Nitric oxide (NO) plays an important role in controlling microcirculatory function, but the effects of exogenous administration of nitrate (NO3-) on the microcirculation have not been well studied. We evaluated whether NO3- could influence the microvascular response to hypoxia in 17 healthy volunteers. We used a vascular occlusion test (VOT) to assess the response of near-infrared spectroscopy-derived indexes to hypoxic stress before and 2 h 15 min after oral administration of 800 mg potassium nitrate. We also monitored changes in the sublingual microcirculation using side-stream dark-field (SDF) video microscopy. The descending (7.3 [6.8-8.1] to 8.2 [7.9-9.8] %/min, p = 0.01) and ascending (201 [180-233] to 240 [197-285] %/min, p = 0.01) thenar oxygen saturation (StO2) slopes were significantly greater during VOT after nitrate administration than before. Sublingual SDF measurements showed increases in the total number of visible perfused vessels (i.e., from 14.1 [13.2-15.5] to 16.3 [15.4-16.7] vessels/mm, p < 0.01) and in the number of visible perfused small vessels (i.e., from 12.2 [11.5-13.7] to 14.2 [13.5-15.3] vessels/mm, p < 0.01) after nitrate administration but no changes in the microvascular flow index or in the proportion of visible perfused vessels, which were already maximal at baseline. Oral administration of nitrate therefore significantly influenced the response to a hypoxic challenge, increasing the number of visible perfused vessels and thus possibly limiting the O2 diffusion distance.

1.
De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL: Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002;166:98-104.
2.
den Uil CA, Lagrand WK, van der Ent M, Jewbali LS, Cheng JM, Spronk PE, Simoons ML: Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2010;31:3032-3039.
3.
Donadello K, Favory R, Salgado-Ribeiro D, Vincent JL, Gottin L, Scolletta S, Creteur J, De Backer D, Taccone FS: Sublingual and muscular microcirculatory alterations after cardiac arrest: a pilot study. Resuscitation 2011;82:690-695.
4.
Gomez H, Torres A, Polanco P, Kim HK, Zenker S, Puyana JC, Pinsky MR: Use of non-invasive NIRS during a vascular occlusion test to assess dynamic tissue O2 saturation response. Intensive Care Med 2008;34:1600-1607.
5.
Jhanji S, Lee C, Watson D, Hinds C, Pearse RM: Microvascular flow and tissue oxygenation after major abdominal surgery: association with post-operative complications. Intensive Care Med 2009;35:671-677.
6.
De Backer D, Hollenberg S, Boerma C, Goedhart P, Buchele G, Ospina-Tascon G, Dobbe I, Ince C: How to evaluate the microcirculation: report of a round table conference. Crit Care 2007;11:R101.
7.
De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, Vincent JL: Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med 2013;41:791-799.
8.
Vincent JL, Zhang H, Szabo C, Preiser JC: Effects of nitric oxide in septic shock. Am J Respir Crit Care Med 2000;161:1781-1785.
9.
Preiser JC, Lejeune P, Roman A, Carlier E, De BD, Leeman M, Kahn RJ, Vincent JL: Methylene blue administration in septic shock: a clinical trial. Crit Care Med 1995;23:259-264.
10.
Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R: Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 2004;32:21-30.
11.
Cauwels A: Nitric oxide in shock. Kidney Int 2007;72:557-565.
12.
Evans T, Carpenter A, Kinderman H, Cohen J: Evidence of increased nitric oxide production in patients with the sepsis syndrome. Circ Shock 1993;41:77-81.
13.
Ochoa JB, Udekwu AO, Billiar TR, Curran RD, Cerra FB, Simmons RL, Peitzman AB: Nitrogen oxide levels in patients after trauma and during sepsis. Ann Surg 1991;214:621-626.
14.
Vaughn MW, Kuo L, Liao JC: Effective diffusion distance of nitric oxide in the microcirculation. Am J Physiol 1998;274:H1705-H1714.
15.
