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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxynitrite is assumed to play a crucial role in brain damage associated with the overproduction of nitric oxide (NO). The purpose of this study is to examine time-dependent changes of nitrite and nitrate (NOx) concentration in the circulation, and peroxynitrite formation as well as the expression of inducible nitric oxide synthase (iNOS) in the penumbra of rat brains during transient middle cerebral artery occlusion (MCAO) of Wistar rat for 2 h and reperfusion for 4-70 h. NOx concentration in the circulation was continuously monitored at the right jugular vein by microdialysis. The expression of iNOS was detected at 22-70 h after reperfusion in vascular walls and the cortex. Nitrotyrosine, a marker of peroxynitrite, appeared 4 h after reperfusion in the cortex, increasing substantially at 22-46 h in vascular walls. NOx level in dialysate increased immediately after MCAO. After a gradual decrease, the level increased again 4 h after reperfusion, reaching a maximum at 46 h. Brain myeloperoxidase activity, a marker of neutrophil infiltration, was not detected 4 h after reperfusion, but greatly increased at 22 h and then decreased. These results suggest that a marked increase of NOx level in the circulation might reflect the expression of iNOS, while neuronal NOS may contribute to peroxynitrite formation in the cortex observed at an earlier phase of reperfusion. This study indicates that monitoring NOx level in the circulation serves to assess the progress of stroke, and to determine appropriate therapeutic measures.
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PMID:Concurrent formation of peroxynitrite with the expression of inducible nitric oxide synthase in the brain during middle cerebral artery occlusion and reperfusion in rats. 1223 64

Naftidrofuryl is a selective inhibitor of the 5-HT2 receptor expressed on human endothelial cells. This drug has been used over the years to cope with cerebral or peripheral ischemic accidents; however, no clear mechanism of action of this molecule has been highlighted to explain its vascular effects. In the present work, we demonstrate that the involvement of nitric oxide can account for the effects of naftidrofuryl. Indeed, naftidrofuryl potently inhibited the TNF-alpha-triggered increase of intercellular adhesion molecule-1 (ICAM-1) expression as well as stress fiber formation in human umbilical vein endothelial cells (HUVEC). Moreover, naftidrofuryl induced the expression of type II nitric oxide synthase (NOS II) messenger and protein, leading to a noticeable increase in nitric oxide synthesis. Furthermore, using the specific NOS II inhibitor 1400W, we verified that the observed effects of naftidrofuryl were NOS II-dependent. The biology of nitric oxide accounts for the reduction of the vasospasm associated with stroke and the strong inhibition of platelet aggregation. In conclusion, our work provides evidence for the inhibition of leukocyte recruitment by downregulation of CD54/ICAM-1, an additional key factor to be dealt with during thrombotic accidents. Importantly, it also highlights a novel NOS II-dependent mechanism of action for naftidrofuryl.
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PMID:Naftidrofuryl-driven regulation of endothelial ICAM-1 involves nitric oxide. 1261 50

In cerebral ischemia, the disappointment related to anti-glutamate strategies in clinical trials has led to examine new targets for the treatment of stroke. In vitro studies demonstrated that overactivation of glutamate receptors leads to nitric oxide (NO) production that contributes to the excitotoxic neuronal death. The role of NO was then studied in in vivo models of cerebral ischemia. In the early phase after ischemia, NO is produced by the constitutive endothelial and neuronal isoforms of NO-synthase (NOS 3 and NOS 1) while in the later phase, the inducible NOS (NOS 2) is responsible for the delayed production of NO. NOS 3 appears beneficial via vasodilatation and inhibition of leukocyte adhesion and platelet aggregation. By contrast NOS 1 and NOS 2 were demonstrated deleterious in cerebral ischemia. This was shown by three distinct strategies: selective inhibitors, mutant mice deficient in NOS 1 or NOS 2, and antisenses directed to one of these isoforms. Moreover it is now thought that NO-induced neuronal death is mainly mediated through the formation of peroxynitrite anions resulting from the reaction between NO and superoxyde anion. Peroxynitrites indeed damage lipids, proteins and nucleic acids. DNA strand breaks in turn activate poly(ADP-ribose) polymerase (PARP). Overactivation of this enzyme in pathological conditions such as cerebral ischemia seems deleterious by depleting ATP stores. Thus inhibition of the NO-peroxynitrites-PARP pathway may lead to neuroprotective therapeutics in stroke.
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PMID:[NO synthases: new pharmacological targets in cerebrovascular accident?]. 1266 62

Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD.
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PMID:Effects of the nitric oxide donor, DEA/NO on cortical spreading depression. 1272 26

