Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences.
The capacity of endothelin-1 to induce severe reductions in cerebral blood flow and ischaemic neuronal damage was assessed in anaesthetised rats. Endothelin-1 (25 microliters of 10(-7)-10(-4) M) was applied to the adventitial surface of an exposed middle cerebral artery and striatal blood flow assessed by the hydrogen clearance technique. Endothelin-1 induced severe dose-dependent reductions in cerebral blood flow (e.g., minimum CBF at 10(-5) M of 9 +/- 11 ml 100 g-1 min-1 compared to 104 +/- 22 ml 100 g-1 min-1 with vehicle, p < 0.05), which persisted for at least 60 min at each concentration of endothelin-1. Application of endothelin-1 to the middle cerebral artery produced dose-dependent ischaemic brain damage (e.g., volume of damage of 65 +/- 34 mm3 at 10(-5) M compared to 0.22 +/- 0.57 mm3 for vehicle, p < 0.01). These data demonstrate that endothelin-1 is capable of reducing blood flow to pathologically low levels and provide a new model of controlled focal ischaemia followed by reperfusion.
Macrae
I M
IM
Wellcome Neuroscience Group, Wellcome Surgical Institute, and Hugh Fraser Neuroscience Laboratories, Glasgow, U.K.
Robinson
M J
MJ
Graham
D I
DI
Reid
J L
JL
McCulloch
J
J
D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D002536:Cerebral Arteries / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013997:Time Factors
D016232:Endothelins