The concentrations of histamine reported vary considerably from species to species. The present studies sought to determine if blood sampling techniques were at least in part responsible for this large variability. Since plasma catecholamines are influenced by the stress associated with blood sampling, these biogenic amines also were measured. Finally, we explored the possible existence of a relationship between plasma histamine and plasma catecholamine concentrations. The present study confirms that concentrations of histamine in rat plasma are particularly large and establishes that the manner (e.g. awake, anesthetized) and site (e.g. intravenous, decapitation) of blood removal influence the concentrations obtained. The lowest histamine values were seen in samples taken from blood vessels in anesthetized rats. Blood obtained after decapitation showed increasing concentrations of plasma histamine in sequentially obtained samples. An inverse relationship appeared to exist between plasma histamine and plasma catecholamines (predominantly epinephrine). An inhibitory role of epinephrine upon decapitation-associated histamine release was suggested by the observation that both adrenalectomy and catecholamine depletion (alpha-methyl-para-tyrosine) elevated histamine concentrations. Our studies with propranolol, as well as work by other investigators, establish an inhibitory role of ?-receptor stimulation on the release of histamine. On the other hand, histamine injected into the perfused rat adrenal caused a marked release of adrenomedullary catecholamines. In summary our study suggests the presence of a complex interaction between catecholamines and histamine in the regulation of the release of the individual amines. Our findings point to the existence of a histamine-adrenal axis in which the release of histamine may facilitate the release of epinephrine which in turn may restrict further release of histamine.