Nitric oxide: an endogenous modulator of leukocyte adhesion.

Abstract

The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors of NO production, NG-monomethyl-L-arginine (L-NMMA) or NG_ nitro-L-arginine methyl ester (L-NAME), and observing single (30-,um diameter) venules by intravital video microscopy. Thirty minutes into the superfusion period the number of adherent and emigrated leukocytes, the erythrocyte velocity, and the venular diameter were measured; venular blood flow and shear rate were calculated from the measured parameters. The contribution of the leukocyte adhesion glycoprotein CD11/CD18 was determined using the CD18-specific monoclonal antibody IB4. Both inhibitors of NO production increased leukocyte adherence more than 15-fold. Leukocyte emigration was also enhanced, whereas venular shear rate was reduced by nearly half. Antibody IB4 abolished the leukocyte adhesion induced by L-NMMA and L-NAME. Incubation of isolated cat neutrophils with L-NMMA, but not L-NAME, resulted in direct upregulation of CD11/CD18 as assessed by flow cytometry. Decrements in venular shear rate induced by partial occlusion of the superior mesenteric artery in untreated animals revealed that only a minor component of L-NAMEinduced leukocyte adhesion was shear rate-dependent. The L-NAME-induced adhesion was inhibited by L-argimnie but not D-arginine. These data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern of leukocyte adhesion and emigration that is characteristic of acute inflammation. ation (2). The observation that SOD does not affect the adhesion of PMNs to biologically inert surfaces (glass or plastic) suggests that superoxide-mediated PMN adhesion is an endothelium-dependent process (2, 3).The mechanism by which superoxide mediates endothelium-dependent leukocyte adhesion has not been defined; however, one possibility is that superoxide may interact with an endothelial cell-derived antiadhesive substance and render it inactive. Nitric oxide (NO) is a biologically active compound produced by vascular endothelium and is rapidly inactivated by superoxide (4, 5). There is circumstantial evidence in the literature that NO may interfere with the ability of PMNs to adhere to microvascular endothelium. It is well established that NO prevents the adhesion of platelets to endothelial monolayers (6). Additionally, NO inhibits neutrophil aggregation in vitro, an effect that is potentiated by SOD (7). The primary objective of this study was to test the hypothesis that endogenous production of NO plays an important role in the modulation of PMN adhesion to endothelial cells in postcapillary venules. This was accomplished by quantifying leukocyte adhesion in cat mesenteric venules that were superfused with NG monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME), analogues of L-arginine that inhibit NO ...

Ultrastructure and histochemistry of rat myocardial capillary endothelial cells in response to diabetes and hypertension

“…The endothelial dysfunction is associated with the imbalance of secreting vasoactive mediators including NO [12,24]. NO modulates various physiological activities such as homeostasis, vascular tone, defensive reactions [25], and its decreased bioavailability contributes to impairment of NO-dependent processes in the myocardium. Reduced NO bioactivity may results from lower NO production [e.g.…”

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

“…NO has important salutary physiological properties like vascular tone regulation, quenching reactive oxygen intermediates and inhibiting leukocyte recruitment in the microcirculation [2,15,17,22,27,29]. Depleted NO production in a transgenic-knockout (BERK) model is associated with increased tyrosine nitration [16], suggesting that hemolysis in this model may trigger the reported hemin-mediated nitrotyrosine formation in the presence of nitrite and hydrogen peroxide (H 2 O 2 ) [38].…”

“…In renal ischemic-reperfusion injury, NO can protect the kidneys against leukocyte adhesion to vascular endothelium [29]. In contrast, inhibition of NO production by L-NAME, a potent nonselective inhibitor of nitric oxide synthase (NOS) causes in an inflammatory response, resulting in increased leukocyteendothelium interaction [17] and oxidant generation [18].…”

Polymorphonuclear leukocyte mediated oxidative inactivation of alpha-1-proteinase inhibitor: Modulation by nitric oxide

“…The pre-treatment of PMNL with LArg caused appreciable decrease in the superoxide and hydroxyl radical generation, the former being LArg concentration dependent. In addition to the mediating endothelial relaxation of vascular smooth muscle (46), inhibiting platelet aggregation and adhesion and mediating tissue damage (47,48) nitric oxide has also been found to modulate superoxide radical generation (11,16,17,18,49). In our studies inclusion of L-Arg.…”