Effects of H1 antagonists on the cutaneous vascular response to histamine and bradykinin: a study using scanning laser Doppler imaging.
Histamine plays an important part in the cutaneous weal and flare response which underlies many allergic skin conditions. It has a direct effect on the local vasculature to promote vasodilatation and increase microvascular permeability and may also initiate the more widely spread neurogenic flare. Quantification of these responses and studies of the mediator mechanisms underlying them have been limited by the lack of appropriate techniques to investigate them. To address this we have used two relatively new techniques, scanning laser Doppler imaging (LDI) and dermal microdialysis to measure changes in skin blood flow and the release of histamine within the weal and flare, following intradermal injection of histamine or bradykinin. These measurements have been made both in the absence and presence of the H1 receptor blockers cetirizine and loratadine. Scanning LDI of the inflammatory response revealed marked differences in both the development and steady state responses to the intradermal injection of histamine (1-3 mumol/L) and bradykinin (1 mumol/L). The development of the flare and the weal response to both histamine and bradykinin was significantly reduced by cetirizine but not by loratadine. The histamine-induced flare area fell by 57 +/- 4% (mean +/- SEM, n = 10, P < 0.001) after cetirizine and the area of the weal fell by 73 +/- 11% (P < 0.009). Bradykinin-induced inflammatory responses were similarly reduced by cetirizine, the weal by 60 +/- 16% (P < 0.02) and the flare by 61 +/- 4% (P < 0.005). Measurement of histamine concentration in skin using microdialysis, in six subjects, confirmed that histamine levels rose in the dialysate collected from the weal to 310 +/- 16 nmol/L following injection of histamine. Histamine levels also rose following bradykinin injection in some subjects (mean 147 +/- 46 nmol/L, range 18-336). Little increase in histamine concentration was seen in the dialysate from the flare following injection of either histamine or bradykinin. The histamine concentration in dialysate from unprovoked skin was 4.19 +/- 0.75 nmol/L. These data reveal differences in the dermal responses to different mediators when assessed using scanning LDI. They confirm that histamine is released within the weal but not the flare response to the intradermal injection of both histamine and bradykinin and that its effects on the local vasculature to cause the oedematous weal and the axon reflex-mediated flare are significantly attenuated by the H1 antagonist cetirizine and to a lesser extent by the H1 antagonist loratadine.
Clough
G F
GF
Immunopharmacology Group, University of Southampton, Southampton General Hospital, U.K. gfc1@soton.ac.uk
Bennett
A R
AR
Church
M K
MK
D000328:Adult; D001920:Bradykinin / Q000037:antagonists & inhibitors; D017332:Cetirizine / Q000494:pharmacology; D017449:Dermatitis, Allergic Contact / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006632:Histamine; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D017078:Laser-Doppler Flowmetry; D017336:Loratadine / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D017551:Microdialysis; D008875:Middle Aged; D012867:Skin / Q000098:blood supply*
D006634:Histamine H1 Antagonists; D017336:Loratadine; D006632:Histamine; D001920:Bradykinin; D017332:Cetirizine