Recombinant human diamine oxidase prevents hemodynamic effects of continuous histamine infusion in guinea pigs

Abstract

Objective To test whether recombinant human diamine oxidase (rhDAO) with a mutated heparin-binding motif (mHBM), which shows an increased alpha-distribution half-life, prevents histamine-induced hemodynamic effects. Material Thirty-eight female guinea pigs were either pretreated with rhDOA_mHBM or buffer. Treatment and methods Guinea pigs received a continuous infusion of histamine. Heart rate (HR), body core temperature and mean arterial pressure (MAP) were measured and blood was collected. Results Continuous intravenous infusion of 8 µg/kg/min histamine increased mean peak plasma histamine levels from 5 (± 0.3 SEM) to 28 ng/mL (± 4.9 SEM) after 30 min but had no effect on oxygen saturation. Guinea pigs pretreated with 4 mg/kg rhDAO_mHBM showed lower mean HR ( p = 0.008), histamine plasma concentrations ( p = 0.002), and higher body core temperatures at the end of the histamine challenge ( p = 0.02) compared to controls. Cessation of histamine infusion led to a rebound increase in MAP, but this hemodynamic instability was prevented by rhDAO_mHBM. Pretreatment with 4 mg/kg rhDAO_mHBM reduced urinary histamine ( p = 0.004) and 1-Methylhistamine ( p < 0.0001) concentrations compared to controls. Conclusions Prophylactic infusion of rhDAO_mHBM prevents hemodynamic effects in a guinea pig model of continuous histamine infusion. These findings might help in the translation from animals to humans and in the selection of the optimal dosing of rhDAO_mHBM during human histamine challenge studies.

Bibliographic Information