Endotoxin Decreases the Contractile Responses of the Porcine Basilar Artery to Vasoactive Substances

1998

Background and Purpose-In brain, several cell types produce tumor necrosis factor-␣ (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. 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) (nϭ6); aCSF with TNF␣ (100 ng/mL; nϭ10); aCSF with TNF␣ and aminoguanidine (0.3 mmol/L; nϭ5), an inhibitor of inducible NO synthase; or aCSF with TNF␣ and dexamethasone (1 mol/L; nϭ6), 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 TNF␣ caused marked, progressive dilatation of cerebral arterioles, with a maximum increase in diameter of 46Ϯ9% (meanϮSEM) at 4 hours. Coapplication of either aminoguanidine or dexamethasone with TNF␣ prevented dilatation of cerebral arterioles compared with TNF␣ alone (4Ϯ2% and 1Ϯ1% dilatation at 4 hours, respectively; PϽ.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. Conclusions-The present study indicates that TNF␣ 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. (Stroke. 1998;29:509-515.)

Section: Tnf␣ and Inducible No Synthasesupporting

confidence: 66%

Tumor Necrosis Factor-α–Induced Dilatation of Cerebral Arterioles

1998

“…95 - 96 A recent study suggests that induction of NO synthase also occurs in response to lipoporysaccharide in cerebral vascular muscle in vitro. 97 This induction was associated with impaired responses of cerebral arteries to vasoconstrictor stimuli. 97 Preliminary evidence suggests that lipopolysaccharide produces marked dilatation of cerebral arterioles in vivo, which is dependent on formation of NO and may be mediated by induction of NO synthase.…”

Section: Inducible Nitric Oxide Synthasementioning

confidence: 99%

Nitric oxide and the cerebral circulation.

1994

494

234

Nitric oxide (NO) is a potent vasodilator that was initially described as the mediator of endothelium-dependent relaxation (endothelium-derived relaxing factor, EDRF). It is now known that NO is produced by a variety of other cell types. Endothelium produces NO (EDRF) under basal conditions and in response to a variety of vasoactive stimuli in large cerebral arteries and the cerebral microcirculation. Endothelium-dependent relaxation is impaired in the presence of several pathophysiological conditions. This impairment may contribute to cerebral ischemia or stroke. Activation of glutamate receptors appears to be a major stimulus for production of NO by neurons. Neuronally derived NO may mediate local increases in cerebral blood flow during increases in cerebral metabolism. NO synthase-containing neurons also innervate large cerebral arteries and cerebral arterioles on the brain surface. Activation of parasympathetic fibers that innervate cerebral vessels produces NO-dependent increases in cerebral blood flow. Increases in cerebral blood flow during hypercapnia also appear to be dependent on production of NO. Astrocytes may release some NO constitutively, but astrocytes and microglia can release relatively large quantities of NO after induction of NO synthase in response to endotoxin or some cytokines. Expression of inducible NO synthase, perhaps in response to local production of cytokines, may exert cytotoxic effects in brain during or after ischemia. Because endothelium, neurons, and glia can all produce NO in response to some stimuli, the influence of NO on the cerebral circulation appears to be very important. Under normal conditions, constitutively produced NO influences basal cerebral vascular tone and mediates vascular responses to a diverse group of stimuli. The inducible form of NO synthase produces much greater amounts of NO that may be an important mediator of cytotoxicity in brain.

“…38 Others have reported that dexamethasone does not alter constrictor or dilator responses of cerebral and extracerebral vessels. 39,40 Dexamethasone does not affect the activity of COX-1 in vivo. 41 Thus, it is unlikely that dexamethasone reduced LPS-induced dilatation by a nonspecific effect on vascular tone.…”

Section: Cox-2 Expression In Brainmentioning

confidence: 99%

Expression and Vascular Effects of Cyclooxygenase-2 in Brain

Moore

1998

Background and Purpose-Cyclooxygenase-2 (COX-2) is an inducible isoform of cyclooxygenase. Several types of brain cells in culture can express COX-2 when treated with lipopolysaccharide (LPS) or some cytokines. LPS produces dilatation of cerebral arterioles in vivo through a mechanism that is partially inhibited by indomethacin. In the present study we examined the hypothesis that LPS causes increased expression of COX-2 in brain as well as COX-2-dependent dilatation of cerebral arterioles. Methods-Cranial windows were implanted in anesthetized rats and used to measure diameter of cerebral arterioles under control conditions and during topical application of various agonists and antagonists. Windows were flushed every 30 minutes for 4 hours with vehicle (artificial cerebrospinal fluid; nϭ5), LPS (100 ng/mL; nϭ8), LPS and NS-398 (100 mol/L; nϭ8), a selective inhibitor of COX-2, or LPS and dexamethasone (1 mol/L; nϭ5), which attenuates expression of COX-2. To examine expression of COX-2 protein in vivo, other animals were injected intracisternally with artificial cerebrospinal fluid (nϭ3) or LPS (40 ng; nϭ4). Four hours after injection, the leptomeninges were harvested and analyzed by Western blot for expression of COX-2 protein.In a third group of experiments, COX-2 expression and prostaglandin E 2 (PGE 2 ) production were determined in leptomeningeal tissue treated for 4 hours ex vivo with vehicle (nϭ4), LPS (100 ng/mL; nϭ4), LPS and NS-398 (100 mol/L; nϭ4), or LPS and dexamethasone (1 mol/L; nϭ4). Results-LPS caused marked, progressive dilatation of cerebral arterioles, with a maximum increase in diameter of 55Ϯ9% (meanϮSEM) at 4 hours. Coapplication of either NS-398 or dexamethasone with LPS reduced dilatation of cerebral arterioles at hours 2 through 4 (PϽ0.05). In contrast, NS-398 did not inhibit dilatation of cerebral arterioles in response to bradykinin or ADP. In animals injected intracisternally with vehicle, COX-2 protein was expressed at a very low level in leptomeningeal tissue. Intracisternal injection of LPS increased COX-2 protein expression by approximately 20-fold (PϽ0.05). In leptomeningeal tissue treated ex vivo with LPS, there was also expression of COX-2. Both dexamethasone and NS-398 markedly reduced COX-2 protein expression in ex vivo LPS-treated tissue. PGE 2 production was detectable under control conditions in leptomeningeal tissue incubated in vehicle ex vivo for 4 hours (6.5Ϯ1.1 pmol/mg protein). LPS treatment significantly increased PGE 2 production to 12.8Ϯ1.1 pmol/mg protein (PϽ0.05). Both dexamethasone and NS-398 significantly attenuated LPS-induced PGE 2 production (PϽ0.05). Conclusions-LPS increased expression of COX-2 protein in leptomeningeal tissue and caused COX-2-dependent dilatation of cerebral arterioles in vivo. Ex vivo, both NS-398 and dexamethasone suppressed LPS-induced PGE 2 production and COX-2 expression in leptomeningeal tissue. Inhibition of LPS-induced dilatation of cerebral arterioles in vivo by NS-398 and dexamethasone suggests that the dilatation was dependent...