Cunha FQ, Assreuy J, Moss DW, Rees D, Leal LM, Moncada S, Carrier M, O'Donnell CA, Liew FY: Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. Immunology 1994;81:211-215.
16.
Morin MJ, Unno N, Hodin RA, Fink MP: Differential expression of inducible nitric oxide synthase messenger RNA along the longitudinal and crypt-villus axes of the intestine in endotoxemic rats. Crit Care Med 1998;26:1258-1264.
17.
Engelberger RP, Pittet YK, Henry H, Delodder F, Hayoz D, Chiolero RL, Waeber B, Liaudet L, Berger MM, Feihl F: Acute endotoxemia inhibits microvascular nitric oxide-dependent vasodilation in humans. Shock 2011;35:28-34.
18.
Boerma EC, Koopmans M, Konijn A, Kaiferova K, Bakker AJ, van Roon EN, Buter H, Bruins N, Egbers PH, Gerritsen RT, Koetsier PM, Kingma WP, Kuiper MA, Ince C: Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial. Crit Care Med 2010;38:93-100.
19.
He X, Su F, Velissaris D, Salgado DR, de Souza BD, Lorent S, Taccone FS, Vincent JL, De BD: Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock. Crit Care Med 2012;40:2833-2840.
20.
Lundberg JO, Weitzberg E, Gladwin MT: The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008;7:156-167.
21.
Keen JT, Levitt EL, Hodges GJ, Wong BJ: Short-term dietary nitrate supplementation augments cutaneous vasodilatation and reduces mean arterial pressure in healthy humans. Microvasc Res 2015;98:48-53.
22.
Duncan C, Dougall H, Johnston P, Green S, Brogan R, Leifert C, Smith L, Golden M, Benjamin N: Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat Med 1995;1:546-551.
23.
Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT: Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003;9:1498-1505.
24.
Lupp C, Baasner S, Ince C, Nocken F, Stover JF, Westphal M: Differentiated control of deranged nitric oxide metabolism: a therapeutic option in sepsis? Crit Care 2013;17:311.
25.
Govoni M, Jansson EA, Weitzberg E, Lundberg JO: The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. Nitric Oxide 2008;19:333-337.
26.
Bahra M, Kapil V, Pearl V, Ghosh S, Ahluwalia A: Inorganic nitrate ingestion improves vascular compliance but does not alter flow-mediated dilatation in healthy volunteers. Nitric Oxide 2012;26:197-202.
27.
Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, MacAllister R, Hobbs AJ, Webb AJ, Ahluwalia A: Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 2010;56:274-281.
28.
Mancini DM, Bolinger L, Li H, Kendrick K, Chance B, Wilson JR: Validation of near-infrared spectroscopy in humans. J Appl Physiol 1994;77:2740-2747.
29.
Fry BC, Roy TK, Secomb TW: Capillary recruitment in a theoretical model for blood flow regulation in heterogeneous microvessel networks. Physiol Rep 2013;1:e00050.
30.
Orbegozo Cortes D, Puflea F, Donadello K, Taccone FS, Gottin L, Creteur J, Vincent JL, De Backer D: Normobaric hyperoxia alters the microcirculation in healthy volunteers. Microvasc Res 2015;98:23-28.
31.
Ellsworth ML, Pittman RN: Arterioles supply oxygen to capillaries by diffusion as well as by convection. Am J Physiol 1990;258:H1240-H1243.
32.
Ince C, Sinaasappel M: Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 1999;27:1369-1377.
33.
Engelke KA, Halliwill JR, Proctor DN, Dietz NM, Joyner MJ: Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm. J Appl Physiol (1985) 1996;81:1807-1814.
34.
Nagababu E, Ramasamy S, Abernethy DR, Rifkind JM: Active nitric oxide produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction. J Biol Chem 2003;278:46349-46356.
35.
Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Hogg N, Schechter AN, Gladwin MT: Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 2005;115:2099-2107.
36.
Larsen FJ, Schiffer TA, Weitzberg E, Lundberg JO: Regulation of mitochondrial function and energetics by reactive nitrogen oxides. Free Radic Biol Med 2012;53:1919-1928.
