{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:39:25Z","timestamp":1791398365859,"version":"4.3.3"},"reference-count":74,"publisher":"American Physiological Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Applied Physiology"],"published-print":{"date-parts":[[2004,2]]},"abstract":"<jats:p>Hyperoxia is a popular model of oxidative stress. However, hyperoxic gas mixtures are routinely used for chemical denervation of peripheral O<jats:sub>2<\/jats:sub>receptors in in vivo studies of respiratory control. The underlying assumption whenever using hyperoxia is that there are no direct effects of molecular O<jats:sub>2<\/jats:sub>and reactive O<jats:sub>2<\/jats:sub>species (ROS) on brain stem function. In addition, control superfusates used routinely for in vitro studies of neurons in brain slices are, in fact, hyperoxic. Again, the assumption is that there are no direct effects of O<jats:sub>2<\/jats:sub>and ROS on neuronal activity. Research contradicts this assumption by demonstrating that O<jats:sub>2<\/jats:sub>has central effects on the brain stem respiratory centers and several effects on neurons in respiratory control areas; these need to be considered whenever hyperoxia is used. This mini-review summarizes the long-recognized, but seldom acknowledged, paradox of respiratory control known as hyperoxic hyperventilation. Several proposed mechanisms are discussed, including the recent hypothesis that hyperoxic hyperventilation is initiated by increased production of ROS during hyperoxia, which directly stimulates central CO<jats:sub>2<\/jats:sub>chemoreceptors in the solitary complex. Hyperoxic hyperventilation may provide clues into the fundamental role of redox signaling and ROS in central control of breathing; moreover, oxidative stress may play a role in respiratory control dysfunction. The practical implications of brain stem O<jats:sub>2<\/jats:sub>and ROS sensitivity are also considered relative to the present uses of hyperoxia in respiratory control research in humans, animals, and brain stem tissues. Recommendations for future research are also proposed.<\/jats:p>","DOI":"10.1152\/japplphysiol.00892.2003","type":"journal-article","created":{"date-parts":[[2004,1,31]],"date-time":"2004-01-31T01:14:01Z","timestamp":1075511641000},"page":"784-791","source":"Crossref","is-referenced-by-count":150,"title":["Hyperoxia, reactive oxygen species, and hyperventilation: oxygen sensitivity of brain stem neurons"],"prefix":"10.1152","volume":"96","author":[{"given":"Jay B.","family":"Dean","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel K.","family":"Mulkey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Richard A.","family":"Henderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie J.","family":"Potter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Putnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(94)90043-4"},{"key":"REF2","doi-asserted-by":"crossref","unstructured":"Ahdab-Barmada J, Moossy J, and Painter M.Pontosubicular necrosis and hyperoxemia.Pediatrics66: 840-847, 1980.","DOI":"10.1542\/peds.66.6.840"},{"key":"REF3","unstructured":"Balentine JD.Pathology of Oxygen Toxicity.New York: Academic, 1982, p. 395."},{"key":"REF4","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1996.81.4.1683"},{"key":"REF5","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.161.6.9908106"},{"key":"REF6","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(98)00260-3"},{"key":"REF7","unstructured":"Bingmann D, Kolde G, and Speckmann EJ.Effects of elevated Po2values in the superfusate on the neural activity in hippocampal slices. In:Physiology and Pharmacology of Epileptogenic Phenomenon, edited by Klee MR, Lux HD, and Speckmann EJ. New York: Raven, 1982, p. 97-104."},{"key":"REF8","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.165.2.2009061"},{"key":"REF9","unstructured":"Camporesi MD.Hyperbaric Oxygen Therapy: A Committee Report.Kensington, MD: Undersea and Hyperbaric Medical Society, 1996."},{"key":"REF10","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(98)00067-0"},{"key":"REF11","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1991.71.6.2198"},{"key":"REF12","unstructured":"Chance Band Boveris A.Hyperoxia and hydroperoxide metabolism. In:Extrapulmonary Manifestations of Respiratory Disease, edited by Robin ED. New York: Dekker, 1978, p. 185-237."},{"key":"REF13","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1996.80.6.2102"},{"key":"REF14","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1986.sp015946"},{"key":"REF15","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1921.sp001972"},{"key":"REF16","doi-asserted-by":"publisher","DOI":"10.1159\/000241346"},{"key":"REF17","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2000.89.2.807"},{"key":"REF18","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00920.2002"},{"key":"REF19","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(03)00432-4"},{"key":"REF20","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(01)03057-8"},{"key":"REF21","doi-asserted-by":"crossref","unstructured":"Dripps RDand Comroe JH Jr.The effect of the inhalation of high and low oxygen concentration on respiration, pulse rate, ballistocardiogram and arterial oxygen saturation (oximeter) of normal individuals.J Physiol149: 277-291, 1947.","DOI":"10.1152\/ajplegacy.1947.149.2.277"},{"key":"REF22","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2001"},{"key":"REF23","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2000.83.4.2022"},{"key":"REF24","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(01)00306-1"},{"key":"REF25","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(02)00962-0"},{"key":"REF26","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.014142"},{"key":"REF27","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(86)90049-6"},{"key":"REF28","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1989.67.3.1150"},{"key":"REF29","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1998.85.1.129"},{"key":"REF30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1972.tb01268.x"},{"key":"REF31","unstructured":"Gyllensten L.Influence of oxygen exposure on the differentiation of the cerebral cortex in mice.Acta Morphol Neer Scand2: 311-330, 1959."