TohokuJ.Exp.Med.

,2003,200,8
5-9
2

Effe
ctsofKe t
amineandPr opof
olontheRat
ioof
Int
erleuki
n-6toI
nterl
euki
n-10duri
ng
Endotoxemiai
nRat s
TAKUMI TANIGUCHI, HIROKO KANAKURA, YASUHIRO TAKEMOTO,
YOKO KIDANI andKEN YAMAMOTO
Depar tment of Emergency and Cr itical Car
e Medicine, and Department of
Anesthesiology and Intensive Car e Medicine, Gr aduate School of Medical
Science, Kanazawa University, Kanazawa 920 -8641

TANIGUCHI,T. ,KANAKURA,H. ,TAKEMOTO,Y. ,KIDANI,Y.andYAMAMOTO,Y.

Effects of Ketamine and Pr opofol on the Ratio of Inter leukin-6 to Inter leukin-10
dur ing Endotoxemia in Rats. TohokuJ .Exp.Me d.,2 003,20 0( 2 )
,8 5-92 Our
pr eviouss tudyr eportedt hatt hec hangei nt her atioofi nt e
r leuki n( IL)-6t oI L-1 0
influe nc e
st hes ever i
tyofs epsisi npat ientswi ths yste mici nflammat oryr e spons e
syndr ome . Wee valuat edt hec hangei nt her atioofI L- 6toI L- 10af teradmi nis t
r a-
tionofke tamineorpr opof oli ne ndotoxi n-expos edr atsi nor de rt oe val uat et he
relat i
ons hip of pr o-i
nflammat ory and ant i-inflammat oryc yt okine sf ollowi ng
ke tami ne orpr opofoladmi nistration dur ing e ndot oxe mi a. We r andoml y as -
signe d4 0r atstooneoff oure qualgr oups :e ndot oxinal one,r e ce i
vingEscher ichia
coli e ndotoxin( 15mg/kg,i .v.);saline c ont rol;ke tami ne ( 10mg･ kg ･h ,i .v.)
be fore and dur ing e xpos uret oe ndotoxi n;and pr opof ol( 10mg･kg ･h ,i .v.)
be foreanddur i
nge xpos ur et oe ndotoxin. Weme asur edt hepl asmac onc entr a-
tionsoft umorne crosisfac tor( TNF) -
α,I L-6 ,andI L- 10andc alc ulate dther atioof
IL- 6t oI L- 1
0i ne ach gr oup. The c urrents tudy s howe dt hatke t
ami ne and
pr opof oladmi nistr
at i
onat t
e nuat edt hei nc reas ei nTNF- α,I L- 6,andI L- 10,and
ke tami ne attenuate dt he i nc reas ei nt he r at io ofI L- 6t oI L- 1 0,butpr opof ol
inc reas edt hisrat i
oi nr at sr e ceiving a s ingl ei ntrave nousbol usofe ndot oxi n.
Whi let heme chanismsr espons iblefort hei nhi bitorye ffectsre qui ref urthe ri nve sti-
gat ion,ourr esultssugge stt hatpr ope ruseofke t
ami neasanane s theti
cage ntmay
off erc ertain advant age si nt he manage me ntofpat i
e nts wi the ndot oxe mi a.
cytokiner e
spons e;ke tami ne;lipopol ysac char i
de ;pr opof ol;se ps is
Ⓒ2 003TohokuUni versityMe dicalPr ess

Rece
ivedMar ch14,2003
;revi
sionacc
e pte
df orpubli
cati
onJune24,20
03.
Addressforrepri
nts:TakumiTaniguchi,Depart
me ntofEmerge
ncyandCrit
icalCar
eMe di
cine
,Gr
aduat
e
Sc
hoolofMe di
calScience
,KanazawaUni versi
ty,13-1Takara-
machi,Kanaz
awa9 20-8
641
,Japan.
e-
mail:taniyan＠me d.
kanazawa-u.
ac.
jp
85
 8
6 T.
Tani
guc
hie
tal
.

