CEREBRAL ISCHEMIA--ENDOTHELIN-1 AND NITRIC OXIDE

点击翻译按钮获取中文摘要

We have explored the possibility of imbalance between the production of endothelin-1 (ET-1) and nitric oxide (NO) which may exacerbate brain injury. ET-1 a known potent vasoconstrictor peptide and NO, an endothelial relaxing factor, are produced among other vasoactive mediators in the vascular endothelium and in other cells in the brain. It has been suggested that an imbalance between the production of ET-1 and NO in the endothelium may play a role in cerebrovascular disorders. In particular, the observed increased ET-1 levels in plasma and/or cerebrospinal fluid (CSF) of patients with stroke, hypertension and vasospasm implicate ET-1 in the pathogenesis of cerebrovascular disease process. The aim of this study was to establish whether cerebral ischemia leads to CSF elevation of ET-1 which could be additionally altered by inhibition of NO synthase (NOS). Bilateral carotid artery occlusion (15 min) alone or with release (5-120 min) in gerbils served as a model for cerebral ischemia. The treatment consisted of either nitro-L-arginine (NLA) or D-nitro-L-arginine methyl ester (D-NAME) 40 mg/kg b.w.) in Ringer's solution (0.5ml) or the solvent alone given intraperitoneally 4 hr prior to the induction of ischemia. Similarly treated sham-operated animals were used as controls. Systemic blood pressure (SBP), cerebral blood flow (CBF), temporal and rectal temperature were continuously monitored in anesthetized (halothane 1.5% and NO2/O2 1%) and spontaneously ventilated gerbils. CSF was obtained from the cisterna magna at the end of each experimental period. The level of ET-1 in CSF was measured by radioimmunoassay. Temperature was not significantly affected by either treatment. SBP was only elevated in NLA- treated animals during pre- and postischemia (NLA 77.67 plus minus 1.88 and 85.33 plus minus1.75 mm Hg, respectively; others 66.67 plus minus 3.45 and 72.5 plus minus 2.17 mm Hg, respectively), although ischemia induced a similar rise in SBP in all groups of gerbils. CBF was reduced (0.5% of control) during ischemia in all groups. NLA treatment but not D-NAME prevented the initial complete recovery of CBF during reperfusion (7.5 min). In the CSF, the ET-1 level was raised 2-3 fold over controls in early reperfusion after 15 min of ischemia. The NLA-treated animals already showed the increased content of ET-1 in the CSF after ischemia alone with reperfusion. This is the first demonstration of changes in ET- 1 content of CSF in ischemia/reperfusion. NOS inhibition produces an early and persistent rise in ET-1 levels of CSF in addition to SBP elevation and incomplete recovery of CBF during ischemia/reperfusion.