Effects of LEX032, a novel recombinant serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester induced leukocyte-endothelial cell interactions.
We studied the effects of LEX032, a novel serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester (L-NAME) induced leukocyte-endothelium interactions in vivo, utilizing intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME, a nitric oxide (NO) inhibitor, for 90 min resulted in a significant and time-dependent increase in leukocyte rolling, leukocyte adherence, and transmigration of leukocytes, compared to control rats superfused with Krebs-Henseleit (K-H) solution. However, systemic administration of LEX032 (15 mg/kg bolus injection followed by a 15 mg/kg per hour infusion) to L-NAME superfused rats significantly attenuated leukocyte rolling and adherence along the venular endothelium of the rat mesentery, and also inhibited transmigration of leukocytes through the microvascular endothelial wall. Moreover, no significant changes were observed in mean arterial blood pressure or local venular shear rates following systemic administration of LEX032. Our data demonstrate that systemic inhibition of serine proteases by LEX032 reduces enhanced leukocyte-endothelium interactions provoked by inhibition of NO synthesis. These results also explain some of the beneficial effects exerted by serine protease inhibitors in ischemia-reperfusion and other inflammatory states.
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D008643:Mesentery / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D015843:Serpins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C095800:LEX 032; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D015843:Serpins; D019331:NG-Nitroarginine Methyl Ester