NONMAST-CELL HISTAMINE KINETICS. IV. INTERRELATION-SHIPS BETWEEN SYNTHESIS, BINDING AND CATABOLISM OF ³H-HISTAMINE IN VIVO

¹ Life Sciences Research, Stanford Research Institute, Menlo Park, Californis

Mechanistic studies of histamine physiology and pharmacology frequently involve the use of inhibitors of histidine decarboxylase, such as -hydrazinohistidine, and of agents, such as aminoguanidine, which inhibit histamine destruction. The present study examines the interrelationships between these two aspects of histamine metabolism. Several methods were used, including one based on the concept of equilibration of exogenous isotopic with endogenous noninast cell histamine. Isotopic data indicated a striking similarity between the actions of aminoguanidine and -hydrazinohistidine. Inhibition of catabolism by both agents was indicated by similar enhancement of retention of exogenous ³H-histamine and reduction of metabolites in tissues. Inhibition of histamine synthesis by aminoguanidine was indicated by a reduction in the accumulation of isotopic amine in tissues of rats administered ³H-histidine. In kinetic experiments with exogenous ³H-histnmine , the effects of aminoguanidine varied depending upon whether the drug was administered before or after the labeled amine. In the latter case a reduced rate of ³H-histamine decline in tissues was consistent with an inhibition of turnover. However, when aminoguanidine or -hydrazinohistidine was administered prior to injection of isotopic amine, enhanced retention was followed, in most tissues, by a period in which the decline of labeled amine was unaffected or accelerated compared to controls. In the heart it was apparent that aminoguanidine pretreatment converted the decline of ³H-histamine from biphasic to monophasic kinetics. Graphic interpretations of results suggested that equilibration of exogenous with endogenous amine may be limited under conditions of prior inhibition of histamine catabolism. Fndings in vitro were consistent with such an interpretation. After administration of ³H-histamine to control and aminoguanidine-pretreated animals, the labeled amine declined more rapidly in vitro in lung and stomach from treated animals. The presence of aminoguanidine in vitro, however, did not alter the rate of ³H-histamine decline in tissues from control animals. Similarly, reserpine, which partially depletes endogenous histamine, might interfere with binding of the amine formed endogenously. Reserpine reduced the in vivo accumulation of ³H-histamine in pyloric stomach and lung after injection of the labeled precursor, even though this drug has been shown to stimulate gastric mucosal histamine synthesis in vitro. The results emphasize limitations in measurements of endogenous isotopic and nonisotopic amine levels and urinary histamine as indications of effects on histidine decarboxylase in vivo. The findings also raise questions concerning the validity of routinely treating animals with aminoguanidine in order to prevent histamine destruction in such experiments.