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 microscopy of the rat mesentery microcirculation to examine effects of locally administered heparin on leukocyte rolling and chemoattractant-induced firm adhesion. 2. It was found that topical application of heparin reduced N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced leukocyte adhesion. Notably, the inhibitory action of heparin was not dose-dependent, 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 significantly reduced adhesion, whereas an intermediate dose (200 iu ml(-1)) was less effective. 3. Heparin, 2 and 20 iu ml(-1), decreased rolling leukocyte flux, while having no effect on blood flow or total leukocyte flux. By contrast, heparin, 200 and 1000 iu ml(-1), increased total leukocyte flux in parallel with a rise in volume blood flow resulting in recovery of the rolling leukocyte flux at these doses. Thus, the biphasic inhibitory action of heparin on fMLP-induced firm adhesion could in part be attributed to changes in leukocyte delivery (i.e. blood flow) and rolling leukocyte flux induced by heparin. 4. When compensating for the influence of different rolling levels on fMLP-evoked adhesion, a dose-related inhibitory effect of heparin on the firm adhesive response per se was revealed. Similar results were obtained in a static adhesion assay in vitro where heparin 200 and 1000 iu ml(-1) (but not 2 and 20 iu ml(-1)) significantly inhibited fMLP-induced leukocyte adhesion in the absence of any modulatory influence on changes in rolling. 5. Our data show that locally administered heparin inhibits leukocyte rolling as well as chemoattractant-induced firm adhesion in vivo which thus may contribute to the postulated anti-inflammatory activity of this compound. However, because of interference with several microvascular 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.
Xie
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Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Thorlacius
H
H
Raud
J
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Hedqvist
P
P
Lindbom
L
L
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology*; D007082:Ileum / Q000098:blood supply; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014699:Venules / Q000187:drug effects / Q000502:physiology
D000893:Anti-Inflammatory Agents; D002630:Chemotactic Factors; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006493:Heparin