From the Departments of Anesthesia (J.E.B.) and Internal Medicine and
Pharmacology (F.M.F.), Cardiovascular Center, University of Iowa College of
Medicine, Iowa City.
Correspondence to J.E. Brian, Jr, MD, Department of Anesthesia 6 JCP, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail eddie-brian{at}uiowa.edu
Background and Purpose—In brain,
several cell types produce tumor necrosis factor-
Methods—Cranial windows were implanted in anesthetized
rats and used to measure the diameter of cerebral arterioles. Windows
were flushed every 30 minutes for 4 hours with artificial cerebrospinal
fluid (aCSF) (n=6); aCSF with TNF
Results—Application of TNF
Conclusions—The present study indicates that TNF
Cardiovascular
Pharmacology WW,
SmithKline Beecham Pharmaceuticals,
King of Prussia, Pennsylvania
© 1998 American Heart Association, Inc.
Original Contributions
Tumor Necrosis Factor-
–Induced Dilatation of Cerebral Arterioles
(TNF) after
injury or exposure to endotoxin. TNF alone or in combination with
endotoxin or other cytokines can cause expression of inducible
nitric oxide (NO) synthase. We have previously demonstrated that
endotoxin caused NO-dependent dilatation of cerebral arterioles in
vivo. In the present study we examined the hypothesis that TNF
causes NO-mediated dilatation of cerebral arterioles in vivo. (100 ng/mL; n=10); aCSF with
TNF and aminoguanidine (0.3 mmol/L; n=5), an
inhibitor of inducible NO synthase; or aCSF with TNF and
dexamethasone (1 µmol/L; n=6), which attenuates
expression of inducible NO synthase. In some animals, brain from
beneath the cranial window was examined by immunocytochemistry for
inducible NO synthase expression. caused marked, progressive
dilatation of cerebral arterioles, with a maximum increase in diameter
of 46±9% (mean±SEM) at 4 hours. Coapplication of either
aminoguanidine or dexamethasone with TNF prevented
dilatation of cerebral arterioles compared with TNF alone (4±2%
and 1±1% dilatation at 4 hours, respectively; P<.05).
Dexamethasone did not inhibit dilatation of cerebral
arterioles in response to adenosine diphosphate. However, 2
hours of aminoguanidine treatment produced moderate inhibition of
adenosine diphosphate–induced dilatation of cerebral
arterioles. After treatment with TNF, immunocytochemistry for
inducible NO synthase demonstrated expression in perivascular and
arachnoid cells but not brain cells. There was no detectable expression
of inducible NO synthase after treatment with aCSF. causes
cerebral vasodilatation and expression of inducible NO synthase in
perivascular and arachnoid cells. Inhibition of TNF-induced
dilatation by aminoguanidine and dexamethasone suggests
that the vasodilatation was due predominantly to expression of
inducible NO synthase. These findings support the concept that cerebral
vasodilatation that occurs during
pathophysiological conditions associated with
increased TNF production in brain is mediated by expression
of inducible NO synthase.
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