title: Endogenous but not exogenous nitric oxide decreases TNF-alpha-induced leukocyte rolling.
abstract: Inhibition of nitric oxide (NO) synthesis in mesenteric microvessels increases leukocyte rolling. The objective of this study was to determine whether inducible NO synthase (iNOS) can modulate tumor necrosis factor-alpha (TNF-alpha)-induced leukocyte rolling. Leukocyte rolling was examined using intravital microscopy of TNF-alpha-treated feline mesenteric microvasculature. Leukocyte rolling increased progressively over 3 h of TNF-alpha treatment. Pretreatment with the selective iNOS inhibitor aminoguanidine further doubled TNF-alpha-induced leukocyte rolling. Aminoguanidine alone did not affect baseline blood pressure or leukocyte kinetics. However, in the same animals NG-nitro-L-arginine methyl ester caused a rapid increase in blood pressure, confirming that constitutive NOS activity persisted in aminoguanidine-treated animals. Furthermore, aminoguanidine did not affect leukocyte rolling in an acute model of leukocyte recruitment (ischemia/reperfusion), suggesting that the exacerbated rolling induced by aminoguanidine with TNF-alpha as a stimulus was not a nonspecific effect. Addition of the NO donor spermine-NO had no effect on TNF-alpha-associated leukocyte rolling. These data raise the possibility of a physiological role for the increased production of NO from iNOS, i.e., regulation of leukocyte rolling and potentially the inflammatory response.
authors.affiliation: Department of Physiology and Biophysics, University of Calgary, Alberta, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Kubes
authors.forename: E
authors.initials: E
authors.lastname: Sihota
authors.forename: M J
authors.initials: MJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D002465:Cell Movement / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008833:Microcirculation / Q000502:physiology*; D018715:Microscopy, Video; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012039:Regional Blood Flow / Q000187:drug effects; D013152:Splanchnic Circulation; D013997:Time Factors; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014699:Venules / Q000187:drug effects / Q000502:physiology
chemical_list: D006146:Guanidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester