Enlarged Infarcts in Endothelial Nitric Oxide Synthase Knockout Mice are Attenuated by Nitro-L-Arginine

Abstract

Infarct size and vascular hemodynamics were measured 24 h after middle cerebral artery (MCA) occlusion in mice genetically deficient in the endothelial nitric oxide synthase (eNOS) isoform. eNOS mutant mice developed larger infarcts (21%) than the wild-type strain when assessed 24 h after intraluminal filament occlusion. Moreover, regional CBF values recorded in the MCA territory by laser-Doppler flowmetry were more severely reduced after occlusion and were disproportionately reduced during controlled hemorrhagic hypotension in autoregulation experiments. Unlike the situation in wild-type mice, nitro-L-arginine superfusion (1 mM) dilated pial arterioles of eNOS knockout mice in a closed cranial window preparation. As noted previously, eNOS mutant mice were hypertensive. However, infarct size remained increased despite lowering blood pressure to normotensive levels by hydralazine treatment. Systemic administration of nitro-L-arginine decreased infarct size in eNOS mutant mice (24%) but not in the wild-type strain. This finding complements published data showing that nitro-L-arginine increases infarct size in knockout mice expressing the eNOS but not the neuronal NOS isoform (i.e., neuronal NOS knockout mice). We conclude that NO production within endothelium may protect brain tissue, perhaps by hemodynamic mechanisms, whereas neuronal NO overproduction may lead to neurotoxicity.

Cerebral Microvascular Damage Occurs Early after Hypoxia–Ischemia via nNOS Activation in the Neonatal Brain

“…In contrast to the neuroprotective effect observed in nNOS and iNOS knockout mice, eNOS knockout mice are quite susceptible to ischemic injury, suggesting that eNOS activation during hypoxia is protective. 28 In conclusion, discovering how neurovascular protection early after HI may salvage neurons can lead to new treatment of neonatal HI brain injury. The microvasculature, acting as a factor contributing to the development and progression of HI, may become a major therapeutic target in the treatment of neonatal HI encephalopathy.…”

Evidence for induction of the ornithine transcarbamylase expression in Alzheimer's disease

“…On the other hand, NO is likely involved in neuroprotection. 38 For instance, as a powerful vasodilator, NO may compensate local hypoperfusion, 39 as observed in the brain of AD cases.…”

Improved functional outcome after spinal cord injury in iNOS-deficient mice

“…In ischaemic CNS injury, however, eNOS is considered to be neuroprotective, based on the observation that eNOSÀ/À mice develop larger infarcts than wild types after experimental cerebral ischaemia. 17 The finding that pretreatment with L-NAME before experimental SCI inhibits recovery of motor function, may therefore be attributed to inhibition of eNOS. 7 Taken together, the role of NO in the secondary mechanisms after SCI seems to be complex but the present report supports ideas of a mainly destructive influence of iNOS-derived NO.…”