title: Inhaled NO reaches distal vasculatures to inhibit endothelium- but not leukocyte-dependent cell adhesion.
abstract: Nitric oxide (NO), in addition to being a potent vasodilator, also prevents leukocyte adhesion in the microvasculature. Based on the antiadhesive properties of NO and work suggesting that NO is transported by proteins in the circulation, we tested the possibility that inhaled NO could impart antiadhesive effects in peripheral microvessels. We also determined the underlying mechanisms of actions. Three well-established models that induce local microvascular changes (either endothelium or leukocyte) were used. Hydrogen peroxide (H(2)O(2); 100 microM) was superfused onto the cat mesentery to induce an endothelium-derived, P-selectin- and platelet-activating factor-dependent, oxidant-dependent leukocyte recruitment. In a second series of experiments, the cat mesentery was superfused with histamine (100 microM) to induce rapid endothelium-derived, P-selectin- and platelet-activating factor-dependent, oxidant-independent leukocyte recruitment. Finally, in a third series of experiments to target the leukocyte (but not the endothelium) directly in the periphery, the chemotactic molecule leukotriene B(4) (20 nM) was superfused onto the cat mesentery. The above experiments were performed with and without cats breathing NO (80 parts/million). Intravital microscopy was used to visualize the mesenteric microcirculation. Inhaled NO reduced the increased leukocyte rolling and adhesion associated with H(2)O(2) superfusion of the feline mesentery via a cGMP-dependent mechanism. In contrast, inhaled NO had no effect on the histamine-induced increase in leukocyte rolling flux but partially inhibited the subsequent adhesion. The leukocyte chemotactic mediator leukotriene B(4) induced a significant increase in leukocyte adhesion, but NO inhalation did not impair this chemotactically induced leukocyte recruitment. These data suggest that inhaled NO can reach the endothelium in the distal microvasculature and alter the response to an oxidative and a nonoxidative activator of endothelium but imparts no antiadhesive effect directly on circulating leukocytes.
authors.affiliation: Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: A
authors.initials: A
authors.lastname: Fox-Robichaud
authors.forename: D
authors.initials: D
authors.lastname: Payne
authors.forename: P
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000166:cytology / Q000276:immunology; D018715:Microscopy, Video; D009569:Nitric Oxide / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D019007:P-Selectin / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D016877:Oxidants; D019007:P-Selectin; D010972:Platelet Activating Factor; D011810:Quinoxalines; D007975:Leukotriene B4; D009569:Nitric Oxide; D006632:Histamine; D006861:Hydrogen Peroxide; D006152:Cyclic GMP