UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of NO synthesis promotes P-selectin expression on endothelial cells; however, the precise mechanism is unclear. Because No has been shown to inhibit protein kinase C (PKC) activity, we examined the hypothesis that the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) stimulates P-selectin expression on platelets via PKC activation. Ten-minute incubation with either phorbol 12-myristate 13-acetate (PMA), thrombin, or L-NAME significantly increased P-selectin expression on platelets (as assessed by flow-cytometric analysis) and PKC activity of platelet membranes. Increased P-selectin expression induced by either PMA, thrombin, or L-NAME was significantly attenuated by the selective PKC inhibitor UCN-01 (7-hydroxystaurosporine). Furthermore, L-NAME-induced P-selectin expression was significantly attenuated by either L-arginine, 8-bromo-cGMP, or sodium nitroprusside (SNP). Interestingly, L-NAME further potentiated P-selectin upregulation by thrombin. L-NAME, thrombin, and PMA also significantly increased polymorphonuclear leukocyte adherence to the coronary artery endothelium, an effect that was significantly attenuated by the anti-P-selectin monoclonal antibody PB1.3 or by UCN-01, L-arginine, 8-bromo-cGMP or SNP but not by D-arginine or he nonblocking anti-P-selectin monoclonal antibody NBP1.6. These results indicate that inhibition of NO synthesis induces rapid P-selectin expression, which appears to be at least partially mediated by PKC activation in platelets. Similar effects and mechanisms of L-NAME on P-selectin function were also observed in endothelial cells, another site of P-selectin expression.
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PMID:Inhibition of nitric oxide biosynthesis promotes P-selectin expression in platelets. Role of protein kinase C. 758 91

Inflammatory cell deposition in atherosclerotic blood vessels has been thought to relate to loss of endothelium-derived nitric oxide (NO). To examine whether cell deposition correlates temporally with the loss of NO activity, rat aortic rings were incubated with buffer, native LDL (n-LDL), oxidized LDL (ox-LDL), or the endothelium-derived relaxing factor synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) for 2 hours, and vascular contractile response to norepinephrine and relaxant response to acetylcholine, thrombin, and calcium ionophore A23,187 were examined. Thereafter, the rings were exposed to biotin-fluorescein isothiocyanate-labeled fluorescent or unlabeled leukocytes for 30 minutes. Cell adhesion was quantitated by fluorescent microscopy as well as by scanning electron microscopy. Incubation with n-LDL or ox-LDL did not affect either the contractile or the relaxant response of rings. However, leukocyte adhesion increased markedly in all ox-LDL-treated rings but not in those treated with n-LDL. Thus, leukocyte adhesion occurred independent of NO activity. In keeping with this concept, pretreatment of rings with the NO precursor L-arginine failed to influence leukocyte adhesion to rings incubated with ox-LDL. Treatment of rings with L-NAME also resulted in adhesion of a large number of leukocytes. Furthermore, all rings treated with ox-LDL or L-NAME demonstrated marked expression of P-selectin leukocyte adhesion molecules, determined by immunohistochemistry. Pretreatment of rings with the P-selectin blocking antibody PB1.3 markedly decreased deposition of leukocytes in rings exposed to ox-LDL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxidized low-density lipoproteins facilitate leukocyte adhesion to aortic intima without affecting endothelium-dependent relaxation. Role of P-selectin. 758 92

The mechanisms by which nitric oxide modulates microvascular albumin exchange were investigated by monitoring leukocyte-endothelial cell adhesion and fluorescein isothiocyanate-albumin leakage in rat mesenteric venules exposed to NG-nitro-L-arginine methyl ester (L-NAME). L-NAME elicited an initial rapid increase followed by a slower rate of albumin accumulation in the interstitial space. The initial phase of albumin leakage preceded the L-NAME-induced leukocyte adherence and emigration, whereas the magnitude of the albumin leakage observed in the later phase of L-NAME exposure was highly correlated with the number of adherent and emigrated leukocytes in the same segment of venule. Monoclonal antibodies (MAbs) directed against adhesion molecules CD11/CD18, ICAM-1, or P-selectin, but not a nonbinding MAb, attenuated the albumin leakage induced by L-NAME. WEB2086, a platelet activating factor antagonist, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) reduced the leukocyte adherence and emigration as well as the increased albumin leakage. Only 8-br-cGMP and the P-selectin MAb attenuated the platelet-leukocyte aggregation elicited by L-NAME. Phalloidin, which promotes endothelial junctional integrity, inhibited both the early and late phases of albumin leakage. Overall, these findings suggest that the increased albumin leakage observed in postcapillary venules after inhibition of nitric oxide production involves a mechanism that includes a role for cGMP, platelet activating factor, leukocyte-endothelial cell adhesion, and the endothelial cell cytoskeleton.
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PMID:Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage. 768 51

