Tumor necrosis factor-alpha-induced dilatation of cerebral arterioles.

Abstract

In brain, several cell types produce tumor necrosis factor-alpha (TNFalpha) after injury or exposure to endotoxin. TNFalpha 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 TNFalpha causes NO-mediated dilatation of cerebral arterioles in vivo. 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 TNFalpha (100 ng/mL; n=10); aCSF with TNFalpha and aminoguanidine (0.3 mmol/L; n=5), an inhibitor of inducible NO synthase; or aCSF with TNFalpha and dexamethasone (1 micromol/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. Application of TNFalpha 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 TNFalpha prevented dilatation of cerebral arterioles compared with TNFalpha 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 TNFalpha, 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. The present study indicates that TNFalpha causes cerebral vasodilatation and expression of inducible NO synthase in perivascular and arachnoid cells. Inhibition of TNFalpha-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 TNFalpha production in brain is mediated by expression of inducible NO synthase.