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

To obtain information about the role of nitric oxide (NO) in the development of hypertensive cerebral lesions, we used immunohistochemical methods to study the distribution and level of nitric oxide synthase (NOS) in the brain of stroke-prone spontaneously hypertensive rats (SHRSPs). The early changes in the brain of SHRSPs were petechiae, edema and massive glial accumulation around fibrin deposits, which contained necrotized microvessels, whereas advanced cerebral lesions comprised massive bleeding, cavity formation and diffuse degeneration of the white matter. In the normotensive control rats, immunoreactivity for NOS was demonstrated in scattered neuronal cells, as has been reported previously, but there was no reactivity in glial cells. In the present study in SHRSPs, however, considerable NOS immunoreactivity was observed in most reactive astrocytes and in a proportion of the microglial cells and macrophages in the vicinity of the cortical lesions and in the subcortical white matter both ipsi- and contralateral to the cortical lesion. The nerve cells in the edematous region also showed weak immunoreactivity for NOS. The distribution of increased NOS in SHRSP brains corresponded well with the sites of extravasated plasma fluid as demonstrated by anti-fibrinogen antibody. Based on these findings, we postulate that edema and the simultaneously generated free radicals or some extravasated plasma components may induce expression of NOS in the reactive cells and nerve cells, and that the NO thus generated may be involved in the development of hypertensive cerebral lesions.
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PMID:Altered nitric oxide synthase immunoreactivity in the brain of stroke-prone spontaneously hypertensive rats. 884 57

Differences in alpha(2)-adrenoceptor-induced relaxation of the aorta between stroke-prone spontaneously hypertensive rats (SHRSP) and control normotensive Wistar Kyoto rats (WKY) were studied. Changes in the tension of ring preparations of the aortas were measured isometrically. Relaxation was observed in the preparations precontracted in the presence of ONO-11113, a thromboxane A(2) analogue. The alpha(2)-agonist clonidine and UK-14304 induced dose-dependent relaxation in both the WKY and SHRSP preparations. The relaxation was impaired in the SHRSP preparation. A modified sandwich experiment showed that the relaxing substance from the SHRSP endothelium was decreased. Acetylcholine (ACh) also induced dose-dependent relaxation, and the relaxation was impaired in the SHRSP preparations. alpha(2)-Agonists induced a greater degree of impairment in the relaxation than did ACh. The relaxation induced by alpha(2)-agonists and by ACh was blocked by N G-nitro-L-arginine (L-NNA). Indomethacin improved the relaxation induced by ACh but not that induced by alpha(2)-agonists in the SHRSP aortas. These results suggest that the impairment of relaxation by alpha(2)-agonists in SHRSP is not caused by the increase in the release of endothelium-derived contracting factor (EDCF) but by the reduction in the release of nitric oxide (NO). Alteration of the alpha(2)-adrenoceptors and/or the intracellular mechanism through which NO is synthesized by stimulation of the alpha(2)-adrenoceptors may be the cause of the reduction in relaxation.
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PMID:Endothelium-dependent relaxation by alpha 2-adrenoceptor agonists in spontaneously hypertensive rat aorta. 885 45

1. Delayed neuronal cell death elicited by excess excitatory amino acid concentrations has been strongly implicated in many neurological disorders including head trauma, stroke, motor neurone disease and Huntington's disease. We have used the neurotoxin, L-2-chloropropionic acid (L-CPA) to model cellular events in vivo leading to delayed neuronal cell loss which is confined to the cerebellar cortex and can be prevented by inhibitors of nitric oxide synthase such as NG-nitro-L-arginine methyl ester. 2. Experiments were performed to determine whether the constitutive nitric oxide synthase (NOS) or inducible form of NOS (iNOS) was responsible for the neuronal cell death. Activation of NOS was confirmed by a 39% increase in cerebellar total nitrate and nitrite concentrations in L-CPA-treated brains, as compared to controls (controls = 2.53 +/- 0.10; L-CPA treated = 3.51 +/- 0.31 nmol mg-1 protein, P < 0.01 Student's t tests, n = 6, mean +/- s.e.mean). Biochemical measurements of total NOS activity were made in homogenates of cerebellum 6 h and 48 h following L-CPA administration, times at which L-CPA concentrations are maximal in brain and a time when there is a high proportion of cerebellar granule cell death, respectively. NOS activity as measured by the amount of [3H]-arginine converted to [3H]-citrulline, did not reveal any difference between controls (rats dosed with water) and animals dosed with L-CPA at either 6 or 48 h following dosing. Furthermore the ability of three NOS inhibitors, NG-nitro-L-arginine, 7-bromo-3-nitroindazole and S-methylisothiourea to block the conversion of [3H]-citrulline to [3H]-arginine was identical at 6 and 48 h time points in control and L-CPA treated rats. 3. Quantitative autoradiography using [3H]-NG-nitro-L-arginine was used to measure the relative anatomical distribution and amount of NOS enzyme in the cerebellum of controls and L-CPA-treated rats 48 h following dosing. There was no significant alteration in the binding of [3H]-NG-nitro-L-arginine to granular and molecular layers of the cerebellum of control and L-CPA-treated rat brains. 4. Western blotting using antibodies against the inducible NOS enzyme failed to detect the protein in cerebellums of L-CPA-treated rats when measured 48 h after L-CPA dosing. 5. In conclusion, the increase in cerebellar nitrate/nitrite concentrations in L-CPA-treated rats provides further evidence for activation of NOS in the cerebellum following administration of L-CPA. The failure to demonstrate an increase in NOS activity at 6 or 48 h in L-CPA-treated rats as compared to controls suggests that the source of nitric oxide responsible for the granule cell death must originate from the constitutive NOS enzyme, probably the neuronal form which is highly enriched in the cerebellum. This hypothesis was further substantiated by Western blotting and quantitative autoradiography.
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PMID:Evidence for mediation of L-2-chloropropionic acid-induced delayed neuronal cell death by activation of a constitutive nitric oxide synthase. 888 23

Cortical spreading depression (CSD) has been implicated in the migraine aura and in stroke. This study demonstrates near-infrared spectroscopy (NIRS) for the first time as capable of noninvasive on-line detection of CSD in the pentobarbital-anesthetized rat. CSD was accompanied by a brief and rapid increase of regional CBF (by laser-Doppler flowmetry) to 200-400% baseline. NIRS demonstrates that this hyperperfusion is associated with concentration increases of oxyhemoglobin, while deoxyhemoglobin decreases. Simultaneously, oxygen partial pressure, measured on the brain surface with a solid-state polarographic probe, was shown to be raised by at least 14 mm Hg during CSD. Oxygen-dependent phosphorescence life-time quenching measurements confirmed this finding. NIRS data on cytochrome aa3, however, showed a CSD-related shift toward a more reduced state, despite raised blood oxygenation. This may suggest either limited O2 transport from the blood to mitochondria or decreased oxygen utilization during CSD as supposed by theories about compartmentalization of energy metabolism favoring glycolytic rather than aerobic energy supply during CSD. However, the data on cytochrome aa3 warrant caution and are discussed critically. Nitric oxide synthase inhibition by systemic application of N'-nitro-L-arginine had no significant effect on the perfusion response or the tissue PO2 during CSD. During most CSD episodes, a brief decrease in MABP by 4-8 mm Hg was noted that might be caused by functional decortication during CSD.
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PMID:Systemic nitric oxide synthase inhibition does not affect brain oxygenation during cortical spreading depression in rats: a noninvasive near-infrared spectroscopy and laser-Doppler flowmetry study. 889 81

Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide. Although its reactivity and decomposition are very much dependent on the constituents of the cellular environment, peroxynitrite is considered a potent oxidant that reacts with proteins, lipids, and DNA. Inasmuch as peroxynitrite is formed in many pathophysiological conditions that are associated with NO and/or superoxide overproduction, the investigation of the cytotoxic pathways triggered by peroxynitrite is of major importance. Here we review the evidence that peroxynitrite is a potent initiator of DNA strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly ADP ribosyl synthetase (PARS). We present an overview of experimental data that demonstrate or suggest that the peroxynitrite-PARS pathway, by leading to cell necrosis or apoptosis, contributes to cellular injury in a number of pathophysiological conditions including shock and inflammation, pancreatic islet cell destruction, and diabetes, stroke, and neurodegenerative disorders, as well as the toxic effects of various environmental oxidants or cytotoxic drugs.
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PMID:DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite. 890 31

This paper reports on some interactions of calcium antagonists with nitric oxide and endothelin. It reviews evidence showing that the vasorelaxant action of calcium antagonists is facilitated by nitric oxide and describes the mechanism of this modulation. The interaction of calcium antagonists with endothelin is examined considering functions and production of the peptide. Among the functions examined, attention is drawn to the potentiation of responses to vasoconstrictors evoked by low threshold concentrations of endothelin, an action that could be important in pathology. The production of endothelin is increased by a high-salt diet in spontaneous hypertensive stroke-prone rats, this increased production, related to the overexpression of prepro ET-1mRNA, is responsible for cardiovascular hypertrophy and is blunted, in a blood pressure-unrelated manner, by the calcium antagonist lacidipine. At the same dosage regimen, lacidipine inhibits the hypertrophy of the cardiovascular system evoked by a high-salt diet.
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PMID:Calcium antagonists and endothelial function: focus on nitric oxide and endothelin. 892 57

In an attempt to evaluate the role of nitric oxide (NO) in pathophysiological alterations and multiple organ damage caused by hemorrhagic shock, we employed NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, in anesthetized rats subjected to a prolonged hypovolemic insult (30-35 mmHg for 180 min). Infusion of 2.0 mg/kg L-NMMA at the end of resuscitation diminished the fall in mean arterial pressure (MAP) and significantly increased the cardiac index and stroke volume, together with remarkable protection from multiple organ damage compared with the controls. The 48-h survival rate was significantly improved from 26.7% in the control group to 68.8% in the treatment group (P < 0.05). In contrast, the high dose of 20.0 mg/kg L-NMMA resulted in a strong blood pressure response, but a marked reduction in cardiac index and stroke volume concomitant with an increased total peripheral resistance index within the observation period, and tended to increase damage to various organs at 2 h after treatment. In addition, marked elevation in both endotoxin and tumor necrosis factor levels were observed in animals subjected to shock insult. The results suggest that NO induced by hemorrhagic shock in rats is an important mediator for pathophysiological alterations associated with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. Regulation of NO generation and use of NO inhibitors might provide new aspects in the treatment of hemorrhage-related disorders, whereas the administration of L-NMMA would be either deleterious or salutary in a dose-dependent manner.
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PMID:Significance of NO in hemorrhage-induced hemodynamic alterations, organ injury, and mortality in rats. 892 66

The potential of nitric oxide (NO) to influence positively or negatively the outcome of mechanically induced focal cerebral ischemia is still controversial. Recent evidence suggests that NO of vascular origin, whether synthesized from exogenously administered L-arginine (L-Arg) or from NO donor compounds, is beneficial but that of neuronal origin is not. However, the therapeutic potential of NO to ameliorate stroke induced by arterial thrombosis has not been reported. We assessed the therapeutic effect of L-Arg administration in spontaneously hypertensive rats (SHR) subjected to permanent photothrombotic occlusion of the distal middle cerebral artery (dMCA). The ipsilateral carotid artery was left unligated to enhance L-Arg delivery into the putative penumbral region. Local CBF (LCBF) was assessed at 30 min by the [14C]iodoantipyrine technique (n = 9), while histological infarct volumes and index of peripheral ischemic cell change were determined at 3 days (n = 7). Rats (n = 9) given 300 mg/kg L-Arg at 18 and 3 h before photothrombotic dMCA occlusion and at 5 min afterward displayed no significant differences in LCBF compared with animals (n = 8) injected with water (the carrier vehicle) and similarly irradiated. Infarct volumes were also similar, being 37.0 +/- 9.7 mm3 (SD) in the vehicle-treated and 49.1 +/- 17.2 mm3 (SD) in the L-Arg-treated groups (both n = 7), as were assessments of ischemic neuronal density in the penumbra. In contrast, L-Arg administered intravenously in a dose of 300 mg/kg to nonischemic SHR (n = 5) increased cortical CBF by approximately 75% during a 70-min observation period. We conclude that thrombotic processes superimposed upon cerebral ischemia may facilitate tissue reactions that offset the potentially beneficial effect of L-Arg, and this caveat must be considered when proposing L-Arg for clinical treatment of focal thrombotic stroke.
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PMID:L-arginine does not improve cortical perfusion or histopathological outcome in spontaneously hypertensive rats subjected to distal middle cerebral artery photothrombotic occlusion. 896

Deposits of amyloid beta-peptide (A beta) in senile plaques and cerebral blood vessels is the prominent feature of Alzheimer's disease (AD), regardless of genetic predisposition. The cellular origin of cerebral deposits of A beta or its precise role in the neurodegenerative process has not been established. Recently we demonstrated a novel action of beta-amyloid on blood vessels--vasoactivity and endothelial damage through superoxide radicals. Since endothelial dysfunction is associated with vascular degenerative diseases, we examined the direct action of A beta on endothelial cells in culture. Cells treated with A beta displayed characteristics of necrotic cell death which was prevented by the free radical scavenging enzyme superoxide dismutase. Stimulation of endothelial nitric oxide (NO) production by the calcium ionophore, A23187, or bradykinin was inhibited by beta-amyloid. We conclude that an imbalance of NO and oxygen radicals may mediate the A beta-induced endothelial damage on endothelial cells in culture and may also contribute to a variety of pathophysiological conditions associated with aging: hypertension, cerebral ischemia, vasospasm, or stroke.
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PMID:beta-amyloid-induced endothelial necrosis and inhibition of nitric oxide production. 902 96

The effects of L-arginine (a precursor of nitric oxide, NO) on cerebral blood flow (CBF), cerebrovascular resistance (CVR) and metabolites in the ischemic brain were examined in spontaneously hypertensive rats with bilateral carotid artery occlusion for 30 min followed by 60 min-recirculation. The administration of L-arginine (300 mg/kg, i.v.) increased the CBF by an average of 11 ml x 100 g-1 x min-1 (P < 0.05 vs. at rest), and N(omega)-nitro-L-arginine (L-NNA, an inhibitor of NO synthase, 5 mg/kg, i.v.) reduced the CBF by 5-6 ml x 100 g-1.min-1 with increase in the mean arterial pressure by 26 mmHg. During ischemia the CBF significantly decreased to below 8% of the resting values in all rats. The largest blood flow in postischemic hyperemia was 171 +/- 9% of the resting CBF in the rats with L-arginine (P < 0.05 vs. L-NNA and saline), followed by 126 +/- 5 with saline and 109 +/- 3 with L-NNA. The CVR at 60 min of recirculation was 3.291 +/- 0.144 mmHg . ml-1. 100 g-1 .min-1 in the rats with saline, remained low level of 2.711 +/- 0.124 with L-arginine (P < 0.01 vs. L-NNA and P < 0.05 vs. saline) and in contrast, significantly increased to 5.732 +/- 0.184 with L-NNA (P < 0.01 vs. L-arginine and saline, respectively). Tissue lactate with saline increased 2.3-fold at 60 min of recirculation, whereas the increase was inhibited to 1.4-fold after L-arginine treatment (P < 0.01 vs. L-NNA) and in contrast, significantly increased 5.7-fold with L-NNA. The ATP and glucose levels were better preserved in the rats with L-arginine than in those with L-NNA or saline. These findings support that the enhanced postischemic hyperemia is beneficial to the ischemic brain and the administration of L-arginine may be potentially useful for the treatment of acute stroke.
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PMID:L-arginine ameliorates recirculation and metabolic derangement in brain ischemia in hypertensive rats. 902 84


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