This study was aimed to determine the mechanism by which endogenous nitric oxide suppression promotes leukocyte adhesion in vivo. The rat mesenteric microcirculation was superfused with NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), and intracellular oxidant formation in several microcirculatory cellular components such as arteriolar and venular endothelium and mast cells was visually monitored by digital microfluorography assisted by carboxydichlorofluorescein (CDCF), a hydroperoxide-sensitive fluorogenic probe. Adherent leukocyte density was measured simultaneously. L-NAME induced a significant time-dependent increase in CDCF fluorescence in arteriolar and venular endothelium and mast cells followed by firm adhesion of leukocytes. L-NAME-induced CDCF elevation showed a different spatial distribution compared with that evoked by N-formylmethionyl-leucyl-phenylalanine, in which only local venular segments with adhering leukocytes exhibited CDCF fluorescence enhancement. The level of hydroperoxide formation in arterioles and venules evoked by 60-min L-NAME superfusion was equivalent to that induced by the superfusion of approximately 880 microM tert-butyl hydroperoxide for 10 min. Pretreatment with anti-intracellular adhesion molecule-1, anti-P-selectin, or anti-CD18 monoclonal antibody attenuated L-NAME-elicited venular leukocyte adhesion without abolishing CDCF fluorescence in situ. Pretreatment with desferioxamine (50 mg/kg iv; 1 h before L-NAME superfusion) significantly diminished the iron-catalyzed hydroperoxide formation in arterioles and venules, but not in interstitial mast cells, as well as subsequent venular leukocyte adhesion. These findings indicate that endogenous nitric oxide may modulate oxidative stress in mast cells, arteriolar and venular microvascular endothelium and thereby can play a crucial role in leukocyte recruitment in venules.
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PMID:Microvascular oxidative stress preceding leukocyte activation elicited by in vivo nitric oxide suppression. 802 2

Polymorphonuclear leukocytes (PMNs) play an important role in myocardial ischemia/reperfusion (MI/R) injury. We examined the cardioprotective effects of N,N,N-trimethylsphingosine (TMS) in a murine model of MI (20 min) and R (24 h) injury in vivo, focusing on leukocyte-endothelial interactions. TMS is a synthetic N-methylated sphingosine derivative that has protein kinase C inhibitory activity and has been shown to prevent leukocyte activation. TMS (18 microgram/kg), administered intravenously 1 min prior to reperfusion, significantly attenuated myocardial necrotic injury assessed by myocardial creatine kinase loss compared with MI/R rats receiving only vehicle (P<0.001). Cardiac myeloperoxidase activity, an index of PMN accumulation in the ischemic myocardium, was also significantly attenuated by TMS compared with rats receiving vehicle (P<0.001). We further examined whether TMS can attenuate leukocyte-endothelial interaction by intravital microscopy. TMS significantly attenuated NG-nitro-L-arginine-methyl ester (L-NAME)-stimulated PMN rolling and adherence to the rat microvascular endothelium. This action of TMS appears to be mediated by reduction of P-selectin expression because immunohistochemical analysis demonstrated that TMS significantly attenuated endothelial P-selectin expression in the L-NAME-superfused rat mesenteric microvasculature. Similarly, TMS markedly attenuated rapid P-selectin expression in rat platelets stimulated with either thrombin or L-NAME assessed by flow cytometry. In conclusion, TMS seems to be an effective cardioprotective agent by inhibiting early leukocyte-endothelial interaction, thus preventing leukocyte accumulation in the ischemic reperfused myocardium.
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PMID:Myocardial protection by N,N,N-trimethylsphingosine in ischemia reperfusion injury is mediated by inhibition of P-selectin. 860 8

A novel single stranded polydeoxyribonucleotide (oligotide) was studied for its ability to modulate leukocyte-endothelial cell interaction, by means of intravital microscopy in the rat mesenteric microvasculature. Superfusion of the rat mesentery with 50 microM NG-nitro-L-arginine methyl ester (L-NAME), caused a significant, time-dependent increase in leukocyte rolling and adherence compared to control rats superfused with Krebs-Henseleit solution. However, oligotide (15 mg/kg i.v.) consistently reduced the L-NAME-induced leukocyte rolling (62 +/- 14 vs. 23 +/- 3 cells/min; P < 0.02) and adherence (11 +/- 2 vs. 4 +/- 1 cells/100 microns length of venule P < 0.01), without altering systemic blood pressure or mesenteric venular shear rate. Moreover, immunohistochemical localization of P-selectin expression on mesenteric venules was significantly increased (P < 0.01) after exposure to L-NAME, which was significantly attenuated by oligotide (P < 0.05). Similar results were also obtained by flow cytometric analysis performed on rat platelets. Stimulation of rat platelets with L-NAME significantly (P < 0.05) increased the fluorescence intensity of P-selectin, while the concomitant treatment of isolated rat platelets with L-NAME plus oligotide significantly (P < 0.005) attenuated P-selectin fluorescence intensity. Our data demonstrate that in vivo administration of oligotide can reduce leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression, and confirming the key role of nitric oxide as an important regulator of leukocyte-endothelial cell interaction.
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PMID:Oligotide attenuates leukocyte-endothelial cell interaction via P-selectin in the rat mesenteric vascular bed. 883 55

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.
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PMID:Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism. 891 55

