Effects of defibrotide on leukocyte-endothelial cell interaction in the rat mesenteric vascular bed: role of P-selectin.
The effects of defibrotide on leukocyte-endothelial cell interaction and P-selectin surface expression on the microvascular endothelium were investigated. Intravital microscopy was performed in the rat mesenteric microcirculation. The rat mesentery was superfused either with Krebs-Henseleit solution (i.e., control) or 50 microM NG nitro-L-arginine methyl ester (L-NAME). Defibrotide (40 mg/kg) was intravenously infused to control rats and to L-NAME superfused rats. P-selectin expression on mesenteric venules was also investigated by immunohistochemistry. L-NAME caused a significant, time-dependent increase in leukocyte rolling (13 +/- 5 to 101 +/- 18 cells/ min; p < 0.001) and adherence (1.6 +/- 0.7 to 12 +/- 2.5 cells/100 microns length of venule; p < 0.01) compared to control superfused rats. However, intravenous infusion of defibrotide (40 mg/kg) consistently decreased the L-NAME-induced leukocyte rolling (101 +/- 18 to 9.3 +/- 1.3 cells/min; p < 0.001) and adherence (12 +/- 2.5 to 1.9 +/- 1.1 cells/100 microns length of venule; p < 0.01). Exposure of rat mesentery to L-NAME consistently increased P-selectin surface expression (p < 0.01) on the vascular endothelium which was significantly attenuated by defibrotide (p < 0.05). In vivo administration of defibrotide can reduce leukocyte rolling and adherence in the mesenteric rat microvasculature by attenuating P-selectin expression. Since P-selectin was upregulated by the specific nitric oxide synthase inhibitor L-NAME, the present study also confirms the crucial role exerted by nitric oxide in attenuating leukocyte-endothelial cell interaction during various pathophysiological conditions.
Scalia
R
R
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
Kochilas
L
L
Campbell
B
B
Lefer
A M
AM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019007:P-Selectin / Q000096:biosynthesis*; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects*
D005343:Fibrinolytic Agents; D019007:P-Selectin; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester