: 10.1038/377239a0.
53.
VasconcellosVLacchiniRJacob-FerreiraALB, et al.Endothelial nitric oxide synthase haplotypes associated with hypertension do not predispose to cardiac hypertrophy. DNA Cell Biol2010; 29(4): 171–176. DOI: 10.1089/dna.2009.0955.
54.
PaniaguaOABryantMBPanzaJA. Role of endothelial nitric oxide in shear stress-induced vasodilation of human microvasculature: diminished activity in hypertensive and hypercholesterolemic patients. Circulation2001; 103(13): 1752–1758. DOI: 10.1161/01.cir.103.13.1752.
55.
RuggeriZM. Platelet adhesion under flow. Micro Notes N 19942009; 16(1): 58–83. DOI: 10.1080/10739680802651477.
56.
HathcockJJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol2006; 26(8): 1729–1737. DOI: 10.1161/01.ATV.0000229658.76797.30.
57.
RanaAWesteinENiegoB, et al.Shear-dependent platelet aggregation: mechanisms and therapeutic opportunities. Front Cardiovasc Med2019; 6: 141. DOI: 10.3389/fcvm.2019.00141.
XenosESStevensSLFreemanMB, et al.Nitric oxide mediates the effect of fluvastatin on intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 expression on human endothelial cells. Ann Vasc Surg2005; 19(3): 386–392. DOI: 10.1007/s10016-005-0011-7.
60.
EstevezBDuX. New concepts and mechanisms of platelet activation signaling. Physiol Bethesda Md2017; 32(2): 162–177. DOI: 10.1152/physiol.00020.2016.
61.
WoulfeDYangJBrassL. ADP and platelets: the end of the beginning. J Clin Invest2001; 107(12): 1503–1505. DOI: 10.1172/JCI13361.
62.
KoupenovaMClancyLCorkreyHA, et al.Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res2018; 122(2): 337–351. DOI: 10.1161/CIRCRESAHA.117.310795.
63.
LubosEHandyDELoscalzoJ. Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci J Virtual Libr2008; 13: 5323–5344. DOI: 10.2741/3084.
64.
MonteiroHPRodriguesEGAmorim ReisAKC, et al.Nitric oxide and interactions with reactive oxygen species in the development of melanoma, breast, and colon cancer: a redox signaling perspective. Nitric Oxide Biol Chem2019; 89: 1–13. DOI: 10.1016/j.niox.2019.04.009.
65.
Jourd’heuilDJourd’heuilFLKutchukianPS, et al.Reaction of superoxide and nitric oxide with peroxynitrite. Implications for peroxynitrite-mediated oxidation reactions in vivo. J Biol Chem2001; 276(31): 28799–28805. DOI: 10.1074/jbc.M102341200.
66.
PeekGJFirminRK. The inflammatory and coagulative response to prolonged extracorporeal membrane oxygenation. ASAIO J Am Soc Artif Intern Organs 19921999; 45(4): 250–263. DOI: 10.1097/00002480-199907000-00003.
67.
ChecchiaPABronickiRAMuenzerJT, et al.Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children--a randomized trial. J Thorac Cardiovasc Surg2013; 146(3): 530–536. DOI: 10.1016/j.jtcvs.2012.09.100.
68.
JamesCMillarJHortonS, et al.Nitric oxide administration during paediatric cardiopulmonary bypass: a randomised controlled trial. Intensive Care Med2016; 42(11): 1744–1752. DOI: 10.1007/s00134-016-4420-6.
69.
SchlapbachLJGibbonsKSHortonSB, et al.Effect of nitric oxide via cardiopulmonary bypass on ventilator-free days in young children undergoing congenital heart disease surgery: the NITRIC randomized clinical trial. JAMA2022; 328(1): 38–47. DOI: 10.1001/jama.2022.9376.
70.
NieblerRAChiang-ChingHDaleyK, et al.Nitric oxide added to the sweep gas of the oxygenator during cardiopulmonary bypass in infants: a pilot randomized controlled trial. Artif Organs2021; 45(1): 22–28. DOI: 10.1111/aor.13788.
71.
VuongTARanaMSMooreB, et al.Association between exogenous nitric oxide given during cardiopulmonary bypass and the incidence of postoperative kidney injury in children. J Cardiothorac Vasc Anesth2022; 36(8 Pt A): 2352–2357. DOI: 10.1053/j.jvca.2021.10.007.