The effects of defibrotide on leukocyte-endothelial cell interaction and P-selectin surface expression on the microvascular endothelium were investigated. Intravital microscopy was performed in the rat mesenteric microcirculation. The rat mesentery was superfused either with Krebs-Henseleit solution (i.e., control) or 50 microM NG nitro-L-arginine methyl ester (L-NAME). Defibrotide (40 mg/kg) was intravenously infused to control rats and to L-NAME superfused rats. P-selectin expression on mesenteric venules was also investigated by immunohistochemistry. L-NAME caused a significant, time-dependent increase in leukocyte rolling (13 +/- 5 to 101 +/- 18 cells/ min; p < 0.001) and adherence (1.6 +/- 0.7 to 12 +/- 2.5 cells/100 microns length of venule; p < 0.01) compared to control superfused rats. However, intravenous infusion of defibrotide (40 mg/kg) consistently decreased the L-NAME-induced leukocyte rolling (101 +/- 18 to 9.3 +/- 1.3 cells/min; p < 0.001) and adherence (12 +/- 2.5 to 1.9 +/- 1.1 cells/100 microns length of venule; p < 0.01). Exposure of rat mesentery to L-NAME consistently increased P-selectin surface expression (p < 0.01) on the vascular endothelium which was significantly attenuated by defibrotide (p < 0.05). In vivo administration of defibrotide can reduce leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. Since P-selectin was upregulated by the specific nitric oxide synthase inhibitor L-NAME, the present study also confirms the crucial role exerted by nitric oxide in attenuating leukocyte-endothelial cell interaction during various pathophysiological conditions.
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PMID:Effects of defibrotide on leukocyte-endothelial cell interaction in the rat mesenteric vascular bed: role of P-selectin. 912 Dec 23

Three different stable lipoxin A4 (LXA4) analogs (i.e., 16-phenoxy-LXA4-Me, 15-cyclohexyl-LXA4-Me, and 15-R/S-methyl-LXA4-Me) were studied for their ability to modulate leukocyte-endothelial cell interactions in the rat mesenteric microvasculature. Superfusion of the rat mesentery with 50 micromol/liter NG-nitro-L-arginine methyl ester (L-NAME) caused a significant, time-dependent increase in leukocyte rolling (56 +/- 8 cells/min; P < 0.01 vs. control) and leukocyte adherence (12.5 +/- 1. 2 cells/100 micron length of venule; P < 0.01 vs. control) after 120 min of superfusion. Concomitant superfusion of the rat mesentery with 10 nmol/liter of each of three lipoxin analogs consistently and markedly attenuated L-NAME-induced leukocyte rolling to 10 +/- 4 (P < 0.01), 4 +/- 1 (P < 0.01), and 32 +/- 7 (P < 0.05) cells/min, and adherence to 4 +/- 0.8 (P < 0.01), 1.1 +/- 0.4 (P < 0.01), and 7 +/- 0.7 (P < 0.05) cells/100 micron length of venule (16-phenoxy-LXA4-Me, 15-cyclohexyl-LXA4-Me, and 15-R/S- methyl-LXA4-Me, respectively). No alterations of systemic blood pressure or mesenteric venular shear rates were observed in any group. Immunohistochemical up-regulation of P-selectin expression on intestinal venular endothelium was significantly increased (P < 0.01) after exposure to L-NAME, and this was significantly attenuated by these lipoxin analogs (P < 0.01). Thus, in vivo superfusion of the rat mesentery with stable lipoxin analogs at 10 nmol/liter reduces L-NAME-induced leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. This anti-inflammatory mechanism may represent a novel and potent regulatory action of lipoxins on the immune system.
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PMID:Lipoxin A4 stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: role of P-selectin. 927 35

P-selectin translocation to the surface of endothelial cells is increased after exposure to the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), resulting in increased endothelial adhesiveness. L-NAME (3 mM) was added to human cultured iliac vein endothelial cells for 1, 2, 4, and 6 h, and P-selectin mRNA expression was quantified by a ribonuclease protection assay. In parallel experiments, the NO donor, SPM-5185 (10 microM), was added to human iliac venous endothelial cells, and P-selectin mRNA expression quantified. P-selectin protein synthesis was quantified by Western blot analysis. L-NAME caused increased expression of P-selection RNA at 2-4 h, whereas D-NAME, the stereoisomer lacking NO synthase-inhibitory activity, had no effect. The stimulatory effect of L-NAME was reversed by addition of 3 mM L-arginine. SPM-5185 decreased P-selectin mRNA over the same time period (P < 0.02). The increased P-selectin mRNA expression induced by L-NAME was paralleled by an increase in P-selectin protein synthesis. The effects of SPM-5185 and L-arginine were also paralleled by decreases in P-selectin protein synthesis and in decreased adherence of human neutrophils to human iliac venous endothelial cells. The peak effect of inhibition of NO synthesis or addition of exogenous NO occurred at 2-4 h. These results suggest a regulatory effect of NO on endothelial P-selectin expression that modulates early leukocyte-endothelial cell interactions to preserve vascular homeostasis.
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PMID:Regulation of P-selectin expression in human endothelial cells by nitric oxide. 927 91

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