Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The main objective of this study was to analyse the role and mode of action of the mast cell mediator histamine in leukocyte-endothelium interactions in small venules in vivo. For this purpose, we used a histological approach (combined with intravital microscopy) that allows studies of rapid mediator-induced venular leukocyte accumulation, reflecting leukocyte rolling, in the undisturbed microcirculation of the rat mesentery where rolling is normally absent. 2. We first examined the relative importance of histamine and 5-hydroxytryptamine (5-HT) in acute mast cell-dependent leukocyte recruitment. The mast cell secretagogue compound 48/80 (i.p. for 15 min) induced a marked venular accumulation of polymorphonuclear leukocytes (PMNL) which was almost abolished by combined histamine1 (H1)- and histamine2 (H2)-receptor blockade. In contrast, the 5-HT-receptor antagonist methysergide was inactive in this regard. Moreover, exogenous 5-HT was less active than exogenous histamine in evoking venular PMNL accumulation (histamine response dose-dependent; 5-HT response bell shaped). Prostaglandin D2 did not cause PMNL accumulation. 3. The venular PMNL response to exogenous histamine peaked between 15 min and 1 h, was still significantly elevated at 2 h, and then returned to prechallenge values after 3 h. At all time points, the histamine-induced PMNL accumulation was nearly abolished by i.v. treatment with the polysaccharide fucoidin (which blocks rolling but not firm adhesion per se), suggesting that the PMNL response to histamine was due to rolling rather than firm adhesion over the entire 3 h period. At no time point did histamine trigger accumulation of mononuclear leukocytes (MNL). 4. To examine the role of histamine-receptors in the histamine-induced PMNL accumulation (i.e. rolling), the animals were pretreated with diphenhydramine (H1-receptor antagonist), cimetidine, or ranitidine (H2-receptor antagonists). Diphenhydramine alone inhibited the venular PMNL response to histamine by 52%, while both H2-receptor antagonists were completely inactive. However, the combination of cimetidine and diphenhydramine reduced the histamine-induced PMNL rolling by 82%. Furthermore, in contrast to an H3-receptor agonist, challenge with either the H1-receptor agonist 2-thiazolylethylamine or two different H2-receptor agonists (impromidine, dimaprit) was sufficient to provoke significant venular PMNL accumulation. 5. Treatment with the nitric oxide-synthase inhibitor L-NAME did not affect the histamine-induced PMNL rolling. On the other hand, 3 h pretreatment with dexamethasone reduced the PMNL response to histamine by 73%, and flow cytometric analysis showed that the dexamethasone treatment almost completely inhibited binding of soluble P-selectin to rat isolated PMNLs. 6. We conclude that initial leukocyte recruitment after mast cell activation in the rat mesentery is critically dependent on histamine release. The cellular response to histamine was specifically due to PMNL rolling, involved activation of both H1- and H2-receptors, and lasted for 2 3 h. Moreover, the histamine-induced PMNL rolling was not dependent on nitric oxide synthesis, but was sensitive to glucocorticoid treatment, possibly via inhibition of expression or function of leukocytic P-selectin ligand(s).
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PMID:Characteristics of histamine-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery. 950 78

The anti-inflammatory role of nitric oxide (NO) was studied in a model of hepatic ischemia-reperfusion (I/R) in rats. Male Fischer rats were subjected to 30 min of no-flow ischemia of the left and median lobes of the liver, and animals were examined for a 4-h period of reperfusion. The animals were divided into the following groups: control-vehicle; I/R-vehicle; I/R-Nomega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg iv, 10 min before reperfusion); sham control-L-NAME, and I/R-S-nitroso-N-acetyl-penicillamine (SNAP, 25 micromol/kg iv, 10 min before reperfusion, followed by 20 micromol. kg-1. h-1 in 1.0 ml saline infused for 4 h). Results showed that mean arterial blood pressure was significantly increased in the sham control-L-NAME or I/R-L-NAME groups compared with either the I/R-vehicle or I/R-SNAP groups. However, cardiac index (CI) and stroke volume index (SVI) were markedly decreased, and systemic vascular resistance index (SVRI) was dramatically increased. Interestingly, the CI and SVI in rats treated with SNAP were markedly improved over that of the I/R group. Plasma nitrate and nitrite levels were significantly decreased in the I/R-L-NAME group; however, superoxide generation in the ischemic lobes and plasma alanine aminotransferase activity were higher compared with I/R-SNAP rats. The L-NAME-induced enhancement of hepatic injury in rats with I/R may be due in part to neutrophil infiltration, which was significantly increased compared with animals subjected to I/R or I/R-SNAP. The mechanism of L-NAME-enhanced neutrophil infiltration may be due to the fact that the ratios of P-selectin and intercellular adhesion molecule 1 (ICAM-1) mRNA to glyceraldehyde-3-phosphate dehydrogenase mRNA extracted from the ischemic lobes of I/R-L-NAME rats were significantly increased when compared with the I/R-SNAP group. These results suggest that 1) endogenous NO reduces the SVRI and permits an increased CI and SVI; 2) exogenous NO further improves CI and SVI; and 3) endogenous, but not exogenous, NO decreases P-selectin and ICAM-1 mRNA expression, thereby reducing polymorphonuclear neutrophil-dependent reperfusion tissue injury.
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PMID:NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R. 984 19

Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to lower serum cholesterol levels and normalize endothelial cell function. Moreover, HMG-CoA reductase inhibitors exert beneficial effects in coronary artery and cerebrovascular diseases. We examined the effects of simvastatin on leukocyte-endothelial cell interaction in vivo by intravital microscopy. Simvastatin (12.5 or 25 microg per rat) was given 18 hours before study. Superfusion with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 50 micromol/L) significantly increased leukocyte rolling from 12+/-2 to 60+/-8 leukocytes per minute, increased adherence to the mesenteric endothelium from 1.8+/-0.5 to 17+/-1.2 leukocytes per 100 microm of venular length, and raised leukocyte transmigration from 2.5+/-1.0 to 10+/-2 leukocytes per perivessel area (P<0.01). Similar results were obtained with thrombin (0.5 U/mL) superfusion of the mesentery. In contrast, pretreatment with simvastatin (25 microg per rat IP) significantly attenuated L-NAME-stimulated leukocyte rolling, to 12+/-2 (P<0.01); adherence, to 5+/-0.5 leukocytes per 100 microm (P<0.01); and leukocyte transmigration, to 3.5+/-1.5 leukocytes per perivessel area (P<0.01). Similar results were obtained in thrombin-superfused mesenteries. Moreover, immunohistochemical analysis demonstrated significantly increased P-selectin expression on the mesenteric venular endothelium after superfusion with either L-NAME (P<0.01) or thrombin (P<0.01), which was significantly attenuated by simvastatin. These results clearly demonstrate that simvastatin is a potent and effective endothelium-protective agent that reduces leukocyte-endothelial cell interactions independently of its well-known lipid-lowering effects. This effect was found to be at least partially mediated via downregulation of P-selectin expression on the microvascular endothelium. Thus, HMG-CoA reductase inhibitors like simvastatin have important anti-inflammatory effects besides their well-known lipid-lowering action.
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PMID:Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. 1059 66

We previously reported that chronic inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces inflammatory changes (monocyte infiltration, myofibroblast formation, and monocyte chemoattractant protein-1 [MCP-1] and transforming growth factor-beta1 [TGF-beta1] expression) in the rat heart and vessel. There is debate regarding whether TGF-beta1 exhibits proinflammatory or anti-inflammatory activities. We used the rat model to investigate the role of TGF-beta in the pathogenesis of such inflammatory changes. We show here that infiltrating monocytes and myofibroblasts in the inflammatory lesions produced TGF-beta1 on the third day of L-NAME administration. Cotreatment with a monoclonal antibody against TGF-beta1, but not with control IgG, prevented the L-NAME-induced cardiac inflammation. The antibody also significantly inhibited the gene expression of MCP-1, P-selectin, and intercellular adhesion molecule-1. In summary, the antibody against TGF-beta1 prevented inflammatory changes in rat heart and vessel induced by chronic inhibition of NO synthesis, suggesting that increased production of TGF-beta1 is involved in the inflammatory changes in this model.
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PMID:Role of transforming growth factor-beta1 in cardiovascular inflammatory changes induced by chronic inhibition of nitric oxide synthesis. 1064 80

A novel synthetic phosphorothioate analog of oleoyl lysophosphatidic acid LXR-1035 was studied for its ability to modulate leukocyte-endothelial cell interactions using intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME elicited a significant, time-dependent increase in leukocyte rolling, adherence, and transmigration compared to control rats superfused with Krebs-Henseleit solution. However, superfusion of the rat mesentery with 300 nM LXR-1035 consistently attenuated 65-87% of the L-NAME-induced leukocyte rolling, adherence, and transmigration, without altering systemic blood pressure or mesenteric venular shear rate. Similar results were also obtained in rats subjected to 90 min of hemorrhage followed by 90 min of reperfusion. Resuscitation from hemorrhage increased significantly the number of rolling, adherent, and transmigrated leukocytes in the rat mesenteric microcirculation. However, superfusion of the rat mesentery with LXR-1035 markedly attenuated the leukocyte-endothelium interaction occurring after hemorrhage and reinfusion by 75+/-12%. Immunohistochemical localization of P-selectin expression on mesenteric venular endothelium was significantly increased after exposure to L-NAME and after hemorrhage-reinfusion, which was significantly attenuated by LXR-1035 (P<0.05). In addition, treatment of isolated rat neutrophils with 300 nM LXR-1035 significantly attenuated leukotriene B4-induced up-regulation of CD18 (P<0.05). Our data clearly demonstrate that LXR-1035 can potently inhibit the recruitment of leukocytes in the mesenteric rat microvasculature by attenuating cell-surface expression of adhesion molecules.
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PMID:A novel lysophosphatidic acid analog, LXR-1035, inhibits leukocyte-endothelium interaction via inhibition of cell adhesion molecules. 1064 94

