Common Carotid Artery Thrombosis Research Articles

Successful surgical intervention in traumatic carotid artery thrombosis after a motor vehicle accident: a case report

Blunt carotid artery injury can lead to impaired brain perfusion due to ischemic stroke and thromboembolic events. To reduce the risk of potential neurological complications, it is critical to determine the diagnosis and management protocol as quickly as possible after a detailed clinical examination. This report presents successful surgical treatment of a young male patient who developed a traumatic left common carotid artery thrombosis after a motor vehicle accident.

Study on the antithrombotic effect and physiological mechanism of okanin

The objectives of this study were to investigate the antithrombotic effect and physiological mechanism of okanin, a flavonoid monomer in Coreopsis tinctoria Nutt. The antithrombotic effects of okanin were determined by the anticoagulant activity test in vitro and in vivo, the venous thrombosis and arterial thrombosis test in rats. To study the antithrombotic physiological mechanisms of okanin, UV spectrophotometer and enzyme-linked immunosorbent assay (ELISA) were used to determine the effects of three concentrations of okanin on the contents of 6-keto-prostaglandin F1α (6-Keto-PGF1α), thromboxane B2 (TXB2), endothelin-1 (ET-1), antithrombin III (AT-Ⅲ), protein C (PC) and von willebrand factor (vWF) in the plasma of rats with arterial thrombosis; ELISA was used to detect the effects of okanin on the contents of plasminogen (PLG), tissue plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1) in the plasma of mice and Chinese white rabbits. The results showed that okanin could prolong the coagulation time in vitro and in vivo of animals (P < 0.01 in the high dose group) and the activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) of human venous blood (ATPP of medium dose group P < 0.01; PT, TT P < 0.05. P < 0.01 in the high dose group); inhibit the maximum platelet aggregation rate of rabbits (P < 0.05 in the low dose group; P < 0.01 in the medium and high dose groups), decrease the dry and wet weight of venous thrombosis and the wet weight of common carotid artery thrombosis in rats (low dose group, P < 0.05; medium and high dose groups, P < 0.01); increase the levels of 6-Keto-PGF1α, AT-Ⅲ, PLG and t-PA in animal plasma; decrease the levels of TXB2, ET-1, vWF and PAI-1 in animal plasma. It is concluded that okanin can significantly inhibit thrombosis, and its physiological mechanisms were related to affecting the activation of related coagulation factors in endogenous and exogenous coagulation pathways, affecting the physiological characteristics of platelets, repairing damaged vascular endothelial cells and enhancing the activity of the fibrinolytic system.

Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial STAT3 to promote the development of arterial thrombosis

BackgroundThrombotic events cannot be completely prevented by antithrombotics, implicating a therapeutic gap due to inflammation, a not yet sufficiently addressed mechanism. Neutrophil extracellular traps (NETs) are an essential interface between inflammation and thrombosis, but exactly how the NETotic process is initiated and maintained during arterial thrombosis remains incompletely understood.Methods and resultsWe found that the plasma concentrations of C5a were higher in patients with ST-elevation myocardial infarction (STEMI) than in patients with angina and higher in mice with left common carotid artery (LCCA) thrombosis induced by FeCl3 than in control mice. We observed that the thrombus area and weight were decreased and that NET formation in the thrombi was reduced in the group treated with the selective C5aR1 receptor inhibitor PMX53 compared with the NaCl group. In vitro, NETosis was observed when C5a was added to neutrophil cultures, and this effect was reversed by PMX53. In addition, our data showed that C5a increased the production of mitochondrial reactive oxygen species (ROS) and that the promotion of NET formation by C5a was mitochondrial ROS (Mito-ROS) dependent. Furthermore, we found that C5a induced the production of Mito-ROS by inhibiting mitochondrial STAT3 activity.ConclusionsBy inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis.

A Nano-Based P1Cminimum Probe to Monitor Thrombosis in Grafts and Improve Cardiac Function After Coronary Artery Bypass Grafting Surgery.

Magnetic resonance imaging is widely used to identify and monitor thrombi in grafted vessels following coronary artery bypass grafting surgery (CABG). We produced a biosensor, P1Cm-SPIO-Cy5.5, composed of P1Cm peptide, superparamagnetic iron oxide nanoparticles (SPIO), and polyethylene glycol (PEG), for use in MRI thrombus imaging. Activated platelets induced by adenosine diphosphate were used for combination tests in vitro. A rat model of common carotid artery thrombosis was used for anti-thrombus experiments in vivo. P1Cm-SPIO-Cy5.5 remains stable in vitro and has good anticoagulation capacity. It can bind specifically to activated platelets and thrombi. In rats that underwent bypass surgery, P1Cm-SPIO-Cy5.5 could detect and label thrombi over a long period, and prevent thrombosis in grafted vessels. P1Cm-SPIO-Cy5.5 improved cardiac function in rats following CABG surgery. P1Cm-SPIO-Cy5.5 is a potential sensor for use in MRI for the early diagnosis and prevention of thrombosis after CABG surgery.

Two-stage contralateral combined microvascular and wide-lumen anastomosis inTwo-stage contralateral combined microvascular and wide-lumen anastomosis in a patient with acute ischemic stroke patient with acute ischemic stroke

Common carotid artery (CCA) thrombosis is a rare cause of ischemic stroke. In available literature, we found no studies devoted to cerebral revascularization for CCA occlusion in acute period of ischemic stroke. Successful treatment of concomitant occlusion of CCA, internal (ICA) and external carotid arteries (ECA) with microvascular anastomoses is very interesting for various specialists. To demonstrate the possibility of contralateral cerebral revascularization in a patient with CCA, ECA and ICA occlusion in acute period of ischemic stroke. Two-stage intervention was performed in a patient with ischemic stroke and carotid artery occlusion. At the first stage, EICMA was formed between the right superficial temporal artery and the M4 branch of the middle cerebral artery (MCA), at the second stage - anastomosis between the right and left ECAs using an autologous arterial graft from the radial artery. There is no generally accepted surgical strategy for CCA occlusion. Contralateral revascularization with blood flow redirecting from the right carotid artery to the left one makes it possible to avoid thrombectomy from the affected CCA and ECA. We have undertaken this method for the first time. We have not found such an approach in the available literature. This report demonstrates the possibility of successful cerebral revascularization in acute period of ischemic stroke in patients with combined occlusion of CCA, ICA and ECA.

Antithrombotic effects and related mechanisms of Salvia deserta Schang root EtOAc extracts

Salvia deserta Schang (SDS) belongs to the same family as Salvia miltiorrhiza bunge, one of the antithrombotic Chinese herbal medicines. In our study, EtOAc root extracts were analyzed for their effects on adenosine diphosphate (ADP)-induced platelet aggregation in rabbits and FeCl3-induced rat common carotid artery thrombosis as well as on rat blood plasma concentrations of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1α), antithrombin-III (AT-III), protein C (PC), plasminogen (PLG), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue-type plasminogen activator (t-PA). EtOAc extracts from SDS roots had significant inhibitory effects on ADP-induced maximum platelet aggregation rate (10.2 ± 2.6 vs control 35.7 ± 5.2; P < 0.05), reduced the FeCl3-induced rat common carotid artery thrombus weight and thrombus area ratio (P < 0.05), significantly decreased plasma TXB2, vWF and PAI-1 levels and increased 6-keto-PGF1α and t-PA levels in a dose dependent manner (all P < 0.05). Thus, the ratio of TXB2/6-keto-PGF1α was significantly decreased (P < 0.05), while the ratio of t-PA/PAI-1 was significantly increased (P < 0.05). In addition, enhanced AT-III and PC activities indicated coagulation inactivation effects of EtOAc SDS root extracts. EtOAc extraction from SDS showed antithrombotic effects, which are likely due to platelet adhesion and aggregation inhibition as well as anticoagulant activities.

Propofol Prevents Thrombosis in a Rat Common Carotid Artery Thrombosis Model

Aim: The aim of this study was investigated the beneficial effect of propofol on thrombosis in a rat carotid artery thrombosis model. Methods and results: Sprague-Dawley rats underwent iron chloride3 (FeCl3)-induced carotid artery thrombosis model surgery were treated with vehicle (M group), low- (PL group), middle- (PM group) or high-dose propofol (PH group). Rats were received sham operation served as control (C group). As compared with the M group, propofol treatment significantly inhibited thrombus weights and improved the degree of embolization. Propofol also markedly improved blood CD62P intensity. Moreover, as compared with C group rats, the levels of plasma TXA2, PGI2, t-PA, t-PA/PAI-1 ratio, and P-selectin were harmful altered in M group rats in response to FeCl3 induction; these effects were improved in the PL and/or PM and PH groups. Conclusions: These findings suggested that the beneficial anti-thrombotic effect of propofol is likely attributable, at least in part, to attenuation of the endothelia injury, platelet activation and fibrinolytic inactivation induced by FeCl3 in a rat carotid artery thrombosis model.

