Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation

Davenpeck, Kelly L.; Gauthier, Theresa W.; Lefer, Allan M.

doi:10.1016/0016-5085(94)90229-1

Cited by 257 publications

(145 citation statements)

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“…Leukocyte-endothelium interaction now is known to be a multistep process involving sequential activation of specific cell adhesion molecules (26,27). P-selectin, a member of the selectin family of adhesion glycoproteins, is believed to play a significant role in the initial phase of leukocyte contact, which is rolling of leukocytes along the vascular endothelial surface (14,20). PMN rolling serves to tether the unstimulated neutrophil to the activated endothelium, thus bringing the neutrophil in closer contact with the endothelial cells, allowing adherence to occur (13,20).…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, L-NAME has been effectively used to up-regulate leukocyte-endothelium interaction, because the increased adherence mediated by L-NAME is not due to direct leukocyte activation (19). Despite the fact that L-NAME inhibits NO synthase primarily in endothelial cells, upregulation of P-selectin leads to enhanced leukocyteendothelium interaction, which, in turn, leads to subsequent leukocyte activation (20).…”

Section: Discussionmentioning

confidence: 99%

“…Mean arterial blood pressure was recorded on a Grass Model 7 oscillographic recorder using a Statham P23AC pressure transducer (Gould, Cleveland). The abdominal cavity was opened via a midline laparotomy, and a second incision was made through the skin and abdominal musculature on the right flank as described earlier (20).…”

Section: Methodsmentioning

confidence: 99%

“…Endothelial dysfunction, characterized by a reduced release of nitric oxide (NO), also has been shown to be critically related to increased leukocyteendothelium interaction via up-regulation of endothelial cell adhesion molecules (19). We previously have established a functional relationship between the loss of endotheliumderived NO and the expression of P-selectin (20). Similarly, others have shown that blocking NO synthesis via N Gmonomethyl-L-arginine or N G -nitro-L-arginine methyl ester (L-NAME) increases leukocyte adherence and emigration in the mesenteric microcirculation as well as enhances microvascular permeability (21,22).…”

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Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Scalia

Gefen

Petasis

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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105

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Three different stable lipoxin A 4 (LXA 4 ) analogs (i.e., 16-phenoxy-LXA 4 -Me, 15-cyclohexyl-LXA 4 -Me, and 15-R/S-methyl-LXA 4 -Me) were studied for their ability to modulate leukocyte-endothelial cell interactions in the rat mesenteric microvasculature. Superfusion of the rat mesentery with 50 mol/liter N G-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 m 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 m length of venule (16-phenoxy-LXA 4 -Me, 15-cyclohexyl-LXA 4 -Me, and 15-R/S-methyl-LXA 4 -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-inf lammatory mechanism may represent a novel and potent regulatory action of lipoxins on the immune system.Lipoxins represent a relatively new class of arachidonic acid derivatives (i.e., trihydroxytetraene eicosanoids) that are produced by activated leukocytes, which, in turn, are able to modulate leukocyte functions (1). In vitro data indicate that one member of the naturally occurring lipoxins, (i.e., lipoxin A 4 , namely LXA 4 ), inhibits both neutrophil and eosinophil chemotaxis at nanomolar concentrations (2, 3) and blocks polymorphonuclear neutrophil (PMN) transmigration across epithelial cells (4) and endothelial monolayers (5). Similar actions also are demonstrable in vivo where LXA 4 exerts vasodilator properties (6-9), blocks both PMN diapedesis from postcapillary venules (10), and inhibits PMN entry in inflamed renal tissues in animal models of glomerulonephritis (11).Nevertheless, we know of no specific information elucidating detailed mechanisms by which naturally occurring lipoxins and their synthetic stable analogs can directly modulate the interaction of leukocytes with vascular endothelial cells. LXA 4 , as with other autacoids, is rapidly inactivated in the local extracellular milieu. Analogs of LXA 4 were designed and prepared by total organic synthesis so that they resist rapid inactivation and retain potent biological activities (12). A goal of this study was to use these metabolically stable analogs to investigate the i...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Scalia

Gefen

Petasis

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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105

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“…This endothelial dysfunction is characterized by loss of endothelium-derived nitric oxide (NO). In this regard, we have previously established a functional relationship between the loss of endothelium-derived NO and increased leukocyte-endothelium interaction [12]. Nevertheless, little information is available regarding the mechanisms by which activation of the microvascular endothelium by specific inflammatory mediators relates to PECAM-1-modulated leukocyte extravasation.…”

