MICROVASCULAR ACTIONS OF HISTAMINE - SYNERGISM WITH LEUKOTRIENE B-4 AND ROLE IN ALLERGIC LEUKOCYTE RECRUITMENT

Background Previous studies have shown that antihistamines provide lit tle or no protection against the recruitment of leucocytes in allergic inflammation. Objective We wanted to examine if threshold doses of hi stamine can potentiate chemoattractant-induced leukocyte adhesion and if complete inhibition of histamine-induced microvascular effects is n ecessary to reduce allergic leucocyte recruitment. Methods The role of histamine in allergic leucocyte recruitment was examined by use of in travital microscopy of the hamster cheek pouch microcirculation. Resul ts We found that topical administration of histamine caused a concentr ation-dependent increase in microvascular permeability in the cheek po uch; i.e. 0.3 mu M histamine caused no detectable plasma leakage, whil e 1 mu M and 10 mu M histamine resulted in 29 +/- 9.3 and 356 +/- 47 l eakage sites/cm(2) cheek pouch area, respectively. The percentage of p ostcapillary venules with more than five adherent leucocytes (an index of early leucocyte recruitment) was 1.1 +/- 0.51% in the control situ ation, and did not increase significantly after stimulation with hista mine alone (0.3-10 mu M) or With 1 nM leukotriene B-4 (LTB4). On the o ther hand, coapplication of 10 mu M histamine and 1 nM LTB4 increased leucocyte adhesion 24-fold. In fact, the 10 times lower dose of histam ine (1 mu M) together with 1 nM LTB4 increased leucocyte adhesion to a similar extent (20 fold). The increase in vascular permeability evoke d by exogenous 10 mu M histamine (with or without LTB4), or by histami ne released from activated mast cells (antigen challenge), was complet ely reversed by local pretreatment with the H-1-receptor antagonist me pyramine. This mepyramine treatment also abolished the enhanced leucoc yte adhesion in response to coapplication of histamine and LTB4. Moreo ver, mepyramine, which had no effect on leucocyte recruitment evoked b y 3 nM LTB4 per se, reduced antigen-induced recruitment of leucocytes to the extravascular tissue by 79.5 +/- 14.8%. Conclusion We conclude that threshold concentrations of histamine can strikingly potentiate c hemoattractant-induced leucocyte responses, and that in order to reduc e allergic leucocyte recruitment it may be necessary to use antihistam ines in doses high enough to abolish the microvascular actions of hist amine.