Studies on New Activities of Enantiomers of 2-(2-Hydroxypropanamido) Benzoic Acid: Antiplatelet Aggregation and Antithrombosis.

R-/S-2-(2-Hydroxypropanamido) benzoic acid (R-/S-HPABA), a marine-derived anti-inflammatory drug, however, the antiplatelet and antithrombotic effects have not been investigated. In this paper, the in vitro antiplatelet activities and in vivo antithrombotic effects of R-/S-HPABA were investigated, for the first time. The effects of R-/S-HPABA on platelet aggregation induced by adenosine diphosphate (ADP), collagen (COLL) and arachidonic acid (AA) were evaluated. In addition, the in vivo bleeding time, clotting time, collagen-epinephrine induced pulmonary thrombosis and common carotid artery thrombosis were also investigated in rats. R-/S-HPABA significantly inhibited ADP, COLL and AA induced platelet aggregation in rabbit platelet rich plasma in vitro compared with control group, to a degree similar to that of aspirin. Besides, R-/S-HPABA prolonged bleeding time and clotting time as well as increased the recovery rate obviously in pulmonary thrombosis. Moreover, the level of thromboxane B2 (TXB2) was decreased while the production of 6-keto-prostaglandin F1α (6-keto-PGF1α) was increased markedly by R-/S-HPABA. Furthermore, R-/S-HPABA reduced carotid artery thrombosis weight. These results illustrated that R-/S-HPABA could be a potent antiplatelet aggregation and antithrombotic agent.

Common Carotid Artery Thrombosis With Recurrent Cerebral Emboli Treated With Ligation

Common Carotid Artery Thrombosis With Recurrent Cerebral Emboli Treated With Ligation

Ferric chloride-induced arterial thrombosis in mice.

Because of its high sensitivity and reproducibility, the FeCl3 -induced arterial thrombosis mouse model is widely used to study molecular mechanisms as well as the efficacy of antithrombotic agents. The model also carries the additional advantages of being relatively easy to establish and requiring minimal instrumentation. However, the various parameters that influence the outcome must be optimized to the experimental requirements and the individual laboratory conditions. Here, we describe a standard protocol for FeCl3 -induced common carotid artery thrombosis, parameters that influence thrombus growth, ways to optimize the experiment, and interpretation of the data.

Effect of domestic bivalirudin on platelet activation function in rat model of thrombus

Objectives To explore the effect of domestic bivalirudin on platelet activation function in rat model of carotid artery thrombosis.Methods A rat model of common carotid artery thrombosis was established.The rats were then randomized to control group (n =6),model group (n =10),domestic bivalirudin plus urokinase group (B&UK,n =10),and heparin plus urokinase group (H&UK,n =10).GMP-140 content and thrombus weight were detected before and after treatment.Results As compared with the model group,thrombus weight was obviously reduced in B&UK group and H&UK group.There was no significant difference in thrombus weight between B&UK group and H&UK group.GMP-140 content was remarkably greater in the model group,H&UK group,and B&UK gourp than in the control group.After treatment,GMP-140 content was significantly increased in H&UK gourp but obviously reduced in B&UK gourp.Conclusions Domestic bivalirudin can effectively inhibit formation of thrombosis in the rat model.As compared to heparin,domestic bivalirudin inhibits platelet activation function and platelet aggregation.During inhibition of thrombus formation,domcstic bivalirudin has more effects on platelet activation function. Key words: Bivalirudin; Heparin; Carotid arterial thrombosis; Rat; Platelet activation function

Antithrombotic activity of a 2-kDa heparin fragment in an experimental model of carotid artery thrombosis in rats.

The antithrombotic activity of a 2-kDa heparin fragment was studied in a rat model of common carotid artery thrombosis that causes a completely occlusive thrombus with cessation of the blood flow within 10-15 min. The compound reduced thrombus formation in a dose-dependent manner, starting from an intravenous dose of 5 mg kg-1. A dose of 20 mg kg-1 completely prevented thrombus formation and apparently induced the almost complete lysis of the already formed occlusive thrombus. At none of the doses used did the compound cause increased bleeding or the formation of haematomas. The present results indicate that low molecular weight heparins, which have an established, highly beneficial effect in venous thromboembolism, are also highly effective in an animal model of arterial thrombosis.

