Attenuation of iNOS mRNA exacerbates hypoperfusion and upregulates endothelin-1 expression in hippocampus and cortex after brain trauma.
Nitric oxide (NO, a vasodilator) and endothelin-1 (ET-1, a powerful vasoconstrictor) participate in the regulation of brain's microcirculation influencing each other's expression and synthesis. Following injury to the brain, NO is derived largely from the inducible form of nitric oxide synthase (iNOS). We used Marmarou's model of traumatic brain injury (TBI) to study the cerebral blood flow and expression (mRNA) of ET-1 in rats that were pretreated with antisense iNOS oligodeoxynucleotides (ODNs). Intracerebroventricular application of iNOS ODNs resulted in reduced synthesis of iNOS as detected by Western blot analysis. The cerebral blood flow (measured by laser Doppler flowmetry), generally decreased after TBI, was further markedly reduced in the treated animals and remained at low levels up to 48 h post-TBI. The expression of ET-1 (detected by in situ hybridization in cortex and hippocampus) was increased 2-3-fold following TBI alone and this increase reached 5-6-fold in animals pretreated with antisense iNOS ODNs. The results indicate that most likely, NO, generated primarily by iNOS, suppresses ET-1 production and that a decrease of NO results in upregulation of ET-1 via transcriptional and translational mechanisms. Increased availability of ET-1 at the vascular bed and the neuropil may contribute to the altered microvascular reactivity and reduced perfusion of the brain following TBI.
Steiner
J
J
Department of Anatomy and Cell Biology, Wayne State University, School of Medicine, 540 East Canfield Ave., Detroit, MI 48201, USA.
Rafols
D
D
Park
H K
HK
Katar
M S
MS
Rafols
J A
JA
Petrov
Th
T
D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000098:blood supply*; D002560:Cerebrovascular Circulation; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply*; D017403:In Situ Hybridization; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000201:enzymology / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015854:Up-Regulation
D019332:Endothelin-1; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D016650:Fluorescein-5-isothiocyanate