The use of inhaled phosphodiesterase inhibitors has been investigated as an alternative or adjunct to NO inhalation. 1 The potential for intrapulmonary selectivity (vasodilation of well-ventilated areas) and the possibility of avoiding percutaneous prostacyclin analog have made these medications attractive options for PAH therapy. INOMAX (nitric oxide) gas, for inhalation is an inhaled drug that is approved by the US Food and Drug Administration (FDA) for treating hypoxic respiratory failure (HRF) in newborns. Proc Natl Acad Sci U S A 1995; 92: 7162–6, Lin KT, Xue JY, Nomen M, Spur B, Wong PY: Peroxynitrite-induced apoptosis in HL-60 cells. Figure 3. Co-factors for NOS include oxygen, NADPH, tetrahydrobiopterin and flavin adenine nucleotides. Inhaling through the mouth may not accomplish this. J Biol Chem 1986; 261: 14704–9, Schechter AN: NO therapy? inhalational agent (inhaled nitric oxide, iNO) an inorganic gas; MECHANISM OF ACTION. Eur Respir J 1994; 7: 698–702, Högman M, Frostell C, Arnberg H, Hedenstierna G: Inhalation of nitric oxide modulates methacholine-induced bronchoconstriction in the rabbit. Am J Physiol 1995; 269: L158–64, Robbins CG, Davis JM, Merritt TA, Amirkhanian JD, Sahgal N, Morin FC, Horowitz S: Combined effects of nitric oxide and hyperoxia on surfactant function and pulmonary inflammation. J Immunol. The mechanism that explains improvement with the use of iNO in these patient populations are not well understood but does not appear to be solely a result of sustained improvement in oxygenation. BMJ (2007) 334(7597):779.10.1136/bmj.39139.716794.55 J Immunol 1991; 147: 1816–22, Xiao L, Eneroth PH, Qureshi GA: Nitric oxide synthase pathway may mediate human natural killer cell cytotoxicity. 12.1 Mechanism of Action. INOmax is Inhaled NO has made a rapid journey from the laboratory bench to the bedside because of its unique selective pulmonary vasodilator activity and its ready availability.  |  Eur Respir J 1996; 9: 2401–9, Sitbon O, Brenot F, Denjean A, Bergeron A, Parent F, Azarian R, Herve P, Raffestin B, Simonneau G: Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. J Thorac Cardiovasc Surg 1994; 108: 487–94, Curran RD, Mavroudis C, Backer CL, Sautel M, Zales VR, Wessel DL: Inhaled nitric oxide for children with congenital heart disease and pulmonary hypertension. • Mechanism of action: • Relaxes smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic-guanosine 3, 5-monophosphate leading to vasodilation • With inhaled nitric oxide there is minimal effect on systemic vasculature because of the efficient scavenging by Am J Pathol 1985; 121: 212–23, Jones R, Adler C, Farber F: Lung vascular cell proliferation in hyperoxic pulmonary hypertension and on return to air:[, Wink DA, Cook JA, Pacelli R, Liebmann J, Krishna MC, Mitchell JB: Nitric oxide (NO) protects against cellular damage by reactive oxygen species. J Clin Invest 1992; 90: 1116–21, Gaboury J, Woodman RC, Granger DN, Reinhardt P, Kubes P: Nitric oxide prevents leukocyte adherence: Role of superoxide. J Clin Invest 1997; 100: 955–6, Roberts JD Jr: Inhaled nitric oxide for treatment of pulmonary artery hypertension in the newborn and infant. Am J Physiol 1995; 269: H473–9, Ziegler JW, Ivy DD, Fox JJ, Kinsella JP, Clarke WR, Abman SH: Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus. Am J Med Sci 1996; 312: 166–74, Steinberg MH: Determinants of fetal hemoglobin response to hydroxyurea. J Thorac Cardiovasc Surg 1994; 107: 1129–35, Miller OI, Celermajer DS, Deanfield JE, Macrae DJ: Very-low-dose inhaled nitric oxide: A selective pulmonary vasodilator after operations for congenital heart disease. Am J Physiol 1996; 271: L225–9, Kinsella JP, Parker TA, Galan H, Sheridan BC, Halbower AC, Abman SH: Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease. Circ Res 1997; 81: 865–9, Head CA, Brugnara C, Martinez-Ruiz R, Kacmarek RM, Bridges KR, Kuter D, Bloch KD, Zapol WM: Low concentrations of nitric oxide increase oxygen affinity of sickle erythrocytes in vitro and in vivo. 2016 Jun 27;2016(6):CD002787. Am J Physiol 1996; 271: H2045–51, Chen LY, Mehta JL: Downregulation of nitric oxide synthase activity in human platelets by nitroglycerin and authentic nitric oxide. Annu Rev Immunol 1997; 15: 323–50, Cannon RO: Role of nitric oxide in cardiovascular disease: Focus on the endothelium. Am J Physiol 1994; 267: L242–9, Hallman M, Bry K: Nitric oxide and lung surfactant. Whether this is because of inappropriate study design, the complex nature and spectrum of ARDS, inefficacy of NO, inappropriate dosing, or counterbalancing toxic effects of NO is unknown. Objective: To compare the effects of inhaled nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO) on oxygenation, hemodynamics, and lymphatic drainage in an oleic acid lung injury model in sheep. J Pediatr 1993; 122: 743–50, Zayek M, Wild L, Roberts JD, Morin FC III: Effect of nitric oxide on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension. Am J Respir Crit Care Med 1996; 153: 128–35, Högman M, Frostell CG, Hedenstrom H, Hedenstierna G: Inhalation of nitric oxide modulates adult human bronchial tone. Inhalational nitric oxide: A selective pulmonary vasodilator for treatment of persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med 1998; 157: A683, Munzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA, Freeman BA, Harrison DG: Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. Anesth Analg (2011) 112(6):1411–21.10.1213/ANE.0b013e31820bd185 Circ Res 1995; 76: 215–22, Cornwell TL, Arnold E, Boerth NJ, Lincoln TM: Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. J Neurosci 1993; 13: 4130–45, Yoshizumi M, Perrella MA, Burnett JC Jr, Lee ME: Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Proc Natl Acad Sci U S A 1994; 91: 3559–63, Wink DA, Osawa Y, Darbyshire JF, Jones CR, Eshenaur SC, Nims RW: Inhibition of cytochromes P450 by nitric oxide and a nitric oxide-releasing agent. Am J Respir Cell Mol Biol 1997; 16: 629–39, Dupuy PM, Shore SA, Drazen JM, Frostell C, Hill WA, Zapol WM: Bronchodilator action of inhaled nitric oxide in guinea pigs. Lancet 1996; 347: 436–40, Yoshida M, Taguchi O, Gabazza EC, Kobayashi T, Yamakami T, Kobayashi H, Maruyama K, Shima T: Combined inhalation of nitric oxide and oxygen in chronic obstructive pulmonary disease. A NESTHESIOLOGY 1997; 86: 676–88, Hallman M, Bry K, Turbow R, Waffarn F, Lappalainen U: Pulmonary toxicity associated with nitric oxide in term infants with severe respiratory failure. Current data from multicenter trials suggest that the mortality rate in moderate lung injury is not significantly changed by NO inhalation. Purpose: Although the analogy of nitric oxide (NO) to Endothelium-derived Relaxing Factor remains controversial, medical use of exogenous NO gas by inhalation has grown exponentially. Br J Pharmacol 1997; 121: 485–90, Lefer DJ, Scalia R, Campbell B, Nossuli T, Hayward R, Salamon M, Grayson J, Lefer AM: Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemia-reperfusion injury in rats. Nitric oxide is a colorless, almost odorless gas that is slightly soluble in water (2 or 3 mM). Nitrous oxide, commonly known as laughing gas or nitrous, is a chemical compound, an oxide of nitrogen with the formula N 2 O.At room temperature, it is a colourless non-flammable gas, with a slight metallic scent and taste.At elevated temperatures, nitrous oxide is a powerful oxidiser similar to molecular oxygen. Kinsella JP, Abman SH. Dependence on kinetics of NO release. iNO has been demonstrated to improve outcomes in term and near-term infants with hypoxic respiratory failure associated with pulmonary hypertension. J Appl Physiol 1997; 83: 1968–75, Adrie C, Hirani WM, Holzmann A, Keefer L, Zapol WM, Hurford WE: Selective pulmonary vasodilation by intravenous infusion of an ultrashort half-life nucleophile/nitric oxide adduct. 302. Anatomic and physiologic correlates. A report of survival and modifying factors. Proc Natl Acad Sci U S A 1996; 93: 6770–4, Xia Y, Zweier JL: Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. A new action for an old drug. Ann Thorac Surg 1996; 62: 750–5, Fullerton DA, Jones SD, Jaggers J, Piedalue F, Grover FL, McIntyre RC Jr: Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation. Science 1976; 193: 897–9, Gruetter CA, Barry BK, McNamara DB, Gruetter DY, Kadowitz PJ, Ignarro L: Relaxation of bovine coronary artery and activation of coronary arterial guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosoamine. The relevance of the nitrogen oxides for clinical medicine has been recognized for over a century. Br Heart J 1984; 52: 557–71, Roberts JD Jr, Lang P, Bigatello LM, Vlahakes GJ, Zapol WM: Inhaled nitric oxide in congenital heart disease. Role of macrophage-target interaction coupled to nitric oxide generation, but independent of tumor necrosis factor production. Nitric oxide synthase inhibitors suppress the bronchodilator actions of nonadrenergic noncholinergic–mediated bronchodilation, suggesting that endogenous NO synthesis is involved in the control of bronchial tone. Crit Care Med 1997; 25: 153–8, Rovira I, Chen TY, Winkler M, Kawai N, Bloch KD, Zapol WM: Effects of inhaled nitric oxide on pulmonary hemodynamics and gas exchange in an ovine model of ARDS. The Inhaled Nitric Oxide Study Group. Animals: Thirty female sheep, weighing 35 to 40 kg. 2020 Mar 5:885066620906800. doi: 10.1177/0885066620906800. J Appl Physiol 1992; 73: 2505–10, Belvisi MG, Ward JK, Mitchell JA, Barnes PJ: Nitric oxide as a neurotransmitter in human airways. Reprinted with permission from Ichinose  et al. N Engl J Med 1996; 334: 624–9, Rimar S, Gillis CN: Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation. Am J Physiol 1996; 270: L273–80, Ayad O, Wong HR: Nitric oxide decreases surfactant protein A gene expression in H441 cells. Nitric oxide (NO) is an important determinant of local blood flow and is formed by the action of NO synthase (NOS) on the semi-essential amino acid L-arginine in the presence of molecular oxygen. Comparison of Fixed-Dose Inhaled Epoprostenol and Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome in Critically Ill Adults. ROS Signaling in the Pathogenesis of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). Administration of nitric oxide by inhalation has been shown to acutely improve hypoxemia associated with pulmonary hypertension … Chem Res Toxicol 1996; 9: 836–44, Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and ugly. Stereoselective S-nitrosothiol recognition sites. Br J Pharmacol 1995; 116: 1829–34, Dong Z, Staroselsky AH, Qi X, Xie K, Fidler IJ: Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. J Am Coll Cardiol 1995; 25: 1656–64, Channick RN, Newhart JW, Johnson FW, Williams PJ, Auger WR, Fedullo PF, Moser KM: Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: An ambulatory delivery system and initial clinical tests. Methods Enzymol 1996; 269: 230–43, Denicola A, Rubbo H, Rodriguez D, Radi R: Peroxynitrite-mediated cytotoxicity to Trypanosoma cruzi. NO is produced from the amino acid L-arginine by the enzymatic action of nitric oxide synthase (NOS). Am J Respir Crit Care Med 1998; 157: 1372–80, Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G: Inhaled nitric oxide in acute respiratory distress syndrome. Inhibition of nitric oxide limits infarct size in the in situ rabbit heart. Intensive Care Med 1997; 23: 163–9, Uchida T, Nakazawa K, Yokoyama K, Makita K, Amaha K: The combination of partial liquid ventilation and inhaled nitric oxide in the severe oleic acid lung injury model. Nat Med 1995; 1: 804–9, Bredt DS, Hwang PM, Snyder SH: Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nevertheless, such newly designed NO