Endothelin-1-Induced Reductions in Cerebral Blood Flow: Dose Dependency, Time Course, and Neuropathological Consequences

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Abstract
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 μl 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.