Nitrik Oksit`in Etkileri ve Patolojik Rolleri

Transkript

Nitrik Oksit’in Etkileri ve Patolojik Rolleri
Dr. Yusuf Türköz1,
Dr. Elif Özerol1
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PHPHOL KFUH YH GRNXODUÕQÕQ IRQNVL\RQODUÕQÕ G]HQOHGL÷L DQODúÕOPÕúWÕU 12 DUJLQLQLQ QLWULN RNVLW VHQWHWD]
126 HQ]LP DLOHVL WDUDIÕQGDQ RNVLWOHQPHVL\OH \D NRQVWLWXWLI HVDV YH NDOVL\XPD ED÷ÕPOÕ \D GD LQGNOHQHELOLU
YH NDOVL\XPGDQ ED÷ÕPVÕ] RODUDN VHQWH]OHQLU (QGRMHQ RODUDN UHWLOHQ 12 NRQDN VDYXQPDVÕ YH LPPQLWH\L
HWNLOHGL÷L JLEL NDQ GDPDU WRQXVX YH Q|URQDO LOHWL GDKLO ELUoRN IL]\RORMLN ROD\ODUÕQ G]HQOHQPHVLQGH |QHPOL ELU
rol oynar. NO, benzersiz bir biyolojik haberci moleküldür. Sinir sisteminde fizyolojik ve patolojik rolleri
YDUGÕU 6LQLU VLVWHPL PRUIRJHQH]LQGH YH VLQDSVODUÕQ úHNLOOHQPHVLQGH URO R\QDU Q|URWUDQVPLWWHU VDOÕQÕPÕQÕ YH
JHQ HNVSUHV\RQXQX G]HQOH\HELOLU 12 DúÕUÕ UHWLOPHVL KDOLQGH oHúLWOL VLQLU VLVWHPL KDVWDOÕNODUÕQGD |QHPOL
ELU Q|URWRNVLQ RODUDN NDUúÕPÕ]D oÕNPDNWDGÕU $\UÕFD ELU oRN oDOÕúPDGD 12¶LQ LQIODPDWXYDU FHYDSODUÕ
PRGOH HWPHGH NRPSOHNV ELU URO R\QDGÕ÷Õ DQODúÕOPÕúWÕU >7XUJXW g]DO 7ÕS 0HUNH]L 'HUJLVL 461]
Anahtar Kelimeler: Nitrik oksit, nitrik oksit sentetaz, NO, NOS, nörotoksin
Nitric oxide : actions and pathological roles
Nitric oxide (NO), first identified as an endothelium-derived relaxation factor (EDRF), is now recognized
as a regulator of many mammalian cells and tissue functions. It is synthesized via the oxidation of arginine
by a family of nitric oxide synthases (NOS) which are either constitutive and calcium-dependent or inducible
and calcium-independent. The endogenous production of NO plays a vital role in regulating physiological
processes, e.g., blood vessel tone and neurotransmission, as well as in host defense and immunity. NO is a
unique biological messenger molecule. Nitric oxide have physiological and pathophysiological roles in the
nervous system. Nitric oxide may regulate neurotransmitter release, and it may play a key role in nervous
system morphogenesis and synaptic plasticity and regulate gene expression. Under conditions of excessive
formation, nitric oxide is emerging as an important neurotoxin in a variety of disorders of the nervous
system. In addition, in many studies it has been found that nitric oxide plays a complex role in modulating
the inflammatory response. [Journal of Turgut Özal Medical Center 1997;4(4):453-461]
Key Words: Nitric oxide, nitric oxide synthase, NO, NOS, neurotoxin
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Journal of Turgut Özal Medical Center 4(4):1997
453
Nitrik oksit’in etkileri ve patolojik rolleri
Y. Türköz ve ark.
12 UHQNVL] ELU JD]GÕU <NVHN NRQVDQWUDV\RQGDNL
NO oksijensiz ortamda oldukça stabil olup suda erime
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sürede O2
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nazaran
DIILQLWH\OH
ED÷ODQÕU
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KHPRJORELQH
+HPRJORELQ
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nitrata (NO3
GRODúÕPGDNL
NDW
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2’e
12
LVH
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12
LoLQ
VUHGH
g]HOOLNOH
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inhibitördür. NO, nitrite de (NO2) okside olabilir
DQFDN
QLWULW
WHNUDU
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NÕVD
VUHGH
QLWUDWD
G|QúP J|VWHULU 12 GL÷HU VHUEHVW UDGLNDOOHU JLEL
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126
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VHQWH]OHQHQ 12
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Çünkü hücre içi iyonize kalsiyum konsantrasyonu
D]DOPD\D EDúODGÕ÷Õ DQ HQ]LP LQDNWLI IRUPD JHoHUHN
12
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(Q]LP
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QHGHQL
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LOH
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NRQVWLWXWLI126
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NRQVDQWUDV\RQXQXQ
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ND]DQPDNWDGÕU 'úN
ùHNLO 126¶ÕQ DNWLYH HGLOPHVL YH 12 VHQWH]OHQPHVL
GH÷LúLN
øQGNOHQHELOLU QLWULN RNVLW VHQWHWD] L126: Bu
tip NOS, konstitutif
tipin aksine hücre içinde
bulunmaz. Özellikle makrofaj (monosit, nötrofil,
GRNXODUÕQGDQ GDPDU HQGRWHOL EH\LQ PDNURIDM ULQHU
KHSDWRVLW
VLVWHP
GRNXODUÕ
YE
L]ROH
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IL]LNRNLP\DVDO
YH
YH
GL÷HUOHUL
VLWRNLQOHUOH
DNWLYDV\RQX
VHQWH]LQH
\RO
ve
NRQVDQWUDV\RQGD
NLQHWLN
|]HOOLNOHUL
NDWDOL]H
HWWL÷L
J|VWHULOPLúWLU
PDNURIDMODU
LQFHOHQPLúWLU
UHDNVL\RQ
UHDNVL\RQ
KFUHOHULQGH
126
ÕQ
LQGNVL\RQX
PLNWDUGD
12
12
EDNWHUL
interferon-γ veya
OLSRSROLVDNNDULWOH
oRN
YH
g]HOOLNOH
yüksek
X\DUÕODQ
UHWHUHN
\DEDQFÕ
D\QÕ
126
LQ
ùHNLO
]DPDQGD
¶GH
l-arjinin-
nitrik oksit yolu olarak ta bilinmektedir.
NOS, incelenen fiziko-kimyasal ve kinetik
|]HOOLNOHULQH J|UH LNL JUXED D\UÕOPDNWDGÕU
1-Konstitutif nitrik oksit sentetaz (cNOS): Bu
øQGNVL\RQ
JQOHUFH
PLNWDUGD
12
12
HGHELOLU
VHQWH]L
VHQWH]L
$QFDN
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YH
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X]XQ
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KDWWD
VUHOL
DúÕUÕ
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GD
harabiyete yol açar. Enzim indüksiyonu l-arjinin
DQDORJODUÕ
YH
JOXNRNRUWLNRLGOHUFH
LQKLEH
edilebilmektedir. Bu indüksiyon, nonspesifik hücre
LPPQLWHVL
LOH
JHOPHNWHGLU
periferik ve santral sinir sistemi gibi dokularda
LQGNOHQHELOLU
ORNDOL]H ROPXúWXU 126 EX GRNXODUGD KHU ]DPDQ
++
PHYFXWWXU DQFDN DNWLI GH÷LOGLU +FUH LoL L\RQL]H &D
VRQUDVÕ
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L]RHQ]LP |]HOOLNOH GDPDU HQGRWHOL LGUDU \ROX GRNXODUÕ
454
HQGRWHO
hücrelerde (bakteri, parazit, tümör hücresi) sitostatik
ve/veya sitotoksik etki meydana getirirler (13).
EL\RNLP\DVDO
%X
GDPDU
DoPDNWDGÕU
lipopolisakkaritleri
ùHNLO . L-Arjinin-nitrik oksit yolu
YH
sentez edilmektedir (4). Bu hücrelerin spesifik
LOLúNLOL
(Q]LP
ELU
ELOLQHQ
YH\D
PHNDQL]PD\OD
EX
PH\GDQD
|]HOOLNOHULQGHQ
NDOVL\XPGDQ
GROD\Õ
ED÷ÕPVÕ]126
RODUDN LVLPOHQGLULOPLúWLU 7XUJXW g]DO 7ÕS 0HUNH]L 'HUJLVL Türköz Y, et al.
Birçok hormon ve ilaçlar hücre içi etkilerini hücre
\]H\LQGH
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$03
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12
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SURWHLQOHUH
YH
KFUH
DUWWÕUDUDN
JHoHUHN
ED÷ODQDUDN
GHPLU
HWNLVLQL
çevirmektedir. Bu durumda insan ve hayvanlarda
HQGRWHO
ND\QDNOÕ
ROGX÷X
VDGHFH
LoLQ
YD]RGLODWDV\RQ
KLSHUWDQVL\RQ
VLVWHPLN
GRODúÕPÕQ
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D\UÕFD
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G]
1RQNROLQHUMLN YH QRQDGUHQHUMLN WHUPLQDOOHUGHQ VDOÕQDQ
PHPEUDQÕQGD
EXOXQDQ
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VLNOD]Õ
GD
UHJOH
aktive eder. Guanilat siklaz ise GTP’den bir ikincil
12
KDEHUFL
düzenlenmektedir (4,9).
F*03
RODQ
VLNOLN
NHQGLQH
*03
X\DQ
F*03
NDV
ROXúXPXQX
JHYúHPHVL
DUWWÕUÕU
VLQDSVWDQ
YD]RGLODWDW|U
JLEL
KFUH
LoL
SURVHVOHUL
UHJOH
HGHU
HWNL\OH
JLEL
RUJDQODUGD
HWPHNWHGLU
NDQ
EDVÕQFÕ
YH
DNÕúÕQÕ
X\DUÕ
%X
JHoLúL
EH\LQ
12
VD÷ODPDNOD
NDOPD]
KFUH
NDUDFL÷HU
LQKLEH
JHOPHNWHGLU
göstermektedir (9). NO özellikle nöronlar ve damar
NDV
NDOS
PHNDQL]PDVÕ
PH\GDQD
YD]RGLODWDV\RQ
PHNDQL]PDVÕ
GDKLOL
ELU
%|\OHFH
NO, guanilat siklaz aktivitesini etkileyerek damar
QLWURYD]RGLODWDV\RQ
göstermektedir.
