Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The intercellular adhesion of circulating leukocytes to vascular endothelium is a prerequisite for leukocyte emigration from the blood to extravascular tissues. This process is facilitated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Both cultures contained similar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectively). Adhesion molecule expression was up-regulated by interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were more sensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expression were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke.
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PMID:Adhesion molecules on normotensive and hypertensive rat brain endothelial cells. 790 12

Calcitonin gene-related peptide (CGRP) is a potent vasodilatory neuropeptide, which may play a role in vascular dysfunction during septic shock. Sixteen pigs (25-50 kg) were anesthetized with ketamine and isoflurane in O2, and administered 100 micrograms/kg Escherichia coli lipopolysaccharide i.v. (LPS; n = 8) or saline vehicle (n = 8). Pigs were instrumented for hemodynamic determinations and blood sampling for CGRP assay (pg/ml) from the portal vein (PV) and the pulmonary (PA) and carotid (CA) arteries. Blood samples were collected into EDTA and aprotinin before (baseline) and at 60, 120, and 180 min after LPS administration. LPS caused significant deterioration in indices of hemodynamic function and a significant increase in plasma CGRP concentration at all sampling sites by 120 min (P < 0.01). No significant difference between sampling sites was recorded at any time. Plasma CGRP concentrations displayed significant negative correlations with mean arterial pressure, cardiac index, and left ventricular stroke work. These data confirm our previous findings of CGRP elevations in endotoxemic rats, and indicate that 1) LPS is a potent stimulus for the systemic release of CGRP, 2) increasing plasma CGRP concentrations temporally correlates with cardiovascular deterioration during LPS shock, and 3) there is little evidence that the portal circulation is a major source of circulating CGRP levels during LPS shock. Vasoactive neuropeptides, such as CGRP, may interact with other documented mediators of vascular dysfunction in the pathogenesis of septic shock.
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PMID:Elevations in circulating calcitonin gene-related peptide correlate with hemodynamic deterioration during endotoxic shock in pigs. 802 80

We sought to determine if a recombinant amino terminal fragment of bactericidal/permeability increasing protein (rBPI23) alters the hemodynamic responses to endotoxin. Experiments were performed on Sprague Dawley rats anesthetized with Ketamine and xylazine. In rats challenged with a 30 min infusion of 0.25 mg/kg lipopolysaccharide (LPS; Escherichia coli 0111:B4), there were early (30-90 min), significant increases in cardiac index, heart rate, and stroke volume, accompanied by significant decreases in blood pressure and total peripheral resistance. For the remainder of the 210 min observation period, cardiac index, and stroke volume progressively declined to levels significantly below those of control rats receiving only vehicles. At the same time, blood pressure and total peripheral resistance steadily increased above the vehicle control group. Infusion of 3 mg/kg of rBPI23 abolished these LPS-induced hemodynamic responses. A dose of 1.0 mg/kg of rBPI23 was associated with a modest, significant inhibition of changes evoked by LPS, whereas 0.3 mg/kg was without significant effect. Thaumatin, a control cationic protein with molecular weight and isoelectric point similar to those of rBPI23, failed to alter any responses to LPS. These results indicate that rBPI23 produces a dose-dependent inhibition of hemodynamic changes, associated with endotoxemia, and provides further support for the potential utility of rBPI23 as a therapeutic agent in the treatment of gram-negative sepsis and infection.
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PMID:Recombinant amino terminal fragment of bactericidal/permeability-increasing protein prevents hemodynamic responses to endotoxin. 826 47

Endotoxemia occurs when intestinal ischemia allows bacterial lipopolysaccharide to translocate from colonic flora into the bloodstream, which triggers release of cytokines that can cause hypotension, rigors, fever, shock, and even death. Recently, blood endotoxin levels were shown to be higher in athletes needing medical attention (330 pg.ml-1) than in their competitors with similar performances (81 pg.ml-1). Though there were no data showing that these athletes had elevated core temperatures or severe illness, speculation followed that endotoxin may play a causal role in heat stroke. We examined the relationship between endotoxemia and mild post-exertional illness in 39 cyclists after a 100-mile ride. Thirteen cyclists had at least one of the following: orthostatic hypotension, rigors, nausea, vomiting, diarrhea, or syncope. Only 2/26 case-controls had any of these symptoms. Data were collected on vital signs, hemoglobin, sodium, creatine kinase, creatinine, and uric acid. Endotoxin titer was determined by chromogenic assay; tumor necrosis factor alpha (TNF-alpha) titer was determined by ELISA. One ill cyclist had an endotoxin level of 330 pg.ml-1, one control had an endotoxin level of 150 pg.ml-1, but endotoxin level was < or = 64 pg.ml-1 in all others. Comparison of pre- and post-ride data showed that controls increased creatine kinase activity (154 +/- 34 vs 561 +/- 191 IU.dl, P < 0.05), creatinine concentration (1.5 +/- 0.0 vs 1.6 +/- 0.0 mg.dl-1, P < 0.05), and uric acid concentration (5.4 +/- 0.3 vs 6.3 +/- 0.3 mg.dl-1, P < 0.05). Ill cyclists had lower serum sodium than post-ride controls (138 +/- 2 vs 142 +/- 0.6 mEq.l-1, P < 0.05), but there were no differences between groups in CK, creatinine, or uric acid. These findings suggest that endotoxemia may complicate, but does not cause mild post-exertional illness in cyclists.
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PMID:Exercise-associated collapse in cyclists is unrelated to endotoxemia. 853 21

1. A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically-instrumented Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 micro g kg(-1) h(-1)) for 32 h. Over the first 2 h of LPS infusion, there was a transient hypotension and tachycardia, accompanied by a marked increase in renal flow and vascular conductance, although there were reductions in cardiac and stroke index. Between 4-8 after the start of LPS infusion, there was slight hypotension and tachycardia, and a transient rise in mesenteric flow and conductance, but reductions in the hindquarters vascular bed; the hyperaemic vasodilatation in the renal vascular bed was maintained. At this stage, all cardiac haemodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association with marked increases in peak aortic flow, dF/dtmax and total peripheral conductance; these changes were well-maintained over the following 8 h of LPS infusion. 2. By 2 h after the start of LPS infusion, only lung inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, liver, spleen, heart and aorta. (43.3 +/- 7.8, 28.8 +/- 3.3, 50.8 +/- 7.2, 3.04 +/- 0.29, 3.76 +/- 0.94 pmol min(-1) mg(-1) protein, respectively). However, by 24 h after the start of LPS infusion, iNOS activity was not elevated significantly in any tissue examined, and kidney iNOS activity did not change significantly during LPS infusion. Plasma nitrite/nitrate levels were increased after 2 h infusion of LPS (from 6.07 +/- 1.23 to 29.44 +/- 7.08 micromol l(-1)), and further by 6 h (228.10 +/- 29.20 micromol l(-1)), but were less 24 h after onset of LPS infusion (74.96 +/- 11.34 micromol l(-1)). Hence, the progressive hypotension, increasing cardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infusion, occurred when tissue iNOS activity and plasma nitrite/nitrate levels were falling. 3. Pretreatment with NG-monomethyl-L-arginine (L-NMMA, 30 mg kg(-1) bolus, 30 mg kg(-1) h(-1) infusion) 1 h before LPS infusion did not prevent the early hypotension, but abolished the initial renal vasodilatation and the later (6-8 h) fall in mean arterial pressure (MAP), and the additional renal vasodilatation.
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PMID:Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, endotoxaemic rats. 864 Mar 39

Porcine hypodynamic shock was induced by continuous infusion of 5 micrograms lipopolysaccharide/kg per hour. This resulted in a decrease of cardiac output from baseline values of 3.5 +/- .9 L/min to 1.5 +/- .8 L/min and a reduced left ventricular stroke work index in the endotoxin-group (n = 6 animals). Pretreatment with the H1-antagonist dimethindene (2 mg/kg) in a second group (n = 6) significantly prevented these effects. Furthermore animals pretreated with the H1-antagonist showed a stable mean arterial blood pressure, whereas the control endotoxin-treated group revealed a drastic reduction in mean arterial blood pressure (99 +/- 4.7 mmHg versus 65.8 +/- 10 mmHg after 240 min, respectively). Pulmonary function and systemic vascular resistance were not ameliorated by the H1-antagonist in hypodynamic shock. Gastrointestinal mucosal pH (pHi), which indicates oxygenation of the mucosa, was decreased by endotoxin-infusion (7.45 +/- .32 baseline value to 6.92 +/- .24 after 120 min). This parameter as well as base excess values and lactate levels were significantly improved by dimethindene-pretreatment (p < .05). These results may indicate a beneficial effect of H1-antagonist-pretreatment on endotoxin-induced deterioration of the microcirculation. Furthermore our results clearly demonstrated that only pretreatment before endotoxemia with H1-antagonism is effective, since infusion of H1-antagonist in hypodynamic shock 45 min after addition of endotoxin (n = 6 animals) did not improve the cardiovascular system or the microcirculation.
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PMID:H1-antagonism improves intestinal mucosal pH and heart function in porcine hypodynamic endotoxic shock. 869 86

The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.
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PMID:Attenuation of endotoxin-induced pathophysiology by a new potent PAF receptor antagonist. 872 86

