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

Vascular contractile hyporesponsiveness is an important mechanism underlying orthostatic intolerance after microgravity. Baroreceptor reflexes can modulate both pulmonary resistance and capacitance function and thus cardiac output. We hypothesized, therefore, that pulmonary vasoreactivity is impaired in the hindlimb-unweighted (HLU) rat model of microgravity. Pulmonary artery (PA) contractile responses to phenylephrine (PE) and U-46619 (U4) were significantly decreased in the PAs from HLU vs. control (C) animals. N(G)-nitro-L-arginine methyl ester (10(-5) M) enhanced the contractile responses in the PA rings from both C and HLU animals and completely abolished the differential responses to PE and U4 in HLU vs. C animals. Vasorelaxant responses to ACh were significantly enhanced in PA rings from HLU rats compared with C. Moreover, vasorelaxant responses to sodium nitroprusside were also significantly enhanced. Endothelial nitric oxide synthase (eNOS) and soluble guanlyl cyclase expression were significantly enhanced in PA and lung tissue from HLU rats. In marked contrast, the expression of inducible nitric oxide synthase was unchanged in lung tissue. These data support the hypothesis that vascular contractile responsiveness is attenuated in PAs from HLU rats and that this hyporesponsiveness is due at least in part to increased nitric oxide synthase activity resulting from enhanced eNOS expression. These findings may have important implications for blood volume distribution and attenuated stroke volume responses to orthostatic stress after microgravity exposure.
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PMID:Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide. 1174 40

Nitric oxide (NO), a molecular messenger synthesized by nitric oxide synthase (NOS) from L-arginine and molecular oxygen, is involved in a number of physiological and pathological processes in mammalians. Three structurally distinct isoforms of NOS have been identified: neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). Although NO mediates several physiological functions, overproduction of NO by nNOS has been reported in a number of clinical disorders including acute (stroke) and chronic (schizophrenia, Alzheimer s, Parkinson s and AIDS dementia) neurodegenerative diseases, convulsions and pain; overproduction of NO by iNOS has been implicated in various pathological processes including septic shock, tissue damage following inflammation and rheumatoid arthritis. On the contrary, NO produced by eNOS has only physiological roles such as maintaining physiological vascular tone. Accordingly, selective inhibition of nNOS or iNOS vs eNOS may provide a novel therapeutic approach to various diseases; in addition selective inhibitors may represent useful tools for investigating other biological functions of NO. For these reasons, after the identification of N-methyl-L-arginine (L-NMA) as the first inhibitor of NO biosynthesis, design of selective NOS inhibitors has received much attention. In this article the recent developments of new molecules endowed with inhibitory properties against the various isoforms of NOS are reviewed. Major focus is placed on structure-activity-selectivity relationships especially concerning compounds belonging to the non-amino acid-based inhibitors.
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PMID:Progress in the development of selective nitric oxide synthase (NOS) inhibitors. 1181 67

Mild hypothermia is neuroprotective, but the reasons are not well known. Inflammation contributes to ischemic damage; therefore, we examined whether the protection by hypothermia may be attributable to alterations in the inflammation. We examined whether hypothermia might alter the inflammatory cell-associated inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) and peroxynitrite generation in experimental stroke and inflammation. Rats underwent 2 hr of middle cerebral artery occlusion (MCAO). Brain inflammation was modeled by intravenous lipopolysaccharide (LPS) (2 mg/kg) injection. Temperature was maintained at 33 degrees C for 2 hr immediately after MCAO and LPS injection, delayed 2 hr after MCAO or maintained at 38 degrees C. Cultured microglia were activated with LPS and then incubated at 33 or 37 degrees C. Both intraischemic and delayed mild hypothermia attenuated infarct size by 40% (p < 0.05). Immunohistochemistry was performed to identify cell type, iNOS, and peroxynitrite. The majority of iNOS- and peroxynitrite-positive cells were activated microglia-macrophages, and mild hypothermia significantly decreased the numbers of immunoreactive cells at 72 hr by >50% (p < 0.05). After ischemia, mild hypothermia decreased NO production by 40%. Similarly, hypothermia attenuated NO and iNOS in LPS-injected rats, as well as in cultured microglia. Aminoguanidine, an iNOS inhibitor, also attenuated infarct size and NO in ischemic and inflammation models. We conclude that mild hypothermia significantly inhibits the inflammatory response by affecting microglial iNOS-NO generation. Therapies directed against microglia or their activation may be useful in treating stroke.
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PMID:Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. 1201 11

Trypanosoma cruzi (T. cruzi) is a tissue parasite causing American trypanosomiasis or Chagas' disease (ChD) affecting, mostly, the cardiovascular and gastrointestinal systems. We have recently found that people infected by T. cruzi are also more prone to developing ischemic strokes than the general population, even without heart complications; the pathomechanism of it is not yet well understood. However, after infection occurs, immune response induces endothelial dysfunction due to an endothelial nitric oxide synthase (eNOS) inhibition and increased activity of inducible nitric oxide synthase (iNOS). These factors are active in inducing vasoconstriction and cerebral microvascular spasms, leading to ischemic stroke. In addition, patients with ChD, regardless of cardiopathy, also have autonomic dysfunction, all of which may enhance the risk of developing ischemic stroke. Moreover, the possibility that these neuroimmunomodulatory pathways are disturbed in patients with other types of stroke seems possible, and is worthy of investigation.
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PMID:Immune response, nitric oxide, autonomic dysfunction and stroke: a puzzling linkage on Trypanosoma cruzi infection. 1205 71