Section: Introductionmentioning

confidence: 99%

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

Scalia

Lefer

1998

Journal of Leukocyte Biology

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Abstract:The relationship between acute endothelial dysfunction and the extravasation of leukocytes was studied in vivo with intravital microscopy of the rat mesenteric microvasculature. Acute endothelial dysfunction of the rat mesenteric microvasculature was induced in vivo by superfusing the mesentery for 90 min with one of three different stimulating agents: N G -nitro-L-arginine methyl ester (L-NAME, 50 µM), thrombin (0.5 U/mL), or hydrogen peroxide (H 2 O 2 , 50 µM). All three agents induced a similar increase in leukocyte rolling and adherence, which was significantly greater than that observed in control rats superfused with KrebsHenseleit solution (P F 0.01). Transendothelial migration of leukocytes into the perivascular space was also increased by superfusion with L-NAME, thrombin, or H 2 O 2 . However, there was a greater increase in the number of migrated leukocytes in the rat mesentery after L-NAME and H 2 O 2 superfusion than that observed during thrombin superfusion. In vivo infusion of a neutralizing antibody against platelet-endothelial cell adhesion molecule-1 (PECAM-1) specifically inhibited L-NAMEinduced and H 2 O 2 -induced migration of leukocytes but did not prevent extravasation of leukocytes induced by thrombin. In rat mesenteries superfused with the three different stimuli, immunohistochemical analysis of endothelial cell adhesion molecules expressed on the microvascular endothelium revealed a significant increase of ICAM-1, but not PECAM-1, endothelial cell surface expression (P F 0.01 and P G 0.05 vs. control rats, respectively). Our data confirm a key role for PECAM-1 acutely in leukocyte extravasation in vivo and indicate that the involvement of constitutively expressed PECAM-1 in leukocyte transendothelial migration is preferentially correlated to oxidative stressrelated stimuli in the microvascular endothelium.

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Nitric Oxide and Thromboxane A2–Mediated Pulmonary Microvascular Dysfunction

Wright

Kim²,

Rogers

et al. 1999

Arch Surg

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To examine whether the lung releases nitric oxide (NO) in response to thromboxane A 2 and to examine the local release of NO as a protective compensatory mechanism by which the lung responds to the proinflammatory and vasoactive effects of thromboxane A 2. Design: The lungs of anesthetized Sprague-Dawley rats were perfused in vitro with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (nitroglycerinenitro-L-arginine methyl ester [L-NAME]) (10 −4 mol/L), an NO donor (sodium nitroprusside) (10 −8 mol/L), or perfusate alone. Following equilibration, the thromboxane A 2 receptor agonist 9,11-dideoxy-11␣, 9␣-epoxymethanoprostaglandin F 2␣ (U-46 619) (7.1 ϫ 10 −8 mol/L) was added to the perfusate. Fifteen minutes later, the capillary filtration coefficient, pulmonary arterial pressure, and vascular resistance were measured. Pulmonary NO release was assessed by quantitating the release of cyclic guanosine monophosphate into the perfusate. Results: The capillary filtration coefficient of lungs exposed to U-46 619 was 3.5 times greater than that of lungs perfused with buffer alone (PϽ.05). The addition of sodium nitroprusside reduced the increase in capillary filtration coefficient associated with U-46 619 by 50% (PϽ.05) whereas L-NAME had no effect. The addition of U-46 619 to the perfused lung caused a 3.0 ± 0.4 mm Hg increase in pulmonary artery pressure (PϽ.01) with a corresponding rise in total vascular resistance (PϽ.05). This effect was exacerbated by L-NAME (PϽ.05) and inhibited by sodium nitroprusside (PϽ.05). Exposure of the isolated lungs to U-46 619 caused a 4-fold increase in cyclic guanosine monophosphate levels within the perfusate. Conclusion: These data are consistent with the hypothesis that NO release may be an important protective mechanism by which the lung responds to thromboxane A 2 .

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Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation

Cited by 257 publications

References 27 publications

Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

Nitric Oxide and Thromboxane A2–Mediated Pulmonary Microvascular Dysfunction

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Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation

Cited by 257 publications

References 27 publications

Lipoxin A4stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Lipoxin A4stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

In vivo regulation of PECAM-1 activity during acute endothelial dysfunction in the rat mesenteric microvasculature

Nitric Oxide and Thromboxane A2–Mediated Pulmonary Microvascular Dysfunction

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Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin

Lipoxin A₄stable analogs inhibit leukocyte rolling and adherence in the rat mesenteric microvasculature: Role of P-selectin