Characteristics of histamine‐induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery

Abstract

1 The main objective of this study was to analyse the role and mode of action of the mast cell mediator histamine in leukocyte-endothelium interactions in small venules in vivo. For this purpose, we used a histological approach (combined with intravital microscopy) that allows studies of rapid mediatorinduced venular leukocyte accumulation, re¯ecting leukocyte rolling, in the undisturbed microcirculation of the rat mesentery where rolling is normally absent. 2 We ®rst examined the relative importance of histamine and 5-hydroxytryptamine (5-HT) in acute mast cell-dependent leukocyte recruitment. The mast cell secretagogue compound 48/80 (i.p. for 15 min) induced a marked venular accumulation of polymorphonuclear leukocytes (PMNL) which was almost abolished by combined histamine 1 (H 1 )-and histamine 2 (H 2 )-receptor blockade. In contrast, the 5-HTreceptor antagonist methysergide was inactive in this regard. Moreover, exogenous 5-HT was less active than exogenous histamine in evoking venular PMNL accumulation (histamine response dose-dependent; 5-HT response bell shaped). Prostaglandin D 2 did not cause PMNL accumulation. 3 The venular PMNL response to exogenous histamine peaked between 15 min and 1 h, was still signi®cantly elevated at 2 h, and then returned to prechallenge values after 3 h. At all time points, the histamine-induced PMNL accumulation was nearly abolished by i.v. treatment with the polysaccharide fucoidin (which blocks rolling but not ®rm adhesion per se), suggesting that the PMNL response to histamine was due to rolling rather than ®rm adhesion over the entire 3 h period. At no time point did histamine trigger accumulation of mononuclear leukocytes (MNL). 4 To examine the role of histamine-receptors in the histamine-induced PMNL accumulation (i.e. rolling), the animals were pretreated with diphenhydramine (H 1 -receptor antagonist), cimetidine, or ranitidine (H 2 -receptor antagonists). Diphenhydramine alone inhibited the venular PMNL response to histamine by 52%, while both H 2 -receptor antagonists were completely inactive. However, the combination of cimetidine and diphenhydramine reduced the histamine-induced PMNL rolling by 82%. Furthermore, in contrast to an H 3 -receptor agonist, challenge with either the H 1 -receptor agonist 2-thiazolylethylamine or two di erent H 2 -receptor agonists (impromidine, dimaprit) was su cient to provoke signi®cant venular PMNL accumulation. 5 Treatment with the nitric oxide-synthase inhibitor L-NAME did not a ect the histamine-induced PMNL rolling. On the other hand, 3 h pretreatment with dexamethasone reduced the PMNL response to histamine by 73%, and¯ow cytometric analysis showed that the dexamethasone treatment almost completely inhibited binding of soluble P-selectin to rat isolated PMNLs. 6 We conclude that initial leukocyte recruitment after mast cell activation in the rat mesentery is critically dependent on histamine release. The cellular response to histamine was speci®cally due to PMNL rolling, involved activation of both H 1 -and H 2 -receptors, ...

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