Endot oxe mi ai samaj orc aus eoft hes ys- eval

uatedt he change i
nt he relat
ionship of
temi ci nflammat or yr es pons es yndr ome( SI RS) pro-
inf
lammat oryandant i
-i
nflammat or
yc yto-
(Tr ac eye t al .1 9 86). Ci r culating e ndot oxi n kine
saf t
erketamineorpropofoladministr
ati
on
induc est heac tivat ionofc ompl eme ntandt he inendotoxi
n-exposedrat
s.
releas eofpr o- inf lammat or yc yt oki ne ss uc has
tumorne cr os isf ac tor( TNF) -α andi nt erle uki n METHODS
(IL)-6,whi chi nt ur nc an c ausei nf iltrat ion of Animal pr
epar
ation
leukoc yte si nt hel ungs( Mi nghi nie tal .1 99 8)
. Al le xpe rime nt al pr oc e dur es we re ap-
Inf l
ammat or y me di at or sf rom l e ukoc yte sc an pr ove d by t he Ani mal Car e Commi t t
e e of
pr oduc e hypot ens i
on,me tabol ic ac idosis ,and Kanaz awaUni ve rsi
tySc hoolofMe dicine ,and
tissuedamaget hatmayl eadt oor gandys func - we rei nac c ordanc ewi t
ht heNat ionalI ns titut e
tion( Lar se ne tal .1 99 8). Ourpr e viouss tudy of He al t
h gui deline sf or ani malus e. Mal e
repor te dt hatt hec hangei nt her at ioofI L- 6t o Wi starr at s( n＝3 2 )
, we i
ghi ng3 8 0±1 5g( me an±
IL- 10i nf l
ue nc est hes e ve ri
ty ofSI RS pat ie nts S.D.),we reane sthe t
iz edwi thani nt rape ritone al
(Tani guc hie tal .1 9 99 a). inje ction ofpe nt obar bi
tals odi um ( 30mg/ kg) .
Cr itical lyi llpat ient swi ths e ps iss uf f era Ve ntilationwaspe rforme dt hr oughat rac he al
highde gr eeofs tr es sduet opai n,anxi etyand tube( 7Fr .Int ernaldi ame ter )af tert rache ot omy.
or gan-s pe cificr e spons e by s eps i
s . An i mpor - The f emor al ar tery was c annul ated( 24G,
tant obj e ctive i nt he manage me nt of t he se Ve nul aCat he t er,Top,Tokyo)t omoni tort he
pat ientsi st oac hi e veanade quat el eve lofs e da- blood pr es sur e and t o dr aw bl ood s ampl es.
tion. Al thought hene edf orade quat es e dat i
on Lac tatedRi nge rss olutionc ont ai
ni ngamus cle
ins ept icpat ie nt si sge ne rallyac ce pt ed,t he rei s re l
axant ( panc ur onium br omi de ,0 .02mg/ml )
no c ons ens us r e gar ding t he c hoi ce ofdr ugs . and pe ntobar bitals odium ( 0.5mg/ml )wasi n-
Int r
ave nousane sthe ticss uchaskat ami neand fus edc ont inuous lyatar ateof1 0ml ･kg ･ h
pr opof olar ewi de lyus edf ort he sepur pos e s. thr oughaf emor alve inc annul a( 24G,Ve nul a
Ke tami ne ,aphe nc yc li
di nede rivat ive ,pr o- Cat heter ,Top,Tokyo) . Thehe artr ate( HR)
duc esdos e-re late dunc ons cious ne ssandanal ge- wasr e corde df rom l e adI Ioft hee l
e ctroc ar dio-
sia,andhasbe e nr ec omme nde df orane st he sia gr am. Ther at swe rec onne c t
e dt oapr essur e-
and s edat ion ofs ept icors eve relyi llpat ie nts cont roll
e d ve ntil
at or ( Se rvo 9 00B,Si e me ns-
be caus e of i ts s timul ating c ar di ovas c ul ar El ema,Sol na,Swe de n)de live ring1 00 % oxyge n
effec ts. Pr opof olbe longst oagr oupofal kyl- ata f reque ncy of3 0 br eat hs /mi n. wi t h an
phe nol st hathaveahypnot ice ffec tonani mal s
, ins pirator y:e xpi rator yr atioof1: 1. Theani -
and be caus e pr opof oli se asilyt itr atabl e and mal st he nwe rer estedf oratl eas t1 5mi nut e st o
off erst hepr ospe c tofr api dr e cove r yf ort he allow f orhe modynami c par ame ters,f ollowe d
pat ient,i ti sus e df ors edat ion ofc ritical lyi l
l bybas eliner eadi ngsofHR ands ys toli
car te rial
pat ients . pr essur e( SAP) .
Ourpr evi ouss tudi eshavedoc ume nt edt hat
ke tami neandpr opof olat tenuat et hepr oduc t i
on Exper
imental pr
otocols
and r eleas eofpr o-inf lammat or yc yt oki ne si n Af
terbase
linemeas
urement
s,theanimal
s
endot oxi n- expos edr at s( Tani guc hie tal .2 00 0
, wer
eal
locat
edrandoml
ytooneofthefol
lowi
ng
20 01). Howe ve r,t he re ar ef ew r epor tst hat f
ourgr
oups(n＝8pe rgr
oup).
have s tudi ed t he r elat ions hi p of pr o-
inflammat or yandant i-inflammat or yc yt oki ne s Endotoxin gr
oup
aft erke tami neorpr opof oladmi nis trat i
ondur - Endot
oxi
nshock wasi
nduc
ed by a bol
us
ing e ndot oxe mi a i n vi vo. We t he re for e i
nje
cti
on of endot
oxin (
15mg/kg), us i
ng
 Cyt
oki
neBal
ancebyKet
ami
neandPr
opof
ol 87

