INHIBITORY EFFECT OF LOCALLY ADMINISTERED HEPARIN ON LEUKOCYTE ROLLING AND CHEMOATTRACTANT-INDUCED FIRM ADHESION IN RAT MESENTERIC VENULES IN-VIVO

1 Anti-inflammatory actions of heparin and related glycosaminoglycans have been described in the literature. Here, we used intravital micros copy of the rat mesentery microcirculation to examine effects of local ly administered heparin on leukocyte rolling and chemoattractant-induc ed firm adhesion. 2 It was found that topical application of heparin r educed N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced leukocyt e adhesion. Notably, the inhibitory action of heparin was not dose-dep endent, but rather a biphasic dose-response was found, i.e. low (2 and 20 iu ml(-1)) and high (1000 iu ml(-1)) concentrations of heparin sig nificantly reduced adhesion, whereas an intermediate dose (200 iu ml(- 1)) was less effective. 3 Heparin, 2 and 20 iu ml(-1), decreased rolli ng leukocyte flux, while having no effect on blood flow or total leuko cyte flux. By contrast, heparin, 200 and 1000 iu ml(-1), increased tot al leukocyte flux in parallel with a rise in volume blood flow resulti ng in recovery of the rolling leukocyte flux at these doses. Thus, the biphasic inhibitory action of heparin on fMLP-induced firm adhesion c ould in part be attributed to changes in leukocyte delivery (i.e. bloo d flow) and rolling leukocyte flux induced by heparin. 4 When compensa ting for the influence of different rolling levels on fMLP-evoked adhe sion, a dose-related inhibitory effect of heparin on the firm adhesive response per se was revealed. Similar results were obtained in a stat ic adhesion assay in vitro where heparin 200 and 1000 iu ml(-1) (but n ot 2 and 20 iu ml(-1)) significantly inhibited fMLP-induced leukocyte adhesion in the absence of any modulatory influence on changes in roll ing. 5 Our data show that locally administered heparin inhibits leukoc yte rolling as well as chemoattractant-induced firm adhesion in vivo w hich thus may contribute to the postulated antiinflammatory activity o f this compound. However, because of interference with several microva scular functions, strict dose-dependent responses to heparin treatment were not found, which illustrates the complex interplay between local blood flow, leukocyte rolling and chemoattractant-induced adhesion as determinants of leukocyte recruitment to tissues in inflammation.