A rat model of endothelin-3-induced middle cerebral artery occlusion with controlled reperfusion

Surge hyperemia and mechanical damage to the cerebrovascular endothelium ma y serve to exacerbate the neuropathological outcome in animal models of foc al cerebral ischemia. We have modified an existing model of endothelin-1 -i nduced middle cerebral artery (MCA) occlusion to enable controlled reperfus ion without damage to the cerebral vasculature. Endothelin-1 (ET-1) and end othelin-3 (ET-3) were injected via a double-injection cannula into brain pa renchyma adjacent to the MCA of anesthetized rats to produce focal cerebral ischemia. ET-1 and ET-3 produced large ischemic lesions that were restrict ed to those cortical and subcortical structures supplied by the MCA. The vo lume of ischemic damage produced by 100 pmol of ET-I and ET-3 was similar. The endothelin-A (ETA) receptor antagonist FR139317 (3 or 30 nmol) injected 10 min after ET-1 did not significantly alter the volume of damage. By con trast, the lesion produced by ET-3 was completely inhibited by FR139317 at the 10 min time-point. FR139317 partially attenuated the ET-3-induced lesio n when administered 30 min post-occlusion, but injection 90 min following E T-3 produced a lesion nor different to that produced by ET-3 alone. These f indings were supported by laser Doppler flowmetry which determined FR139317 induces reperfusion when injected 10 or 90 min following ET-3. ET-3-induce d MCA occlusion is therefore amenable to reversal by the ETA receptor antag onist FR139317, and this model may offer a means to investigate the neuropa thology of reperfusion without the procedure-related artifacts associated w ith some reperfusion models. (C) 1999 Published by Elsevier Science B.V. Al l rights reserved.