li
popol ysacchari
de prepar
edf r
om Escherichia changesduringt hestudywe reanal yzedus ing
coli (
0 11
1 :
B4 ;Dif
co Laboratori
es,Det
roit
,MI , two-way anal ysi
s ofvariance wi t
hr epeated
USA)as e ndot
oxin. Aftert he i
nje
cti
on of me as
uresfollowedbypost hoc t
e st(
Bonf erroni
endot oxin,0.
9 %sali
newasi nfuse
dconti
nuous ly sme thod). Stati
sti
calsi
gnif
icancewasde f
ined
(1ml ･kg ･h ) . atp＜0 .0
5. St at
ist
icalanalyses we r
e pe rfor-
me d usi
ng the StatView applicati
on (ve r
sion
Contr
ol gr
oup 5.
0,Mac i
ntosh;Abac us Conc epts, Ber keley,
A bol
usi
nject
ionof0 .
9%s ali
ne(1.
0ml/kg) CA,USA) .
wasf oll
owed by an i
nfusi
on of0 .
9% sali
ne.
Animalsi nthi
s group were notexpose
dt o RESULTS
endot
oxin. Plasma cytokine concentr
ations
Al lbas elineval ue swe res imi lari nt hef our
Ketamine gr
oup gr oups( Fig. 1). Endot oxi ni nj ec ti
on i nc rease d
Aft
erini
ti
ati
onofthei
nfusionofket
ami
ne the TNF- α c onc entr ation i nt he e ndot oxi n,
(
10mg･kg ･h ),abol
usofe ndotoxi
n(1
5mg/ ke tami ne ,andpr opof olgr oups ,butt hec once n-
kg)wasgi
ven. tration r emai ne ds igni ficant ly hi ghe ri nt he
endot oxi ngr oupt hani nt heot he rtwogr oupsat
Pr
opofol gr
oup 2hour saf te ri njection. The rewasnos i
gni fi
-
Afte
ri nit
iati
onoft heinfusionofpr opofol cantdi fferenc ebe twe enke tami neandpr opof ol
(10mg･kg ･h ) ,abolusofe ndotoxin(15mg/ gr oup af teri nj ecti
on. Pl asma c onc entrations
kg)wasgi ven. ofI L- 6be camee levat edaf tere ndot oxi ni njec-
Rectal t emperature was mai nt ained tion. Pl asmac once nt rat ionsofI L- 6at5hour s
be t
we en3 6 and 3 8°
C us i
ng a he at
ing pad. aft erinje ctioni ne ndot oxi n,c ont rol,ke tami ne,
Ar teri
albloods amples(1.
5ml )we redrawnf or and pr opof ol gr oups we re3 41 5±6 4 5pg/ ml ,
theme as
ureme ntofplasmac ytokineconce ntra- 12 5±5 8pg/ml ,4 56±2 35pg/ml ,and 1 5 78±3 45
tionsat2 ,4,and5hour saftert heendotoxi nor pg/ml ,r e spe ctively. Ke tami ne and pr opof ol
salineinj
e c
tion. gr oupss howe ds i
gni fic ant lyl owe rc onc e
nt ra-
tionst handi dt hee ndot oxi ngr oupat5hour s
Sample analysis aft eri nj ection. The I L- 6c onc entr ation of
Bloodus edforde t
er minationofc ytokine ke tami negr oupwasl owe rt hant hatofpr opof ol
concentrat
ionswasc entrif
uge df or1 0mi nutes gr oupat5hour saf teri nje ct
ion. Pl as mac on-
at3 000
×g at4 °
C. Pl asmawasde cante dand ce ntrationsofI L-1 0at5hour saf terinje cti
oni n
storedat−7 0°
C untilanal ysi
s. Cyt okinec on- endot oxi n,c ont r
ol ,ke tami ne ,and pr opof ol
centrat
ions(TNF- α,IL-6 ,andI L-10)we reme a- gr oupswe r
e6 8 8±8 6pg/ml ,95 ±4 5pg/ ml ,248±
sured us i
ng e nzyme -l
inke d i mmunos orbent 82pg/ml , and 4 08±5 6pg/ml ,r espe cti
ve ly.
assays(BioSource,Camar i
llo,CA,USA) . The Thec onc ent rationswe res ignific antlyl owe ri n
lowerlimitsofde te
ctionf orTNF- α,I L-6,and theke tami neandpr opof olgr oupst hant hos ei n
IL-10we re4.5pg/ml,7 .
0pg/ml ,and6 .
5pg/ml , thee ndot oxi ngr oupat5hour saf teri njecti
on.
respect
ivel
y. TheI L- 10c onc entrat ionofke tami negr oupwas
lowe rt hant hatofpr opof olgr oup at5hour s
Statistical analysis aft erinje ct
i on.
Dat a ar
e pr ese
nted as the me an±S.D. Ther at i
osofI L- 6t oI L-1 0c onc entrations
Diff
e re
ncesbetwe en gr
oupsatbas e
line wer e int hec ont r olandke tami negr oupswe r establ e
analyzedbySt udentunpai
redt -
tes
tandMann- aft ersal i
neore ndot oxi n,butt her atiosofI L- 6
Whi tneysU-test
. He modynami candc ytoki
ne toI L- 10i nt hee ndot oxi nandpr opof olgr oups
 8
8 T.
Tani
guc
hietal
.

