Analysis of the pharmacological effects of selective monoamine oxidase inhibitors

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Abstract

The simultaneous oxidation of labelled monoamines in the presence and absence of selective monoamine oxidase (MAO) inhibitors (deprenyl and clorgyline) by rat liver and brain mitochondrial MAO was studied with the double labelling technique. 5 Hydroxytryptamine (5HT), phenylethylamine (PEA), benzylamine (BZA) and tyramine (TYR) inhibit the oxidation of each other. According to the Lineweaver Burk analysis the inhibition was found to be non competitive between 5HT and BZA, and competitive between BZA and PEA, TYR and BZA, and 5HT and TYR. The nictitating membrane contracting effects of intravenous 5HT, tryptamine, PEA, TYR and BZA in cats before and after exclusion of the liver from the circulation and under the influence of MAO inhibitors (tranylcypromine, nialamide, pargyline, (-) deprenyl and clorgyline) were measured. Taking the dose related increase of the effects of an amine as an index of the in vivo rate of biotransformation, the existence of two different enzymes, namely phenylethylamine oxidase, selectively inhibited by (-) deprenyl, and 5 hydroxytryptamine oxidase, selectively blocked by clorgyline, was deduced. Striking differences in the effects of (-) deprenyl and clorgyline on isolated organs (guinea pig ileum and vas deferens, cat papillary muscle) supported this view. Clorgyline was found to possess a high affinity for the 5HT receptor, blocking it in a non competitive manner. Characteristic differences in the responsiveness of the field stimulated isolated guinea pig and rat vas deferens were demonstrated. Noradrenaline appears to be the transmitter in both organs but profound differences in the transmission machinery seem to exist. In the 'pure' system of the rat an unrestricted noradrenaline release from the granules follows nerve stimulation and in the 'mixed' system of the guinea pig vas deferens stimulation is supposed to release both noradrenaline and PEA from the granules, and the latter may increase the outflow of noradrenaline from a cytoplasmic pool. Prostaglandin restricts the release of noradrenaline in the 'mixed' system only. There is a cholinergic modulation of noradrenergic transmission in the rat vas deferens, and in the guinea pig vas 5HT also serves as a modulator. The therapeutic aspects of the selective inhibitors were evaluated. (-) Deprenyl combined with phenylalanine is hoped to be efficient in certain types of depression and combined with L dopa in Parkinson's disease. In contrast to clorgyline and other MAO inhibitors, (-) deprenyl inhibits MAO activity slightly in the intestine, antagonizes the effects of tyramine and inhibits the outflow of [3H]noradrenaline from brain synaptosomes; consequently the absence of hypertonic crises in patients treated with (-) deprenyl can be expected.

Original languageEnglish
Pages (from-to)135-161
Number of pages27
JournalUnknown Journal
VolumeNo. 39
Publication statusPublished - Jan 1 1976

ASJC Scopus subject areas

  • Medicine(all)

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