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PubMed1983

[Effect of protein denaturing reactions on retardation of the activity of rat liver mitochondrial monoamine oxidase by clorgyline and deprenyl].

The denaturating effects of urea on clorgyline-produced inhibition of serotonin and tyramine deamination and deprenyl-produced inhibition of beta-phenylethylamine and tyramine oxidation were studied. It was shown that after preincubation of mitochondria with 1 and 2 M urea the intensity of inhibition by clorgyline and deprenyl of oxidation of these amines was not changed. With urea concentration of 3 and 4 M the inhibitory effect of clorgyline on deamination of serotonin and tyramine was increased, while that of deprenyl on oxidation of beta-phenylethylamine and tyramine was decreased. As a result of mitochondria treatment with 3 and 4 M urea the selectivity in inhibition by clorgyline of serotonin and tyramine deamination typical for intact mitochondria was reduced in the case of 3 M urea and eliminated in the case of 4 M urea. In intact mitochondria the intensity of inhibition by clorgyline of tyramine deamination in the presence of benzyl alcohol (competitive reversible MAO inhibitor) was increased, but the additive effect was not achieved. However, after preincubation of mitochondria with 3 M urea the summation of the inhibitory effects of clorgyline and benzyl alcohol was observed. The data obtained provide further evidence for the important role of spatial configuration of the monoamine oxidase molecule; the data are discussed in terms of arrangement on the protein molecule surface of the essential groups involved in the binding and deamination of amines for the inhibitory effects of clorgyline and deprenyl.

Animals↗

PubMed1982

[Cardiovascular effects of (+)- and (-)-tranylcypromine compared to other monoamine oxidase inhibitors in animal studies (author's transl)].

The effect of (+)- and (-)-tranylcypromine (TCP), (-)-deprenyl and pargyline was tested and the interaction of these MAO inhibitors with tyramine and noradrenaline was compared on the circulation of the cat and on the isolated guinea-pig atria. 1. Anesthetised cats: An i.v. injection of 1 mg/kg of (+)- as well as (-)-TCP leads to an increase in the blood pressure and dp/dtmax. This effect is getting weaker on repeated doses. (-)-Deprenyl and pargyline decrease blood pressure and dp/dtmax. After a preadministration of (+)-TCP or pargyline the effect of tyramine on the blood pressure and contractility is prolonged. (-)-TCP prolongs slightly the cardiac effect of tyramine and is less effective than (+)-TCP. (-)-Deprenyl does not influence the effect of tyramine. The noradrenaline effect is not affected by the MAO-inhibitors. 2. Conscious cats: An i.v. injection of (+)- as well as (-)-TCP increases the blood pressure and decreases the heart rate. Desipramine (DMI) blocks this effect. Preadministration of (+)- as well as (-)-TCP and pargyline, but not (-)-deprenyl, potentiates the effect of tyramine on the blood pressure. According to this activity one can arrange these MAO-inhibitors as follows: (+)-TCP greater than (-)-TCP greater than pargyline. 3. Atrial preparations of guinea pigs: (+)- and (-)-TCP have a positive inotropic effect at concentrations from 10(-6) to 10(-5) mol/l, which is blocked by bupranolol and DMI. A pretreatment with reserpine prevents the effect of (-)- and weakens that of (+)-TCP. (+)-TCP, pargyline and (-)-deprenyl potentiate the effect of tyramine, while that of noradrenaline is potentiated by (+)- as well as (-)-TCP and (-)-deprenyl.

Animals↗

PubMed2002

Accumulation of tyrosol glucoside in transgenic potato plants expressing a parsley tyrosine decarboxylase.

As part of the response to pathogen infection, potato plants accumulate soluble and cell wall-bound phenolics such as hydroxycinnamic acid tyramine amides. Since incorporation of these compounds into the cell wall leads to a fortified barrier against pathogens, raising the amounts of hydroxycinnamic acid tyramine amides might positively affect the resistance response. To this end, we set out to increase the amount of tyramine, one of the substrates of the hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)-transferase reaction, by placing a cDNA encoding a pathogen-induced tyrosine decarboxylase from parsley under the control of the 35S promoter and introducing the construct into potato plants via Agrobacterium tumefaciens-mediated transformation. While no alterations were observed in the pattern and quantity of cell wall-bound phenolic compounds in transgenic plants, the soluble fraction contained several new compounds. The major one was isolated and identified as tyrosol glucoside by liquid chromatography-electrospray ionization-high resolution mass spectrometry and NMR analyses. Our results indicate that expression of a tyrosine decarboxylase in potato does not channel tyramine into the hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)-transferase reaction but rather unexpectedly, into a different pathway leading to the formation of a potential storage compound.

Chromatography, High Pressure Liquid↗

PubMed2003

Dual-electrode voltammetry of catecholamine transport: simultaneous monitoring of uptake and efflux.

Dual-electrode voltammetry is used to characterize induced efflux of dopamine by m-tyramine via the norepinephrine transporter, stably expressed in a LLC-PK(1) cell line. A rotating disk electrode measures solely the dopamine oxidation current, while a stationary electrode held at a higher potential measures both the dopamine and m-tyramine concentrations. The ratio of the rate of dopamine efflux to the rate of m-tyramine uptake exhibits a hyperbolic dependence on initial dopamine concentration (half-maximal initial concentration of 4 microM) and is independent of the concentration of m-tyramine used to induce efflux for the two concentrations of tyramine tested (3 and 10 microM). These results are consistent with the alternating access model of transport, in which the ratio is shown to be independent of the nature of the external substrate used to induce efflux. At a representative initial dopamine concentration of 1 microM, the ratio of efflux to uptake is approximately 0.15 at the time of external substrate addition (zero internal tyramine). The result suggests that at this point, the transporter reorients to the external facing configuration without dopamine approximately 85% of the time, or expressed differently, seven external substrate molecules are taken up, on average, for each one transported outward.

Animals↗

PubMed1987

Effects of methamphetamine on the twitch response in the rat isolated vas deferens.

The effect of methamphetamine, an indirectly acting sympathomimetic amine, on presynaptic adrenergic regulation in isolated rat vas deferens was studied by comparing it with those of tyramine, cocaine and clonidine. These drugs markedly attenuated the twitch response to electrical field stimulation in a concentration-dependent manner. The relative order of potency for the drugs was: clonidine (10(-10)-3 x 10(-8) M) greater than methamphetamine (10(-8)-3 x 10(-6) M) greater than tyramine (10(-7)-10(-4) M) greater than cocaine (10(-6)-3 x 10(-5) M). Only tyramine (3 x 10(-6)-10(-4) M) elicited a concentration-dependent contractile response, which was abolished by prazosin (10(-6) M) and the reserpinization. The twitch inhibitory effect of these drugs was antagonized by yohimbine (10(-8)-10(-6) M). Both the methamphetamine- and tyramine-induced twitch inhibition were partially (about 50%) attenuated by chronic reserpinization (3 mg/kg, s.c., twice) in combination with alpha-methyl-p-tyrosine (200 mg/kg, s.c., twice), while the clonidine-induced inhibition was not affected by this application at all, and the cocaine-induced twitch inhibition was abolished by the reserpinization. Both the clonidine- and tyramine-induced twitch inhibition were not affected by pretreatment with cocaine (10(-5) M) in combination with estradiol (4 x 10(-5) M), whereas the effect of methamphetamine was slightly attenuated. These results suggest that methamphetamine as well as tyramine and cocaine indirectly activates presynaptic alpha-2 adrenoceptors via norepinephrine released from adrenergic nerves to inhibit the twitch response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1987

The role of alpha 1- and alpha 2-adrenoceptors in the coronary vasoconstrictor responses to neuronally released and exogenous noradrenaline in the dog.

1. Coronary vasoconstriction was examined in response to the neuronal release of noradrenaline produced by bilateral carotid occlusion and the infusion of tyramine (5-50 micrograms/kg/min i.v.) in anaesthetized dogs which had been vagotomized and treated with the beta-adrenoceptor antagonist propranolol (1.0 mg/kg i.v.). These responses were compared to those produced by the infusion of noradrenaline (0.1-0.5 micrograms/kg/min i.v.). 2. Similar increases in late diastolic coronary resistance were produced by bilateral carotid occlusion (0.70 +/- 0.25 mm Hg min/ml), and intravenous infusions of tyramine, 20 micrograms/kg/min (0.70 +/- 0.12 mm Hg min/ml) and noradrenaline, 0.5 micrograms/kg/min (0.59 +/- 0.11 mm Hg min/ml). 3. Selective antagonism at alpha 1-adrenoceptors with prazosin (0.5 mg/kg i.v.) attenuated the coronary constrictor response to bilateral carotid occlusion (0.36 +/- 0.09 mm Hg min/ml), tyramine (0.12 +/- 0.06 mm Hg min/ml) and noradrenaline (0.18 +/- 0.07 mm Hg min/ml). Antagonism at alpha 2-adrenoceptors with idazoxan (1 mg/kg i.v.) attenuated the coronary vasoconstriction produced by bilateral carotid occlusion (0.30 +/- 0.06 mm Hg min/ml), tyramine (0.17 +/- 0.08 mm Hg min/ml) and noradrenaline (0.12 +/- 0.03 mm Hg min/ml). Combined antagonism at both alpha 1- and alpha 2-adrenoceptors with prazosin and idazoxan abolished the responses to bilateral carotid occlusion, tyramine and noradrenaline. 4. These results show that coronary vasoconstriction produced by either neuronally released or exogenous noradrenaline is mediated by both alpha 1- and alpha 2-adrenoceptors. It appears that in the coronary resistance vessels of the dog postjunctional alpha 1- and alpha 2-adrenoceptors are both innervated by sympathetic nerves.

Adrenergic alpha-Antagonists↗

PubMed1993

Characterization of the tyraminergic system in the central nervous system of the locust, Locusta migratoria migratoides.

Tyramine occurs in the central nervous system (CNS) of the migratory locust, Locusta migratoria migratoides. The distribution of tyramine within the CNS does not parallel that of octopamine. Tyramine is synthesised from tyrosine in the presence of tyrosine decarboxylase. A second decarboxylase in the CNS is active against 5HTP and DOPA. The locust ganglia incorporate tyramine by high- and low-affinity uptake processes that appear to be independent of dopamine and octopamine. Depolarisation of the locust ganglia by high potassium concentration results in calcium-dependent release of incorporated [3H]tyramine.

Animals↗

PubMed2004

Influence of reactive oxygen species production by monoamine oxidase activity on aluminum-induced mitochondrial permeability transition.

Treatment of Ca2+-loaded mitochondria with both aluminum and tyramine results in a swelling of higher amplitude than with aluminum alone, while tyramine alone is ineffective. The phenomenon is accompanied by H2O2 production and thiol and pyridine nucleotide oxidation. Cyclosporin A, N-ethylmaleimide or dithioerythritol completely prevent these effects, while catalase exhibits a lower inhibition, pointing to the induction of the permeability transition (MPT) by an oxidative stress. Reactive oxygen species are generated by the interaction of aluminum with the inner membrane and the oxidation of tyramine by monoamine oxidase on the outer membrane. This different localization determines the oxidation of critical thiol groups located on both internal and external sides of pore-forming structures, resulting in MPT induction. The reduced effect by aluminum or the inefficacy by tyramine, when implied alone, can be attributable to the oxidation of thiol groups located only on the internal or external side, respectively. Ultrastructural observations show that aluminum plus tyramine induce the typical configuration of mitochondria that have undergone the MPT. Instead, with aluminum alone, the sensitive subpopulation, although swollen, preserves the outer membrane and shows an apparently orthodox configuration.

Aluminum↗

PubMed2001

Iron (III) attenuates hydroxyl radical generation accompanying non-enzymatic oxidation of noradrenaline in the rat heart.

The present study examined the effect of iron (III) on the generation of free hydroxyl radicals (*OH) in the extracellular fluid of rat myocardium. The generation of *OH was assessed by infusing sodium salicylate in Ringer's solution (0.5 nmol/microl per min) directly into the myocardium of the anaesthetised rat through a microdialysis probe and measuring the non-enzymatic reaction product 2,3-dihydroxybenzoic acid (DHBA) trapped in the dialysate. Tyramine increased the level of 2,3-DHBA concentration dependently. However, in the presence of iron (III) (50 microM), the effect of tyramine was abolished. When iron (III) (50 microM) was administered to tyramine (1 mM)-pre-treated animals, the tyramine-induced stimulation of noradrenaline did not change, but the level of 2,3-DHBA decreased significantly ( n=6, P<0.05). When desferrioxamine (DES), a strong iron (III) chelator, was administered to tyramine (1 mM)-pre-treated animals, a marked increase in 2,3-DHBA formation was seen. Administration of iron (II) to the DES-pre-treated animals increased 2,3-DHBA markedly compared with the iron (II)-only treated group, with a positive linear correlation between iron (II) concentration and *OH trapped as 2,3-DHBA ( R(2)=0.987). DES can reduce iron (III) and thus markedly increases *OH formation. To examine the effect of iron (III) on ischaemia/reperfusion of the myocardium, the heart was subjected to myocardial ischaemia for 15 min by occlusion of the left anterior descending branch of the coronary artery. On reperfusion, noradrenaline and 2,3-DHBA rose markedly in the heart dialysate. The presence of iron (III) (50 microM) abolished the elevation of 2,3-DHBA. Iron (III) also significantly blunted the rise of serum creatine phosphokinase, an index of myocardial damage. The present study demonstrates that the suppression of *OH formation by iron (III) may play a key role in the cardioprotective effect of iron (III) in the rat heart.

Animals↗

PubMed2003

A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition.

Three studies were performed using a fast dissolving formulation of selegiline hydrochloride designed for buccal absorption "Zydis Selegiline". The aim of the first study was to compare the therapeutic efficacy of Zydis Selegiline (1.25 mg or 10 mg) with conventional selegiline hydrochloride tablets "conventional selegiline tablets" (10 mg) in patients with Parkinson's disease (PD) who were previously treated with conventional selegiline tablets as an adjunct to levodopa/dopamine agonist therapy. Patients were observed for 4 weeks to ensure that they were stable. Stable patients (n=197) were then randomised to continue with conventional selegiline tablets 10 mg (n=68), or to treatment with Zydis Selegiline 1.25 mg (n=64) or Zydis Selegiline 10 mg (n=62) for 12 weeks in this randomised, parallel group study. A further aim was to establish the acceptability of Zydis Selegiline compared with conventional selegiline tablets. Patient preference for Zydis Selegiline was also evaluated in a second study, a single-dose, randomised, two-way crossover study conducted in patients with PD (n=148). Patients were stratified by the presence or absence of swallowing and salivation problems and were randomised to either Zydis Selegiline 5 mg or a placebo fast-dissolving formulation. In a third study, the degree of potentiation of the tyramine pressor effect following Zydis Selegiline was compared with that following conventional selegiline tablets in healthy volunteers. A total of 24 healthy volunteers were randomised to receive Zydis Selegiline 1.25 mg or conventional selegiline tablets 10 mg for 14-16 days in an open-label, randomised parallel group study. Both Zydis Selegiline (1.25 mg and 10 mg) treatments were shown to be therapeutically equivalent to conventional selegiline tablets 10 mg based on comparison of mean total Unified Parkinson's Disease Rating Scale (UPDRS) scores. Therapeutic equivalence was defined a priori as the 90% confidence interval (CI) for the difference in total UPDRS scores between groups to lie entirely within the range +/-5. The difference (90% CI) in mean adjusted total UPDRS between Zydis Selegiline 1.25 mg and conventional selegiline tablets 10 mg was -2.50 (-4.84, -0.17), and for Zydis Selegiline 10 mg and conventional selegiline tablets 10 mg, 0.04 (-2.30, 2.38). For the motor subscores of the UPDRS, differences between adjusted means (90% CI) compared with the conventional selegiline tablets group were: Zydis Selegiline 1.25 mg, -2.14 (-3.94, -0.33) and Zydis Selegiline 10 mg, -0.90 (-2.70, +0.91). Patients who switched from conventional selegiline tablets to Zydis Selegiline 1.25 mg showed a slight improvement in UPDRS scores following 12 weeks of treatment (standard error of difference 1.039; p=0.01). In the single-dose crossover study, most (61%) patients liked Zydis Selegiline 5 mg; a significantly greater proportion than the null hypothesis of 50% (p<0.002). However, only 62 patients (46%) indicated that they liked the taste of Zydis Selegiline. Nevertheless, the proportion of patients who preferred Zydis Selegiline (65%) to their usual medication was significantly greater than the null hypothesis of 50% (p<0.001). Similar findings were demonstrated in the 12-week study where a higher proportion of patients who received up to 3 months of treatment indicated a preference for either Zydis Selegiline 1.25 mg (90%) or Zydis Selegiline 10 mg (86%) over conventional selegiline tablets 10 mg. More than 90% of patients found Zydis Selegiline easy to take, with 61% rating it as extremely easy. Most (81%) patients taking Zydis Selegiline 1.25 mg liked the taste compared with 45% taking Zydis Selegiline 5 mg (in the previous study). Zydis Selegiline did not potentiate the tyramine effect: a pressor effect was elicited after 400 mg tyramine both before and after 14 days of treatment with Zydis Selegiline 1.25 mg. In contrast, after 14 days treatment with conventional selegiline tablets 10 mg, the threshold dose required to elicit the tyramine pressor response was significantly (p<0.0001) reduced from 400 mg to 200 mg. In summary, Zydis Selegiline at doses of 1.25 mg and 10 mg was therapeutically equivalent to conventional selegiline tablets 10 mg. The Zydis Selegiline formulation was well-liked by all patients, with most preferring Zydis Selegiline 1.25 mg to their usual selegiline tablet. Furthermore, Zydis Selegiline was well tolerated and, unlike conventional selegiline tablets, appeared to retain specificity for inhibition of monoamine oxidase type B (MAO-B), since it did not potentiate the pressor response to tyramine.

Administration, Oral↗

PubMed1986

Use of alternate substrates to probe the order of substrate addition to dopamine beta-hydroxylase.

In order to determine the order of substrate binding to dopamine beta-hydroxylase during catalysis, the effect of alternate substrates upon kinetic parameters was examined. The V/K value for ascorbate was unchanged when tyramine, phenylpropylamine, p-Cl-phenethylamine, p-CH3O-phenethylamine, or phenethylamine was the hydroxylated substrate. The V/K values for tyramine and oxygen were similarly unchanged when ferrocyanide was used as the reductant in place of ascorbate. In order to use ferrocyanide as reductant it was necessary to include copper to alleviate the substrate inhibition seen with this substrate. The pattern of substrate inhibition observed with ferrocyanide was consistent with a small amount of free cyanide present in the ferrocyanide. With ferrocyanide as reductant and [2,2-2H2]tyramine as substrate, there was a measurable isotope effect on the V/K value for oxygen, but none on the values of Vmax or V/K for tyramine. These results are consistent with a ping-pong mechanism in which tyramine binds to the enzyme after the release of oxidized ascorbate. Subsequently, oxygen binds to form a ternary complex.

Ascorbic Acid↗

PubMed1976

Uptake and release of catecholamines in sympathetic nerve fibres in the spleen of the cod, Gadus morhua.

The effects of drugs known from mammalian experiments to interfere with uptake and release of adrenergic transmitters in the sympathetic nerve terminals have been investigated on perfused spleen and isolated spleen strips from the cod. Cocaine and desipramine inhibit the accumulation of 3H-noradrenaline in the perfused spleen, probably by interfering with uptake mechanisms. Both drugs also shift to the left the dose-response curves for noradrenaline and adrenaline on isolated strips, cocaine being most potent. The maximal contraction force of isolated strips also increases after cocaine when noradrenaline is the agonist, but not when methacholine is used or on chronically denervated strips. This effect of cocaine is therefore not due to a general postsynaptic effect. Tyramine and amphetamine both release stored 3H-noradrenaline from the perfused spleen, and tyramine also contracted the spleen strips. In contrast to the situation in mammals, the dose-response curve for tyramine is not affected by cocaine, and tyramine (up to 10(-3) M) present in the bath does not potentiate the dose-response curve for noradrenaline on isolated strips. Different uptake mechanisms for tyramine and noradrenaline into the nerve terminal are therefore suggested for the cod sympathetic fibres. The alpha-adrenoceptor blocking agent phentolamine produces an increase in overflow of label during nerve stimulation at 5Hz in the perfused spleen preloaded with 3H-noradrenaline. An alpha-adrenoceptor-mediated control of the release of catecholamines, similar to that in mammals, appears to be present in the cod.

Amphetamine↗

PubMed1978

Indirect sympathomimetic agents and cerebral blood flow and metabolism.

The effects upon cerebral blood flow (CBF) and oxygen consumption (CMRO2) of the infusion into the internal carotid artery of tyramine and amphetamine were investigated in 24 anaesthetized baboons. The infusion of tyramine was without effect upon CBF and CMRO2 at normocapnia, even at concentrations which significantly raised arterial blood pressure. However, marked reductions in cerebral blood flow were noted at hypercapnia during the infusion of tyramine (2.5 X 10(-7) moles/kg/min). The infusion of amphetamine (7.5 X 10(-10) moles/kg/min) resulted in significant increases in CBF (32%) and CMRO2 (37%). However, an increased concentration of amphetamine (2.5 X 10(-7) moles/kg/min) significantly reduced CBF (22%) and CMRO2 (20%). It is suggested that amphetamine, by virtue of being able to cross the blood--brain barrier and interact with the cerebral monoamine systems, is able to influence cerebral blood flow by inducing changes in cerebral metabolism, and that the minimal reactivity of the cerebral circulation to the infusion of tyramine is the result of the inability of tyramine to cross the blood--brain barrier.

Animals↗

PubMed1992

Preparation and application of radioiodinated sulfhydryl reagents for the covalent labeling of SH-proteins present in minute quantities.

In this study we have searched for sulfhydryl reagents which can be radiolabeled and detect minute quantities of SH-proteins. Iodoacetamidotyramine reacts with sulfhydryls at a low rate, having a pseudo-first order rate constant, kappa obs = 3 +/- 0.2 M-1 s-1, at neutral pH. In contrast, N-ethylmaleimide-containing reagents, such as tyrosine-MIB and tyramine-MIB were three orders of magnitude more reactive in alkylating sulfhydryls. Pseudo-first order rate constants, kappa obs, were in the range of 5200-5700 M-1 s-1. Therefore, a simple and convenient procedure was designed for the synthesis and the radioactive labeling of tyramine-MIB. Simplification was attained by virtue of the specific-'affinity' adsorption of [125I]tyramine-MIB (and not the other intermediates) to small Sephadex G-10 column and its elution with ethanol. [125I]Tyramine-MIB was stable for weeks in dried form and for hours in acidic to neutral aqueous solutions. The reagent, when radiolabeled to high specific activity (0.5 Ci/mumol), detected sulfhydryl proteins at concentrations as low as 1-10 pM. The applicability of the reagent in studying biological systems was demonstrated by adding it to intact adipocytes and the consequent labeling of a single protein with an apparent Mr = 32,000, which is most likely an externally oriented surface plasma membrane SH-protein. [125I]Tyramine-MIB reactivity and sensitivity exceeds that of protein-tyrosyl radioiodination by the chloramine-T procedure and is expected to assist in studying minute quantities of SH-proteins.