Ephedrine is a mixed adrenergic agonist, stimulating both alpha- and beta-adrenergic receptors. The effects of ephedrine use include increases in heart rate, cardiac output, peripheral resistance, and blood pressure, and its use is associated with serious cardiovascular events such as stroke, arrhythmias, and myocardial infarction. The vascular endothelium plays a fundamental role in the regulation of vascular tone by releasing vasoactive factors such as nitric oxide (NO). The loss of NO bioactivity, often referred to as endothelial dysfunction, is characterized by the loss of endothelium-dependent vasodilation and is thought to be a common pathway for cardiovascular events such as vasospasm, hypertension, and myocardial infarction. Since endothelial dysfunction is characterized by loss of NO activity, and since ephedrine and endothelial dysfunction may be associated with similar cardiovascular events, the current study was undertaken to determine the effect of inhibition of NO production on responses to ephedrine in the rat. A sodium nitroprusside (SNP) infusion procedure was used to restore baseline vascular parameters to pre-L-NAME levels, allowing for direct comparison of agonist responses before and after NOS inhibition. The results demonstrate that the vascular response to ephedrine in the rat is modulated by NO and that NO production in response to ephedrine may be secondary to beta 2-receptor stimulation.
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PMID:Effect of inhibition of nitric oxide synthase on the vasopressor response to ephedrine. 1460 14

The pulmonary hypertensive response to bacterial lipopolysaccharide (LPS, endotoxin) varies widely among individual broilers, leading to the suggestion that innate variability may exist in the proportions or profiles of chemical mediators released during the ensuing inflammatory cascade. LPS induces the expression of nitric oxide synthase (iNOS), which produces the vasodilator nitric oxide (NO) to modulate the responses to concurrently produced vasoconstrictors. In experiment 1, broilers were given the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), followed by a supra-maximal dose of LPS while the pulmonary arterial pressure was recorded. In experiment 2 the cardiac output also was recorded before and following the i.v. injection of L-NAME. In both experiments, injection with L-NAME modestly increased the pulmonary arterial pressure when compared with control values, confirming previous reports that tonic/basal NO synthesis is required to promote flow-dependent pulmonary vasodilation in chickens. This response to L-NAME occurred in spite of a tendency for cardiac output and stroke volume to decline and, therefore, can be attributed to pulmonary vasoconstriction (an increase in the pulmonary vascular resistance) rather than an increase in pulmonary blood flow. When L-NAME was used to block NO synthesis induced by LPS, an early peak of pulmonary hypertension was revealed that rarely develops in broilers in the absence of L-NAME, and that has been correlated with the release of platelet activating factor and thromboxane A2 in mammals. The control group responded to LPS with a delayed-onset pulmonary hypertension that was typical in timing, amplitude, and duration of the responses previously observed in broilers and that has been attributed to endothelin-mediated thromboxane A2 synthesis in mammals. This delayed-onset pulmonary hypertensive response to LPS was longer in duration and higher in amplitude in the L-NAME group when compared with the control group. These observations are consistent with the hypothesis that NO modulates the responses to vasoconstrictors released concurrently during the LPS-mediated inflammatory cascade. Inhibition of NOS by L-NAME apparently reduced the modulatory influence of NO and exposed a more dramatic pulmonary hypertensive response to LPS.
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PMID:N(omega)-nitro-L-arginine methyl ester (L-NAME) amplifies the pulmonary hypertensive response to endotoxin in broilers. 1504 3

The use of estrogen for protection against vascular dysfunction is limited due to its effects on the reproductive system, particularly in males. We postulated that daidzein, an isoflavone with estrogen-like effects on the systemic vasculature but not the reproductive system, might enhance nitric oxide (NO)-mediated cerebral vasodilatation. Male rats were administered vehicle, 17beta-estradiol (0.1 mg/kg s.c.), or daidzein (0.2 mg/kg s.c.) daily for 7 days. Basal and acetylcholine-stimulated NO release was assessed in vitro via carotid arterial rings or in vivo by measuring changes in basilar artery diameter. Levels of protein expression of endothelial NO synthase (eNOS), caveolin-1, and calmodulin were assessed in carotid arteries using Western analysis. Plasma NO levels were doubled by daidzein or 17beta-estradiol. NO production and endothelium-dependent contraction in response to the NOS inhibitor NG-nitro-L-arginine (L-NNA; 100 microM) was enhanced by 50 to 100% in carotid arteries from rats treated with daidzein or 17beta-estradiol. Acetylcholine-induced relaxation was selectively enhanced in carotid arteries from rats treated with daidzein. Similarly, constrictor responses of the basilar artery to L-NNA in vivo were selectively augmented by approximately 100% by 17beta-estradiol treatment and tended to be approximately 50% greater in daidzein-treated rats. Expression of caveolin-1 was decreased, and calmodulin was increased, in vessels from daidzein- or 17beta-estradiol-treated rats. eNOS expression was unaffected by the treatments. These data suggest that short-term administration of daidzein or 17beta-estradiol modulates cerebral artery reactivity in males by enhancing synthesis and release of endothelium-derived NO. Isoflavone therapy may therefore be a feasible approach to protect against cerebrovascular disease and stroke.
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PMID:Effect of short-term phytoestrogen treatment in male rats on nitric oxide-mediated responses of carotid and cerebral arteries: comparison with 17beta-estradiol. 1505 17