},{"key":"REF32","doi-asserted-by":"publisher","DOI":"10.1177\/088307389601100603"},{"key":"REF33","unstructured":"Jain KK.Role of hyperbaric oxygenation in the management of stroke. In:Textbook of Hyperbaric Medicine(2nd ed.), edited by Jain KK. Seattle, WA: Hogrefe and Huber, 1996, p. 253-273."},{"key":"REF34","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1987.62.5.1924"},{"key":"REF35","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1953.5.12.803"},{"key":"REF36","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1953.5.9.487"},{"key":"REF37","doi-asserted-by":"publisher","DOI":"10.1038\/35093117"},{"key":"REF38","doi-asserted-by":"publisher","DOI":"10.1038\/35093186"},{"key":"REF39","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-9877(97)90091-8"},{"key":"REF40","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.91.1.379"},{"key":"REF41","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(75)90068-7"},{"key":"REF42","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(91)90083-U"},{"key":"REF43","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.90.5.1887"},{"key":"REF44","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00864.2002"},{"key":"REF45","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00865.2002"},{"key":"REF46","unstructured":"Mulkey DK, Henderson RA III, Ritucci NA, Putnam RW, and Dean JB.Oxidative stress decreases intracellular pH and Na+\/H+exchange and increases excitability of solitary complex (SC) neurons from rat brain slices.Am J Physiol Cell Circ Physiol.In press."},{"key":"REF47","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-1375-9_12"},{"key":"REF48","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1983.tb13574.x"},{"key":"REF49","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1990.69.5.1761"},{"key":"REF50","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2000.88.6.2287"},{"key":"REF51","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.165.7.2104126"},{"key":"REF52","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200208070-00007"},{"key":"REF53","doi-asserted-by":"publisher","DOI":"10.1054\/mehy.1998.0833"},{"key":"REF54","doi-asserted-by":"publisher","DOI":"10.1054\/mehy.1997.0696"},{"key":"REF55","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2000.89.2.655"},{"key":"REF56","doi-asserted-by":"publisher","DOI":"10.1016\/0378-3782(82)90002-0"},{"key":"REF57","doi-asserted-by":"publisher","DOI":"10.1067\/mem.2002.129723"},{"key":"REF58","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-197908000-00001"},{"key":"REF59","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(01)00298-5"},{"key":"REF60","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(91)90026-G"},{"key":"REF61","unstructured":"Simon AJand Torbati D.Effects of hyperbaric oxygen on heart, brain and lung functions in rat.Undersea Biomed Res9: 263-275, 1982."},{"key":"REF62","unstructured":"Sparks LDand Hunsaker JC III.Neuropathology of sudden infant death (syndrome): literature review and evidence of a probable apoptotic degenerative cause.Childrens Nervous System18: 568-592, 2002."},{"key":"REF63","doi-asserted-by":"publisher","DOI":"10.1016\/0165-3806(95)00005-X"},{"key":"REF64","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199606203342506"},{"key":"REF65","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(92)90070-W"},{"key":"REF66","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1989.67.6.2351"},{"key":"REF67","doi-asserted-by":"crossref","unstructured":"Unknown.Too much oxygen.N Engl J Med10: 1073-1074, 1966.","DOI":"10.1056\/NEJM196611102751912"},{"key":"REF68","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1940.tb01499.x"},{"key":"REF69","doi-asserted-by":"crossref","unstructured":"Watt JG, Dumke PR, and Comroe JH Jr.Effects of inhalation of 100 per cent and 14 per cent oxygen upon respiration of unanesthetized dogs before and after chemoreceptor denervation.Am J Physiol138: 610-617, 1943.","DOI":"10.1152\/ajplegacy.1943.138.4.610"},{"key":"REF70","doi-asserted-by":"publisher","DOI":"10.1054\/mehy.2001.1328"},{"key":"REF71","doi-asserted-by":"crossref","unstructured":"Wilkinson MH, Berger PJ, Blanch N, Brodecky V, and Jones CA.Paradoxical effect of oxygen administration on breathing stability following post-hyperventilation apnoea in lambs.J Physiol504.1: 199-209, 1997.","DOI":"10.1111\/j.1469-7793.1997.199bf.x"},{"key":"REF72","unstructured":"Yamada M.The Haldane-Henderson method for estimating the tension of alveolar carbon dioxide and the influence of oxygen of the stimulability of the respiratory centers (Abstract in English).J Chem Soc (Lond)114: 511, 1918."},{"key":"REF73","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.448"},{"key":"REF74","doi-asserted-by":"publisher","DOI":"10.1016\/S1566-0702(02)00025-5"}],"container-title":["Journal of Applied Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/japplphysiol.00892.2003","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T20:22:35Z","timestamp":1682626955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/japplphysiol.00892.2003"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,2]]},"references-count":74,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2004,2]]}},"alternative-id":["10.1152\/japplphysiol.00892.2003"],"URL":"https:\/\/doi.org\/10.1152\/japplphysiol.00892.2003","relation":{},"ISSN":["8750-7587","1522-1601"],"issn-type":[{"value":"8750-7587","type":"print"},{"value":"1522-1601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,2]]}}}