donor drugs appear promising as a selective pulmonary vasodilator and provide an alternative to NO inhalation. Kellner M, Noonepalle S, Lu Q, Srivastava A, Zemskov E, Black SM. J Investig Med 1997; 45: 69–74, Sheehy AM, Burson MA, Black SM: Nitric oxide exposure inhibits endothelial NOS activity but not gene expression: A role for superoxide. It is this action that has been studied in intensive care medicine, especially in relation to hypoxic vasoconstriction associated with acute respiratory distress syndrome (ARDS). Circulation 1991; 83: 2038–47, Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J: Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Cancer Res 1991; 51: 2531–5, Yim CY, McGregor JR, Kwon OD, Bastian NR, Rees M, Mori M, Hibbs JB Jr, Samlowski WE: Nitric oxide synthesis contributes to IL-2-induced antitumor responses against intraperitoneal Meth A tumor. Mechanism of Action After inhalation, NO diffuses rapidly across the alveolar-capillary membrane into the subjacent smooth muscle of pulmonary vessels to activate soluble guanylate cyclase (Figure 1). Pulm Circ. J Am Chem Soc 1963; 85: 2901–6, Nishimura M, Hess D, Kacmarek RM, Ritz R, Hurford WE: Nitrogen dioxide production during mechanical ventilation with nitric oxide in adults. A dose-response study and comparison with prostacyclin. Stroke 1997; 28: 1283–8, Fukumura D, Jain RK: Role of nitric oxide in angiogenesis and microcirculation in tumors. J Cardiovasc Pharmacol 1996; 27: 80–5, Bocchi EA, Bacal F, Auler Junior JO, Carmone MJ, Bellotti G, Pileggi F: Inhaled nitric oxide leading to pulmonary edema in stable severe heart failure. Clin Chest Med 1983; 4: 199–217, Kneussl MP, Lang IM, Brenot FP: Medical management of primary pulmonary hypertension. Implications for interpretation of lung biopsy findings in early childhood. doi: 10.1002/14651858.CD000399.pub3.  |  This site needs JavaScript to work properly. 156,157 The expression of various NOS isoforms in peripheral nonadrenergic noncholinergic nerve endings 158 and in human bronchial epithelium 159 supports this finding. -, Afshari A, Brok J, Møller AM, Wetterslev J. J Appl Physiol 1989; 66: 929–35, Yoshimura K, Tod ML, Pier KG, Rubin LJ: Effects of a thromboxane A, Lindeborg DM, Kavanagh BP, Van MK, Pearl RG: Inhaled nitric oxide does not alter the longitudinal distribution of pulmonary vascular resistance. Vasc Med 1996; 1: 25–33, Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. INOmax is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm). This physiological action of inhaled NO is recognized by competitive athletes, especially runners. J Appl Physiol 1995; 78: 341–8, Shirai M, Shimouchi A, Kawaguchi AT, Sunagawa K, Ninomiya I: Inhaled nitric oxide: Diameter response patterns in feline small pulmonary arteries and veins. Pharm Res 1996; 13: 649–62, Szabo C: The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. A NESTHESIOLOGY 1991; 75: 990–9, Shah NS, Nakayama DK, Jacob TD, Nishio I, Imai T, Billiar TR, Exler R, Yousem SA, Motoyama EK, Peitzman AB: Efficacy of inhaled nitric oxide in a porcine model of adult respiratory distress syndrome. J Appl Physiol 1996; 80: 252–60, Roberts JD Jr, Roberts CT, Jones RC, Zapol WM, Bloch KD: Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. Cardiovasc Res 1996; 32: 743–51, DeCaterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MAJ, Shin WS, Liao JK: Nitric oxide decreases cytokine-induced endothelial activation. Arch Biochem Biophys 1993; 304: 279–86, Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA: Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. HHS Am J Physiol 1996; 271: L981–6, Bigatello LM, Hess D, Bloch KD, Ritz R, Hurford WE: Effect of inhaled nitric oxide on plasma cyclic GMP in ARDS patients (abstract). Buckley MS, Agarwal SK, Garcia-Orr R, Saggar R, MacLaren R. J Intensive Care Med. 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