72.
KamenshchikovNOAnfinogenovaYJKozlovBN, et al.Nitric oxide delivery during cardiopulmonary bypass reduces acute kidney injury: a randomized trial. J Thorac Cardiovasc Surg2022; 163(4): 1393–1403. DOI: 10.1016/j.jtcvs.2020.03.182.
73.
LeiCBerraLRezoagliE, et al.Nitric oxide decreases acute kidney injury and stage 3 chronic kidney disease after cardiac surgery. Am J Respir Crit Care Med2018; 198(10): 1279–1287. DOI: 10.1164/rccm.201710-2150OC.
74.
HuJSpinaSZadekF, et al.Effect of nitric oxide on postoperative acute kidney injury in patients who underwent cardiopulmonary bypass: a systematic review and meta-analysis with trial sequential analysis. Ann Intensive Care2019; 9: 129. DOI: 10.1186/s13613-019-0605-9.
75.
GreenbergJWHogueSRaeesMA, et al.Exogenous nitric oxide delivery protects against cardiopulmonary bypass–associated acute kidney injury: histologic and serologic evidence from an ovine model. J Thorac Cardiovasc Surg2023; 166: e164. DOI: 10.1016/j.jtcvs.2023.03.030.
76.
SunWWangSChenZ, et al.Impact of high mechanical shear stress and oxygenator membrane surface on blood damage relevant to thrombosis and bleeding in a pediatric ECMO circuit. Artif Organs2020; 44(7): 717–726. DOI: 10.1111/aor.13646.
77.
O’MearaCTimpaJPeekG, et al.Nitric oxide on extracorporeal life support-circuit modifications for a safe therapy. J Extra Corpor Technol2022; 54(2): 142–147. DOI: 10.1182/ject-142-147.
78.
ChilettiRHortonSBednarzA, et al.Safety of nitric oxide added to the ECMO circuit: a pilot study in children. Perfusion2018; 33(1): 74–76. DOI: 10.1177/0267659117720495.
79.
BennettMThuysCAugustinS, et al.The safe addition of nitric oxide into the sweep gas of the extracorporeal circuit during cardiopulmonary bypass and extracorporeal life support. J Extra Corpor Technol2018; 50(4): 260–264.
80.
MattkeACJohnsonKGibbonsK, et al.Nitric oxide on extracorporeal membrane oxygenation in neonates and children (NECTAR trial): protocol for a randomized controlled trial. JMIR Res Protoc2023; 12: e43760. DOI: 10.2196/43760.
81.
FallonBPMychaliskaGB. Development of an artificial placenta for support of premature infants: narrative review of the history, recent milestones, and future innovation. Transl Pediatr2021; 10(5): 1470–1485. DOI: 10.21037/tp-20-136.
82.
FallonBPLautner-CsorbaOMajorTC, et al.Extracorporeal life support without systemic anticoagulation: a nitric oxide-based non-thrombogenic circuit for the artificial placenta in an ovine model. Pediatr Res. Published online April2023; 1. DOI: 10.1038/s41390-023-02605-2.
83.
OliveiraFRMBAssreuyJSordiR. The role of nitric oxide in sepsis-associated kidney injury. Biosci Rep2022; 42(7): BSR20220093. DOI: 10.1042/BSR20220093.
84.
HeemskerkSMasereeuwRRusselFGM, et al.Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nat Rev Nephrol2009; 5(11): 629–640. DOI: 10.1038/nrneph.2009.155.
85.
RautMSMaheshwariA. Inhaled nitric oxide, methemoglobinemia, and route of delivery. Saudi J Anaesth2017; 11(3): 364. DOI: 10.4103/sja.SJA_82_17.
86.
HamonIGauthier-MoulinierHGrelet-DessiouxE, et al.Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatr2010; 99(10): 1467–1473. DOI: 10.1111/j.1651-2227.2010.01854.x.
87.
ChandrasekharanPLakshminrusimhaSAbmanSH. When to say no to inhaled nitric oxide in neonates?Semin Fetal Neonatal Med2021; 26(2): 101200. DOI: 10.1016/j.siny.2021.101200.
88.
CentorrinoRShankar-AguileraSFolignoS, et al.Life-threatening extreme methemoglobinemia during standard dose nitric oxide therapy. Neonatology2019; 116(3): 295–298. DOI: 10.1159/000501462.
