[Defect in deamination of biogenic amines in spontaneous hypertension]. / Narushenie dezaminirovaniia biogennykh aminov pri spontannoi gipertenzii.

Activity of monoamine oxidases (MAO) of the types A and B (substrates: 5-hydroxytryptamine, 2-phenylethylamine, tyramine) has been studied in mitochondrial fractions from brain, heart, liver and kidney of 24-week-old rats of the normotonic strain Wistar Kyoto (WKY) and spontaneously hypertonic rats (SHR). As compared with the WKY rats, in the SHR strain the activity of MAO-A in heart mitochondria was increased 1.5-1.7-fold; in liver mitochondria the activities of both MAO-A and -B were increased 2.6-2.7-fold. In brain mitochondria there was noted only slight tendency towards an increase in MAO-A (substrate: 5-hydroxytryptamine) and MAO-B (substrate: 2-phenylethylamine) activities in the SHR strain as compared with the normotonic animals of the same age. However, in experiments with tyramine as a substrate of MAO the enzymatic activity in SHR brain mitochondria was increased 1.5-fold (P less than 0.05) as compared with the WKY rats. In kidney mitochondria of SHR the activity of MAO (substrates: 5-hydroxytryptamine, 2-phenylethylamine, tyramine) did not exhibit any alterations as compared with the control WKY rats.

[Inhibition of brain monoamine oxidase in the rat by multiple pyrazidol administration]. / Ingibirovanie monoaminoksidazy mozga krysy v usloviiakh mnogokratnogo vvedeniia pirazidola.

Pyrazidol, which is chemically 2,3, 3a, 4, 5, 6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k] carbazole hydrochloride (international name pirlindole) administered repeatedly (21 days) to rats at a dose of 25 mg/kg per os maintained the selectivity of its inhibitory effect toward type A MAO. When administered repeatedly the inhibitory effect of pyrazidol was 1.5-2-fold higher than after a single administration. The effect of pyrazidol on rat brain MAO was reversible whatever the route of administration. The enzymatic activity returned to normal within 24 h after the last administration. The data obtained suggest that the capacity of selective inhibiting the deamination of the neurotransmitters such as serotonin and noradrenaline in human brain is of paramount importance for therapeutic effect of pyrazidol.

[Inhibition of gamma-amylase of the rabbit liver by biogenic amines and products of their oxidative deamination]. / Ingibirovanie gamma-amilazy pecheni krolika biogennymi aminami i produktami ikh okislitel'nogo dezaminirovaniia.

Products of oxidative deamination of biogenic amines (aldehydes) exhibited an inhibitory effect on rabbit liver gamma-amylase activity. The aldehydes, formed after serotonin and 2-phenylethylamine oxidation, proved to be most effective in these systems. Dopamine, noradrenaline and tyramine also caused a slight inhibitory action under these conditions. Biogenic amines and corresponding aldehydes participate apparently in regulation of gamma-amylolysis of glycogen in human and animal organisms.

[Selective inhibition by pyrazidol of monoamine oxidase type A in different human and animal tissues]. / Izbiratel'noe ingibirovanie pirazidolom monoaminoksidaz tipa A v razlichnykh tkaniakh cheloveka i zhivotnykh.

Pyrazidol (2,3,3a,4,5,6-Hexahydro-8-methyl-1-H-pyrazino (3,2,1-j,k) carbazol hydrochloride) blocked selectively the type A monoamine oxidase (MAO) in mitochondria of different human and animal tissues, irrespective of substrate specificity of the type A MAO in the tissues studied. Thus, in tissues containing both types of MAO (rat, bovine and human brain, rat liver and intestine tissues) pyrazidol inhibited selectively the deamination of serotonin and did not affect the deamination of 2-phenylethylamine--the main substrates in these tissues of the type A and the type B MAO, respectively. In human placenta and rat heart containing only the type A MAO, which catalyzes deamination of 2-phenylethylamine, pyrazidol also inhibited the deamination of serotonin, tyramine and 2-phenylethylamine at comparatively low concentrations and in equal degree. Pyrazidol did not affect significantly the type B MAO in bovune liver and kidney tissues, although the latter enzyme catalyzed deamination of serotonin. The degree of inhibition by pyrazidal of dopamine deamination in various tissues depended on the particular type of MAO mainly involved in oxidation of the amine.

