Tumor necrosis factor-α-induced dilatation of cerebral arterioles. Commentary

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