Microvascular actions of histamine: synergism with leukotriene B4 and role in allergic leucocyte recruitment


Dr J. Raud, Department of Physiology and Pharmacology, Karolinska Institute, Division of Physiology 1, Doktorsringen 6A, S-171 77 Stockholm, Sweden.


Background Previous studies have shown that antihistamities provide little or no protection against the recruitment of leucocytes in allergic inflammation.

Objective We wanted to examine if threshold doses of histamine can potentiate chemoattractant-induced leukocyte adhesion and if complete inhibition of histamine-induced microvascular effects is necessary to reduce allergic leucocyte recruitment.

Methods The role of histamine in allergic leucocyte recruitment was examined by use of intravital microscopy of the hamster cheek pouch microcirculation.

Results We found that topical administration of histamine caused a concentration-dependent increase in microvascular permeability in the cheek pouch; i.e. 0.3 μM histamine caused no detectable plasma leakage, while 1 μM and 10 μM histamine resulted in 29 ± 9.3 and 356 ± 47 leakage sites/cm2 cheek pouch area, respectively. The percentage of postcapillary venules with more than five adherent leucocytes (an index of early leucocyte recruitment) was 1.1 ± 0.51% in the control situation, and did not increase significantly after stimulation with histamine alone (0.3–10μM) or with 1 nM ieukotriene B4 (LTB4). On the other hand, coapplication of 10μM histamine and 1 nM LTB4 increased leucocyte adhesion 24-fold. In fact, the 10 times lower dose of histamine (1 μM) together with 1 nM LTB4 increased leucocyte adhesion to a similar extent (20 fold). The increase in vascular permeabihty evoked by exogenous 10μM histamine (with or without LTB4), or by histamine released from activated mast cells (antigen challenge), was completely reversed by local pretreatment with the H1-receptor antagonist mepyramine. This mepyramine treatment also abohshed the enhanced leucocyte adhesion in response to coapplication of histamine and LTB4. Moreover, mepyramine, which had no effect on leucocyte recruitment evoked by 3 nM LTB4per 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 chemoattractant-induced leucocyte responses, and that in order to reduce allergic leucocyte recruitment it may be necessary to use antihistamines in doses high enough to abolish the microvascular actions of histamine.