Characterization of a thromboembolic photochemical model of repeated stroke in mice

Many stroke research groups utilize the model of middle cerebral artery occlusion induced by insertion of an intraluminal thread, owing to its pragmatism and reliability of cerebral infarct generation. However, 75% of stroke cases result from a thromboembolic event and 10% from occlusive atherothrombosis in situ. Here, we characterize a mouse model of repeated thromboembolic stroke, which closely mimics the intravascular pathophysiology of arterial thrombus generation from an atherosclerotic plaque, and subsequent release of a thrombus into the cerebral circulation as an embolus. Common carotid artery thrombosis (CCAT) was induced photochemically leading to non-occlusive platelet aggregation in C57/BL6 male mice (n=35), and was followed by mechanical assistance to facilitate release of the thrombus (MRT) and thus promote embolism. Six experimental groups, differing by changes in the surgical protocol, were used for the purpose of determining which such procedure yielded the most reliable and consistent brain infarct volumes with the lowest mortality at 3 days after surgery. The group which best satisfied these conditions was a double insult group which consisted of animals that underwent CCAT for 2min by means of argon laser irradiation (514.5nm) at an intensity of ca. 130W/cm2, with concomitant injection of erythrosin B (EB) (35mg/kg infused over those same 2min), followed by MRT 1min later; the entire procedure was repeated 24h later. This group showed a percent of brain lesion volume of 15±4% (mean±S.D.) with no associated 3-day mortality. Compared to a single insult group which sustained a percent brain lesion volume of 7±3%, there was a statistically significant (p<0.05) increase in the volume of infarction in the double-insult group.

Endothelial nitric oxide synthase pathophysiology after nonocclusive common carotid artery thrombosis in rats.

Although vascular dysregulation has been documented in patients with extracranial vascular disease, transient ischemic attacks, and stroke, the pathomechanisms are poorly understood. To model thromboembolic stroke in rats, photochemically induced nonocclusive common carotid artery thrombosis (CCAT) was used to generate a platelet thrombus in the carotid artery of anesthetized rats. After CCAT, platelet aggregates break off the thrombus, travel to the distal cerebral vasculature, damage blood vessels, and cause small infarctions. The authors hypothesized that deficits in the endothelial nitric oxide synthase (eNOS) pathway may be responsible for vascular dysfunction after embolic stroke. To examine the functional status of the eNOS system, they measured eNOS-dependent dilation after CCAT by applying acetylcholine through a cranial window over the middle cerebral artery. The authors also measured eNOS mRNA and protein in the middle cerebral artery to determine whether functional changes were caused by alterations in expression. eNOS-dependent dilation was reduced at 6 hours, elevated at 24 hours, and returned to baseline 72 hours after CCAT. Endothelial nitric oxide synthase mRNA increased at 2 hours and was followed by a rise in protein 24 hours after CCAT. Changes in the eNOS system may account for some of the observed vascular deficits in patients with cerebrovascular disease.

Temporal profile of enhanced vulnerability of the postthrombotic brain to secondary embolic events.

Patients with vascular or cardiac disease may experience recurrent thrombosis and embolization to the cerebral vasculature. Transient distal platelet accumulation after common carotid artery thrombosis (CCAT) leads to hemodynamic, metabolic, and molecular events that may influence the response of the postthromboembolic brain to secondary emboli. We investigated the effect of repeated embolic episodes on histopathological outcome at various time intervals using a clinically relevant model of embolic stroke. Six groups of rats underwent either photochemically induced CCAT followed by sham surgery or 2 episodes of CCAT separated by 10 minutes or 1, 3, 5, or 7 days. Outcome measures included routine histopathological analysis and determination of the number of infarct loci and their total volume. Rats that underwent a second CCAT at 1, 3, or 5 days after the first insult had 20 to 30 times larger infarct volumes than rats in the single-CCAT group (P<0.05). In addition, rats in the 10-minute and 1-, 3-, and 5-day groups had 2 to 3 times as many infarcts as those in the single-CCAT group (P<0.05). Infarcts produced by double insults commonly extended through the neuraxis and were necrotic, edematous, and sometimes hemorrhagic. A prior thromboembolic event puts the brain at risk for severe infarction after a second embolic event. These findings cannot be explained solely by a greater number of infarcts. Elucidating pathomechanisms responsible for the vulnerability of the postthromboembolic brain may provide targets for new treatment strategies to prevent the severe consequences of embolic stroke.

Thromboembolic events lead to cortical spreading depression and expression of c-fos, brain-derived neurotrophic factor, glial fibrillary acidic protein, and heat shock protein 70 mRNA in rats.