Fi
g.1. Change sofpl asmac ytoki
nec onc
ent
rati
onsatbas e
lineandafteri
njec
tionofendot
oxi
nor
sali
ne( mean±S. D.
).
A:Tumorne crosisfact
or(TNF) -α;B:i
nterl
eukin(IL)
-6;C:IL-10
.
Closedc i
rcle
s ,endotoxi
ngr oup;opencir
cle
s,controlgroup;cl
osedsquares,ke
taminegr
oup;
opens quares,propofolgroup.
p＜0 .
05vs .base l
inewithi
ngr oup. p＜0 .0
5vs .endot
oxingroup.

increase
ds ignif
icant
ly( Fig.2)
. The r ati
o of ke
tami
negr
oup.
IL-6t oIL-
10c oncentr
ati
onsi nke tami
negr oup
wass i
gnif
icantl
yl owert han t
hatofpr opofol DISCUSSION
group at 5 hour s afte
re ndotoxininjecti
on Int he pre s
ent e xperi
me nts,inject
ion of
(ketaminegr oup;1.8
±0 .
9and pr opof
olgr oup; endotoxin alone i ncreased pro-infl
ammat ory
3.9
±1 .
2)
. cytokines (TNF- α and I L- 6) and ant i
-
infl
ammat oryc ytokine( IL-
10)
,andt heratioof
Hemodynamics IL-6toI L-1
0. Ke tami neadmi nist
rationinhi
b-
No s i
gni
fic
antdi f
fer
e nc
eswe re note
di n ite
dt hec yt
oki ner esponseandat tenuatedthe
base
lineHR orSAP be t
we en groups( Fi
g.3)
. incre
aseinther atioofI L-6toIL- 1
0 . Howe ver
,
Endotoxininjec
tion de
creased SAP int heen- propofoladmi nist
ration incr
ease dther ati
o of
dot
oxi n and pr
opofolgroups,butnoti nthe IL-6toI L-10,butne ve r
thel
essat tenuate
dt he
 Cyt
oki
neBal
ancebyKe
tami
neandPr
opof
ol 8
9

Fi
g.2. Change soft herati
osofI L-6t
oIL-1
0c oncentrati
onsatbas el
ineand aft
erinj
ect
ion of
endotoxinors al
ine(mean±S.D.).
Close
dc i
rcle
s ,endotoxi
ngr oup;openci
rcl
es,controlgroup;clos
eds quar
es,ket
aminegroup;
opens quares,propofolgroup.
p＜0.05vs .bas e
linewithi
ngr oup. p＜0.0
5vs .endotoxingroup.

Fi
g.3. A:Thehe ar
tr at
e,B:ands ys
tol
icar
teri
alpres
sureatbaseli
neandaft
erendot
oxi
norsaline
(mean±S.D.
).
Close
dc i
r c
les,e
ndotoxingr oup;opencirc
les,c
ontrolgroup;clos
edsquare
s,ket
aminegroup;
opensquares,propofolgroup.
p＜0.05vs.baseli
newi thi
ngr oup. p＜0 .
05vs.endotoxi
ngr oup.
 9
0 T.
Tani
guc
hie
tal
.

cyt oki ner e spons e. Thus ,ke tami neat tenuat ed Ofpar ti
c ular i nte resti st he r elat i
ons hi p
the i nc reas ei nt he r at io ofI L- 6t oI L- 10i n betwe en pr o-i
nf lammat or yc yt oki ne and ant i
-
endot oxi n- expos edr at s,r e pr es ent i
ng t hemos t infl
ammat or yc yt oki neunde rane sthe sia. Sal o
impor t antf indi ngsoft hec ur re nts tudy. etal .(1 997 )e val uat edt her el
at ions hipbe twe en
Cr itical lyi llpat ient swi ths eps iss uffera pro- inf lammat or y cyt oki ne and ant i
-
highde gre eofs tressduet opai n,anxi etyand infl
ammat or yc yt oki newi thpr opof oli nvi tro,
or gan- spe c ificr espons e by s eps is. An i mpor - ands howe dt hatpr opof oli ncreas e dt her at i
oof
tant obj e ctive i nt he manage me nt of t he s e infl
ammat or yc yt oki ne( inter f
e ron- γ)t o ant i
-
pat ient si st oac hieveanade quat el eve lofs e da- infl
ammat or yc yt oki ne( IL- 4). Howe ve r,t he re
tion. Al thought hene e df orade quat es e dat ion aref ew r e por t
s on t he r elations hip be twe en
ins e pt icpat ient si sge ne rallyac c ept ed,t he rei s pro- inf lammat or y cyt oki ne and ant i
-
noc ons ens usr egar dingwhi c hdr ugss houl dbe infl
ammat or y c yt oki ne r espons e f ol lowi ng
us ed. Ourf i
ndi ngss ugge stt hatke tami nemay ketami ne or pr opof ol admi nis t
r ation dur ing
bemor ee ffect i
veonpr e ve ntingi nflammat or y endot oxe mi a i n vi vo. The pr e s
e nt s t
udy
cyt oki ner espons est hanpr opof olf ort hes e da- showe dt hatke tami neadmi nis tration di d not
tionofs ept icpat ie nts. increas et her atio ofI L-6t oI L- 10dur ing e n-
Pr evi ousr epor tss howe dt hatt hei nc re as e dotoxe mi a,t houghpr opof oladmi nistrat ioni n-
ofpl asmaI L-6c onc e
nt rationc or re l
at eswi t ht he crease dt her at ioofI L- 6t oI L-1 0. Ourf inding
seve r i
tyofs ept i
cpat ient sandt hatt her eleas eof sugge stst hatj udgi ngf r om t hes tabl ec yt oki ne
IL- 6f rom l eukoc yt esc anpr oduc ehypot ens ion, balanc eke tami neadmi ni strat i
onwass upe rior
me tabol icac i
dos i
s ,andt iss uedamaget hatmay tot hatofpr opof ol .
lead t o or gan dys func tion( Pi ns ky e tal .1 9 93; Pr evious r e por ts have de sc ri
be d how
Mos c ovi tze tal .1 9
9 4). Se ve rali nve stigat or s ketami neandpr opof olhavei nhi bi t
or ye ff
e cts
repor tedt hatI L- 10wasi nduc e dbyTNF- αand onc yt oki ner e spons ei ns e ps i
s. Kawas akie tal .
IL- 6and di mi nishe dt hec yt oki ner es pons ei n (1999)de mons trat edt hatke tami ne s uppr e
s ses
vitroandi nvi vo( Fior entino1 9 91 ;Ge rar de tal . endot oxi n-induc ed TNF- α,I L- 6and I L- 8pr o-
19 93). The r e l
at ions hip of pr o-inflammat or y ductioni nhumanwhol ebl oodi nvi tro. Gal leye t
andant i-
inf lammat or yc yt oki ne si sve ryi mpor - al.(19 98)s howe dt hatpr opof ols uppr e sse dI L- 8
tanti ns e pt i
c pat ie
nt s. The i nc re asei nt he secretionf r om humanl e ukoc yte si nvi tr o. Our
rat i
oofI L- 6t oI L- 10i st houghtt os igni fyt hat previous s tudie ss howe dt hat ke tami ne and
thepr o-inf lammat oryr espons ei ss t ronge rt han propof ol at tenuat e d i nf lammat or y c yt oki ne
theant i-inf lammat oryr espons e. Ourpr evious respons es( TNF- α and I L- 6)dur ing e ndot ox-
repor tss howe dt hatt hei nc r eas ei nt her at i
oof emi ai nvi vo( Tani guc hie tal .2 0 00, 2001 ). The
IL- 6t oI L- 1 0andt heout comec or relat edwi th presents tudyal s os howe dt hatbot hke tami ne
the r at i
oi n SI RS pat ient s( Tani guc hie tal . andpr opof olat tenuat edani nc reas ei nTNF- α
19 99a) ,andt hatt her at ioofI L- 6t oI L- 10c or - andI L-6dur i
nge ndot oxe mi ai nvi vo.
relat edwi tht hes eve rityofi nj ur yaf tert rauma We e val uat ed TNF- α and I L-6 as pr o-
(Tani guc hie t al .1 999 b). Mor eove r,s eve ral infl
ammat or yc yt oki ne ,and I L- 10 as ant i
-
studi esi ndi cat edt hatt her elat ions hipbe twe en infl
ammat or y c yt oki ne . The pr esent s tudy
pr o-inflammat or yandant i-inf lammat or yc yt o- showe dt hatI L-6andI L- 1 0i nc reas edc ont inu-
kine si nf lue nc est hes eve rityofs eps i
s( Wal leye t ously af te re ndot oxi ni nj ection,but TNF- α
al.1 996 ;Gogose tal .2 000;Rodr i
ngue z -Gas par increas edunt il2hour saf te re ndot oxi ni nj ection
etal .2 00 1). The pr es ents tudy s howe dt hat andde c r
e as ed2hour saf te re ndot oxi ni nje ction.
injec tionofe ndot oxi nal onei nc r eas edt her atio Thus ,i n or de rt oe val uat et he r elat i
ons hi p
ofI L- 6t oI L-10andc aus edhypot ens ioni nr at s. betwe e n pr o-i
nf lammat or yc yt oki ne and ant i
-
 Cyt
oki
neBal
ancebyKet
ami
neandPr
opof
ol 9
1

inflammat or yc ytoki ne ,weus e dI L-6andI L- 1

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