Endogenous but not exogenous nitric oxide decreases TNF-alpha-induced leukocyte rolling.
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.
Kubes
P
P
Department of Physiology and Biophysics, University of Calgary, Alberta, Canada.
Sihota
E
E
Hickey
M J
MJ
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
D006146:Guanidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester