The inhibition of histamine formationin vivo

Abstract

Histamine formation was measured by the [14C]histamine content of the stomach following injection of [14C]histidine into rats. Carbonyl reagents (e.g. oxyamines) which inactivate pyridoxal phosphate, the co-enzyme of histidine decarboxylase, were the most effective inhibitors of histamine formation in vivo. Although the oximes prepared from imidazol-4(5)-ylmethoxyamine and pyridoxal or pyridoxal phosphate cannot inactivate the co-enzyme, they proved sufficiently potent to merit further study as inhibitors of histamine formation in vivo.Many compounds of diverse chemical structure are active in vitro as histidine decarboxylase inhibitors. Of these only a few, mainly carbonyl reagents such as oxyamines and hydrazine derivatives which inactivate the co-enzyme pyridoxal phosphate (PLP), have been shown to inhibit histamine formation in vivo (Levine, Sat0 & Sjoerdsma, 1965;Johnston & Kahlson, 1967;Reilly & Schayer, 1968;Hakanson & Liedberg, 1972;Kobayashi, Kupelian & Maudsley, 1970;Menon, Clark & Aures, 1971). Carbonyl reagents are generally extremely potent inhibitors of histidine decarboxylase, but because of their action on the co-enzyme they lack specificity and may thus also inhibit other PLP-dependent enzymes.A procedure for the screening of potential inhibitors of histidine decarboxylase in vivo is now described and applied to the evaluation of compounds selected from those previously studied in vitro (Mole & Shepherd, 1972). MATERIALS A N D METHODS DrugsWe Oxime (PLPZMA) of pyridoxal phosphate and imidazol-4(5)-ylmethoxyamineImidazol-4(5)-ylmethoxyamine dihydrochloride (IMA) (Mole & Shepherd, 1972) (1.86 g, 0.01 mol) was dissolved in 50 ml water and added to solid pyridoxal phosphate monohydrate (2.658, 0.01 mol). The mixture was stirred until a clear solution was obtained (about 30 min) and set aside at 4" for 2 h. Sodium bicarbonate (1*68g, 0.02 mol) in 50 ml water was added during 30 min to the stirred solution which was then left overnight at 4". The yellow solid which separated was removed by filtration and washed carefully with ice-cold water to give 2.80g (78 %) of oxime, mp 178-183".

Ventricular histamine concentrations and arrhythmias during acute myocardial ischaemia in rats

“…Rhodanine has been reported to be a selective histidine decarboxylase inhibitor. When given to rats by intraperitoneal injection in corn oil suspension, it causes remarkable reduction in histamine synthesis by the rat stomach [20]. Similar results were obtained in the present investigation; rhodanine-pretreated rats had significantly lower ventricular histamine concentrations when compared with the corn oil-pretreated controls.…”

Effect of histidine decarboxylase inhibitors and other drugs on histamine formation in vivo

“…MOLE and SHEPHERD [23] have recently reported effects of some drugs on 14C-histamine content of stomach following injection of ~4C-Lhistidine; however, as they used rats, and killed them 2 hours post-14C-L-histidine, their data can not be usefully compared with ours.…”