Experimental and clinical data suggest that iron has a key role in cerebral ischaemia. We measure infarct volume and analyse the nitric oxide responses to brain injury in rat stroke model after increased oral iron intake. Permanent middle cerebral artery occlusion (MCAO) was performed in a group of 20 male Wistar rats, 10 of which were fed with a control diet and 10 of which were fed with iron-enriched diet containing 2.5% carbonyl iron for 9 weeks. L-arginine and nitric oxide metabolites were determined in blood samples before and at 2, 6, 8 and 48 h after MCAO. Infarct volume, thiobarbituric acid reaction substances (TBARS) and tissue iron were measured at 48 h. Infarct volume was 66% greater in the iron-fed rats than in the control group. Iron-fed animals showed significantly higher levels of TBARS. Liver iron stores (3500 +/- 199 vs 352 +/- 28 microg Fe/g, p<0.0001) but not brain iron stores (131 +/- 11 vs 139 +/- 8 microg Fe/g, p=0.617), were significantly higher in the iron-fed group. L-arginine levels were slightly lower in iron-fed rats and decreased significantly in both groups at 6 and 8 hours after MCAO. The levels of the stable end products of NOS (NOx = nitrite + nitrate) were significantly higher in iron-fed rats before MCAO (16.2 +/- 2.2 vs. 9.6 +/- 0.8 micromol x L(-1), p<0.05), with a further increase during the six first hours after MCAO in both groups. These results suggest that the iron overload that increases both superoxide and nitric oxide production leads to peroxynitrite formation, thus enhancing brain damage.
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PMID:Does nitric oxide contribute to iron-dependent brain injury after experimental cerebral ischaemia? 1516 43

Stroke is the third leading cause of death as dementia is a main symptom of Alzheimer's disease. One of the important mechanisms in the pathogeny of stroke is free radical production during the reperfusion period, therefore the effects of a type of natural antioxidant, i.e. Crataegus flavonoids (CF), on brain ischemic insults were investigated in Mongolian gerbil stroke model. Results showed that pretreatment of the animals with CF decreased reactive oxygen species (ROS) production, thiobarbituric acid reactive substances content, and nitrite/nitrate concentration in brain homogenate, increased the brain homogenate-associated antioxidant level in a dose-dependent manner. CF pretreatment increased the amount of biologically available NO by scavenging of superoxide anion produced during reperfusion. At same time, in the process of ischemia/reperfusion brain damage, the content of nitrite/nitrate (the end product of NO) increased, and of NO detected by ESR decreased. Oral pretreatment with CF decreased the nitrite/nitrate content in the brain homogenate and increased the biologically available NO concentration in a dose-dependent manner. The increasing effect of antioxidant on NO might be due to its scavenging effect on superoxide anion, which could react with NO into peroxynitrite. iNOS was implied in delayed neuron death after brain ischemic damage and it was found that pretreatment with CF could decrease the protein level of tumor necrosis factor (TNF)-alpha and nuclear factor-kappa B (NF-kappaB), and increase the mRNA level of NOS estimated by western blotting and RT-PCR. More neurons survived and fewer cells suffered apoptosis in the hippocampal CA1 region of CF treated animal brain. These results suggest that oral administration of this antioxidant increases the antioxidant level in the brain and protects the brain against delayed cell death caused by ischemia/reperfusion injury.
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PMID:Oral administration of Crataegus flavonoids protects against ischemia/reperfusion brain damage in gerbils. 1519 80

Inhibitors of the family of nitric oxide synthases (NOS-I-III; EC 1.14.13.39) are of interest as pharmacological agents to modulate pathologically high nitric oxide (NO) levels in inflammation, sepsis, and stroke. In this article, we discuss the approach for targeting the unique (6R)-5,6,7,8-tetrahydro-L-biopterin (H4Bip) binding site of NOS by appropriate inhibitors. This binding site maximally increases enzyme activity and NO production from the substrate L-arginine upon cofactor binding. The first generation of H4Bip-based NOS inhibitors was based on 4-amino H4Bip derivatives in analogy to anti-folates such as methotrexate. In addition, we discuss the structure-activity relationship of a related series of 4-oxo-pteridine derivatives. Furthermore, molecular modeling studies provide an understanding of pterin antagonism on a structural level based on favorable and unfavorable interactions between protein binding site and ligands. These techniques include 3D-QSAR (CoMFA, CoMSIA) to understand ligand affinity and GRID/consensus principal component analysis (CPCA) to learn about selectivity requirements. Collectively these approaches, in combination with the presented SAR and structural data, provide useful information for the design of novel NOS inhibitors with increased isoform selectivity.
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PMID:Biology and chemistry of the inhibition of nitric oxide synthases by pteridine-derivatives as therapeutic agents. 1522 85


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