Source and cause of endothelin-1 release into cerebrospinal fluid after subarachnoid hemorrhage

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✓ Despite years of research, delayed cerebral vasospasm remains a serious complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors examined this hypothesis in a series of experiments. In a primate model of SAH, serial ET-1 levels were measured in samples from the perivascular space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vasospasm. To determine whether elevated ET-1 production was a direct cause of vasospasm or acted secondary to ischemia, the authors also measured ET-1 levels in plasma and CSF after transient cerebral ischemia. To elucidate the source of ET-1, they measured its production in cultures of endothelial cells and astrocytes exposed to oxyhemoglobin (10 µM), methemoglobin (10 µM), or hypoxia (11% oxygen).

There was no correlation between the perivascular levels of ET-1 and the development of vasospasm or its resolution. Cerebrospinal fluid and plasma levels of ET-1 were not affected by vasospasm (CSF ET-1 levels were 9.3 ± 2.2 pg/ml and ET-1 plasma levels were 1.2 ± 0.6 pg/ml) before SAH and remained unchanged when vasospasm developed (7.1 ± 1.7 pg/ml in CSF and 2.7 ± 1.5 pg/ml in plasma). Transient cerebral ischemia evoked an increase of ET-1 levels in CSF (1 ± 0.4 pg/ml at the occlusion vs. 3.1 ± 0.6 pg/ml 4 hours after reperfusion; p < 0.05), which returned to normal (0.7 ± 0.3 pg/ml) after 24 hours. Endothelial cells and astrocytes in culture showed inhibition of ET-1 production 6 hours after exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothelial cells at 24 hours (6.4 ± 0.8 pg/ml vs. 0.1 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05) and at 48 hours (6.4 ± 0.6 pg/ml vs. 0 ± 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05), but in astrocytes hypoxia induced an increase of ET-1 at 6 hours (1.5 ± 0.6 vs. 6.4 ± 1.1 pg/ml, control vs. hypoxic astrocytes; p < 0.05).

Endothelin-1 is released from astrocytes, but not endothelial cells, during hypoxia and is released from the brain after transient ischemia. There is no relationship between ET-1 and vasospasm in vivo or between ET-1 and oxyhemoglobin, a putative agent of vasospasm, in vitro. The increase in ET-1 levels in CSF after SAH from a ruptured intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.

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Address reprint requests to: Edward H. Oldfield, M.D., Surgical Neurology Branch, Building 10, Room 5D-37, National Institutes of Health, Bethesda, Maryland 20892.

© AANS, except where prohibited by US copyright law.

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    Upper: Graph displaying ET-1 levels in the perivascular space measured in the microdialysate that was collected for 12 days after placement of a clot around the semipermeable membrane and the right MCA in six cynomolgus monkeys that developed moderate vasospasm on Day 7 after placement of the clot. Bars indicate SD. Lower: Bar graph showing ET-1 levels in plasma and CSF in eight cynomolgus monkeys. Samples were collected from the basal cisterns during the operation for placement of a clot around the right MCA (control), and on postoperative Day 7 samples were collected from the cisterna magna at the time of mild-to-moderate vasospasm of the right MCA (28 ± 7% decrease in the area of the right MCA compared with preoperative values; range 18–41%). Bars indicate SD.

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    Graph depicting ET-1 levels in plasma and CSF in five cynomolgus monkeys with transient cerebral ischemia. Plasma and CSF samples were collected from the cisterna magna before, during, and after 30-minute bilateral occlusion of the ICA and CCA. The occlusion produced a 37 ± 5% decrease in CBF for 30 minutes. Plasma and CSF also were collected at 24 hours from two monkeys that survived without neurological deficits. Cerebrospinal fluid ET-1 levels, but not plasma ET-1 levels, significantly increased at 4, 5, and 6 hours and returned to normal 24 hours after transient brain ischemia. Asterisks indicate a significant difference (p < 0.05) with baseline values. Bars indicate SD.

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    Bar graphs displaying ET-1 levels in the medium of cultured human brain endothelial cells and rat astrocytes exposed to a 10-µmol solution of oxyhemoglobin for 6, 24, and 48 hours. Upper: Production of ET-1 by the endothelial cells was inhibited by exposure to oxyhemoglobin for 24 and 48 hours (p < 0.05). Center: Production of ET-1 by astrocytes was also inhibited by exposure to oxyhemoglobin for 24 and 48 hours (p < 0.05). Lower: Thrombin stimulated production of ET-1 by astrocytes. The ET-1 levels were measured in the cells (pg/mg of protein). The ET-1 production in thrombin-stimulated and control astrocytes was equally inhibited by oxyhemoglobin (10 µM) and methemoglobin (10 mmol). Asterisks indicate a significant difference (p < 0.05) between control or thrombin-stimulated cultures and cultures exposed to oxyhemoglobin or methemoglobin. Bars indicate the SD for three repetitions of each experiment.

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    Bar graphs showing ET-1 levels in the media of human brain endothelial cells and cultured rat astrocytes exposed to hypoxic conditions for 6, 24, and 48 hours (PO2 50–89 vs. 143–169 mm Hg). Upper: Production of ET-1 by endothelial cells was inhibited at 6 and 24 hours and completely stopped at 48 hours. Lower: Production of ET-1 by astrocytes was increased at 6 hours (p < 0.05); this increase was followed by a complete inhibition of ET-1 production at 24 and 48 hours. Asterisks indicate a significant difference (p < 0.05) between control cell cultures and cell cultures under hypoxia. Bars indicate the SD for three repetitions of each experiment.

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