We have proposed that an interaction between perivascular macrophages and endothelium via cytokines could underlie the increased risk of stroke in hypertension. Therefore, the activation of monocytes, the endothelial expression of intercellular adhesion molecule-1 (ICAM-1), and the numbers of monocytes/macrophages in carotid arteries, as well as the cytokine production in carotid tissue, of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto and Sprague-Dawley rats were studied. The total number of blood monocytes (890 +/- 153 cells/mm3, n = 10) and the number of activated (nitro blue tetrazolium-positive) monocytes (220 +/- 51 cells/mm3, n = 10) were significantly greater (P < 0.05) in SHR than in WKY rats (440 +/- 81 and 40 +/- 16 cells/mm3, respectively, n = 10). Patchy endothelial expression of ICAM-1 was found in 77 +/- 9% of carotid sections from stroke-prone SHR (SHR-SP, n = 5) and in 75 +/- 7% of the sections from SHR (n = 7) but in none of the sections from the two normotensive rat strains (n = 7). The number of endothelium-attached monocytes/macrophages per millimeter of internal elastic lamina was significantly greater in SHR-SP than in SHR [5.1 +/- 0.7 (n = 4) and 3.3 +/- 0.3 (n = 6), P < 0.05], whereas no monocytes were found around the endothelium in either of the normotensive rat strains (n = 7 in each group). Incubation of the carotid arteries with lipopolysaccharide (30-300 ng/ml) induced a concentration-dependent expression of mRNAs for interleukin-1 beta and release of tumor necrosis factor-alpha to a significantly greater degree in the SHR than in the Wistar-Kyoto rats. The results demonstrate that hypertension is associated with activation of monocytes and endothelium and an increased endothelial adhesion and subendothelial accumulation of monocytes/macrophages and with an increased vascular capacity to produce cytokines.
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PMID:Evidence for activation of endothelium and monocytes in hypertensive rats. 876 65

It is our central hypothesis that periodontal diseases, which are chronic Gram-negative infections, represent a previously unrecognized risk factor for atherosclerosis and thromboembolic events. Previous studies have demonstrated an association between periodontal disease severity and risk of coronary heart disease and stroke. We hypothesize that this association may be due to an underlying inflammatory response trait, which places an individual at high risk for developing both periodontal disease and atherosclerosis. We further suggest that periodontal disease, once established, provides a biological burden of endotoxin (lipopolysaccharide) and inflammatory cytokines (especially TxA2, IL-1 beta, PGE2, and TNF-alpha) which serve to initiate and exacerbate atherogenesis and thromboembolic events. A cohort study was conducted using combined data from the Normative Aging Study and the Dental Longitudinal Study sponsored by the United States Department of Veterans Affairs. Mean bone loss scores and worst probing pocket depth scores per tooth were measured on 1,147 men during 1968 to 1971. Information gathered during follow-up examinations showed that 207 men developed coronary heart disease (CHD), 59 died of CHD, and 40 had strokes. Incidence odds ratios adjusted for established cardiovascular risk factors were 1.5, 1.9, and 2.8 for bone loss and total CHD, fatal CHD, and stroke, respectively. Levels of bone loss and cumulative incidence of total CHD and fatal CHD indicated a biologic gradient between severity of exposure and occurrence of disease.
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PMID:Periodontal disease and cardiovascular disease. 891 Aug 31

The novel drug lubeluzole, but not its (-)-R-isomer, protects against sensorimotor deficits provoked by photochemical stroke in rats. We studied the mechanism of protection of lubeluzole against glutamate toxicity in primary hippocampal cell cultures. In a model for glutamate antagonism, i.e., treatment of the cultures with compound during the glutamate trigger, lubeluzole was not protective. In contrast, after prolonged pretreatment, i.e., administration of compound to the culture for 7 days before glutamate, lubeluzole was neuroprotective. It had an IC50 of 48 nM and its R-isomer was nine times less active. Under these conditions, lubeluzole inhibited glutamate-stimulated guanosine 3',5'-cyclic monophosphate production (IC50 37 nM). Again the R-isomer was seven times less active. The compounds did not affect nitric oxide synthase activity, guanylate cyclase activity or arginine uptake. After prolonged pretreatment, lubeluzole attenuated citrulline production in the culture, which could not be compensated for by excess arginine. Because prolonged lubeluzole treatment does not inhibit glutamate-activated [Ca+2]i rise in these cultures, the findings may indicate that expression of nitric oxide synthase or levels of its cofactors were reduced. Treatment of C6 glioma cells with lubeluzole did not affect lipopolysaccharide/gamma interferon induced guanosine 3',5'-cyclic monophosphate levels, suggesting that lubeluzole does not inhibit the glial nitric oxide synthase pathway. In conclusion, the long-term neuroprotective property of lubeluzole against glutamate toxicity in hippocampal cultures is reflected by the fact of interference with the glutamateactivated nitric oxide synthase pathway. Prolonged treatment may reduce expression of nitric oxide synthase or levels of its cofactors.
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PMID:Lubeluzole, a novel long-term neuroprotectant, inhibits the glutamate-activated nitric oxide synthase pathway. 893 Jan 81


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