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

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.