Anti-ischaemic efficacy of a nitric oxide synthase inhibitor and a N-methyl-D-aspartate receptor antagonist in models of transient and permanent focal cerebral ischaemia.

1. We have recently developed a new model of transient focal ischaemia in the rat utilising topical application of endothelin-1 to the left middle cerebral artery (MCA). In order to validate this approach the present study assessed the neuroprotective efficacy of the NMDA receptor antagonist dizocilpine (MK-801) in the endothelin-1 model. The anti-ischaemic efficacy of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was subsequently evaluated, and contrasted with its efficacy against permanent focal ischaemia, to determine the utility of the endothelin-1 model for identification of novel pharmacoprotective agents. 2. MK-801 (0.12 mg kg-1 bolus, 108 micrograms kg-1 h-1 infusion i.v., either 1 or 2.5 h pre-transient MCA occlusion (MCAO)) induced hypotension that persisted for approximately 1.5 h so that mean arterial blood pressure (MABP) at the time of MCAO was significantly lower in the 1 h group compared with control (MABP: 86 +/- 11, 68 +/- 6 and 84 +/- 4 mmHg (mean +/- s.d.) for saline, 1 h MK-801 and 2.5 h MK-801 groups respectively). The 2.5 h pretreatment schedule resulted in significant reduction (71%) in the volume of hemispheric damage (assessed 4 h post onset of ischaemia) while the 1 h pretreatment schedule did not (volumes of hemispheric damage: 59 +/- 38, 51 +/- 51 and 17 +/- 28 mm3 for saline, 1 h and 2.5 h MK-801 groups). 3. Thus the considerable neuroprotective effect of MK-801 in the endothelin-1 model of transient focal cerebral ischaemia was highly sensitive to drug-induced hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)