Richard A. Henderson, III Jay B. Dean, Daniel K. Mulkey, Alfredo J. Garcia, III, Robert W. Putnam and

28 Pages·2003·0.53 MB·English

Jay B. Dean, Daniel K. Mulkey, Alfredo J. Garcia, III, Robert W. Putnam and
Richard A. Henderson, III
J Appl Physiol 95:883-909, 2003. doi:10.1152/japplphysiol.00920.2002
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invited review JApplPhysiol95:883–909,2003;
10.1152/japplphysiol.00920.2002.
Neuronal sensitivity to hyperoxia, hypercapnia, and
inert gases at hyperbaric pressures
Jay B. Dean,1 Daniel K. Mulkey,1 Alfredo J. Garcia III,1
Robert W. Putnam,1 and Richard A. Henderson III1,2
1DepartmentofPhysiologyandBiophysics,EnvironmentalandHyperbaricCellBiologyFacility,
and2DepartmentofCommunityHealth,WrightStateUniversitySchoolofMedicine,
CollegeofScienceandMathematics,Dayton,Ohio45435
Dean,JayB.,DanielK.Mulkey,AlfredoJ.GarciaIII,RobertW.
Putnam, and Richard A. Henderson III. Neuronal sensitivity to
hyperoxia,hypercapnia,andinertgasesathyperbaricpressures.JAppl
Physiol95:883–909,2003;10.1152/japplphysiol.00920.2002.—Asambi-
ent pressure increases, hydrostatic compression of the central nervous
system, combined with increasing levels of inspired PO2, PCO2, and N2
partial pressure, has deleterious effects on neuronal function, resulting
in O toxicity, CO toxicity, N narcosis, and high-pressure nervous
2 2 2
syndrome. The cellular mechanisms responsible for each disorder have D
o
been difficult to study by using classic in vitro electrophysiological w
methods, due to the physical barrier imposed by the sealed pressure nlo
chamber and mechanical disturbances during tissue compression. Im- a
d
proved chamber designs and methods have made such experiments e
d
afetamsoibslpeheinresmaabmsmolaultiean(AnTeAu)r.oHnse,reeswpeecisaulmlymaatriazmebtiheenstepmreestshuordess, t(cid:1)h5e fro
m
physiologically relevant test pressures, potential research applications, ja
andresultsofpreviousresearch,focusingonthesignificanceofelectro- p
physiologicalstudiesat(cid:1)5ATA.IntracellularrecordingsandtissuePO2 .ph
measurementsinslicesofratbraindemonstratehowtodifferentiatethe ys
neuronaleffectsofincreasedgaspressuresfrompressureperse.Exam- io
ples also highlight the use of hyperoxia ((cid:1)3 ATA O ) as a model for log
2 y
studyingthecellularmechanismsofoxidativestressinthemammalian .o
centralnervoussystem. rg
o
anesthesia;carbondioxidetoxicity;freeradicals;high-pressurenervous n
M
syndrome; membrane potential; nitrogen narcosis; oxidative stress; ox-
a
ygentoxicity;polarographicoxygenelectrode rc
h
2
6
, 2
0
MOST HUMANS ARE PHYSIOLOGICALLY adapted to live and ATA (221), to ocean depths as great as 2,300 ft. of sea 1
work near sea level, where ambient pressure is (cid:2)1 water(fsw),wherePBincreasesto(cid:2)70ATA(18).These 0
atmosphereabsolute(ATA).1Nonetheless,weexploita situationsarethepressureextremesofourinhabitable
continuum of barometric pressure (PB) ranging from environment, which only relatively few highly trained
the near vacuum of outer space, which we survive individuals have ever occupied.
during Space Shuttle extravehicular activity by wear- Militarypersonnel,medicalpersonnel,andotherhu-
inga4.3lb./in.2absolute(psia)pressuresuit(30,300ft. mans, however, frequently encounter levels of hyper-
pressureequivalent,0.29ATA)(120,220),downtothe baric pressure (i.e., (cid:3)1 ATA) of lesser degrees in their
summit of Mt. Everest at 29,029 ft., where PB is 0.31 normalworkenvironments.Examplesofmoderatehy-
perbaric environments (e.g., (cid:1)5 ATA) include the fol-
lowing: patients and medical attendants undergoing
Address for reprint requests and other correspondence: J. B.
hyperbaric O therapy (HBOT) (38, 203); diving with
Dean,Dept.ofAnatomyandPhysiology,WrightStateUniv.,3640 2
Colonel Glenn Highway, Dayton, OH 45435 (E-mail: jay.dean an underwater breathing apparatus for recreational,
@wright.edu). professional (oil and salvage companies), and combat
1OneATAisthePBatsealevel,whichisequivalentto760Torr. purposes (89); simulated dry and wet dives for hyper-
ATGisdefinedaschamberpressureminusroompressure;thusat
baric research and dive training (217); and working in
sealevel(1ATA),2ATAinsideapressurechamberis1ATG,3ATA
isequivalent2ATG,andsoforth.Ambientpressureincreases1atm thecompressedatmosphereofasubterraneanenviron-
forevery33fswdepth.Therefore,1ATA(cid:4)0fsw,2ATA(cid:4)33fsw, ment (117). Abnormal work environments resulting
3ATA(cid:4)66fsw,etc.TheSIunitforpressureisthekilo-Pascal(kPa), from catastrophic accidents while at sea (32, 165) or
where1ATA(cid:4)101.3kPa.Othercommonlyusedpressureequiva-
underground(155)alsocanresultinprolongedbreath-
lents for 1 ATA include 14.7 psia, 0.101 mega-Pascal (MPa), and
1.013bars. ing of hyperbaric gases. For example, submariners
http://www.jap.org 8750-7587/03$5.00Copyright©2003theAmericanPhysiologicalSociety 883
884 INVITEDREVIEW
breathe a hyperbaric atmosphere while awaiting res- In 1979 and 1980, Wann and colleagues reviewed
cue inside a disabled submarine (DISSUB) (165). Al- hyperbaric electrophysiological methods (215) and
though submarine accidents rarely occur, the sinking summarized the effects of large hydrostatic pressures
oftheRussiansubmarineKurskintheBarentsSeain ((cid:3)100 ATA) on cellular excitability (213). Research at
August2000,in356fsw(11.8ATA),withlossofall117 that time was based primarily on studies of large
crewmembers,isasomberreminderoftheimportance robust neurons, axons, and muscle cells in the inver-
of preparing for DISSUB emergencies. Furthermore, tebrate CNS (iCNS). Given the technical advances
the need to prepare for similar DISSUB scenarios on made in this field during the past two decades, which
land, in which men are trapped under increased pres- haveincreasedtheproductivityofsingle-cellstudiesin
sure, was demonstrated recently when nine Pennsyl- the mCNS (58, 72–74, 150, 152–154), we have reas-
vania coal miners were stranded for 77 h inside a sessed the methods used in hyperbaric electrophysiol-
water-filledmine.Exposuretoambientpressuresupto ogy along with their potential research applications.
40 fsw [1.21 atmospheres gauge pressure (ATG), or Unlike previous reviews of hyperbaric electrophysiol-
2.21 ATA] necessitated hyperbaric medical support by ogy, which focused exclusively on the effects of hyper-
medical officers and divers from the US Navy’s diving baria exceeding 50 or 100 ATA (89, 114, 130, 213), we
and salvage community (155). Presently, the US Navy haveemphasizedtheimportanceofstudyingneuronal
maintains agreements with (cid:3)20 countries for assis- barosensitivity and chemosensitivity to hyperbaric
tance with DISSUB events (68). gases at PB (cid:1)5 ATA. The various methods used to
Hyperbaric environments present many physiologi- differentiatetheeffectsonneuronsofgaspartialpres-
cal challenges, affecting especially the lungs, hollow sures vs. pressure per se are summarized (APPENDIXES
viscera,andnervoussystem.Withrespecttothemam- A–D).Moreover,barodependentdisordersofthemCNS D
malian central nervous system (CNS; mCNS), breath- are summarized, presenting their clinical signs and ow
ingair,pureO2,ormixturesofO2andinertgases(N2, symptomsandthepressureranges(totalpressureand nlo
H2,andHe),andaircontaminatedwithCO2,athyper- gaspartialpressures)overwhichtheyoccur,asanaid ad
baric pressure for extended periods, can impair the to designing physiologically relevant in vitro studies ed
normal functioning of neural networks (28, 89). Com- (see OVERVIEW OF BARO-RELATED DISORDERS OF THE MCNS). fro
monneurologicalproblemsassociatedwithhyperbaric Specific examples are presented to demonstrate how m
environmentsincludedO2toxicity,whichisthoughtto hyperbaric pressure per se (see CENTRAL EFFECTS OF jap
occurthroughincreasedoxidativestress,aswellasN2 PRESSURE PER SE) and increased gas partial pressures .ph
narcosis (inert-gas narcosis), CO2 toxicity, and high- (see NARCOTIC AND TOXIC PROPERTIES OF GASES) can alter ys
pressure nervous syndrome (HPNS) (18, 43, 89, 203).2 neuronal excitability. In particular, we emphasize the iolo
Inneurophysiology,oneofthecommonlyusedexper- use of hyperoxia under pressure [i.e., hyperbaric O2 gy
imental approaches to identify how changes in gas (HBO )]notonlyasaninvitromodelforstudyingCNS .o
tension affect neural function is to conduct an electro- 2 rg
O2 toxicity, but also as a new model for studying the o
physiological study of single neurons in an isolated n
tissue preparation of the rodent CNS, such as brain cellular mechanisms by which acute oxidative stress M
[i.e., reactive O species (ROS)] alters neuronal activ- a
slices or the neonatal brain stem-spinal cord, while ity. Accordingly2, we have critically evaluated the con- rch
manipulatingthePO2,PCO2,and/orN2partialpressure trollevelsandexperimentallevelsoftissuePO2(PtiO) 26
(PN2) of the perfusate at room pressure (i.e., normo- thatareusedintheratbrainslicemodel(3,151,1692), , 2
baricpressure)(54,65,98).However,makingasingle- 0
cell recording in an isolated tissue preparation of the comparing each to levels of PtiO2 that occur in the 10
intact mCNS when breathing normobaric air, normo-
rodent CNS, which is maintained inside a hyperbaric
chamber, while increasing ambient pressure, has barichyperoxicgasmixtures, andHBO2 (see RESEARCH
proventobetechnicallychallengingduetothephysical APPLICATION: HYPEROXIA AND O2 TOXICITY).
barrier imposed by the sealed pressure chamber and
mechanical disruption of the recording microelectrode Glossary
andneuronduringtissuecompressionanddecompres-
ATA Atmospheres absolute pressure
sion(191,192).Consequently,relativelylittleisknown
ATG Atmospheres gauge pressure
about how hyperbaric gases and increased hydrostatic
CNS Central nervous system
pressure affect the intracellular properties of neurons
DISSUB Disabled submarine
in the mCNS. Recent improvements in hyperbaric
(cid:5)E Change in internal energy
chamber designs, however, have now made intracellu-
larrecordingsofmammalianneurons,maintainedun- FIgasx Fractionalconcentrationofinspiredgasx,
der hyperbaric conditions, technically feasible (58, 59, where gas x is either O2, CO2, or N2
150, 152, 153). (FIO, FICO, FIN)
2 2 2
fsw Feet of sea water
(cid:5)G Change in free energy
2Decompression sickness, commonly known as the “bends” and (cid:5)H Enthalpy change
“chokes,” is not covered here because it is a problem that occurs
HBHe Hyperbaric helium
subsequent to decompression while diving and/or flying, and this
HBO Hyperbaric oxygen
review focuses on neurophysiological challenges that occur while 2
breathinghyperbaricgases;i.e.,gasesinthecompressedstate. HBOT Hyperbaric oxygen therapy
JApplPhysiol(cid:127)VOL95(cid:127)SEPTEMBER2003(cid:127)www.jap.org
INVITEDREVIEW 885
HPLC High-pressure liquid chromatography OVERVIEW OF BARO-RELATED DISORDERS
HPNS High-pressure nervous syndrome OF THE MCNS
iCNS Invertebrate central nervous system When designing a hyperbaric electrophysiological
K Equilibrium constant experiment, it is important to consider the ranges of
k Reaction rate constant pressures that are physiologically relevant, which in-
mCNS Mammalian central nervous system cludes 1) the partial pressure of each gas in the in-
NO(cid:1) Nitric oxide radical spired atmosphere and 2) the surrounding ambient
NOS Nitric oxide synthase pressure, or PB, which exerts a force against the body,
P Pressure resulting in hydrostatic compression of all tissues, in-
PB Barometric pressure cludingneuraltissue.Thefollowingfoursectionssum-
P Partial pressure of a gas, where gas x is marize the major neurological problems encountered
gasx
either O2, CO2, N2, or He (PO2, PCO2, when humans and other animals breathe hyperbaric
PN2, PHe) gases containing O2, N2, CO2, He, or H2. Our discus-
PIgasx Partial pressure of inspired gas x, where sion will focus on the major signs and symptoms of
eachbaro-relateddisorderandthepressurerangeover
gas x is either O2, CO2, or N2 (PIO,
2 which these signs and symptoms occur.
