Diamine oxidase knockout mice are not hypersensitive to orally or subcutaneously administered histamine

Abstract

Objective To evaluate the contribution of endogenous diamine oxidase (DAO) in the inactivation of exogenous histamine, to find a mouse strain with increased histamine sensitivity and to test the efficacy of rhDAO in a histamine challenge model. Methods Diamine oxidase knockout (KO) mice were challenged with orally and subcutaneously administered histamine in combination with the β-adrenergic blocker propranolol, with the two histamine-N-methyltransferase (HNMT) inhibitors metoprine and tacrine, with folic acid to mimic acute kidney injury and treated with recombinant human DAO. Core body temperature was measured using a subcutaneously implanted microchip and histamine plasma levels were quantified using a homogeneous time resolved fluorescence assay. Results Core body temperature and plasma histamine levels were not significantly different between wild type (WT) and DAO KO mice after oral and subcutaneous histamine challenge with and without acute kidney injury or administration of HNMT inhibitors. Treatment with recombinant human DAO reduced the mean area under the curve (AUC) for core body temperature loss by 63% (p = 0.002) and the clinical score by 88% (p < 0.001). The AUC of the histamine concentration was reduced by 81%. Conclusions Inactivation of exogenous histamine is not driven by enzymatic degradation and kidney filtration. Treatment with recombinant human DAO strongly reduced histamine-induced core body temperature loss, histamine concentrations and prevented the development of severe clinical symptoms.

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

“…When calculating the total excretion of histamine and 1-Methylhistamine in urine after 60 min, less than 2% of the infused histamine was excreted by the kidneys. The disappearance of > 95% of histamine was also observed in mice, which showed much lower histamine plasma concentrations than expected [ 15 ]. In previous mouse experiments, a similar rapid shift of intravenously infused radioactive histamine from the blood to other compartments was published [ 30 , 31 ] .…”

“…In recent experiments, our group used the same intravenous dose of 4 mg/kg rhDAO_mHBM in mice after receiving 5 mg/kg histamine subcutaneously. rhDAO_mHBM reduced the maximum plasma histamine levels from ~ 800 to 200 ng/ml, reduced the induced drop in body temperature from – 4.4 °C to – 1.6 °C, and mitigated clinical symptoms [ 15 ]. The present data show a significantly lower body temperature ( p = 0.02) at the end of the histamine infusion in guinea pigs receiving buffer compared to 4 mg/kg rhDAO_mHBM (Supplementary Fig.…”

“…Diamine oxidase is a copper-containing amine oxidase that rapidly degrades histamine and therefore represents a promising therapeutic approach for the treatment of severe anaphylactic reactions [ 14 ]. Treatment with rhDAO_mHBM reduced the histamine-induced decrease in body temperature and plasma histamine concentrations and prevented the development of severe clinical symptoms in mice [ 15 ] . However, most rodents including mice and rats are insensitive to histamine, which is demonstrated by the difference in the half-lethal dose (LD 50 ) of intravenously administered histamine of 630 and 595 mg/kg for rats and mice, respectively, compared to 2 mg/kg for rabbits and likely much lower for humans [ 16 , 17 ].…”

Protective Effect of Ticagrelor Against Infective Endocarditis Induced by Virulent Staphylococcus aureus in Mice

“…In the presently used mouse model of IE, it has previously been shown that bacteria adhesion to the valve occurs almost immediately (within minutes) after catheter insertion and histamine infusion. 11 Moreover, since histamine has a very short half-life in vivo (several minutes), 34 the inflammation-triggered bacteria adhesion is limited in time, and mice that do not show bacteria on their valve immediately after infusion will not develop endocarditis 3 days later. Therefore, the observed inhibition of bacterial adhesion to inflamed EC in our in vitro experimental setting in which bacteria were grown in the presence of ticagrelor before being washed and used in the adhesion assays fairly reproduces what happens in vivo when bacteria are injected intravenously after ticagrelor administration.…”