The Effect of Nitric Oxide Synthase Inhibition on Acute Platelet Accumulation and Hemodynamic Depression in a Rat Model of Thromboembolic Stroke

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Abstract
The relative importance of hemodynamic factors in the pathogenesis of thrombotic or embolic stroke is unclear. Of particular therapeutic interest are those substances that facilitate vasodilation and the clearance of platelet aggregates in the compromised microvasculature. A likely contributor to these functions is nitric oxide because it is known to inhibit platelet aggregability and promote vascular relaxation. To investigate the involvement of nitric oxide in the hemodynamic changes after experimental ischemia, photochemically induced nonocclusive common carotid artery thrombosis (CCAT) was studied. CCAT is a rat model of unilateral carotid artery stenosis and platelet embolization to the brain. This study characterized the acute hemodynamic consequences of CCAT and the resultant pattern of platelet deposits with and without nitric oxide synthase inhibition by nitro-l-arginine methyl ester (l-NAME). In addition, the subacute local cerebral blood flow changes were studied at 24 hours. Right CCAT was produced in 30 male Wistar rats injected with 111In-labeled platelets. Between 5 and 15 minutes after thrombosis, rats were treated with either 15 mg/kg of l-NAME (intravenously) or saline vehicle. Hemodynamic changes were studied 30 to 45 minutes after thrombosis using [14C]iodoantipyrine autoradiography. Eight coronal levels were analyzed, and cortical and subcortical regions of interest were defined. Significant increases were observed in total platelets in the ipsilateral hemisphere after l-NAME treatment, and in the distribution of platelets in the anterior frontal and occipital cortices with nitric oxide synthase inhibition, encompassing the anterior and posterior border zone areas of the ipsilateral cortex. Otherwise, foci of labeled platelets were detected throughout the ipsilateral and contralateral hemispheres. Mean local cerebral blood flow images (n = 5) revealed a moderate bilateral global reduction in flow acutely, which normalized in the untreated thrombosed group by 24 hours. In contrast, the l-NAME–treated groups (sham and experimental) had lasting, widespread reductions in flow of approximately 25%. Pairwise comparisons between groups showed that CCAT/l-NAME was significantly different from shams in the corpus callosum and different from L-NAME shams in the internal capsule ( P < 0.05) These hemodynamic and platelet accumulation changes may partially account for the aggravation of cognitive and sensorimotor deficits previously reported in this model of thromboembolic stroke.

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