[Properties of intestinal monoamine oxidase in the rat]. / O svoistvakh monoaminoksidazy kishechnika krysy.

Monoamine oxidase (MAO) activity (substrate: tyramine) has been studied in rat intestinal wall mitochondrial fractions identified by monitoring succinate dehydrogenase and cytochrome oxidase activities. The MAO activity, which was not due to contamination with mitochondria, has been also found in nuclear and microsomal (+hyaloplasm) fractions. Deamination of tyramine, serotonin and dopamine by rat intestinal mitochondrial MOA obeyed the Michaelis--Mentern kinetics. The Vmax values were the highest for deamination of tyramine, the lowest--for norepinephrine. The lowest Km value was recorded in the systems with 2-phenylethylamine. Data on the inhibitory effect of low concentrations of deprenyl suggest that 50% of the total tyramine deaminating activity in rat intestinal mitochondria was due to presence of MAO type B. Low concentrations of chlorgyline inhibited the deamination of tyramine in these systems by 20-30% suggesting a possibility of presence in the rat intestinal mitochondria of a tyramine deaminating activity distinct from MAO type A. Pyrazidol or harmine, which are selective inhibitors of the MAO type A, caused only partial (30-40%) inhibition of MAO activity (substrate: tyramine) in rat intestinal mitochondria. Controlled heating experiments indicated higher thermostability of MAO type B (substrate: 2-phenylethylamine) as compared with MAO type A (substrate: serotonin) in rat intestinal mitochondria. The data obtained suggest that rat intestinal mitochondria, contrary to human intestinal mucosa (cf. ref. 2), contain about 50% of MAO type B, which is comparatively thermostable and does not resemble in this respect the MAO type B in many other biological sources.

[Effect of pyrazidole and deprenyl on monoamine oxidase in the rat intestine]. / Vliianie pirazidola i depranila na monoaminoksidazu kishechnika krysy.

Pyrazidol (1,10-trimethylene-3-methyl-1,2,3,4-tetrahydropyrazino(1,2-a)indole hydrochloride) in low concentrations (0.005 mM) completely blocks the deamination of serotonin, partially that of tyramine, and does not virtually affect the deamination of 2-phenylethylamine by the mitochondria of intestinal cells. There is evidence for the presence of types A and B monoamine oxidases in the rat intestine. Pyrazidol appears to be a selective inhibitor of type A monoamine oxidase of the rat intestine.

[Selective inhibition of type A monoamine oxidase by pyrazidol]. / Izbiratel'noe ingibirovanie pirazidolom monoaminoksidazy tipa A.

Effect of a new antidepressant pyrazidol (1,10-trimethylene-8-methyl-1,2,3,4-tetrahydropyrazino /1,2-/ indole) on the liver and brain MAO activity of rats was studied in experiments in vivo and in vitro. Pyrazidol selectively blocks type A MAO (the substrates serotonin and noradrenaline) and does not virtually affect or has a far less action on type B MAO (the substrate 2-phenylethylamine).

[Monoamine oxidation in the mitochondrial fraction of bovine kidney catalyzed by monoamine oxidase type B]. / Okislenie monoaminov v mitokhondrial'noi fraktsii pochek byka, kataliziruemoe monoaminoksidazoi tipa B.

Oxidative deamination of tyramine, serotonin and benzyl amine in bovine kidney mitochondria was inhibited by low concentrations of deprenil (but not clorgylline). These data and the patterns of the plots of residual enzymatic activity against concentration of the inhibitors as well as the "mixed substrates" experiments suggest occurrence in bovine kidney mitochondria of monoamine oxidase of the B type only, which has to be considered in studies on the nature of monoamine oxidases using bovine kidney mitochondria as a rich source of monoamine oxidase activity.

[Spectrophotometric method of determining monoamine oxidase activity in human thrombocytes]. / Spektrofotometricheskii metod opredeleniia aktivnosti monoaminoksidazy v trombotsitakh cheloveka.

A method for estimation of monoamine oxidase activity in human thrombocytes is developed. The method is based on coupling of monoamine oxidase and alcohol dehydrogenase reactions. The method was highly reproducible. Small volumes of blood were required for analysis. Values of MAO activity, obtained by the method, were in good agrement with the data published in literature.