VLVWHPLQLQ
Çünkü
YDUOÕ÷ÕQÕ
nitrogliserin
ve
Na-
GLODWDV\RQX VLQLUOHUGHQ X\DUÕ JHoLúL JLEL IRQNVL\RQODUÕ
QLWURSUXVVLG JLEL QLWURELOHúLNOHUL X]XQ \ÕOODU NOLQLNOHUGH
JHUoHNOHúWLUPHNWHGLU
(QGRWHO
ND\QDNOÕ
12
KLSHUWDQVL\RQXQ
WHGDYLVLQGH
NXOODQÕOPÕúWÕU
9FXGD
GDPDU G] NDVODUÕQÕQ JHYúHPHVLQL VD÷OD\DUDN NDQ DNÕúÕ
YHULOHQ EX PDGGHOHU VRQXoWD 12
H G|QúHUHN HWNLOHULQL
YH
EDVÕQFÕQÕQ
D\DUODQPDVÕQÕ
VD÷ODPDNWDGÕU
%X
HWNL
J|VWHUPHNWHGLUOHU ùHNLO VLVWHPLN
NDOS
GRODúÕPGD
EH\LQ
PH\GDQD
NDUDFL÷HU
JHOGL÷L
JLEL
ORNDO
JDVWURLQWHVWLQDO
RODUDN
VLVWHPOHUGH
gözlenebilmektedir (4,18).
'DPDU
HQGRWHOLQGHQ
VDOÕQDQ
12
LQ
G] NDV KFUHOHULQGH JXDQLODW VLNOD]ÕQ
HWNLVL
GDPDU
DNWLYDV\RQX
LOH
EDúODU KFUH LoL VLNOLN JXDQR]LQ PRQR IRVIDW F*03
12
PHUNH]L
VLQLU
VLVWHPLQGH
KDIÕ]D
ROXúXPX
NRQVDQWUDV\RQXQXQ DUWÕúÕ YH G] NDVODUÕQ JHYúHPHVL LOH
GHQJH
X\DUÕ
JHoLúL
NRNX
GHVWHNOH\HQ
ELU
DOPD
JLEL
ELUoRN
VRQODQÕU IRQNVL\RQODUÕ
Q|URWUDQVPLWWHU
RODUDN
fonksiyon göstermekte ve etki etmektedir (19).
Periferik sinir sisteminde ise nonadrenerjik ve
nonkolinerjik sinirleri etkileyerek vazodilatasyon,
trombosit
VROXQXP JHQLWRULQHU YH PLGH EDUVDN IRQNVL\RQODUÕQÕQ
sentez ederek trombosit aktivasyonunun kontrolüne
UHJOH HGLOPHVLQH NDWNÕGD EXOXQPDNWDGÕU NDWNÕGD EXOXQPDNWDGÕUODU 'RODúÕP
VLVWHPLQGH
DGH]\RQXQXQ
WURPERVLW
HQJHOOHQPHVL
G]HQOHQPHVL
JLEL
ROD\ODUD
12¶LQ EX IRQNVL\RQODUÕ
KFUH
LoL
VLNOLN
GD
JXDQLODW
*03
DJUHJDV\RQXQXQ
NDOS
YH
NDVÕOPDVÕQÕQ
LúWLUDN
VLNOD]ÕQ
HWPHNWHGLU
DNWLYDV\RQX
NRQVDQWUDV\RQXQXQ
12
SURVWDVLNOLQOH
VLQHUMLVW
agregasyonunu
HQJHOOHPHNWHGLU
ELU
HWNLOHúLPOH
ve
$\UÕFD
adezyonunu
WURPERVLWOHU
GH
12
Kliniklerde, nitrovazodilatörler (nitrogliserin, NaQLWURSUXVVLG
JLEL
LOH
SURVWDVLNOLQ
YH\D
DQDORJODUÕQÕQ
kombine edilmesi çok etkili bir antitrombotik tedavi
VD÷OD\DELOLU
DUWÕúÕ
12¶LQ
oRN
|QHPOL
ELU
GL÷HU
HWNLVL
GH
O|NRVLW
úHNOLQGH FHUH\DQ HWPHNWHGLU Nitrik oksidin fizyolojik ve patolojik rolü
Kardiovasküler ve pulmoner sistemlerde nitrik
oksit:
(QGRWHO
12
ND\QDNOÕ
ROGX÷X
VD\ÕGD
oDOÕúPD
DQDORJODUÕ
1,2
YH
RUDQODUGD
LOH
VRQUDNL
/11$
126
LQKLEH
\ÕOODUGD
HWPHNWHGLU
('5)
\DSÕODQ
g]HOOLNOH
/1$0(
LQKLELW|UOHUL
HQGRWHO
ile
IDNW|UQQ
GR÷UXODQPÕúWÕU
/10$
GL÷HU
GHQHPHOHULQGH
edilmesi
JHYúHPH
KLSRWH]L
/&3$
HQ]LPL
<DSÕODQ
ND\QDNOÕ
vazokonstriksiyon
oRN
ODUMLQLQ
/
GH÷LúLN
LQKLELV\RQ
126
LQ
ve
LQKLEH
sonuçta
KLSHUWDQVL\RQ RUWD\D oÕNPDNWDGÕU Bu inhibitörlerin insan ve hayvanlara verilmesi,
ùHNLO 1LWURELOHúLNOHULQLQ HQGRWHO YH
12
VHQWH]LQL
GXUGXUXODUDN
YH\D
D]DOWDUDN
12¶ÕQ
G]
NDV
KFUHOHULQGH
12
H
G|QúP
JHUHNOL
ROGX÷X
EWQ
IRQNVL\RQODUÕ
WHUVLQH
455
aktivasyonunu
engelleyerek
Y. Türköz ve ark.
lökositlerin
damar
GXYDUÕ\OD NDUúÕOÕNOÕ HWNLOHúLPL HQJHOOHPHVLGLU D]DOGÕ÷Õ
YH
12¶LQ SDWRORMLN RODUDN VDOÕQÕPÕ
.DQ
EDVÕQFÕQÕQ
X\DUÕODQ
'DPDU
HQGRWHOL
LQGNOHQHELOLU
YH
126
G]
ED]Õ
NDVODUÕQGD
VLWRNLQOHU
EXOXQDQ
YH\D
DUWÕUDQ
HQGRWRNVLQ
LQGNOHQLU
HQGRWHOL
JHOPHNWHGLU
)L]\RORMLN
PH\GDQD
ROXúDQ
YH
JHOLU
ELU
G]
NDVODUÕQGD
øQGNVL\RQ
%X
GLUHQo
ROD\
úDUWODUGD
D\QÕ
VRQXFX
VDGHFH
DQGD
LIDGH
HGLOHELOLU
NDUúÕ
126
ÕQ
indüksiyonu
NOS
inhibitörleri
ve
glukokortikosteroidler ile engellenebilir. Bununla
LOJLOL
RODUDN
KD\YDQODUGD
FHYDEÕQ
YH\D
DVHWLONROLQ
WDUDIÕQGDQ
DUWHULRVNOHUR]OX
KDVWDODUGD
sigara tiryakilerinde ve ailesel yüksek kolesterollü
ER]XOPDNWDGÕU
HQGRWRNVLN
YH
VHSWLN
úRNWD
YDVNOHU
%X
KDVWDODUD
IRQNVL\RQ
ODUMLQLQ
ER]XNOX÷XQX
düzeltebilmektedir (37,38 ).
PH\GDQD
YD]RGLODWDV\RQ
YD]RNRQVWULNW|UOHUH
RODUDN
NDUúÕ
OLSRSROLVDNNDULWOHU
konstitutif NOS (cNOS) aktiftir (4). Bu indüksiyon,
GDPDU
DMDQODUD
VLWRNLQ
YHULOPHVL
WDUDIÕQGDQ
DUWÕúÕ
YD]RGLODWDV\RQ
oRFXNODUGD
VDOÕQÕPÕQÕ
YD]RNRQVWULNW|U
VÕNOÕNOD ]D\ÕIODGÕ÷Õ WHVSLW HGLOPHNWHGLU (QGRWHO ND\QDNOÕ
KDVWDODUGD
12
GD
VHQWH]LQLQ
EX
KDVWDODUGD
KLSHUWDQVL\RQD
/10$
KLSHUWDQVLI
GXUXPGD
KLSHUWDQVL\RQOX
dQN
VHEHS
(NVSHULPHQWDO oDOÕúPDODUGD KD\YDQD
LQKLELW|U
YHULOPHVL
JHUoHN
DNVDPDVÕ
ROPDNWDGÕU 126
JHYúHPH
D]DOPDNWDGÕU
JORPHUOHU
/1$0(
FHYDEÕ
KDVDU
YH
GL÷HUOHUL
DUWÕUPDNWDGÕU
YH
VRG\XP
%X
DWÕOÕPÕQGD
KLSRWDQVL\RQ PH\GDQD JHOLúL |UQHN YHULOHELOLU azalma meydana gelmektedir (41,42). Hipertansiyona
meyilli hayvanlara l-arjinin verilmesi hipertansiyon
Yine kanserli hastalarda sitokin tedavisi de bu yolla
ROXúXPXQX
KLSRWDQVL\RQD QHGHQ ROPDNWDGÕU ùHNLO JHUoHN
12
VHQWH]LQLQ
DúÕUÕ
DUWÕúÕ
YH
EXQD
ED÷OÕ
RODUDN
NXYYHWOH
HQJHOOHPHNWHGLU
KLSHUWDQVL\RQOX
HQI]\RQX
VLVWROLN
GúUPHNWHGLU
YH
YH
VD÷OÕNOÕ
GLDVWROLN
LQVDQODUD
EDVÕQFÕ
dQN
ODUMLQLQ
NÕVD
VUHGH
$QMLRWHQVLQNRQYHUWLQJ
HQ]LP
inhibitörleri ile tedavide bradikinin, endotelden NO
VDOÕQÕPÕQÕ
VLWLPOH
DUWÕUPDNWD
YH
HGHUHN
12
YD]RGLODWDV\RQD
NRQVDQWUDV\RQX
QHGHQ
ROPDNWDGÕU
(QGRWHO ND\QDNOÕ JHYúHPHQLQ GLDEHWOL KD\YDQODUÕQ NDQ
GDPDUODUÕQGD YH NDOSDNFL÷HU WUDQVSODQWDV\RQX \DSÕODQ
LQVDQODUÕQ
YH
L]ROH
DNFL÷HU
DUWHUOHULQGH
YD]RNRQVWULNW|UOHUH
FHYDEÕQ
ROGXNoD
D]DOGÕ÷Õ
]D\ÕIODGÕ÷Õ
WHVSLW
HGLOPLúWLU L-arjinin metil türevleri (L-NMA, L-NAME ve
GL÷HUOHUL
QRUPDO
DWÕOPDNWDGÕU
ùHNLO . NOS ve NO’in indüksiyonunu etkileyen faktörler
Kardiovasküler
NO'in önemi
E|EUHN
ve pulmoner sistemlerde
%X
úDUWODUGD
\DSÕODUÕQ
\HWPH]OL÷L
RODQ
LGUDUOD
SOD]PD
KDVWDODUGD
YFXW
GÕúÕQD
G]H\OHUL
DúÕUÕ
DNXW
GHUHFHGH
yükselmektedir (44). Bu inhibitörlerle NO sentezinin
inhibisyonu, hipertansiyon ve lökositlerde fonksiyon
ER]XNOX÷XQD QHGHQ ROPDNWDGÕU
126¶Õ ODUMLQLQ PHWLO
WUHYOHUL GÕúÕQGD LPLGD]RO WUHYOHUL YH DPLQRJXDQLGLQ
(QGRWHO\DO
ROPDNWDGÕU
ND\QDNOÕ
$UWHU
12
HQGRWHO
dilatasyona neden
YD]R
GRNXVX
YHQ
dokusuna göre daha fazla NO sentez edebilmekte ve
EX
QHGHQOH
JHYúHPHGHQ
özellikle
DUWHUOHUGHNL
GDKD
arteriyel
ID]OD
veya
JHYúHPH
ROPDNWDGÕU
venöz
YHQOHUGHNL
%X
koroner
gibi kimyasal ajanlar da inhibe etmektedir (45).
HQGRWHO
%D]Õ
DNFL÷HU
KDVWDOÕNODUÕQGD
KDVWD\D
LQKDODV\RQOD
NO verilmesi pulmoner hipertansiyonu normale
çevirebilmektedir (46). 13-36 ppm düzeyinde inhale
IDUNOÕOÕN
bypass
HGLOHQ
12
\HWLúNLQOHUGH
UHVSLUDWXYDU
GLVWUHV
VHQGURPXQX |QOHPHNWHGLU $NFL÷HU IRQNVL\RQODUÕ
JUDIWODUÕQÕ
HWNLOH\HQ
|QHPOL
ELU
IDNW|U
ROXS
DUWHU
ER]XOPXú
JUDIWODUÕQÕQ
YHQ
JUDIWODUÕQD
J|UH
GDKD
VÕN
KDVWDODUGD
JQON
12
WHGDYLVL
VROXQXP
DoÕOPDVÕQÕQ
IRQNVL\RQODUÕQÕ
QRUPDOL]H
HWPHNWHGLU
%X
QHGHQLQL ROXúWXUPDNWDGÕU VRQXoODU
Arteriosklerotik kalp arteri ile normal kalp arteri
HQGRWHO
ND\QDNOÕ
DUWHULRVNOHURWLN
456
JHYúHPH
GDPDU
DoÕVÕQGDQ
NDUúÕODúWÕUÕOÕUVD
KDONDODUÕQGD
12
ER]XNOXNODUÕQÕQ
LQKDODV\RQXQXQ
G]HOPHVLQH
DNFL÷HU
IRQNVL\RQ
\DUGÕPFÕ
ROGX÷XQX
RUWD\D NR\PDNWDGÕU
JHYúHPHQLQ
7XUJXW g]DO 7ÕS 0HUNH]L 'HUJLVL Türköz Y, et al.
øQKDOH HGLOHQ 12
LQ |]HOOLNOH DNFL÷HU DOYHROOHULQGH
NDSLOOHU
GDPDUODUÕ
YHQWLODV\RQSHUI]\RQ
HGLOPLúWLU
DNFL÷HUOHUGH
JHQLúOHWWL÷L
RUDQÕQÕ
6ROXQXPOD
ORNDO
DOÕQDQ
HWNL
YH
G]HOWWL÷L
WHVSLW
12
VDGHFH
J|VWHUPHNWH
VLVWHPLN
GRODúÕPGD KHUKDQJL ELU HWNL PH\GDQD JHWLUPHPHNWHGLU
1RUPDO
SSE
úDUWODUGD
G]H\LQGH
LQVDQODUÕQ
12¶L
VROXQXP
YFXW
KDYDVÕ
GÕúÕQD
LOH
DWWÕ÷Õ
WHVSLW
HGLOPLúWLU 6LUR]XQ
KLSHUGLQDPLN
ID]ÕQGD
NDQGD
\NVHN
NRQVDQWUDV\RQGD HQGRWRNVLQ YD]RNRQVWULNW|UOHUH NDUúÕ
FHYDEÕQ
D]DOPDVÕ
ROPDNWDGÕU
YH
DúÕUÕ
dQN
LQGNOH\HUHN
DúÕUÕ
YD]RGLODWDV\RQD
PHYFXW
12
QHGHQ
HQGRWRNVLQ
VHQWH]LQH
\RO
DoDU
126¶Õ
6LUR]GD
YH
özellikle hepato-renal sendromda NO’in oksidasyon
UQOHUL
RODQ
QLWUDW
J|VWHUPHNWHGLU
YH
QLWULWLQ
%X
VHUXP
DUWÕú
G]H\OHUL
GLUHNW
DUWÕú
HQGRWRNVLQ
NRQVDQWUDV\RQXQD ED÷OÕ RODUDN GH÷LúPHNWHGLU NO’in sinir sistemindeki rolü:
A. Santral sinir sistemi
Fizyolojik rolü:
ùHNLO . Beyin dokusunda arjinin-NO yolu
Spesifik glutamat reseptörünü etkileyen N-metil D-aspartatla (NMDA) stimüle edilen beyin hücreleri
('5)
EHQ]HUL
\DSÕODUGDQ
\DSÕODU
ELUL
oDOÕúPDODUGD
VHQWH]
GH
EH\LQ
12
HGHUOHU
GLU
ùHNLO
GRNXVXQGD
DNWLI
%X
<DSÕODQ
oDOÕúDQ
Patolojik rolü:
Eksite edici amino asitlerin (aspartat, glutamat)
DUMLQLQ
DúÕUÕ
12
\ROXQXQ
YDUOÕ÷Õ
LVSDWODQPÕúWÕU
12
reseptörleri etkilemekte ve hücre içindeki cGMP
NRQVDQWUDV\RQXQX
J|VWHUPHNWHGLU
VLQLUVHO
LOHWL
DUWWÕUDUDN
*OXWDPDW
LúOHPLQGH
IL]\RORMLN
WDUDIÕQGDQ
12
LQ
ELU
VDOÕQÕPÕ
NRQYOVL\RQ
YH
Q|URWRNVLVLWH\H
QHGHQ
EX
ROPDNWDGÕU
X\DUÕOPDVÕ
YH
%X
DPLQR
DVLWOHUOH
