Microvascular actions of histamine: synergism with leukotriene B4 and role in allergic leucocyte recruitment.
BACKGROUND
Previous studies have shown that antihistamines 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 microM histamine caused no detectable plasma leakage, while 1 microM and 10 microM 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 (0.3-10 microM) or with 1 nM leukotriene B4 (LTB4). On the other hand, coapplication of 10 microM histamine and 1 nM LTB4 increased leucocyte adhesion 24-fold. In fact, the 10 times lower dose of histamine (1 microM) together with 1 nM LTB4 increased leucocyte adhesion to a similar extent (20 fold). The increase in vascular permeability evoked by exogenous 10 microM 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 abolished 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 LTB4 per se, reduced antigen-induced recruitment of leucocytes to the extravascular tissue by 79.5 +/- 14.8%.


CONCLUSIONS
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.
Thorlacius
H
H
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Lindbom
L
L
Hedqvist
P
P
Raud
J
J
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002610:Cheek; D006224:Cricetinae; D004357:Drug Synergism; D006632:Histamine / Q000008:administration & dosage*; D006967:Hypersensitivity / Q000209:etiology* / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects* / Q000473:pathology; D007975:Leukotriene B4 / Q000008:administration & dosage*; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects*
D007975:Leukotriene B4; D006632:Histamine