Endothelin-1 induced middle cerebral artery occlusion: pathological consequences and neuroprotective effects of MK801

In the present study we utilise the potent vasoconstrictor properties of endothelin-1 (Et-1) in a new model of middle cerebral artery occlusion in the anaesthetized rat. We evaluate the reproducibility of the model and examine the neuroprotective efficacy of the potent anti-ischaemic agent, MK801. Adult male SD rats received MK801 (5 mg/kg, n = 7) or saline vehicle (n = 7) 30 mins prior to the microinjection of Et-1 (60 pmol in 3 microliters) via a 31-g cannula stereotaxically positioned 0.5 mm above the middle cerebral artery. Three days after the injection of Et-1, rats were perfusion fixed, the brain removed, cryostat sectioned and processed for histological staining. Sections at eight predetermined levels were examined by light microscopy and the volume of infarction calculated. Following administration of Et-1, saline-pretreated rats exhibited a pattern of ischaemic damage similar to that previously reported following permanent occlusion of the rat middle cerebral artery. This pattern was characterised by a large volume of infarction covering the dorsal and lateral neocortex (98 +/- 12 mm3) and striatum (32 +/- 3 mm3) ipsilateral to the insult. Power analysis predicted a group size of 7 would be required for a 50% reduction in ischaemic damage to be recorded as statistically significant at the 5% level. Pretreatment with MK801 reduced cortical tissue damage by 51% (P = 0.026) but did not significantly alter either the pattern or volume of infarction (33 +/- 4 mm3; P = 0.95) in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)