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 μg 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, 1h 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. This result is in contrast to previous studies of permanent MCAO where MK‐801‐induced hypotension did not compromise its neuroprotective action. 4 l‐NAME (3 mg kg−1, i.v. 30 min pre‐MCAO) moderately, but significantly, reduced (16%) the volume of ischaemic damage 4 h post‐permanent MCA occlusion, whereas the 29% reduction in volume of damage achieved in the model of transient focal ischaemia did not attain significance due to the greater variability associated with this model. l‐NAME did not significantly alter MABP in either model. 5 The modest neuroprotection achieved with NO synthase inhibition suggests NO is of relatively minor importance as a mediator of neurotoxicity following permanent focal cerebral ischaemia. In addition the comparable efficacy of l‐NAME against transient focal ischaemia suggests the presence of reperfusion does not enhance the contribution of NO to neuronal injury in the acute (4 h) phase following a focal ischaemic insult.