37.
Heinonen I, Saltin B, Kemppainen J, Sipila HT, Oikonen V, Nuutila P, Knuuti J, Kalliokoski K, Hellsten Y: Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition. Am J Physiol Heart Circ Physiol 2011;300:H1510-H1517.
38.
Loke KE, Laycock SK, Mital S, Wolin MS, Bernstein R, Oz M, Addonizio L, Kaley G, Hintze TH: Nitric oxide modulates mitochondrial respiration in failing human heart. Circulation 1999;100:1291-1297.
39.
Scheeren TW, Schober P, Schwarte LA: Monitoring tissue oxygenation by near infrared spectroscopy (NIRS): background and current applications. J Clin Monit Comput 2012;26:279-287.
40.
Banaji M, Mallet A, Elwell CE, Nicholls P, Tachtsidis I, Smith M, Cooper CE: Modelling of mitochondrial oxygen consumption and NIRS detection of cytochrome oxidase redox state. Adv Exp Med Biol 2010;662:285-291.
41.
Van Beekvelt MC, Colier WN, Wevers RA, Van Engelen BG: Performance of near-infrared spectroscopy in measuring local O2 consumption and blood flow in skeletal muscle. J Appl Physiol (1985) 2001;90:511-519.
42.
Lima A, van Genderen ME, van Bommel J, Klijn E, Jansem T, Bakker J: Nitroglycerin reverts clinical manifestations of poor peripheral perfusion in patients with circulatory shock. Crit Care 2014;18:R126.
43.
Creteur J, Carollo T, Soldati G, Buchele G, De Backer D, Vincent JL: The prognostic value of muscle StO2 in septic patients. Intensive Care Med 2007;33:1549-1556.
44.
Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL: Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med 2004;32:1825-1831.
45.
Trzeciak S, Dellinger RP, Parrillo JE, Guglielmi M, Bajaj J, Abate NL, Arnold RC, Colilla S, Zanotti S, Hollenberg SM: Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med 2007;49:88-98, 98.
46.
Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF: Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 2002;360:1395-1396.
47.
Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT: Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation 2007;116:1821-1831.
48.
Pluta RM, Oldfield EH, Bakhtian KD, Fathi AR, Smith RK, Devroom HL, Nahavandi M, Woo S, Figg WD, Lonser RR: Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers. PLoS One 2011;6:e14504.
49.
Trzeciak S, Glaspey LJ, Dellinger RP, Durflinger P, Anderson K, Dezfulian C, Roberts BW, Chansky ME, Parrillo JE, Hollenberg SM: Randomized controlled trial of inhaled nitric oxide for the treatment of microcirculatory dysfunction in patients with sepsis. Crit Care Med 2014;42:2482-2492.
50.
Siervo M, Lara J, Ogbonmwan I, Mathers JC: Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta-analysis. J Nutr 2013;143:818-826.
51.
Orbegozo Cortes D, Puflea F, De Backer D, Creteur J, Vincent JL: Near infrared spectroscopy (NIRS) to assess the effects of local ischemic preconditioning in the muscle of healthy volunteers and critically ill patients. Microvasc Res 2015;102:25-32.
52.
Shiva S: Nitrite: a physiological store of nitric oxide and modulator of mitochondrial function. Redox Biol 2013;1:40-44.
53.
Cauwels A, Buys ES, Thoonen R, Geary L, Delanghe J, Shiva S, Brouckaert P: Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner. J Exp Med 2009;206:2915-2924.
54.
Theunissen S, Sponsiello N, Rozloznik M, Germonpre P, Guerrero F, Cialoni D, Balestra C: Oxidative stress in breath-hold divers after repetitive dives. Diving Hyperb Med 2013;43:63-66.
55.
National Toxicology Program: Toxicology and carcinogenesis studies of sodium nitrite (CAS No. 7632-00-0) in F344/N rats and B6C3F1 mice (drinking water studies). Natl Toxicol Program Tech Rep Ser 2001;495:7-273.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.