ROLE OF H1 RECEPTORS AND P-SELECTIN IN HISTAMINE-INDUCED LEUKOCYTE ROLLING AND ADHESION IN POSTCAPILLARY VENULES

The objective of this study was to define the nature, magnitude, and m echanisms of histamine-induced leukocyte-endothelial cell interactions in postcapillary venules of the rat mesentery using intravital micros copic techniques. Superfusion of the mesentery with histamine (10(-7)- 10(-5) M) resulted in a dose-related increase in the number of rolling leukocytes, a reduction in rolling velocity, and an increased clearan ce of FITC-labeled rat albumin from blood to superfusate. The histamin e-induced recruitment of rolling leukocytes and increased albumin clea rance were prevented by histamine H1 (hydroxyzine, diphenhydramine) bu t not H2 (cimetidine) receptor antagonists. Because histamine induces expression of the adhesion molecule P-selectin in cultured endothelial cells, a monoclonal antibody directed against rat P-selectin and solu ble sialyl-Lewis(X) oligosaccharide (the carbohydrate ligand to P-sele ctin) were also tested as inhibitors. Both were effective in preventin g the histamine-induced recruitment of rolling leukocytes, but neither agent attenuated the increased albumin clearance. These observations suggest that (a) histamine recruits rolling leukocytes and increases a lbumin leakage in postcapillary venules via H1 receptor activation, (b ) histamine-induced recruitment of rolling leukocytes is mediated in p art by P-selectin expressed on the endothelial cell surface, and(c) th e histamine-induced vascular albumin leakage is unrelated to leukocyte -endothelial cell adhesion. Our results are consistent with the view t hat histamine may act as a mediator of acute inflammatory reactions.