PICO, PIN)
2 2
PtiO2 Partial pressure of oxygen in neural tis- N2 Narcosis
sue
Figure1showsthebroadrangeofambientpressure
pH Intracellular pH
i over which the human body can function. Extended
pH Outside or extracellular pH
o stayatpressuresexceeding(cid:2)4ATA((cid:2)3ATG,(cid:2)99fsw D
psia Pounds per square inch absolute o
depth) is only possible by reducing the fractional con- w
R Gas constant n
R Input resistance (M(cid:6)) centrationofN2intheinspiredairtoavoidthenarcotic loa
in effects of N (N narcosis). For example, nitrox is O - d
ROS Reactive oxygen species 2 2 2 e
enriched air, which is made by lowering the fractional d
(cid:5)ST ETenmtrpoepryactuhraen,gien degrees Kelvin acovnocidenNtratnioanrcoofsiisnswphirieled tNh2e (dFiIvNe2r). iIst aist bdreepatthh.edThtoe from
(cid:5)(cid:5)VV* MAcotliavratvioolnumvoeluchmaengcehange for the rate- brerdeautchtiionn2ginniptraorxtiaallsporersesduurceesoftihnespinirceiddeNn2ce(PoINf2d)ewchomen- jap.p
h
limiting step pression sickness and the time needed for decompres- ys
Vm Membrane potential (mV) sion during ascent. Typically, nitrox is used at depths iolo
g
y
.o
rg
o
n
M
a
rc
Fig. 1. Physiologically relevant ambient pressures h
encountered by humans breathing air and various 26
hyperbaric gas mixtures (left), the neurological , 2
problemsthatcanresult(middle),andtheproposed 0
1
stimulusaffectingneuronalfunction(right).Hyper- 0

baricenvironmentsareencounteredinclinicalmed-
icine [e.g., hyperbaric O therapy (HBOT)], com-
2
pressedairwork(e.g.,subterraneantunneling),div-
ingmedicine,anddisabledsubmarineaccidents.By
breathing an assortment of gas mixtures, to avert
thenarcoticandtoxiceffectsofN andO ,aswellas
2 2
thedirecteffectsofhydrostaticcompressiononthe
mammalian central nervous system (mCNS), hu-
mans are able to inhabit hyperbaric environments
rangingfrom(cid:3)1to(cid:2)70atmospheresabsolutepres-
sure(ATA).Atextremehyperbaricpressures((cid:3)100
ATA), pressure becomes a tool that can be used to
perturbbiologicalsystems(invitro)byalteringpro-
teinconformation,membranefluidity,andconfigu-
rationofthecytoskeleton.Humansandmostmam-
mals, however, have never occupied this range of
ambientpressures.Seetextforfurtherexplanation
of breathing gas mixtures and pressure thresholds
forvariousneurologicaldisorders.ROS,reactiveO
2
species;SCUBA,self-containedunderwaterbreath-
ing apparatus; HPNS, high-pressure nervous syn-
drome;PN2,N2partialpressure.
JApplPhysiol(cid:127)VOL95(cid:127)SEPTEMBER2003(cid:127)www.jap.org
886 INVITEDREVIEW
(cid:3)100 fsw. Symptoms of N narcosis are significantly move CO from the body for homeostasis of tissue pH
2 2
manifested in most individuals when breathing air at (86,156,157,183).Inrats,goingfromairto6%CO in
2
PBof(cid:2)4ATAandthenincreaseinsidiouslybutrapidly air, which stimulates breathing, causes pH of the ce-
with further increasing depth and are best character- rebrospinal fluid to decrease from 7.396 to 7.294 and
ized as a graded rapture, reduction of higher mental intracellularpH(pH)ofneuraltissuetodecreasefrom
i
processes, and impaired neuromuscular coordination, 7.044to6.982.BreathingahigherlevelofCO (11%in
2
usually resembling the symptoms of alcohol intoxica- air) decreases pH of the cerebrospinal fluid even fur-
tion, or similarly, the early stages of anesthesia and ther to 7.190 and pH of neural tissue to 6.910 (187).
i
hypoxia. With increasing depth and PIN, the symp- Under in vitro conditions (brain stem slice), moderate
tomsworsenandeventuallyleadtouncons2ciousnessat levelsofhypercapnicacidosisdecreasepH by(cid:1)0.2pH
i
depths where PB exceeds 10 ATA (18). To date, very units (control pHi is (cid:2)7.24) (56, 78, 176, 177) and
littleelectrophysiologicalresearchhasbeen conducted increaseneuronalexcitabilityincentralCO -chemore-
2
onthecellularmechanismsinvolvedinN narcosis(34, ceptorareasofthemammalianbrainstem(54,78,98).
2
35, 154). This stimulation of putative central CO /H(cid:7)-chemore-
2
ceptor neurons is believed to underlie the reflex stim-
CO Toxicity ulationofventilation,whichisinterpretedasthephys-
2
iologicalresponseoftherespiratorycontrolnetworkto
RetentionofCO2underhyperbaricconditions,dueto hypercapnic acidosis (156, 157, 183).
either increased fractional concentration of inspired As inspired CO increases further to 10–15% CO ,
2 2
CO2 (FICO2) and/or decreased alveolar ventilation, or and end-tidal PCO2 exceeds 50–70 Torr, mental ability
breathing a CO2-contaminated gas mixture, impairs becomesincreasinglyimpairedandischaracterizedby D
neurological function. It is well established that end- confusion, irrational behavior, drowsiness, dizziness, ow
tidal PCO2 increases in a diver due to increased meta- and impaired short-term memory (146, 217). Recovery nlo
bolic CO2 production caused by physical exertion of fromCO2toxicityisoftenassociatedwithseverehead- ad
swimming, working, and breathing underwater, and ache(146).Insomecases,inspiring30%CO2produces ed
duetoreducedventilatoryefficiency(alveolarhypoven- seizures(225).Inrats,breathing75–100%CO2rapidly fro
tilation)causedbytheaddeddeadspaceofabreathing produces ataxia followed by loss of righting reflex and m
apparatus and the increased airway resistance caused pedalreflexes,and,eventually,anesthesia(45).Divers ja
p
bpyresinsucrreea(s7e9d, 1d4e7n,s1it9y4)o.fPrgoabsleesmastasinsoccrieaatseeddwaimthbCieOn2t (lo1s9e4c,o2n1s7c)i,oaunsndepsrsowlohnegnedenedx-ptoidsaulrPeCtOo2(cid:3)ex7c0e%edCsO902 (Tboarlr- .phys
retention are exacerbated in experienced divers, com- anceO )quicklyleadstodeathinanimalmodelsdueto io
pared with nondivers and amateur (recreational) depress2ion of respiratory centers (53). log
divers, because experienced divers typically exhibit Despite the widespread use of extreme hypercapnia y.o
hduigcheedrvleenvteillsatoofryrecshteinmgoseennds-ittiidvaitlyPtCoOi2ncsapuirseeddCbOy2raet- arosnamnenantaelstthoxeticicanatn,dveitrsypliotttelenteilaelctdraonpgheyrsiaosloagnicaelnrvei-- onrg
normobaric pressure (116, 217). For example, mean searchhasbeendoneonthecellularmechanismofCO M
2 a
eTnodrr-t,idwahlePreCaOs2ienxpneornideinvceerdsaNnadvydidviinvegrtsrahiandeeasswigansi4fi0- ttooxbiecitdyu.eT,hineptoaxritc,etoffethctesloafrCgeOa2,cihdoiwficeavteiro,natrheabteolicecvuerds rch 2
hdcaiyvnpeterlrysbhaorifgtiaehnearnindmceerxaeeanrsceeindsed,t-oteind(cid:3)da-5lt0Pid–Ca7Ol02PoTCfOo42r6ri,nTaeonxrpdr.e,rDdieuunrrciinnedgg PwanChdOe2nw(PaalItvCeeOro2,)l.iatBrrePacCpaOiud2slieynCcdrOief2fausisseesesxatitnrehtmoigethhlyleesvcoeellluslbmolefeiimnnsblpirpiarineddes 6, 2010
severeexercise,end-tidalPCO2reached(cid:3)90Torr(116, and through the cytoplasm, where it is hydrated to
194, 217). form carbonic acid, which rapidly dissociates to form
CO2 retention at hyperbaric pressure can produce protons and bicarbonate ions. The effects of extreme
two types of neurological problems. First, retention of levels of hypercapnia (i.e., supercapnia, Ref. 211) on
seuvemnambloydiensctrleeavseelss onfitCriOc2oaxtidheypreardbiacarilc(pNrOes(cid:1))suarnedprree-- bprHaiininsttehme isnlitcaec,thmowCeNvSerr,eemxtarienmseuhnykpneorwcanp.nInia,thwehricaht
sults in cerebral vasodilation (101), which increases also impairs neuronal excitability, decreases pH, on
i
delivery of perfusion-limited gases to neural tissue average, from 7.24 (5% CO ) to 6.71 (33% CO ) to 6.67
2 2
(108, 122). Consequently, the severity of symptoms of (50% CO2) and to 6.49 (100% CO2 at PB (cid:2)1 ATA) in
CNSO2toxicity(andN2narcosis)areenhancedduring locus coeruleus neurons and results in abnormal elec-
respiratory acidosis and/or begin at lower levels of trical activity (56).
hyperbaria (5, 42, 95, 134). Second, tissue PCO2, once
reachingasufficientlyhighlevel,eitherdirectlydueto
O Toxicity
its narcotic properties, or indirectly by the ensuing 2
intracellular acidification, induces CO toxicity with- Pure O is breathed at (cid:3)1 ATA by using the LAR V
2 2
outwarning.Normally,arterialPCO2rangesfrom(cid:2)35 Draeger underwater breathing apparatus on combat
to 45 Torr (arterial pH (cid:2)7.35–7.45), and small in- divingoperationsbySpecialOperationspersonnel(US
creases in arterial PCO2 of only a few Torr stimulate Navy SEALs and Marine Force Reconnaissance units)
both central and peripheral CO /H(cid:7) chemoreceptors, topreventN narcosisatdepth,toreducethelengthof
2 2
activating powerful cardiorespiratory reflexes to re- decompressionstopsduringascent,andtodecreasethe
JApplPhysiol(cid:127)VOL95(cid:127)SEPTEMBER2003(cid:127)www.jap.org
INVITEDREVIEW 887
riskofdecompressionsicknessduringandafterascent (193) and increased production of superoxide, which
(36, 37). However, breathing pure O or nitrox ((cid:3)21% reacts with NO(cid:1) to effectively decrease biologically ac-
2
O )alsoincreasestheriskofCNSO toxicityatgreater tive NO(cid:1), thereby causing vasoconstriction (61–63).
2 2
depths (Fig. 1). Similarly, Fig. 1 shows that, on land, CO retention, however, presumably increases NO(cid:1)
2
HBOT uses intermittent exposure to pure O at (cid:3)1–3 production (101), causing cerebral vasodilation, which
2
ATA to increase arterial PO2, and thus O2 delivery to antagonizes O2-induced cerebral vasoconstriction and
tissues, to treat a variety of clinical disorders due to increases blood flow through neural tissues (13, 122).
diving and nondiving causes.3 Typically, several 20- This, in turn, increases delivery of O to neural tissue
2
to 30-min exposures to HBO are interspersed with 5- (108, 122), thereby increasing Pti at any given level
2 O
2
to 10-min air breaks to avert symptoms of CNS and of inspired PO2 (PIO) (see below, Fig. 4: #2, open
2
pulmonaryO toxicity(38,203).CNSO toxicityman- squares vs. #1, open circles), resulting in increased
2 2
ifests itself ultimately as grand mal convulsions (i.e., production of ROS (60, 61, 63, 70, 107, 205). Tissue
the “Paul Bert effect”), although other autonomic, mo- PCO2 increases during HBO2 by one or more of the
tor, and cardiorespiratory signs and symptoms also following mechanisms: 1) CO -carrying capacity of ve-
2
mayoccur,suchasbradycardia,hyperventilation,dys- nous hemoglobin is decreased because venous hemo-
pnea,andalteredcardiorespiratoryneuralreflexes(43, globin is fully saturated with O , which leads to in-
2
51, 189, 209). Interestingly, Mulkey et al. (152) have creasedtissueandvenousPCO2(i.e.,Haldaneeffect);2)
reported that neurons in the solitary complex, an im- alveolar hypoventilation and CO retention (see CO
2 2
portant cardiorespiratory control center in the dorsal Toxicity above); and 3) breathing CO -contaminated
2
medulla oblongata, are highly sensitive to HBO and gases. In addition, and independently of the increased
2
this sensitivity to oxidative stress may contribute to cerebralbloodflow,itispossiblethatthereisincreased D
the cardiorespiratory perturbations that occur in CNS productionofROSinthepresenceofH(cid:7)andCO2(174, ow
O2 toxicity. 188, 218) that renders neurons more sensitive to hy- nlo
The inter- and intraindividual variations in suscep- peroxia (152). In contrast to moderate hypercapnia, a
d
tibilitytoO2seizuresmakeitdifficulttopredictwhois which enhances CNS O2 toxicity, severe hypercapnia ed
vulnerable to O2 toxicity and when O2 seizures will that produces anesthesia depresses development of fro
occur (43). O seizures per se resulting from acute CNSO toxicityinnewbornratsbyanunknownmech- m
exposuretohy2perbarichyperoxiaarenotbelievedtobe anism 2(15, 211). Obviously, the interactions among ja
p
harmful.If,however,thesubjectisnotremovedimme- CO2, pHi, and ROS during hyperbaric hyperoxia re- .ph
diately from the hyperoxic environment, then contin- quire additional study. The sensitivity of single neu- y
s
ued exposure to HBO can result, first, in permanent rons to HBO will be considered in more detail below io
2 2 lo
neurological damage and paralysis (i.e., the “John (see RESEARCH APPLICATION: HYPEROXIA AND O2 TOXICITY) gy
Bean effect”) and eventually death with prolonged ex- and in the companion paper (152). .o
posure (12). Presently, CNS O toxicity is the limiting rg
2 o
factor in protocols employed for closed-circuit diving He, H , and O Mixtures: HPNS n
2 2 M
operations by combat divers (37) and for HBOT (38).
a
The pressure threshold for onset of seizures can be Figure 1 also includes heliox, which is a He-O2 gas rc
lowered to (cid:1)3 ATA O2, however, by coexisting condi- mspiexctiufircealltyh,a7t9i%s Nbreianthaeirdisatredpelapctehdsw(cid:3)it1h50H–e2t0o0avfsewrt; h 26
tmioentas,bosluicchraatseim(5m, 4er3s,io1n16()3,6a),nedxehrycpisoeveanntdilainticorneaasnedd N2 narcosis, and t2he fractional concentration of in- , 20
1
respiratoryacidosis(5,42,95,223).Forexample,mod- spired O2 (FIO2) is lowered to prevent CNS O2 toxicity 0
(18). Breathing heliox also greatly ameliorates the in-
erate CO retention (respiratory acidosis) lowers the
2
creasing airway resistance at those depths due to
threshold for O toxicity, increases the severity of sei-
2
greatergasdensity.However,divingatdepthsgreater
zures, and decreases survival time in human divers
than(cid:2)15ATAcanalsoresultinHPNS,whichisdueto
and animals (5, 15, 42, 134). One mechanism for this
the effects of pressure per se and not to increased He
increased sensitivity to hyperbaric hyperoxia is due to
CO -induced cerebral vasodilation, which increases partial pressure (PHe), PO2, or PCO2 (18). Signs and
2
symptoms of HPNS include muscular tremors, EEG
neural Pti (101). During exposure to HBO , cerebral
O 2
2 changes, loss of coordination, nausea, respiratory dif-
blood flow initially is reduced by hyperoxia due to
interruption of NO(cid:1) release from S-nitrosohemoglobin ficulties, memory deficit, and seizures (in animals),
which typically begin at (cid:2)15–16 ATA or higher (18,
89). It is likely that seizures would also occur in hu-
3ClinicaladministrationofO2atPB(cid:3)1ATAiscalledHBOTand mans if they were subjected to high enough pressures
itisusedclinicallytohelp“resolvecertainrecalcitrant,expensive,or while breathing heliox; however, this is neither prac-
otherwise hopeless medical problems” (38). Some of the accepted
tical nor ethical for obvious reasons. At even greater
usesofHBOTforacutemedicalemergenciesincludecarbonmonox-
ide poisoning, necrotizing fasciitis, air embolism, decompression depths((cid:3)15ATA),asmallamountofN2isaddedback
sickness, gas gangrene, and radiation necrosis (38). In addition, tothebreathinggasmixturetoproducetrimix(O -He-
2
HBOThasbeenusedtotreatavarietyofneurologicalproblems,such N ; Fig. 1), which increases the depth and pressure a
2
as traumatic brain injury (38, 158). The application of HBOT to
divercanreachbeforeonsetofsymptomsofHPNS(18,
neurological problems is still in its infancy, however, and debated
29).Similarly,H issubstitutedforN toproduceagas
becauseofthelackofrelevantcellularandclinicalresearchonthese 2 2
potentiallyimportantapplicationsofhyperbaricmedicine. mixture of O2-H2-He, referred to as hydreliox (Fig. 1),
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888 INVITEDREVIEW
whichisalsousedfordeepdivestodelayonsetofsigns (89): “... much of the work with excitable cells has
andsymptomsofHPNS(1,18,29).H ,comparedwith beencarriedoutoverthemaximumtoleratedpressure
2
N ,isevenlessdenseandeasierthanHetobreatheat range, which in some cases extend up to 1,000 ATA.
2
pressure,yetitalsoaffordsprotectionfromHPNS.Itis This is clearly appropriate in terms of the studies per
well known that anesthetic gases (e.g., hyperbaric N se, but it is difficult to relate such work to the intact
2
or H ) and hydrostatic pressure have antagonistic ac- mammalian CNS, which would not be expected to
2
tions on neurological function, such that, when com- functionabove100ATA...”Thus,althoughtheuseof
bined,eachreducesthedeleteriouseffectsoftheother test pressures (cid:2)100 ATA will likely increase the mag-
(29, 113, 114). The basis for this interaction between nitude of the cell’s pressure response, if present, it is
anesthetics and pressure is unclear and is one of the also important to report what happens over the pres-
areas of hyperbaric electrophysiology research requir- sure range for which the symptoms of HPNS are
ingadditionalstudy(27,113).Thesensitivityofsingle known to occur for the species being used.
neurons to pressure per se will be considered in more Thereisevidencethatlowerlevelsofhyperbariaalso
detail in the next section and in the companion paper affect excitability of neurons and synapses. Excitable
(153). cells in invertebrates are barosensitive to ambient
pressures ranging from 4 to 10 ATA by using either
CENTRAL EFFECTS OF PRESSURE PER SE true hydrostatic compression or He compression (34,
47, 48, 192). Similarly, neurons in the rat brain stem
Hydrostatic Compression of the Brain
are barosensitive to even smaller pressures of only
Weliveinaseaofgas,andtheweightoftheEarth’s 2.4–4ATAHe(58,150,153),andbriefhydraulicpres-
atmosphere exerts a physical pressure at sea level suresrangingfrom1.17to4.0ATAcanalterneuronal D
equalto1ATA,towhichourbodiesarephysiologically excitability in dorsal root ganglion neurons (90, 138, o
w
adapted. As we descend beneath the ocean surface, 181). For example, Fig. 2A shows the integrated firing n
lo
pressure continues to increase an additional 1 atm rateresponseofaneuroninthesolitarycomplexinthe a
d
eachadditional33fsw(Fig.1).Thusadiverat132fsw caudal-dorsal medulla oblongata in a 300-(cid:8)m-thick e
d
isexposedto4atmofseawater plus 1 atm ofair, or5 submerged slice before, during, and after compression fro
ATA of total pressure. Similarly, a person inside a from 1 to 3 ATA He (PB). Notice that input resistance m
pressure chamber (145, 203, 217), caisson, or subter- (R )decreasedduringHecompression(inset,superim- ja
in p
raneantunnel(117)experiencesanequivalentdepthof posed traces) concomitant with the increased firing .p
h
sea water when the density of gas inside the sealed rate. Typically, membrane potential (Vm) depolarized ys
pressure chamber is increased. by (cid:1)3 mV (not shown) (58, 150, 153). This indicates io
Inahyperbaricenvironment,softtissuesofthebody that 3 ATA pressure caused an increase in membrane log
y
behave as a fluid and rapidly transmit any pressure- conductance(seeFig.2legendforfurtherexplanation). .o
applied force against the surface of the body to the Mulkey et al. (153) have shown that the increased rg
o
adjacent fluid compartments, thereby removing any firing rate response to hyperbaria is retained during n
pressure differential across structures. This results in chemical synaptic blockade, which indicates that it is M
a
hydrostatic compression of the cerebral spinal fluid, an intrinsic membrane property of certain neurons in rc
h
cerebral circulation, and extracellular and intracellu- the solitary complex. Similarly, McCarter et al. (138) 2
larfluidcompartmentsofthemCNS(89,109).Thebest reportedthatabrief,gradedhydraulicpressurepulse, 6, 2
known example of neuronal barosensitivity is HPNS, ranging from 0.17 to 3 ATG, depolarized Vm and in- 01
which was already discussed above (18, 89). The creased inward current in a graded fashion in dorsal 0

threshold pressure for HPNS is variable and affected root ganglion neurons.
by the rate of compression (18). Details regarding the Figure 2B shows a similar response in another
cellular mechanism(s) underlying HPNS are unclear neuron in the solitary complex that was stimulated
(114),butitappearsthatbothsynaptic(74,76,85,228, and displayed increased membrane conductance (de-
229) and intrinsic membrane properties are involved creased R ) during compression to a much higher
in
(72, 73, 191, 192, 216). Several excellent reviews on pressure,20ATAHe.Toourknowledge,thisisthefirst
HPNSexistelsewhere(18,100,104,114).Whenstudy- example of an intracellular recording of a mammalian
inginvitroneuronalactivityasamodelofHPNS,itis neuronthatwasmaintainedcontinuouslyduringcycli-
importanttoremembertherangeofambientpressures calcompressionanddecompressiontothishighlevelof
overwhichsymptomsofHPNSoccur((cid:2)15to(cid:2)70ATA, pressure (compare Refs. 191, 192, 216). The signifi-
Fig. 1). For example, intracellular and extracellular cance of this experiment is that it demonstrates that
recordings of neurons and axons in invertebrates and the electrical activity of individual neurons in the
terrestrialmammalshaveshownthathydrostaticcom- mCNS can be studied over the lower range of ambient
pression, ranging from 100 to 200 ATA and higher, pressures at which symptoms of HPNS are first de-
alters neural activity (72–74, 76, 114, 130, 191, 192, tected (Fig. 1).
197, 198, 216). As a test for studying barosensitivity, The above studies indicate that neurons are sensi-
particularly in the mCNS, the use of extremely large tive to much lower levels of hyperbaric pressure than
levels of pressure is of questionable importance, be- previously believed (50, 114, 130). The importance of
cause terrestrial mammals are never exposed to these barosensitivity to ambient pressures (cid:1)5 ATA remains
levels of hydrostatic pressure. As cautioned by Halsey to be determined; however, it may, like temperature,
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INVITEDREVIEW 889
Fig. 2. Examples of 2 barosensitive neurons in the
solitarycomplex.Intracellularrecordingsfrom2differ-
ent neurons showing that 3 ATA (A) and 20 ATA of
helium (He) (B) decrease input resistance and stimu-
late neuronal firing rate in a reversible manner. In
these2experiments,inputresistancewasmeasuredby
usingaconstanthyperpolarizingcurrentpulse(super-
imposedvoltagetracesinAandB).BasedonOhm’slaw
(voltage (cid:4) current (cid:9) resistance), the change in mem-
brane potential (V ) during hyperpolarizing current
m
injectionthroughthemicroelectrodeisproportionalto
the change in input resistance and inversely propor-
tionaltothemembraneconductance.This,thedecrease
ininputresistancemeasuredduringexposuretohyper-
baricpressure,isindicativeofanincreaseinmembrane
conductance. Action potentials are truncated in B in
insetofVmtraces.Dataareunpublishedexamplesfrom D
thestudybyMulkeyetal.(153).PB,barometricpres- ow
sure; (cid:10)FR, integrated firing rate; Imp/sec, impulses/ n
second. lo
a
d
e
d
fro
m
ja
p
.p
h
y
s
io
lo
g
y
.o
act as another environmental stimulus that deter- intracranialpressurerangesfrom0to10or15mmHg rg
mines how the organism responds and adapts to its in humans (139) and from 8 to 10 mmHg in conscious o
n
environment(114,150,153).Tospeculatefurther,neu- rats(111).Intracranialhypertensionisconsideredasa M
ronal barosensitivity to relatively low levels of hyper- sustainedelevationinintracranial pressureexceeding arc
baric pressure may be the early stage of a pressure 15or20mmHgandgoingashighas(cid:2)100mmHg(139, h
2
continuum that is eventually exhibited as HPNS at 140). Historically, neurological symptoms associated 6
higherpressures.Whatisinteresting,however,isthat with traumatic brain injury have been attributed to , 2
0
not all neurons in the mCNS are equally sensitive to cerebralischemiaandtheresultingtissuehypoxiaand 1
0
moderate levels of hyperbaria (82, 153). For example, acidosis as intracranial pressure approaches cerebral
initial reports indicate that hippocampal neurons do arterial blood pressure. However, it is likely that in-
notrespondto3ATAHeorhydraulicpressure(82,90). creasedtissuepressurealsocontributestoneurological
Similarly, not all neurons in the solitary complex are dysfunctioninthesecasesinamannerthatremainsto
sensitive to 2–4 ATA He (153). This suggests that bedetermined.Inaddition,theinitialtraumaticbrain
neuronal barosensitivity to low levels of hyperbaria is injury itself, which is a fluid-percussive injury, pro-
not a generalized phenomenon, but represents a spe- duces a brief, transient period of hydrostatic compres-
cific physiological response of certain populations of sion ranging from 1.4 to 2.1 ATG that results in pro-
neurons in the mCNS. tracted dysfunction of electrical signaling and cellular
metabolism (64, 181). For the sake of completeness,
Intracranial Hypertension and Increased
retinal cells, which are considered as part of the
Intraocular Pressure
mCNS, are exposed normally to intraocular pressures
Another source of neuronal barosensitivity, which ranging from (cid:2)14 to 16 mmHg, depending on the
occurs on a much smaller pressure scale and indepen- person’s age, race, and gender (123, 173). Intraocular
dentlyofchangesinPB,iscompressionofneuraltissue hypertension and glaucoma are associated with in-
that occurs whenever the mass of tissue inside the traocular pressures (cid:2)21 mmHg, which produce long-
rigid, closed intracranial compartment is increased by termdestructionofnervecellsandtheirfunction(123).
tissue edema and bleeding subsequent to head injury However, the effects of increased intraocular pressure
or by increased production or decreased removal of on the excitability and electrical signaling of retinal
cerebral spinal fluid (4, 33, 140). Typically, normal cells are unknown.
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890 INVITEDREVIEW
Thermodynamic Reactions vs. Mechanical Forces Conversely, at lower levels of hydrostatic pressure,
Macdonald and Fraser (129, 131) have proposed that
The preceding discussion indicates that neuronal
thermodynamic and kinetic effects described by Eqs.
barosensitivity occurs over a very large range of pres-
1–4 would be too small to be of physiological signifi-
sure (89, 90, 114, 130, 138, 150, 153, 192). It has been
cance, based on conventional solute-solvent interac-
suggested that, depending on the level of hyperbaric tions,becausethe(cid:5)Vand(cid:5)V*termswouldhavetobe
pressure, different cellular mechanisms may be re-
astoundingly large for any significant change to occur
sponsibleformediatingcellularbarosensitivity(41,94, in (cid:5)G or k. Traditional dogma maintains that hydro-
129,131,136).Atextremelyhighlevelsofcompression staticpressures(cid:1)15ATAhavenosignificanteffectson
(e.g., (cid:3)100 ATA), hydrostatic pressure is a thermody-
neuronalfunction(18,192,197).However,asproposed
namic intensity parameter, similar to temperature,
in Fig. 1 (“Cellular Barosensitivity”) and illustrated in
which determines various thermodynamic equilibria,
Fig.2andelsewhere(90,138,150,153,192),neuronal
and thus could affect various cellular processes. It can
barosensitivity, as defined by changes in firing rate,
be analyzed theoretically, based on the way in which
V ,andR ,occursat2.5–4ATAandpossiblyaslowas
pressure (P) and the molar volume change ((cid:5)V) com- 10m0 mmHign ((cid:2)1.13 ATA or (cid:2)0.13 ATG) (2). Because
binetochangethefreeenergy((cid:5)G)ofareaction(129–
relatively few studies have attempted to differentiate
131); i.e.
the effects of hydrostatic pressure from gas partial
(cid:5)G(cid:3)(cid:5)H(cid:4)T (cid:1) (cid:5)S (1) pressure in the mCNS, especially at PB (cid:1)5 ATA (89),
we would argue that it is premature to conclude that
(cid:3)(cid:11)(cid:5)E(cid:5)P(cid:1)(cid:5)V) (cid:12) T (cid:1) (cid:5)S (2) small changes in physical pressure do not alter neuro-
Pwh(cid:1)(cid:5)eVre),(cid:5)(cid:5)HEisisthteheencthhaanlpgyecihnainngteerannadliesneeqrugayl,tTo(i(cid:5)sEth(cid:7)e naIlnfufancctt,ioMnaicndtohnealmdCaNndS.Fraser (131) have proposed Dow
that many nonneuronal cells respond to micropres- n
temperature in degrees Kelvin, and (cid:5)S is the entropy lo
sures, which they define as (cid:1)20 kPa (0.2 ATG or 1.2 a
change. At constant T, the equilibrium constant (K), d
(cid:5)V, and P are rela(cid:1)ted by t(cid:2)he following expression AbeTlAo)c,abliyzaedmsehcehaarnaicnadlpstrroacienssfothrcaetsthreesyuhltyipnogthfreosmizethtoe ed fro
dlnK (cid:12)(cid:5)V differential compression of various adjoining cellular m
(cid:4) (3) components, such as lipid bilayers, membrane-bound ja
dP R(cid:1)T p
T proteins, cytoskeletal proteins, and extracellular ma- .p
h
where R is the gas constant. Thus, for a reaction trix. However, they go on to say that “... at present, ys
involving a large (cid:5)V, pressure changes can have a therearenodistinctivecandidates[cellularstructures] io
lo
large effect on the equilibrium of that reaction. andapractical,specificworkinghypothesisislacking” g
y
Pressure can also alter the rate of a chemical reac- (131). If true, however, these same mechanical forces .o
tion by changing the activation volume for the rate- could be a significant factor at small-to-moderate hy- org
limiting step ((cid:5)V*) (50). At constant temperature, the drostatic pressures (e.g., 2–5 ATA) in neurons, which, n
reaction rate constant (k), activation volume, and am- in turn, would alter protein configurations (e.g., ion Ma
bient pressure are related by the following expression channels,postsynapticreceptors,etc.)andthusneuro- rc
(cid:1) (cid:2) h
nalexcitability.Itremainstobedetermined,however, 2
dlnk (cid:4)(cid:12)(cid:5)V* (4) at what range of hydrostatic pressures are shear and 6, 2
dP R(cid:1)T straininvolved,ifatall,inalteringthefunctionofcells 0
T and tissues, and “... at what pressure does the puta- 10

Forareactioninvolvingalarge(cid:5)V*,pressurechanges tive ‘micro-pressure’ effect saturate and orthodox high
can have a large effect on the rate of that reaction. pressure thermodynamics take over” (131).
