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Notes: Abstract Histamine concentrations in canine whole blood and plasma were determined under several pharmacological, pathophysiological, and clinical conditions, using fluorometric methods. The specificity of the assay for whole-blood histamine was investigated by comparing 3 purification procedures for the isolation of histamine from whole blood including butanol extraction (Shore), ion-exchange chromatography on Dowex 50 W-X 8, and the combination of these 2 methods (Lorenz). Histamine in whole blood was identified in analytical and preparative samples by fluorescence spectra, thin-layer chromatography, degradation by diamine oxidase from pig kidney and inactivation by histamine methyltransferase from guinea-pig brain as well as by biological tests on the isolated guinea-pig ileum. Since butanol extraction resulted in significantly higher ‘histamine’ values than the other two purification procedures, ion-exchange chromatography on Dowex 50 was recommended as the method of choice for the specific determination of histamine in dog's whole blood. Normal values of histamine concentrations in canine plasma were tentatively estimated. They depended on the time between pretreatment of the animals (anaesthesia, operation) and the collection of blood and showed an approximately logarithmic normal distribution. The median, the lower/upper quartiles and the range of the plasma histamine levels obtained 30 minutes after the end of pretreatment were 0.2, 0–0.4 and 0–1.2 ng/ml, respectively. Nearly 50% of the values were zero (below 0.1 ng according to the sensitivity of the method), only 1% of them exceeded slightly 1 ng/ml. Thus histamine release by drugs or by other medical treatments was only stated, when plasma histamine levels exceeded 1 ng/ml and decreased in a way to give an elimination curve of approximately first-order kinetics (Bateman function). Histamine concentrations in dog's whole blood showed approximately a logarithmic normal distribution. The median, lower/upper quartiles and range were 47, 34/75 and 13–209 ng/ml respectively. The histamine levels in the whole blood of four circulatory regions did not show any significant differences. The plasma histamine concentrations in the portal vein were slightly higher than in the hepatic veins. The injection of exogenous histamine and the concomitant determination of plasma and whole-blood histamine levels in four circulatory regions showed that the plasma histamine determination was the more sensitive method for measuring histamine elimination curves than the whole-blood histamine assay. The elimination of exogenous histamine administered intravenously was influenced by several drugs including inhibitors of histamine inactivation and histamine receptor antagonists. Aminoguanidine and the H2-receptor antagonist burimamide slowed down the disappearance of histamine from the plasma, the H1-receptor antagonist dimethpyrindene enhanced it, but amodiaquine had no significant effects. Dimethpyrindene and burimamide were capable of releasing histamine in dogs, in some cases to a considerable extent. The plasma substitute Haemaccel®, a chemically modified gelatin, released histamine in dogs. Using batch 3000, from 27 animals investigated, 15 animals showed elevated plasma histamine levels and a hypotensive blood pressure response, whereas in 12 of the dogs it did not show an effect on these parameters. The plasma histamine levels at the time of maximum hypotension showed an approximately logarithmic normal distribution. This frequency distribution in combination with the varying incidence of anaphylactoid reactions depending on the batches used seemed very important for the interpretation of clinical reactions to Haemaccel in human test persons and patients. By histamine determinations in plasma and whole blood of several circulatory regions and in various tissues before and after infusion of Haemaccel it could be demonstrated that the sites of histamine release by Haemaccel in dogs were especially the skin of the upper hemisphere of the body and the liver, whereas the gastro-intestinal tract took up histamine from the circulation. These numerous results under various experimental conditions may be considered as an evidence for the high quality and reliability of the method to study histamine release in the whole animal or in human subjects by evaluating histamine elimination curves in plasma.