APStracts 2:0049H, 1995.

Pentoxifylline inhibits n-formyl-methionyl-leucyl-phenylalanine -induced macromolecular leakage. Nakagawa, Koji, M. D., Frederick N. Miller, Ph. D., Andrew W. Knott, Michael J. Edwards, M. D. Departments of Surgery and Physiology & Biophysics, University of Louisville, Louisville, Kentucky 40292.

APStracts 2:0049H, 1995.

The acute inflammatory responses to chemotactic peptide, N-formyl -Methionyl-Leucyl-Phenylalanine (FMLP) and the effects of pentoxifylline (PTXF) on the responses in vivo were studied. We used intravital microscopy with the rat cremaster muscle preparation to determine inflammatory responses of the microcirculation. Macromolecular leakage from postcapillary venules was evaluated by quantifying the extravasation of fluorescein isothiocyanate conjugated to bovine serum albumin. FMLP induced a rapid increase in macromolecular leakage, an increase in leukocyte-endothelium adhesion, and a decrease in blood flow in the microcirculation. PTXF inhibited FMLP-induced responses in a dose-dependent manner, but failed to block the histamine-dependent leakage induced by Compound 48/80. In addition, diphenhydramine, a histamine receptor blocker, did not affect the macromolecular leakage induced by FMLP. The cell -permeable cyclic adenosine monophosphate (cAMP) analog dibutyryl cAMP mimicked PTXF effects on the microcirculation and also inhibited FMLP-induced macromolecular leakage. PTXF is known to inhibit phosphodiesterase and increase intracellular cAMP which modulates functions of endothelial cells, smooth muscle cells and neutrophils in vitro. Our findings suggest that FMLP induces acute inflammatory responses through activation of neutrophils, independent of endogenous histamine release, and that PTXF inhibits these responses through elevated intracellular cAMP.

Received 13 October 1994; accepted in final form 9 February 1995.
APS Manuscript Number H916-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 February 1995.