AIMTo investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. METHODSThree studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose-response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H 1-and H2-receptor antagonists. Flare and itch were assessed in all studies. RESULTSHistamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min ; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2-receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min -1 histamine: -11.9 ml min -1 100 ml -1 (-4.0, -19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: -403.7 cm 2 (-231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1-receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. CONCLUSIONHistamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2-receptors are important in this process. Our results support further exploration of combined H1-and H2-receptor antagonist therapy in acute allergic syndromes.