VRQUDVÕQGD
126¶ÕQ
UHVHSW|UOHULQ
DNWLYDV\RQX
HWNL
VHUHEUDO
LVNHPL
VHQWH]L
YH
YH
HSLOHSVL
JLEL
GXUXPODUGD
DúÕUÕ
12
LQGNOHQHQ
Q|UDO
GHIHNWOHUH
QHGHQ
ROGX÷X
LOHUL
EXOJXODU
KDOD
Q|URWUDQVPLWWHU
VUOPúWU
%X
KLSRWH]L
GHVWHNOH\HQ
RODUDN URO R\QDGÕ÷Õ WDP RODUDN LVSDW HGLOPLúWLU WDUWÕúPDOÕGÕU
126
LQVDQ
WDUDIÕQGD
oRN
YH
GH÷LúHQ
VD\ÕGD
KD\YDQODUÕQ
RUDQODUGD
oDOÕúPD
12¶LQ
EH\LQ
GRNXVXQXQ
EXOXQPDNWDGÕU
KDIÕ]D
KHU
<DSÕODQ
ROXúXPXQGD
NÕVPHQ
GH ROVD URO DOGÕ÷ÕQÕ RUWD\D NR\PXúWXU øQ YLWUR VSHVLILN
reseptör
stimülasyonundan
ND\QDNWDQ
YH\D
oRN
12
VDOÕQPDNWD
VD\ÕGD
Q|URQX
sonra
YH
postsinaptik
SUHVLQDSWLN
RODUDN
HWNLOHPHNWHGLU
%X
ELU
hücreler,
VDOÕQÕPÕQÕ
GDKD
ID]OD
DUWÕUPDNWD
%H\LQGH
PRQRVLW
indüklenebilen
HGHELOPHNWHGLU
3DUNLQVRQ
%X
tip
KFUHOHU
$O]KHPHLU
WU
NOS
$,'6¶GH
KDVWDOÕ÷Õ
PLNURJOLDO
sentez
KDIÕ]D
0DOWLSO
ND\EÕ
VNOHUR]¶XQ
SDWRJHQH]LQGH GH URO R\QDPDNWDGÕU
$úÕUÕ
UHWLOHQ
12
LQ
QHGHQ
ROGX÷X
EH\LQ
KDVDUÕQD
indüklenebilir veya konstitüv NOS ya da her ikisinin
HWNL
VHEHS
JOXWDPDW
VRQXoWD
ROXS
ROPD\DFD÷Õ
WDP
RODUDN
DQODúÕODPDPÕúWÕU
LVH
$QFDN NRQX LOH LOJLOL DUDúWÕUPDODU \R÷XQ RODUDN GHYDP
VLQDSWLN JHoLú
+DIÕ]D
ROXúXPX
IRQNVL\RQXQXQ
ROGX÷XQX
NR\PXúWXU
J|UPH
DUWÕúOD VRQXoODQPDNWDGÕU
LOH
LOJLOL
ER]XOGX÷X
YH
12
$\UÕFD
LúOHYLQGH
GH
GXUXPODUGD
G]H\LQLQ
12
NRNX
IL]\RORMLN
etmektedir.
oDOÕúPDODU
126
ÕQ
D]DOGÕ÷ÕQÕ
DOPD
D÷UÕ
RODUDN
|÷UHQPH
URO
B. Periferik sinir sisteminde NO
LQKLEH
RUWD\D
GX\XVX
YH
DOPDNWDGÕU
NO, merkezi ve periferik sinir sisteminde bir
nörotransmitter gibi rol oynayarak sinirlerden impuls
JHoLúLQL HWNLOHPHNWHGLU (56).
457
12
GLODWH
KD\YDQODUGD
HGHUHN
$\UÕFD
\HQL
JDVWUR
VILQNWHUOHULQGH
IL]\RORMLN
NRUSXV
LoL
JHYúHPH\H
\RO
NOS
DoDUDN
UHJOH
øQVDQODUGD
NRUSXV
GRNXVXQGD
12
NRQPXúWXU
%XUDGDQ
HWNL ROXúWXUGX÷X ELOGLULOPLúWLU EX
RUJDQODUÕQ
HGLOPHVLQH
NDWNÕGD
O$UMLQLQ12
\ROX
SHQLV
(OHNWULNVHO
JHYúHPHVL
engellenebilmektedir.
oDOÕúPDODUGD
VHQWH]OH\HQ
GD
viruslarda viral replikasyonu inhibe ederek antiviral
|]HOOLNOH
NDYHUQR]XPXQ
inhibitörlerince
øPPQRKLVWRNLP\DVDO
PLGH\L
JHYúHPHVL\OH
VD÷ODPDNWDGÕU
ROXúWXUXODQ
NDUúÕ
VD÷ODPDNWDGÕU
VLVWHPLQ
NDYHUQR]XPXQ
HUHNVL\RQXQX
EDVÕQFD
X\XPXQX
LQWHVWLQDO
IRQNVL\RQODUÕQÕQ
EXOXQPDNWDGÕU
RODUDN
PLGH
GXUXPD
Y. Türköz ve ark.
LQVDQ
VLQLUOHULQ
DQODúÕODFD÷Õ
SHQLVL
YDUOÕ÷Õ
]HUH
RUWD\D
12
SHQLV
ereksiyonunun önemli bir modülatörüdür (61).
Nonadrenerjik ve nonkolinerjik vazodilatasyonlar
WUDNHDQÕQ
12
JHYúHPHVL
VHQWH]LQLQ
JLEL
LQKLEH
12
LOH
HGLOGL÷L
LOLúNLOL
ROD\ODUGÕU
GXUXPODUGD
LGUDU
NHVHVLQLQ NDSDVLWHVLQLQ D]DOGÕ÷Õ WHVSLW HGLOPLúWLU 12¶L
nörotransmitter olarak kullanan sinir sistemleri ;
adrenerjik, kolinerjik ve peptiderjik sinirler kadar
ùHNLO 0DNURIDM
ND\QDNOÕ
KFUHOHULQGH
12
EDNWHUL
oHúLWOL
SDUD]LW
HQ]LPOHULQ
YH
WP|U
IRQNVL\RQXQX
HWNLOH\HUHN VLWRWRNVLN HWNL \DSPDNWDGÕU
|QHPOL
IL]\RORMLN
NO’i
nörotransmitter
VLVWHPOHULQLQ
KDVDUODUD
LúOHYOHU
IRQNVL\RQ
\RO
J|VWHUPHNWHGLU
olarak
kullanan
ER]XNOXNODUÕ
DoPDNWDGÕU
LOJLOL
sinir
GRNXODUGD
gUQH÷LQ
NRUSXV
Makrofajlardan özellikle monositlerde L-ArjininNO yolu; tümör hücreleri, intra- ve ekstrasellüler
NDYHUQR]XPX X\DUDQ VLQLUOHUGHNL IRQNVL\RQ ER]XNOX÷X
PLNURRUJDQL]PDODUD
NDUúÕ
oRN
|QHPOL
ELU
GHIDQV
LNWLGDUVÕ]OÕ÷D QHGHQ ROPDNWDGÕU
PHNDQL]PDVÕGÕU
Sitotoksik ve sitostatik ajan olarak NO:
øQWHUIHURQ
YH\D
EDNWHUL
Nitrik oksidin immünitedeki rolü:
OLSRSROLVDNNDULWOHUL
<ÕOODU
WDUDIÕQGDQ
DNWLYH
HGLOHQ
PDNURIDMODU
E\N
|QFH
QRQVSHVLILN
12
VHQWH]
durumlarda
HGHUOHU
$NWLYDV\RQXQ
makrofajlarda
NOS
DUDúWÕUÕFÕODU
ED]Õ
EDNWHUL
UQOHUL\OH
PLNWDUGD
ELU
PHNDQL]PD
LOH
NDQVHUH
NDUúÕ
GLUHQFLQ
ROPDGÕ÷Õ
bulunmaz.
DUWWÕUÕODELOGL÷LQL
ELOJLOHULPL]H
J|VWHUPLúOHUGLU
J|UH
EX
GLUHQo
%XJQN
DUWÕúÕ
PDNURIDM
øQGNVL\RQGDQ VRQUD HQ]LP VHQWH]L YH GROD\ÕVÕ\OD 12
sentezi meydana gelmektedir. L-Arjinin-NO yolunun
indüklenmesi, saatlerce hatta günlerce devam eden
DNWLYDV\RQX
QRQVSHVLILN
YH
12
ELU
LPPQ
UHDNVL\RQODU
12
VHQWH]LQH
VHQWH]L
QHGHQ
KFUHOHU
JHWLUPHNWHGLU
ROPDNWDGÕU
LoLQ
ROGXNoD
0DNURIDM
$QFDN
DúÕUÕ
]DUDUOÕ
HWNLOHU
PH\GDQD
ND\QDNOÕ
12
12
VHQWH]L
LOH
ROD\GÕU
PDNURIDM
GR÷UXGDQ
ED÷ODQWÕOÕ
1RQVSHVLILN
DNWLYDV\RQX
LPPQ
126¶ÕQ
indüklenmesi, uzun süreli ve çok miktarda NO
sentezinden ibarettir. Bu nonspesifik immünite sadece
EDNWHUL
parazit ve tümör hücreleri üzerinde sitotoksik etki
5(6¶OH
VÕQÕUOÕ
ROPD\ÕS
KHSDWRVLWOHU
YH
DNFL÷HU
KFUHOHULQGH GH WHVSLW HGLOPLúWLU
\DSPDNWDGÕU ùHNLO NO bakteri, parazit gibi birçok patojenin ve tümör
hücrelerinin ATP üreten oksidatif fosforilasyonun
12¶H
YH
ED÷ÕPOÕ
DNFL÷HULQ
QRQVSHVLILN
URO
EX
LNL
LPPQLWHGH
RUJDQÕQ
NDUDFL÷HU
VLUNODV\RQXQ
LPPQRORMLN ILOWUHOHUL JLEL IRQNVL\RQ J|UHFH÷L VWUDWHMLN
XELNLQRQ UHGNWD]
Õ JOLNROL]LQ JOLVHUDOGHKLGIRVIDW
ELU NRQXPGD \HU DOPDVÕQGDQ ND\QDNODQPDNWDGÕU
GHKLGURMHQD]
Õ
LoHUHQ
ED]Õ
7&$
VLNOXVXQXQ
HQ]LPOHULQL
LQKLEH
&LVDNRQLWD]
Õ
HWPHNWH
YH
)H
VRQXoWD
bakteri, parazit, tümör hücrelerini öldürmektedir (7072). NO, hedef hücrelerde (bakteri, parazit, tümör
KFUHVL
'1$
ULERQNOHRWLG
'1$¶VÕQÕQ
HWNL
458
VHQWH]LQLQ
UHGNWD]Õ
GHDPLQDV\RQX
PH\GDQD
JHWLULU
KÕ]
NÕVÕWOD\ÕFÕ
EORNH
LOH
EX
HGHU
HQ]LPL
YH
KFUHOHUGH
$\UÕFD
RODQ
KFUH
VWRVWDWLN
12
LQ
ED]Õ
0DNURIDM
ND\QDNOÕ
12
VHQWH]LQLQ
X]XQ
VUHOL
YH
oRN PLNWDUGD UHWLOPHVL DúÕUÕ ELULNHQ 12 PDNURIDM YH
GL÷HU
KFUHOHUGH
0DNURIDMODUÕQ
glikokortikoid
LQGNOHQHELOLU
KDVDU
DNWLYH
ve
PH\GDQD
ROGX÷X
l-arjinin
126¶ÕQ
Õ126
JHWLUHFHNWLU
GXUXPODUGD
türevlerinin
LQKLELV\RQX
|]HOOLNOH
etkisi,
YH
12
VHQWH]LQLQ D]DOPDVÕ \|QQGH RODFDNWÕU %X LQKLELV\RQD
LODYHWHQ
ED]Õ
PHNDQL]PDODUÕQÕQ
WUDQVNULSVL\RQDO
YDUOÕ÷ÕQGDQ
$QFDN EX PHNDQL]PDODU
GD
LQKLELV\RQ
EDKVHGLOPHNWHGLU
WDP RODUDN DoÕNODQDPDPÕúWÕU
KAYNAKLAR
18. Snyder SH. Nitric oxide: First in a new class of
neurotransmitters. Science 1992;257: 494-6.
19. Dawson TM, Dawson VL, Snyder SH. A novel neuronal
messenger molecule in brain: the free radical, nitric oxide. Ann