Adipose Tissue↗

PubMed1988

Design and early clinical evaluation of selective inhibitors of monoamine oxidase.

1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2003

Inhibition of rat fat cell lipolysis by monoamine oxidase and semicarbazide-sensitive amine oxidase substrates.

It has been demonstrated that amine oxidase substrates stimulate glucose transport in cardiomyocytes and adipocytes, promote adipogenesis in pre-adipose cell lines and lower blood glucose in diabetic rats. These insulin-like effects are dependent on amine oxidation by semicarbazide-sensitive amine oxidase or by monoamine oxidase. The present study aimed to investigate whether amine oxidase substrates also exhibit another insulin-like property, the inhibition of lipolysis. We therefore tested the influence of tyramine and benzylamine on lipolytic activity in rat adipocytes. These amines did not modify basal lipolysis but dose-dependently counteracted the stimulation induced by lipolytic agents. The response to 10 nM isoprenaline was totally inhibited by tyramine 1 mM. The blockade produced by inhibition of amine oxidase activity or by 1 mM glutathione suggested that the generation of oxidative species, which occurs during amine oxidation, was involved in tyramine antilipolytic effect. Among the products resulting from amine oxidation, only hydrogen peroxide was antilipolytic in a manner that was potentiated by vanadate, as for tyramine or benzylamine. Antilipolytic responses to tyramine and to insulin were sensitive to wortmannin. These data suggest that inhibition of lipolysis is a novel insulin-like effect of amine oxidase substrates which is mediated by hydrogen peroxide generated during amine oxidation.

Adipocytes↗

PubMed1982

Will amitriptyline prevent the "cheese" reaction of monoamine-oxidase inhibitors?

Administration of amitriptyline greatly diminished the pressor response to intravenous tyramine in patients receiving monoamine-oxidase inhibitors (MAOIs). Dothiepin and trimipramine, however, produced little change in sensitivity to tyramine. It is suggested that a combination of amitriptyline and an MAOI, started together in a modest dose that is then increased, may protect patients against the potential dangers of eating tyramine-containing foods. However, because MAOIs allow a high proportion of ingested tyramine to be absorbed into the systemic circulation, patients treated with MAOIs, even in combination with amitriptyline, should not be encouraged to eat foods containing tyramine.

Adult↗

PubMed1998

Enhancement of thermal hyperalgesia by alpha-adrenoceptors in capsaicin-treated skin.

This study aimed to investigate whether the endogenous release of noradrenaline would influence hyperalgesia to heat in skin sensitized by the topical application of 0.6% capsaicin. To release endogenous stores of noradrenaline, tyramine was introduced transcutaneously by iontophoresis into the volar aspect of the forearm of 19 healthy subjects. The heat pain threshold fell from 43.7 +/- 3.8 degrees C to 41.3 +/- 4.0 degrees C after the iontophoresis of tyramine in capsaicin-treated skin (P < 0.001), but did not change significantly after tyramine iontophoresis in untreated skin. The heat pain threshold decreased by 0.5 +/- 2.2 degrees C after the iontophoresis of saline, indicating that nonspecific factors did not fully account for the hyperalgesic effect of tyramine. Iontophoresis of the alpha-adrenergic antagonist, phenoxybenzamine, after the capsaicin treatment blocked the hyperalgesic effect of tyramine, suggesting that thermal hyperalgesia was mediated by alpha-adrenoceptors. However, iontophoresis of phenoxybenzamine before the capsaicin treatment was ineffective. These findings suggest that release of endogenous stores of noradrenaline increases sensitivity to heat in skin sensitized by capsaicin. In addition, neurogenic inflammation appears to increase access to the receptors that facilitate thermal hyperalgesia.

Administration, Topical↗