[Effect of new 2-propinylamine derivatives on mitochondrial monoamine oxidase activity]. / Vliianie novykh proizvodnykh 2-propinilamina na aktivnost' mitokhondrial'nykh monoaminoksidaz.

New derivatives of 2-propinyl amine were studied as possible inhibitors of mitochondrial monoamine oxidases (MAO) from rat liver and brain tissues. Kinetics of inhibition of the MAO activity (A and B types) is described for one of the substances studied -- N-(8-quinolyl methyl)-N-methyl-2-propinyl amine. Interaction of N-(8-quinolylmethyl)-N-methyl-2-propinyl amine with MAO of the A type (serotonin as a substrate) and of the B type (beta-phenylethylamine as a substrate) was studied by the kinetic method, which enabled to determine and quantitatively estimate the steps of enzyme-inhibitor complexes formation. The inhibition of the mitochondrial MAO A and B types by the substance was shown to include the steps of formation of dissociating enzyme-inhibitor intermediates with the subsequent irreversible modification of them. The data on K1 values, estimated in experiments with serotonin and beta-phenylethylamine as substrates, show that the affinity of N-(8-quinolyl methyl)-N-methyl-2-propinyl amine towards MAO of the A type was 10-fold higher than the affinity towards MAO of the B type. The rates of these complexes conversion into irreversibly blocked forms of the MAO A and B types was found to be similar.

[Determination of monoamine oxidase activity in a coupled reaction with alcohol dehydrogenase]. / Opredelenie aktivnosti monoaminoksidazy v sopriazhennoi reaktsii s alkogol' degidrogenazoi.

A simple kinetic method is developed for estimation of the monoamine oxidase (MAO) activity in solubilized mitochondria and purified preparations of MAO from rat liver tissue. The method is based on the property of alcohol dehydrogenase (from horse liver tissue) to catalyze the reduction of fatty-aromatic aldehydes (products of the MAO reaction) to appropriate alcohols in presence of NADH2 excess. The rate of the coupled reaction was evaluated spectrophotometrically by a decrease of the optic density at 340 nm. The optimal conditions were ascertained for coupling of these two reactions. Application of several amines was shown to be possible for estimation of the MAO activity by the kinetic method developed.

[Inhibition of the activity of monoamine oxidases type A and B by derivatives of 2-propynylamine]. / O tormozhenii proizvodnymi 2-propinilamina aktivnosti monoaminoksidaz tipov A i B.

Inhibition by N-methyl-2-propynylamine derivatives (pargylline, deprenyl, chlorgyline indamanine) of monoamine oxidases (MAO) type Z (serotonin as a substrate) and type B (substrate: beta-phenylethylamine) in fragments of rat liver mitochondrial membranes was studied by means a kinetic method (15) which enables to detect and to evaluate quantitatively formation of intermediary dissociable enzyme-inhibitor complexes as well as to measure the rate of irreversible modification of these complexes (leading to the irreversible inhibition of MAO). The step of intermediary dissociable enzyme-inhibitor complex formation was involved in the processes of inhibition of mitochondrial MAO types A and B by all the 2-propynylamine derivatives studied. Rates of modification of these complexes into irreversibly inhibited forms of MAO types A and B in presence of different 2-propynylamine derivatives were of the same order of magnitude. But the values of the dissociation constants of the intermediary complexes for both MAO types differed dramatically with alterations of the substituents at the nitrogen atom in molecules of the 2-propynylamine derivatives which probably determines the well recognized properties of the 2-propynylamine derivatives of causing highly selective inhibition of oxidative deamination of various biogenic monoamines.

[Study of the mechanism of action of the new antidepressant pyrazidol]. / Issledovanie mekhanizma deistviia novogo antidepressanta pirazidola

The biochemical mechanism of action produced by a new antidepressant pyrazidol (1,10-trimethylene-8-methyl-1, 2, 3, 4-tetrahydropyrazino[1,2-a] indole hydrochloride) includes the inhibitory influence on the neuronal uptake of norepinephrine and a reversible comparatively short-lived inhibitory effect on the MAO activity.