SOURCE AND CAUSE OF ENDOTHELIN-1 RELEASE INTO CEREBROSPINAL-FLUID AFTER SUBARACHNOID HEMORRHAGE

Despite years of research, delayed cerebral vasospasm remains a seriou s complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors exa mined this hypothesis in a series of experiments. In a primate model o f SAH, serial ET-1 levels were measured in samples from the perivascul ar space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vas ospasm. To determine whether elevated ET-1 production was a direct cau se of vasospasm or acted secondary to ischemia, the authors also measu red ET-1 levels in plasma and CSF after transient cerebral ischemia. T o elucidate the source of ET-1, they measured its production in cultur es of endothelial cells and astrocytes exposed to oxyhemoglobin (10 mu M), methemoglobin (10 mu M), or hypoxia (11% oxygen). There was no co rrelation 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 return ed 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 af ter exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothe lial cells at 24 hours (6.4 +/- 0.8 pg/ml vs. 0.1 +/- 0.1 pg/ml, contr ol 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 h ours (1.5 +/- 0.6 vs. 6.4 +/- 1.1 pg/ml, control vs. hypoxic astrocyte s; p < 0.05). Endothelin-1 is released from astrocytes, but not endoth elial cells, during hypoxia and is released from the brain after trans ient 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 rupture d intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.