BACKGROUND: This study was designed to examine the role of P-selectin expression in leukocyte adhesion to endothelium caused by inhibition of nitric oxide synthesis. METHODS AND RESULTS: Rat aortic rings were treated with the nitric oxide synthesis inhibitor N(omicron)-nitro-l-arginine methyl ester (l-NAME) for 2 hours. Parallel sets of aortic rings were pretreated with the nitric oxide precursor l-arginine or posttreated with a specific monoclonal antibody against P-selectin. Some rings were used for determination of vasoreactivity in response to norepinephrine and acetylcholine, while other rings were incubated with autologous unlabeled leukocytes or Biotin-FITC labeled leukocytes for 30 minutes. Leukocyte adhesion to vascular endothelium was determined by scanning electron microscopy. l-NAME enhanced the contractile response in response to norepinephrine, suppressed the relaxant response to acetyleholine, promoted leukocyte adherence to the endothelium and resulted in P-selectin expression on the aortic endothelium. Pretreatment of aortic rings with l-arginine reversed the l-NAME-mediated changes in vasoreactivity in response to norepinephrine and acetyleholine and attenuated the l-NAME-enhanced leukocyte adhesion to endothelial intima. P-selectin treatment, on the other hand, had no effect on l-NAME-mediated changes. Intraperitoneal administration of l-NAME resulted in a significant decrease in plasma nitrite level, a small, but significant, increase in lung and spleen myeloperoxidase activity, and a significant increase in leukocyte deposition in lung and spleen. The l-NAME-mediated increase in myeloperoxidase activity and leukocyte deposition in the spleen, but not in the lungs, was abolished by treatment of rats with the P-selectin antagonist CY1503 administered 30 minutes prior to l-NAME. CONCLUSIONS: These observations indicate that a reduction in nitric oxide synthesis enhances leukocyte adhesion to aortic endothelium and in visceral tissues. While P-selectin expression is evident in some of the experimental models of leukocyte adhesion to endothelium under conditions of nitric oxide inhibition, the role of P-selectin expression remains unclear.
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PMID:Nitric Oxide Synthesis Inhibition and Role of P-selectin in Leukocyte Adhesion to Vascular Tissues. 1068 48

1. The aim of this study was to examine the changes in leukocyte adhesion and leukocyte-induced contraction in balloon-injured rabbit subclavian artery and to correlate these changes with vessel morphology and expression of adhesion molecules on the injured arteries. 2. Rabbits were anaesthetized and their left subclavian arteries were injured by balloon inflation and withdrawal followed by sacrifice at 2, 24, 48 h or 8 days after injury. The left and right subclavian arteries were removed and leukocytes were isolated from autologous rabbit blood. Leukocyte-induced contraction was measured in 5-HT precontracted artery rings and leukocyte adhesion was measured using (51)Cr-labelled leukocytes. Immunocytochemistry using paraffin-embedded tissue was employed to detect changes in the expression of adhesion molecules on injured arteries. 3. Autologous leukocytes caused a contraction of rabbit subclavian artery rings, which was prevented by L-NAME (10(-3) M). Balloon-induced injury abolished the contractile response to leukocytes, which correlated with loss of carbachol-induced relaxation 4. Balloon injury markedly enhanced the adhesiveness of the subclavian artery for leukocytes, most notably at 24 and 48 h after injury (1.7 and 1.8 fold respectively). Increased leukocyte adhesion at these two time points correlated with an upregulation of E-selectin, P-selectin and VCAM-1 expression on the remaining endothelium of the injured artery. 5. Vessel morphology revealed that balloon inflation had induced an infiltration of inflammatory cells into the vessel wall, the greatest increase being seen at 24 h after injury. 6. It is concluded that an increase in the expression of E-selectin, P-selectin and VCAM-1 following balloon-induced injury leads to enhanced leukocyte adhesion and migration into the injured vessel.
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PMID:Correlation of leukocyte adhesiveness, adhesion molecule expression and leukocyte-induced contraction following balloon angioplasty. 1078 Oct 3