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

The mechanism linking the APOE4 gene with increased susceptibility for Alzheimer's disease (AD) and poorer outcomes following closed head injury and stroke is unknown. One potential link is activation of the innate immune system in the CNS. Our previously published data demonstrated that apolipoprotein E regulates production of nitric oxide, a critical cytoactive factor released by immune active macrophages. To determine if immune regulation is different in the presence of apolipoprotein E4 compared to apolipoprotein E3, we have measured NO production by peritoneal and CNS macrophages (microglia) cultured from transgenic mice that only express the human apoE4 or apoE3 protein isoform. Significantly more NO was produced in APOE4 mice compared to APOE3 transgenic mice that only express human apoE3 protein. Similarly, monocyte derived macrophages from humans carrying APOE4 gene alleles also produce significantly greater NO than those individuals with APOE3. The mechanism for this isoform-specific difference in NO production is not known and multiple sites in the NO production pathway may be affected. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein are not significantly different between the APOE3 and APOE4 mice, suggesting that induction of iNOS is not a primary cause of the increased NO production in APOE4 animals. One alternative regulatory mechanism that demonstrates isoform specificity is arginine transport, which is greater in microglia from APOE4 transgenic mice compared to microglia from APOE3 mice. Increased transport is consistent with an increased production of NO and may reflect a direct or indirect effect of the APOE genotype on microglial arginine uptake and microglial activation in general. Overall, greater NO production in APOE4 carriers where characteristically high levels of oxidative/nitrosative stress are found in diseases such as AD provides a mechanism that potentially explains the genetic association between APOE4 and human diseases.
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PMID:APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress. 1239 81

Lesions in the nervous system induce rapid activation of glial cells and under certain conditions additional recruitment of granulocytes, T-cells and monocytes/macrophages from the blood stream triggered by upregulation of cell adhesion molecules, chemokines and cytokines. Hematogenous cell infiltration is not restricted to infectious or autoimmune disorders of the nervous system, but also occurs in response to cerebral ischemia and traumatic lesions. Neuroinflammation can cause neuronal damage, but also confers neuroprotection. Granulocytes occlude vessels during reperfusion after transient focal ischemia, while the functional role of T-cells and macrophages in stroke development awaits further clarification. After focal cerebral ischemia neurotoxic mediators released by microglia such as the inducible nitric oxide synthase (leading to NO synthesis) and the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are upregulated prior to cellular inflammation in the evolving lesion and functionally contribute to secondary infarct growth as revealed by numerous pharmacological experiments and by use of transgenic animals. On the other hand, cytokine induction remote from ischemic lesions involves NMDA-mediated signalling pathways and confers neuroprotection. After nerve injury T cells can rescue CNS neurons. In the peripheral nervous system neuroinflammation is a prerequisite for successful regeneration that is impeded in the CNS. In conclusion, there is increasing evidence that neuroinflammation represents a double edged sword. The opposing neurotoxic and neuroprotective properties of neuroinflammation during CNS injury provide arich and currently unexplored set of research problems.
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PMID:Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. 1257 18

Administration of tumour necrosis factor-alpha (TNF-alpha) produces progressive reduction in cardiac output (CO) by affecting preload, afterload and cardiac contractility. We have examined the effect of an endothelin receptor antagonist, tezosentan (1, 3 or 10 mg/kg), on CO, heart rate (HR), blood pressure (BP), mean circulatory filling pressure (P(mcf)), resistance to venous return (RVR), arterial resistance (AR), dP/dt, stroke volume (SV), plasma levels of NO(2)(-)/NO(3)(-), and inducible nitric oxide synthase (iNOS) activity in lungs, ex vivo, following treatment with TNF-alpha (30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha alone resulted in significant reduction in CO (40+/-4%), dP/dt (24+/-2%), P(mcf) (24+/-2%), BP (21+/-3%) and SV (38+/-5%) ( n=6; mean +/- SEM), and significant increases in RVR (38+/-9%) and AR (45+/-6%). There were no significant changes in HR or in plasma levels of NO(2)(-)/NO(3)(-) in animals treated with TNF-alpha but there was a modest but significant increase in iNOS activity. Tezosentan alone did not have any effect on haemodynamics, plasma levels of NO(2)(-)/NO(3)(-) or iNOS activity. Tezosentan at the highest dose abolished the effects of TNF-alpha on dP/dt, AR, and RVR. In animals treated with a combination of TNF-alpha and highest dose of tezosentan CO, P(mcf), BP, and SV were reduced by 28+/-5%, 16+/-3%, 21+/-4%, and 27+/-5%, respectively. Tezosentan was able to inhibit the negative impact of TNF-alpha on AR and dP/dt but not on P(mcf). It is likely that the negative impact of TNF-alpha on CO in tezosentan-treated animals could be entirely attributed to reduction in preload.
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PMID:Haemodynamic effects of endothelin receptor antagonist, tezosentan, in tumour necrosis factor-alpha treated anaesthetized rats. 1259 57

Delayed administration of the nitric oxide precursor L-arginine increases brain injury in models of focal cerebral ischemia. We tested the hypothesis that L-arginine worsens the damage by acting as a substrate for inducible nitric oxide synthase (iNOS) and increasing the output of this enzyme. iNOS-null mice or wild-type littermates were treated with L-arginine (300 mg/kg; i.p, three times/day) starting 12 h after occlusion of the middle cerebral artery. Infarct volume was determined 96 h after ischemia. We found that L-arginine enlarges infarct volume in wild-type mice (+28+/-5% in neocortex) but not in iNOS-null mice. Thus, the worsening of ischemic damage produced by L-arginine depends on iNOS. The findings support the hypothesis that L-arginine worsens ischemic injury by increasing the catalytic output of iNOS and suggest that administration of L-arginine should be avoided in patients with acute stroke.
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PMID:L-Arginine increases ischemic injury in wild-type mice but not in iNOS-deficient mice. 1261 54

Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.
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PMID:Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. 1262 12


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