The hypotheses that cerebral embolic events lead to repetitive episodes of cortical spreading depression (CSD) and that these propagating waves trigger the expression of c-fos, brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), and heat shock protein 70 (HSP70) mRNA were tested. Wistar rats underwent photochemically induced right common carotid artery thrombosis (CCAT) (n = 18) or sham (n = 8) procedures. In a subgroup of rats (n = 5), laser-Doppler flowmetry probes were placed overlying the right parietal cortex to record CSD-like changes in cortical blood flow during the initial 2-hour postinjury period. Rats were killed by decapitation at 2 or 24 hours after CCAT, and brains were processed for in situ localization of the gene expression. Two to five intermittent transient hyperemic episodes lasting 1 to 2 minutes were recorded ipsilaterally after CCAT. At 2 hours after CCAT, the widespread expression of c-fos and BDNF mRNAs was observed throughout the ipsilateral cerebral cortex. Pretreatment with the N-methyl-D-aspartate receptor blocker MK-801 (2 mg/kg) 1 hour before CCAT reduced the expression of BDNF mRNA expression at 2 hours. At 24 hours after CCAT, increased expression of GFAP mRNA was present in cortical and subcortical regions. In contrast, multifocal regions of HSP70 expression scattered throughout the thrombosed hemisphere were apparent at both 2 and 24 hours after injury. These data indicate that thromboembolic events lead to episodes of CSD and time-dependent alterations in gene expression. The ability of embolic processes to induce widespread molecular responses in neurons and glia may be important in the pathogenesis of transient ischemic attacks and may influence the susceptibility of the postembolic brain to subsequent insults including stroke.

Thromboembolic events predispose the brain to widespread cerebral infarction after delayed transient global ischemia in rats.

Transient distal platelet accumulation after common carotid artery thrombosis (CCAT) leads to hemodynamic, metabolic, and molecular events that may influence the response of the postthrombotic brain to secondary insults. We investigated how a thromboembolic insult would affect histopathological outcome when combined with an ischemic insult induced 24 hours later. Three groups of rats underwent either (1) CCAT+10 minutes of normothermic 2-vessel occlusion (n=6), (2) CCAT+sham ischemia procedures (n=6), or (3) sham CCAT procedures+10 minutes of 2-vessel occlusion (n=6). At 7 days, rats were perfused for quantitative histopathological and immunocytochemical analysis. Rats undergoing combined insults (group 1) had significantly larger areas of ischemic injury (P<0.05) within the cerebral cortex, striatum, and thalamus compared with the other, single-injury groups. Increased ischemic damage included selective neuronal necrosis, infarction, and focal hemorrhage. By means of glial fibrillary acidic protein immunocytochemistry and lectin histochemistry, reactive astrocytes and microglia were found to be associated with widespread tissue necrosis. In contrast, infrequent infarction or CA1 hippocampal neuronal necrosis was observed in groups 2 and 3, respectively. A prior thromboembolic event is a risk factor for widespread cerebral infarction and hemorrhage when combined with a delayed ischemic insult. The understanding of what factors enhance the susceptibility of the postthrombotic brain to secondary insults may aid in the development of neuroprotective strategies to be applied after transient ischemic attacks to prevent the initiation of stroke.

White matter alterations following thromboembolic stroke: a beta-amyloid precursor protein immunocytochemical study in rats.

Thromboembolic stroke in rats leads to a well-described pattern of histopathological and behavioral abnormalities. However, limited data are available in animal models concerning the response of the white matter to embolic events. The purpose of this study was to document patterns of white matter abnormalities using beta-amyloid precursor protein (betaAPP) immunocytochemistry as a marker of axonal damage. Twelve male Wistar rats underwent photochemically induced right common carotid artery thrombosis (CCAT) or sham procedures. At 3 days after CCAT, rats were perfusion-fixed and sections immunostained for the visualization of betaAPP or stained with hematoxylin and eosin for routine histopathological analysis. As previously described, CCAT produced small ipsilateral embolic infarcts and ischemic cell change within gray matter structures including the medial cerebral cortex, striatum, hippocampus and thalamus. In areas of frank infarction, numerous reactive profiles were observed within borderzones of the damaged site. However, betaAPP immunocytochemistry also revealed reactive axonal profiles within various white matter tracts including the corpus callosum, external capsule and fimbria of the hippocampus. In many cases, the presence of axonal damage could not be appreciated with routine hematoxylin and eosin staining. These data indicate that CCAT leading to platelet embolization to the brain not only produces embolic infarcts but also produces more subtle white matter abnormalities. Previously undetected white matter damage would be expected to participate in the sensorimotor and cognitive behavioral deficits following embolic stroke.

The effect of nitric oxide synthase inhibition on acute platelet accumulation and hemodynamic depression in a rat model of thromboembolic stroke.

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 (111)In-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.

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.