Neurol 1992;32:297-311.
20. Tottrup A, Glavihd EB, Svane D. Involvement of the Larginine-nitric oxide pathway in internal analspinchter
relaxation. Gastroentrology 1992;102:409-15.
1.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G.
Endothelium-derivied relaxing factor produceed and released
from artery and vein is nitric oxide. Proc Natl Acad Sci
USA1987; 84: 9265-9.
2.
Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial
cells synthesize nitric oxide from L-arginine. Nature 1988;
333: 664-6.
22. Calver A, Collier J, Moncada S, Vallance P. Effect of local
intra-arterial NG-monomethyl-L-arginine in patients with
hipertension: the nitric oxide dilator mechanism appears
abnormal. J Hypertens 1992;10:1025-31.
3.
Nussler AK, Billiar TR. Inflammation, immunoregulation and
inducible nitric oxide synthase. J Leukoc Biol (USA)
1993;54(2):171-8.
23. Sogni P, Moreau R, Ohsuga M, Cailmail SiOberti F, Hadengu
A,et al. Evidence for normal nitric oxide-mediated vasodilator
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Lowenstein CJ, Dinerman JL, Snyder SH. Nitric oxide: A
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5.
Moncada S, Palmer RMJ, Higgs A. Nitric oxide: Physology,
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24. McCall TB, Feelisch M, Palmer RMJ, Moncada P.
Identification of N- iminoethyl-L- ornithine as an irreversible
inhibitor of nitric oxide synthase in phagocytic cells. B J
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6.
Star RA. Nitric oxide. Am J Med Sci (USA). 1993;306(5):34858.
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Tayeh MA, Marletta MA. Macrophage oxidation of L-arginine
to nitric oxide, nitrite and nitrate: Tetrahydrobiopterin is
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8.
Moncado S. The L-arginine: Nitric oxide pathway. Acta
Physiol Scand 1992; 145(3): 201-27.
9.
Ignarro LJ. Nitric oxide. A novel signal transduction
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10. Andersson KE, Persson K. Nitric oxide synthase and nitric
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11. Knowles RG, Moncada S. Nitric oxide senthases in mammals.
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12. Marletta MA. Approaches toward selective inhibition of nitrik
oxide synthase. J Med Chem 1994; 37: 1899-907.
13. Cendan JC, Topping DL, Pruitt J, Snowdy J, Copeland EM,
Lind DS. Inflammatory mediators stimulate arginine transport
and arginine-derived nitric oxide production in a murine breast
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14. Dawson VL. Nitric oxide: role neurotoxicity. Clin Exp
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15. Bachmann S, Mundel P. Nitric oxide in the kidney: Synthesis,
localization and fonction. Am J Kid Diseas 1994; 24(1): 11229.
16. Hevel JM, White KA, Marletta MA,: Pürification of the
inducible murine macrophage nitric oxide synthase.
Identification as aflavoprotein. J Biol Chem 1991; 266: 2278991.
17. Geller DA, Lowenstein CS, Shapiro RA, Nussler AK, Disilvio
N, Wang S, et al. Molecular cloning and expression of
inducible nitric oxide synthase from human hepatocytes. Proc
Natl Acad Sci USA 1993; 90: 3491- 5.
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25. Bassenge E. Coronary vasomotor responses: role of
endothelium and nitrovasodilators. Cardiovasc Drugs Ther (U
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