Potentiation of pharmacological effects of histamine by histaminase inhibitors

Abstract

Best showed in 1929 that extracts of animal tissues destroy histamine and named the enzyme system concerned in this reaction histaminase. In 1938 Zeller described an enzyme, diamine oxidase, which destroys the diamines putrescine and cadaverine (Zeller, 1938a), and subsequently concluded that histaminase and diamine oxidase were identical (Zeller, 1938b). This conclusion was based on the finding of a strict parallelism between destruction of histamine and cadaverine by diamine oxidase preparations from different sources; competitive inhibition ofdiamine oxidase by histamine and cadaverine; and inhibition of the destruction of both substances by antagonists of diamine oxidase. More recently, however, Kapeller-Adler (1949, 1951 has questioned the identity of the two enzymes.All carbonyl reagents so far examined inhibit diamine oxidase, often in very low concentrations (Zeller, 1942). Zeller has shown that semicarbazide, thiosemicarbazide and hydroxylamine produce this effect, and has suggested that diamine oxidase itself contains carbonyl groups which interact with diamines and are blocked by carbonyl reagents. Various other compounds also inhibit diamine oxidase, though less actively, e.g. guanidine and iminazole and their derivatives. One of the derivatives of guanidine, however, aminoguanidine, is a powerful inhibitor of diamine oxidase (Schuler, 1952), and it is probably relevant that this compound possesses a reactive amino group like the typical carbonyl reagents.The present experiments started with the observation that in the presence of semicarbazide the action of histamine on guinea-pig intestine was markedly potentiated. Then it was found that other effects of histamine were also potentiated and that other histaminase inhibitors acted like semicarbazide. Experiments dealing with the potentiation of histamine by histaminase inhibitors are described in the first part of this paper. The experiments described in the second part were designed to test whether the potentiating effects of * British Council Scholar.

Effect of Chain Length of Aliphatic Amines on Histamine Potentiation and Release

“…and tubocurarine (1.7 mg./ cadaverine can be explained on similar lines. It 'he activity of the quaternary compound has previously been shown that many inhibitors a I A of histaminase, including cadaverine, selectively potentiate the pharmacological effects of histamine, and that their effectiveness is correlated with their antihistaminase activity (Arunlakshana et al, 1954). This interpretation of the potentiating effect of cadaverine is further supported by the finding that the long-chain diamines CIO and CLsP which produce little or no inhibition of histaminase, also fail to potentiate histamine.…”

“…It would also be expected that potentiation by histamine release would be non-specific. On the contrary, potentiation by cadaverine is specific and only occurs with compounds which are destroyed by histaminase (Arunlakshana et al, 1954).…”

“…Potentiation of histamine contractions of the guinea-pig ileum was estimated in terms of the equivalent histamine dose, taking the dose before adding the potentiator as unity. These methods have been described in detail (Arunlakshana et al, 1954).…”

“…(CH2),, 1.NH2 and diamines NH2. (CH2)..NH2 are found compounds which are destroyed by diamine oxidase (Blaschko and Hawkins, 1950), inhibit the enzyme competitively (Zeller, 1942), potentiate the actions of histamine (Arunlakshana, Mongar, and Schild, 1954), and release histamine (MacIntosh and Paton, 1949). This paper describes the influence of chainlength and pH on these properties.…”

Studies on Mammalian Histidine Decarboxylase

“…dimethylguanidine sulphate Werle (1942); B1 pyrimidine (6-amino-5 -aminomethyl -2-methylpyrimidine), agmatine (l-amino-4-guanidobutane), guanidine, methyl guanidine, and dimethyl guanidine, all of which were tested by Arunlakshana, Mongar, and Schild (1954). Schuler (1952) tested many compounds as histaminase inhibitors amongst which the most active were amino-guanidine and hydrazine sulphate.…”