C-peptide is a cleavage product that comes from processing proinsulin to insulin that induces nitric oxide (NO) -mediated vasodilation. NO modulates leukocyte-endothelium interaction. We hypothesized that C-peptide might inhibit leukocyte-endothelium interaction via increased release of endothelial NO. Using intravital microscopy of the rat mesentery, we measured leukocyte-endothelium interactions after administration of C-peptide to the rat. Superfusion of the rat mesentery with either thrombin or L-NAME consistently and significantly increased the number of rolling, adhering, and transmigrated leukocytes. C-peptide significantly attenuated either thrombin- or L-NAME-induced leukocyte-endothelium interactions in rat mesenteric venules. A control scrambled sequence of C-peptide characterized by the same amino acid composition in a randomized sequence failed to inhibit leukocyte-endothelium interactions. These effects of C-peptide were associated with decreased surface expression of the cell adhesion molecules P-selectin and ICAM-1 on the microvascular endothelium. Endothelial nitric oxide synthase (eNOS) mRNA levels were increased in rats injected with C-peptide. This enhanced eNOS expression was associated with a marked increase in basal NO release from the aorta of C-peptide-treated rats. We conclude that C-peptide is a potent inhibitor of leukocyte-endothelium interaction and that this effect is specifically related to inhibition of endothelial cell adhesion molecules via maintenance of NO release from the vascular endothelium.
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PMID:C-peptide inhibits leukocyte-endothelium interaction in the microcirculation during acute endothelial dysfunction. 1105 58

Inhibiting platelet and endothelial nitric oxide production favours platelet adhesion and aggregation, and arterial vasoconstriction. This study investigated the effect of NG-nitro-l-arginine methyl ester (L-NAME), a stereospecific inhibitor of nitric oxide synthesis, on P-selectin expression on platelets, platelet-derived microparticles and platelet-leucocyte aggregates, and on soluble P-selectin levels. Twelve healthy male volunteers were infused intravenously with L-NAME and then with a 10% solution of either l- or d-arginine. Blood pressure responses were recorded and whole blood and serum collected at baseline and after each infusion. P-selectin expression was analysed in all samples by flow cytometry. Serum levels of soluble P-selectin were batch analysed using an enzyme-linked immunosorbent assay at the end of the study. P-selectin expression on platelets, platelet-derived microparticles and platelet-leucocyte aggregates did not vary significantly from baseline levels following the infusion of L-NAME or l- or d-arginine. However, endothelial nitric oxide synthase inhibition caused a marked elevation of arterial blood pressure (P < 0.01) that was restored to pretreatment values by l- but not d-arginine. Serum levels of the soluble form decreased significantly (P = 0.001) following the infusion of l- and d-arginine compared with samples taken at baseline and following L-NAME infusion. In conclusion, inhibition of constitutive nitric oxide synthase in the endothelium and platelets produced significant increases in blood pressure but did not alter platelet membrane expression of P-selectin.
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PMID:Effect of nitric oxide modulation on systemic haemodynamics and platelet activation determined by P-selectin expression. 1271 82

Angiotensin II (Ang II) may be a key molecule in the development of atherosclerosis. Because the incidence of coronary atherosclerosis in premenopausal women is lower than that observed in men or postmenopausal women, we have investigated the effect of estrogens on Ang II-induced leukocyte recruitment in vivo using intravital microscopy in the rat mesenteric microcirculation. Superfusion for 60 minutes with Ang II induced a significant increase in leukocyte rolling flux, adhesion, and emigration. Administration of 17-beta-estradiol (17-beta-E) after 30 minutes of Ang II superfusion produced a reduction of these leukocyte responses by 55.1%, 72.7%, and 70.9%, respectively, an additional 30 minutes later. The effect observed with 17-beta-E was receptor-mediated and specific. 17-beta-E superfusion did not modify either L-NAME or indomethacin-induced leukocyte responses. Inhibitory responses caused by 17-beta-E were not altered by either 7-nitroindazole or actinomycin D cosuperfusion. Stimulation of endothelial cells with 17-beta-E caused a rapid and dose-dependent release of prostacyclin. Finally, tamoxifen or ICI 182,780 administration provoked a significant increase in leukocyte-endothelial cell interactions 90 minutes later, which were significantly attenuated by systemic preadministration with an Ang II AT(1) receptor antagonist. Tamoxifen-induced leukocyte responses were also reduced by systemic pretreatment with an anti-P-selectin mAb and an anti-CD18 mAb. Hence, the antiatherogenic effects of estrogens may be mediated by inhibition of Ang II-induced leukocyte recruitment through endothelial NO and prostacyclin release. Furthermore, scarcity of estrogens resulted in decreased levels of vasodilators and the exposure of the endothelium to the deleterious action of Ang II, which may explain the higher incidence of coronary atherosclerosis in men and postmenopausal women.
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PMID:Estrogens inhibit angiotensin II-induced leukocyte-endothelial cell interactions in vivo via rapid endothelial nitric oxide synthase and cyclooxygenase activation. 1248 Aug 15


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