Stated another way, Macdonald and Fraser (129, 131)
have proposed that, even for reactions with relatively
NARCOTIC AND TOXIC PROPERTIES OF GASES
smallchangesinmolarvolumeandactivationvolume,
verylargehydrostaticpressurescansignificantlyalter Several of the neurological problems caused by
the equilibrium and rate of the reaction, respectively. breathing hyperbaric gases are related to the narcotic
Forthisreason,asindicatedinFig.1,neuraltissuehas propertiesofthegas,andnotpressureperse,whichwe
beenexposedtoextremelyhighpressures,ontheorder willconsidernow.Theambientpressureatwhichfirst
of hundreds of atmospheres (100 to (cid:3)600 ATA), as a signs and symptoms occur for a specific gas-related
meansofalteringcellularfunctionsthroughchangesin disorderdependsonthecompositionoftheinspiredgas
protein structure (94) and enzymatic activity (103). In mixture.Ingeneral,wecanstatethatthesensitivityof
addition, extremely high pressures can alter mem- the mCNS for a given gas, as defined by PB and frac-
brane fluidity (128) and cause volume changes in cell tional concentration of gas, increases in the following
membranes by bulk compression of lipid bilayers, order (Fig. 1): CO toxicity (a problem at any level of
2
thereby decreasing the intermolecular distances be- PB,dependingonFICO andthusPICO),O2toxicity((cid:2)3
tween acyl chains. Extremely high pressures can also ATAbreathing100%O2 ),N narcosis2((cid:2)4ATAbreath-
2 2
changethehydrationoflipidbilayersandproteinsand ing air; i.e., 79% N ), and He narcosis [usually (cid:2)100
2
the crystalline-to-liquid-crystalline phase transitions ATA or higher as determined in various nonmamma-
in lipid bilayers (127, 128). liantissuemodels(200)].Figure1showsthethreshold
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INVITEDREVIEW 891
PB at which the symptoms or neural responses typi- gion of the cell membrane (141). This presumption,
callyoccurwhentherequisitegasmixtureisbreathed, knownasthe“criticalvolumehypothesisofanesthesia
but these values serve as guidelines only. The thresh- (and narcosis),” has been revised. It is now thought
old ambient pressure at which each neurological prob- that the central effects of a gas are mediated by the
lemdevelopsisnotabsoluteandcanvaryconsiderably direct and indirect actions it has on membrane-bound
in either direction for an individual and between indi- proteins and cytosolic proteins, which perturb ionic
viduals, due to preexisting physiological conditions conductances and neurotransmission (80). Gases such
that affect cerebral blood flow, metabolic rate, body as O and CO also have additional effects on neurons
2 2
temperature, and acid-base status (18, 43). because they react biochemically in the extracellular
Wecanstate,ingeneral,thatthenarcoticpotencyof space, the membrane, and intracellular space to form
agasisdirectlydependentonits1)partialpressurein reactive chemical species, which are important meta-
the inspired gas mixture, blood, and neural tissues, bolicsignalsinnumerousprocessesandwhich,athigh
which increases with increasing PB, and 2) its lipid concentrations, are toxic to cells. For example, O2
solubility in cell membranes, which determines the formsavarietyofhighlyreactiveproducts(e.g.,super-
leveltowhichagasaccumulatesinthecellmembrane oxide, hydroxyl radicals, NO(cid:1), hydrogen peroxide, and
and cytoplasm at any partial pressure (18, 43). Figure peroxynitrite), which can either modulate or disrupt
3 shows the solubility of CO , O , and two inert gases normal cell function (60, 61, 63, 67, 71, 107, 205).
2 2
(He, N ) in a monolayer of egg phospholipid as a func- ExampleswillbeshownbelowofhowHBO stimulates
2 2
tionofincreasinggaspressure,asreportedbyBennett neuronalfiringrateinneuronsofthesolitarycomplex
et al. (19). All gases, excluding He, cause a linear and CA1 hippocampus. Recent work by our laboratory
increase, at differing rates (CO2 (cid:3)(cid:3)(cid:3) O2 (cid:3) N2), in hasshownthatthisexcitatoryeffectofacuteexposure D
monolayerfilmpressureasgaspressureincreases(in- to hyperoxia is most likely mediated by an increased o
w
creased film pressure corresponds to increased mem- production of ROS (152). Moreover, as already stated, n
lo
brane volume). Comparing Figs. 1 and 3, we can see CO forms H ions, which likewise either modulate or a
2 d
thatCO ,whichhasthehighestsolubilityincellmem- disrupt normal cell function, depending on its concen- e
2 d
branesinthisexample(Fig.3),likewisehassignificant tration (56, 137). Molecular O2 and CO2 will also pre- fro
effects on the mCNS at the lowest ambient pressure sumably have narcotic effects on the mCNS (95), as m
(Fig. 1) (43). Conversely, O and N have lipid solubil- predicted by data shown in Fig. 3 (19). The narcotic ja
2 2 p
ities, and, therefore, narcotic effects, which are inter- effects of O2 and CO2, however, will be difficult to .p
h
mediate to CO2 and He and are manifest only at hy- discriminate from the effects of their highly reactive ys
perbaric pressure. He is essentially insoluble in lipid secondary reaction products. io
bilayersandhasnonoticeablenarcoticeffectsoverthe log
y
rangeofambientpressurethatmostmammalsencoun- RESEARCH APPLICATION: HYPEROXIA .o
ter (28). This is why He is used as a compression AND O2 TOXICITY org
medium for many in vitro electrophysiology studies n
(Fig. 2) (e.g., Refs. 58, 75, 191; also see in APPENDIX A, The remainder of this review article, exclusive of M
Csioomn)p.ression media: HBHe vs. hydrostatic compres- A(thrPoyPpEphNeDyrosIXxioEilSao)gAyo–nDt,otfhosectuumsdeCysNtohSnetahenefdfeucwsteshaootffhtihynepcreaerpabpsaerrdoicpPreiltaeitOce-2 arch 2
relTahteedntaorctohteicireaffbeicltistyoftoaegxapsawnedrethfiershtytdhrooupghhobtitcorbee- control and test levels of O2 are in the rat brain slice 6, 20
model. 1
0

Hyperoxia as a Model of Oxidative Stress
Oxidativeconditions,producedbyavarietyofmech-
anisms (e.g., an increase in exogenous or endogenous
oxidizing agent or a decrease in endogenous antioxi-
dant), have wide-ranging effects on the mCNS. Oxida-
tion-reduction(redox)reactionsareinvolvedinnormal
signal transduction mechanisms (67, 71), such as O
2
sensing (121, 125, 126, 172) and modulation of neuro-
nal electrical activity (44, 152, 170). However, at high
levels, oxidative stress has been implicated as a caus-
ative agent, at least in part, in various neurological
disorders and diseases (67, 175).
O toxicity of the mCNS is one of the best known
2
examples of how acute exposure to an oxidative envi-
ronmentcandisruptneurologicalfunction(9,43).Nor-
Fig. 3. Relative solubilities of gases in artificial lipid bilayers. All mally, when animals and humans breathe normobaric
gases, excluding He, cause a linear increase in monolayer film
air, neural Pti is surprisingly low, ranging from 1–3
pressure,whichcorrespondstoincreasedmembranevolume,asgas Torr up to (cid:2)30O–234 Torr, depending on the area of the
pressureincreases.psi,Poundspersquareinch.[FromBennettetal.
(19).ReprintedwithpermissionfromElsevier]. mCNS (71, 135, 151). Thus, for the purpose of this
JApplPhysiol(cid:127)VOL95(cid:127)SEPTEMBER2003(cid:127)www.jap.org