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. 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.
Dawson
D A
DA
Wellcome Surgical Institute, University of Glasgow.
Graham
D I
DI
McCulloch
J
J
Macrae
I M
IM
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002536:Cerebral Arteries / Q000502:physiology; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D016232:Endothelins; D002546:Ischemic Attack, Transient / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D016232:Endothelins; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester