Endothelin levels increase in rat focal and global ischemia.
Endothelin-1, a peptide exhibiting extremely potent cerebral vasoactive properties, is elevated in the cerebrospinal fluid after hemorrhagic stroke and implicated in cerebral vasospasm. The purpose of this study was to determine changes in endothelin in ischemic rat brain by assaying endothelin tissue and extracellular levels. Immunoreactive endothelin levels in ischemic brain tissue following permanent or transient focal ischemia produced by middle cerebral artery occlusion was determined. In addition, endothelin levels were assayed in striatal extracellular fluid collected by microdialysis before, during, and after global ischemia produced by two-vessel occlusion combined with hypotension. Twenty-four hours after the onset of permanent middle cerebral artery occlusion, the ischemic cortex level (0.58 +/- 0.27 fmol/mg protein) of immunoreactive endothelin was significantly (p < 0.05) increased, by 100%, over that in the nonischemic cortex (0.29 +/- 0.13 fmol/mg protein). Transient artery occlusion for 80 min with reperfusion for 24 h also resulted in a similar significant (p < 0.05) increase, 78%, in immunoreactive endothelin in the ischemic zone. Global forebrain ischemia significantly (p < 0.05) increased the level of immunoreactive endothelin collected in striatal microdialysis perfusate, from a basal level of 14.6 +/- 6.7 to 26.5 +/- 7.7 and 26.2 +/- 7.4 amol/microliters (i.e. 82 and 79%). These changes reflect the relative picomolar extracellular concentration increases during ischemia and following reperfusion, respectively. This is the first demonstration of elevated levels of endothelin in focal ischemic tissue and in the extracellular fluid in global ischemia and suggests a role of the peptide in ischemic and postischemic derangements of cerebral vascular function and tissue injury.
Barone
F C
FC
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Globus
M Y
MY
Price
W J
WJ
White
R F
RF
Storer
B L
BL
Feuerstein
G Z
GZ
Busto
R
R
Ohlstein
E H
EH
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism*; D016232:Endothelins / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009422:Nervous System Diseases / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013997:Time Factors
D016232:Endothelins