Amitriptyline affects histamine-N-methyltransferase and diamine oxidase activity in rats and guinea pigs

Histamine participates in numerous physiological and patophysiological processes. Drugs which interfere with the histamine actions are antagonists and agonists of histamine receptors. Histamine degrading enzymes as a possible target for modifying histamine action have so far not been extensively studied. Therefore we examined in vivo and in vitro effects of amitriptyline on two histamine degrading enzymes — diamine oxidase and histamine-N-methyltransferase. We were interested in the in vivo effects of amitriptyline on the diamine oxidase release into guinea pig plasma after heparin stimulation and in effects on the activity and gene expression of both histamine degrading enzymes in different guinea pig tissues. Amitriptyline's in vitro effects on the diamine oxidase and histamine-N-methyltransferase activities were measured in guinea pig and also in rat. Enzyme activities were determined with the radiometric micro-assay. The results showed that amitriptyline in vivo changed the profile of the heparin-induced diamine oxidase release, which could be due to changes in at least three processes: diamine oxidase release into plasma, protein synthesis and enzyme activity at the molecular level. Amitriptyline in some tissues (lung and spleen) amplified the mRNA expression of histamine degrading enzymes. Furthermore, the activities of these enzymes were increased in most examined tissues of amitriptyline treated guinea pigs. In vitro studies indicate that amitriptyline differently affects diamine oxidase and histamine-N-methyltransferase in two different rodent species, guinea pig and rat. Our study proved that amitriptyline enhances the histamine degrading processes in guinea pig, what might importantly contribute to lower histamine levels.