The role of nitric oxide in the pathophysiology of thromboembolic stroke in the rat.
Although nitric oxide (NO) has been shown to play an important role in the pathophysiology of cerebral ischemia, its contribution to the pathogenesis of experimentally induced thromboembolic stroke is unknown. In this study, we pharmacologically manipulated NO levels in the acute post-thrombotic stage and determined the effects on behavior and histopathology. The following drugs were used: nitro-L-arginine-methyl ester (L-NAME), a non-specific endothelial and neuronal nitric oxide synthase (eNOS and nNOS) inhibitor, 3-bromo-7-nitroindazole (7-NI), a specific inhibitor for nNOS, the NO precursor, exogenous L-arginine and the NO-donor, 3-morpholino-sydnonimine (SIN-1). Male Wistar rats (n = 76) were randomly assigned to receive vehicle or drug immediately after common carotid artery thrombosis (CCAT). Regional measurements of cortical NOS activity using the [3H]L-arginine to [3H]L-citrulline conversion assay were decreased 1 h after treatment with L-NAME and 7-NI by 50 and 65%, respectively; hippocampal NOS activity was reduced with L-NAME by 35% and with 7-NI by 65%. L-NAME significantly worsened forelimb placing as compared to other groups. 7-NI accelerated sensorimotor recovery. Water maze retention deficits were noted 48 h after CCAT and these were exacerbated by L-NAME treatment. Histopathological protection was conferred in the hippocampus by 7-NI and SIN-1; conversely, L-NAME increased neuronal injury in the contralateral cortex. L-arginine had no effect on these outcomes. In conclusion, both structural and functional consequences of CCAT can be aggravated by limiting endothelial NO production in the acutely post-thrombotic brain. In contrast, inhibition of nNOS and infusion of an NO donor has a beneficial effect on pathology.
Stagliano
N E
NE
Department of Neurology, University of Miami School of Medicine, FL 33101, USA.
Dietrich
W D
WD
Prado
R
R
Green
E J
EJ
Busto
R
R
D000818:Animals; D001120:Arginine / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000503:physiopathology* / Q000523:psychology; D002956:Citrulline / Q000096:biosynthesis; D003072:Cognition Disorders / Q000209:etiology / Q000523:psychology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002542:Intracranial Embolism and Thrombosis / Q000150:complications*; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D013003:Somatosensory Cortex / Q000187:drug effects / Q000503:physiopathology; D013923:Thromboembolism / Q000150:complications*
D004791:Enzyme Inhibitors; D002956:Citrulline; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester