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Kinetics of intraventricularly injected trace amines and their deuterated isotopomers.

Intraventricular injection into the rat brain of four trace amines and a catecholamine resulted in rapid exponential loss of the amines in the first 30 minutes after injection. The half-lives were: phenylethylamine 3.8 min, para-tyramine 5.1 min, meta-tyramine 7.4 min and dopamine 8.0 min. Tryptamine showed a biphasic loss with half-lives of 4.7 min (over the 5 to 10 min period) and 14.1 min (10 to 30 min). The half-lives were substantially increased by deuterium labeling at the alpha carbon position: phenylethylamine 4.8 min, para-tyramine 8.8 min, meta-tyramine 14.1 min, dopamine 13.0 min and tryptamine 6.0 min (5 to 10 min period) and 28.7 min (10 to 20 min). The loss of the amines was reduced by monoamine oxidase inhibition by pargyline hydrochloride and the deuterium isotope effect was abolished. It is noteworthy that the half-life of dopamine was similar to those of the trace amines in this time period and that the trace amine half-lives after i.v. injection was longer than those obtained from measurements of increases of concentrations of endogenous amines after MAOI in vivo and that of dopamine shorter than values calculated from turnover measurements.

Animals↗

Monoamine oxidase inhibitors and the cheese effect.

The behavior of inhibitors of monoamine oxidase-A (MAO-A) is considered in terms of the possibility of having an effective antidepressant that does not give rise to hypertensive interactions with dietary tyramine. Studies with punch-biopsy samples of human intestine and rat intestinal samples show MAO-A to be the predominant form of the enzyme in both species. Transport studies with everted rat intestinal preparations indicate that tyramine is extensively metabolized during transport through the intestine. Selective inhibition of MAO-A by clorgyline results in a large increase in the amount of unchanged tyramine transported, whereas selective inhibition of MAO-B with L-deprenyl (selegiline) has no significant effect. The behavior of reversible MAO-A inhibitors can significantly reduce, but not entirely eliminate, these effects on the intestinal metabolism of tyramine, but only if the inhibition is competitive in nature.

Animals↗

Biogenic amines in Spanish beers: differences among breweries.

Ten biogenic amines in Spanish beers were studied using HPLC, Agmatine, tyramine and putrescine were the prevailing amines, while histamine, beta-phenylethylamine, tryptamine, cadaverine, spermine and spermidine were detected at relatively low levels (in general < 2 mg/l). On the basis of the wide range of levels observed for tyramine (from 1.90 to 31.55 mg/l), the consumption of beer requires restriction in patients receiving monoamine oxidase inhibitor drugs. Biogenic amine levels in beers of the same type from the same company and from different companies were monitored every month over 1 year. Agmatine and putrescine levels showed minimal fluctuations in beers from the same company as well as from different breweries. Raw materials and brewing conditions would not affect the levels of those amines. However, tyramine levels were subject to wide fluctuations in beers produced by particular breweries irrespective of whether they were produced by the same company. Relatively high levels of tyramine were specific to some breweries.

Agmatine↗

[Elucidation and chemical identification of a heart strength and heart rate-increasing substance from human kidney extracts].

Bioassays involving the measurement of cardioactivity have been used in the past to determine glycoside concentration in post-mortem specimens following glycoside poisoning. This paper describes the presence of a cardioactive principle in alcoholic extracts of kidney that could interfere with these bioassays and which has been identified as tyramine. For the analysis of tyramine a combination of purification methods was employed, including cation exchange with Sephadex CM C-25, gel filtration and HPLC. Detection was achieved using mass spectrometry after careful cation-exchange treatment. The fragmentation pattern with and without prior formation of the TFA-derivative corresponded to that tyramine. IR and UV spectra also indicated the presence of tyramine. Under suitable experimental conditions, positive inotropic and positive chronotropic effects on the right guinea-pig atrium and positive inotropic effect on the left guinea-pig atrium produced by the kidney extract can be shown to differ from those cardiac glycosides. These investigations bring into question earlier court decisions made in legal processes which have been based upon the results of bioassays for the evaluation of cardiac glycoside toxicity.

Animals↗

Enzyme sensor array for the determination of biogenic amines in food samples.

An enzyme sensor array for the simultaneous determination of the three biogenic amines (histamine, tyramine and putrescine) by pattern recognition using an artificial neural network and its application to different food samples is described. A combination of a monoamine oxidase, a tyramine oxidase and a diamine oxidase (with specific activities sufficient for rapid detection) are immobilised each on a separate screen-printed thick-film electrode via transglutaminase and glutaraldehyde to compare these cross-linking reagents with regard to their suitability. To calculate the amount of a specific biogenic amine, the raw data from multichannel software were transferred to a neural network. The sensor array takes 20 min to complete (excluding statistical data analysis) with only one extraction and subsequent neutralisation step required prior to sensor measurement. The lower detection limits with the enzyme sensor were 10 mg/kg for histamine and tyramine, and 5 mg/kg for putrescine with a linear range up to 200 mg/kg for histamine and tyramine and 100 mg/kg for putrescine. The application area of the enzyme sensor array was tested from fish to meat products, sauerkraut, beer, dairy products, wine and further fermented foods and compared with the data of conventional LC analyses (mean correlation coefficient: 0.854).

Amino Acid Oxidoreductases↗

Analysis of the tachycardiac response to 5-hydroxytryptamine in the spinal guinea-pig.

The mechanism of the increase in heart rate caused by 5-hydroxytryptamine (5-HT) in the spinal guinea-pig was investigated. Administration of 5-HT (15, 30, 60 and 120 micrograms.kg-1 i.v.) elicited dose dependent increases in heart rate. The responses to 5-HT were not modified by methiothepin (0.5 and 1.5 mg.kg-1), ketanserin (0.5-4.5 mg.kg-1) or MDL 72222 (0.5-4.5 mg.kg-1) but were antagonized by the beta-adrenoceptor antagonists, propranolol (0.1-1 mg.kg-1) or atenolol (0.5-4.5 mg.kg-1). Indalpine, which is known to interfere with the uptake of 5-HT by nerve terminals and blood platelets, significantly reduced the effects of 5-HT at a dose (5 mg.kg-1) that also affected the tachycardia elicited by tyramine. The increase in heart rate caused by tyramine in reserpinized animals was attenuated and, unlike normal animals where the responses to 5-HT remained constant after repeated administration, there was a quickly developing tachyphylaxis to 5-HT. These results show that the increase in heart rate elicited by 5-HT in spinal guinea-pigs is not mediated by any of the currently characterized 5-HT receptors ('5-HT1-like', 5-HT2 and 5-HT3), and that a major part of the tachycardia seems to be mediated by a release of catecholamines by a mechanism similar, though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides though perhaps not identical, to that for tyramine. Another as yet unidentified mechanism could be involved besides this action.

Adrenergic beta-Antagonists↗

Peroxidase secretion from rat lacrimal gland cells in vitro: II. The role of calcium in stimulus-secretion coupling.

The role of calcium in stimulus-secretion coupling in rat lacrimocytes was investigated. Monolayers of lacrimocytes released peroxidase into the incubation medium upon stimulation with calcium ionophore A 23187, L-norepinephrine, L-phenylephrine and tyramine. Our lacrimocyte preparation can be considered free of endogenous catecholamines, because lacrimocytes derived both from normal and from reserpinized rats responded to tyramine with respect to peroxidase secretion. Phenoxybenzamine, cocaine, verapamil and sodiumorthovanadate failed to inhibit the L-phenylephrine-evoked peroxidase secretion. The stimulatory effects of A 23187, L-norepinephrine and L-phenylephrine required extracellular Ca2+ and could be blocked by phentolamine. The action of tyramine was insensitive to all these measures. It is suggested that the stimulus-secretion of peroxidase from lacrimocytes may consist of a Ca2+-dependent phase for stimulants as A 23187, L-norepinephrine and L-phenylephrine and a Ca2+-independent phase for the non-specific tyramine action.

Animals↗

Effect of chlordimeform and clonidine on the turnover of P-octopamine in rat hypothalamus and striatum.

The effect of the invertebrate octopamine agonists chlordimeform and clonidine on the concentration and turnover of p-octopamine and m- and p-tyramine was determined in rat hypothalamus and striatum. Clonidine (0.25 mg/Kg, s.c.) did not alter the concentration of p-octopamine in the hypothalamus or p-tyramine in the striatum. Administration of chlordimeform (50 mg/Kg, i.p.) resulted in an increase in p- and m-tyramine concentrations in the striatum but not that of p-octopamine in the hypothalamus. This increase in the tyramine isomers is consistent with the ability of chlordimeform and its metabolite, demethylchlordimeform, to inhibit monoamine oxidase (MAO). The concurrent administration of chlordimeform (50 mg/Kg, i.p.) and pargyline (75 mg/Kg, i.p.) produced a significant decrease in the accumulation of octopamine in the hypothalamus but not in the striatum. In contrast, the concurrent administration of clonidine (0.25 mg/Kg, s.c.) and pargyline (75 mg/Kg, i.p.) caused a significant decrease in the accumulation of octopamine in the striatum but not hypothalamus. These results show that the turnover of octopamine in the hypothalamus and striatum is decreased by chlordimeform and clonidine, respectively. Further, clonidine is known to modulate the turnover of amines in mammalian noradrenergic nerve terminals by an action at presynaptic adrenergic receptors. These data suggest that two mechanisms, one involving presynaptic adrenergic receptors in the striatum, and the other involving as yet unidentified receptors in the hypothalamus, modulate the turnover of octopamine in the mammalian brain.

Amidines↗

Effect of monofluoromethyldopa (MFMD) on trace amine levels.

The concentrations of the trace amines, m-tyramine, p-tyramine, phenylethylamine and tryptamine, were measured in the striatum of the brain and in the kidney of adult rats treated with alpha-monofluoromethyldopa (MFMD), an inhibitor of aromatic amino acid decarboxylase. While MFMD decreased the levels of all four amines in the kidney, only phenylethylamine and tryptamine levels were decreased in the striatum compared to control. Striatal p-tyramine levels were not affected, while striatal m-tyramine levels were increased by MFMD. When the rats were injected with a monoamine oxidase (MAO) inhibitor before MFMD administration, similar changes in striatal and kidney trace amine levels were observed compared to MFMD alone.

Animals↗

Attempts to attenuate the 'cheese effect'. Combined drug therapy in depressive illness.

Although earlier results, employing intravenous tyramine challenge, had indicated that a tricyclic antidepressant plus monoamine oxidase inhibitor drug combination might be free from the 'cheese effect', the experiments reported here, involving oral tyramine challenge during the combined therapy, showed that relaxation of a tyramine-free diet during such a drug regimen might be unsafe. Preliminary observations indicated that combined (-)-deprenyl plus nonselective monoamine oxidase inhibitor therapy might lead to an unacceptable degree of orthostatic hypotension without reduction in tyramine sensitivity.

Adult↗

Newer aspects of the reversible inhibitor of MAO-A and serotonin reuptake, brofaromine.

1. The reasons for developing second-generation MAOI are outlined. The expected advantage of reversibility as a safety valve with respect to tyramine potentiation is discussed. 2. Earlier data from in vitro and some ex vivo experiments had suggested an irreversible interaction of brofaromine with MAO-A, whereas the short duration of action, the absence of cumulation of effect and the displaceability by endogenously released substrates indicated reversibility. This apparent conflict could be solved by the demonstration that brofaromine behaves as a tight-binding reversible inhibitor. 3. In in vivo binding experiments with [3H]brofaromine given i.v., clorgyline, brofaromine and moclobemide were shown to dose-dependently displace the radioligand from MAO-A in the rat brain when administered after it. In corresponding experiments in the rat intestine in which the radioligand was administered p.o., similar results were obtained. Moreover, tyramine given orally in pressor doses after the radioligand also displaced it, confirming the idea that reversibility could act as a safety valve. 4. The evidence from animal and human experiments is presented that brofaromine is safer than classical MAO inhibitors with respect to tyramine potentiation. 5. Based on computer simulations, it is suggested that reduced liability of the new MAO reversible inhibitors to cause tyramine potentiation may potentially be linked to a reduced therapeutic efficacy. 6. The evidence is discussed that 5-HT uptake inhibition by brofaromine is relevant in its therapeutic effect in humans and may synergize with MAO-A inhibition, thus enhancing the impact of the latter on serotonergic transmission.

Animals↗

Contribution of L-3,4-dihydroxyphenylalanine metabolism to the inhibition of gluconeogenesis in rabbit kidney-cortex tubules.

The circulating L-3,4-dihydroxyphenylalanine, the drug of choice in the therapy of Parkinson's disease (PD), is efficiently extracted by kidney and converted to dopamine, known to control several renal functions. As: (i) in addition to liver, kidney is an important source of glucose in mammals and (ii) the action of this drug on renal gluconeogenesis has not yet been studied, the aim of the present investigation was to estimate the influence of L-3,4-dihydroxyphenylalanine metabolism on glucose formation in isolated kidney-cortex tubules incubated with various gluconeogenic substrates. The data indicate that a rapid intracellular degradation of L-3,4-dihydroxyphenylalanine and tyramine (at 100 and 200 microM concentrations) is accompanied by 25-40% decrease in glucose production from pyruvate, alanine + glycerol + octanoate and dihydroxyacetone due to augmented generation of hydrogen peroxide via monoamine oxidase B, resulting in a decline of glutathione redox state by 40%. Moreover, following inhibition of monoamine oxidase B by deprenyl or substitution of pyruvate by aspartate + glycerol + octanoate both L-3,4-dihydroxyphenylalanine and tyramine affect neither the rate of gluconeogenesis nor glutathione redox state. In view of: (i) L-3,4-dihydroxyphenylalanine- and tyramine-induced changes in intracellular levels of gluconeogenic intermediates, and (ii) a significant decline of phosphoenolpyruvate carboxykinase activity by 500 microM oxidized glutathione, it is likely that L-3,4-dihydroxyphenylalanine- and tyramine-evoked disturbances in the glutathione redox state might diminish flux through phosphoenolpyruvate carboxykinase and in consequence decrease glucose formation in renal tubules, suggesting a new potential side-action of L-3,4-dihydroxyphenylalanine treatment.

Alanine↗

Increased counteracting effect of eNOS and nNOS on an alpha1-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats.

OBJECTIVE: The hypertension in spontaneous hypertensive rats (SHR) may result from a hyperactive sympathetic nervous system or from insufficient bioactive nitric oxide (NO) due to increased oxidative stress. The present investigation aimed to elucidate the balance between these two systems by studying the ability of NO to oppose an adrenergic rise in total peripheral vascular resistance (TPVR). METHODS: In anesthetized, open-chest SHR and normotensive controls (WKY) on a respirator, blood pressure was recorded in the femoral artery and cardiac output measured by ascending aorta flow. Tyramine infusion (15 min, intravenously) was used to stimulate neuronal noradrenaline release. RESULTS: Tyramine induced an immediate but transient increase in TPVR, which was 4.5 times greater in SHR. After the non-selective NO synthase (NOS) inhibitor (L-NAME: N(omega)-nitro-L-arginine methyl ester), DeltaTPVRimm was 8.6 and 5.3 times increased in SHR and WKY, respectively, and TPVR remained elevated throughout the infusion period. Addition of alpha1-adrenoceptor antagonist (prazosin+L-NAME) abolished the TPVR response to tyramine. Neuronal NOS inhibitor (7-introindazole) increased DeltaTPVRimm only in SHR (2.1 times), and TPVR remained elevated. Inducible NOS inhibitor (1400W), free radical scavenger (tempol), NAD(P)H oxidase inhibitor (apocynin), angiotensin AT1 receptor antagonist (losartan), and ganglion blocker (hexamethonium) had no effect on the tyramine TPVR response in either strain. DeltaTPVR to hexamethonium, prazosin, and L-NAME were greater in SHR than WKY, and hexamethonium reduced DeltaTPVR to L-NAME in SHR only. CONCLUSIONS: The alpha1-adrenoceptor TPVR response to endogenous noradrenaline release was increased in SHR. This was not due to reduced bioavailable NO; on the contrary, NO counteraction was greatly increased, derived from endothelial NOS, with an additional role of neuronal NOS not seen in WKY. An influence of oxidative stress on these responses was not detected in either strain. In addition, a central eNOS sympathoinhibitory component appeared to influence baseline TPVR in SHR.

Adrenergic Uptake Inhibitors↗

Adrenergic reactivity after inhibition of nitric oxide synthesis in the cerebral circulation of awake goats.

The interaction between nitric oxide (NO) and adrenergic reactivity in the cerebral circulation was studied using in vivo and in vitro preparations. Blood flow to one brain hemisphere (cerebral blood flow) was electromagnetically measured in conscious goats, and the effects of norepinephrine, tyramine and cervical sympathetic nerve stimulation were recorded before (control) and after inhibition of NO formation with Nw-nitro-l-arginine methyl ester (l-NAME). The responses to norepinephrine, tyramine and electrical field stimulation were also recorded in segments, 4 mm in length, from the goat's middle cerebral artery under control conditions and after l-NAME. In vivo, l-NAME (10 goats, 47 mg kg-1 administered i.v.) reduced resting cerebral blood flow by 37+/-2%, increased mean systemic arterial pressure by 24+/-3%, reduced heart rate by 35+/-2%, and decreased cerebrovascular conductance by 52+/-2% (all P<0.01). Norepinephrine (0.3-9 microgram), tyramine (50-500 microgram), and supramaximal electrical sympathetic cervical nerve stimulation (1. 5-6 Hz) decreased cerebrovascular conductance, and these decreases were significantly higher after l-NAME than under control conditions, remaining higher for about 48 h after this treatment. Norepinephrine (10-8-10-3 M), tyramine (10-6-10-3 M) and electrical field stimulation (1.5-6 Hz) contracted isolated cerebral arteries, and the maximal contraction, but not the sensitivity, was significantly higher in the arteries treated than in non-treated with l-NAME (10-4 M). Therefore, the reactivity of cerebral vasculature to exogenous and endogenous norepinephrine may be increased after inhibition of NO synthesis. This increase might be related, at least in part, to changes at postjunctional level in the adrenergic innervation of the vessel wall, and it might contribute to the observed decreases in resting cerebral blood flow after inhibition of NO synthesis.

Animals↗

Prazosin attenuates hydroxyl radical generation in the rat myocardium.

The present study examined whether tyramine-induced hydroxyl radical (*OH) generation via noradrenaline release was attenuated by prazosin. A flexibly mounted microdialysis technique was used to detect the generation of *OH in in vivo rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anaesthetized rats and Ringer's solution was used. To measure the level of *OH, sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused directly through a microdialysis probe to detect the generation of *OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA). Tyramine (0.1, 0.5 and 1.0 mM) increased the level of 2,3-DHBA in a concentration-dependent manner. However, in the presence of prazosin (10 microM), the effect of tyramine was abolished. To confirm the generation of *OH by a Fenton type reaction, iron (II) was infused through a microdialysis probe. A positive linear correlation between iron (II) and the formation of 2,3-DHBA (R2 = 0.982) was observed. To examine the effect of prazosin on ischemic/reperfused rat myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery. When the heart was reperfused, a marked elevation of the level of 2,3-DHBA was observed. However, in the presence of prazosin (10 microM), the elevation of 2,3-DHBA was not observed in ischemic/reperfused rat heart. Prazosin was shown to have a *OH scavenging effect. These results suggest that tyramine-induced noradrenaline causes *OH generation, an effect which is inhibited by prazosin as Na+ channel blocker, but not through its alpha1-adrenoceptor antagonistic action of prazosin.

Adrenergic alpha-Agonists↗

Cyclic AMP in normal and sympathetically aneural chick hearts during development.

Basal levels of cyclic adenosine monophosphate (cAMP) were measured in embryonic chick hearts at various times during development. Basal cAMP was highest on incubation day 5 and decreased throughout the remaining incubation period. Cyclic AMP could not be stimulated above basal level by intravenous in ovo administration of isoproterenol or tyramine on incubation day 5; however, there was a decrease in cAMP 2 mins after intravenous injection which was identical to the decrease in cAMP in controls injected with saline. Heart rate decreased following intravenous injection of saline on incubation day 5, but a similar decrease was not observed following intravenous isoproterenol injection. Functional sympathetic innervation of the heart does not occur until incubation day 16, and this fact is responsible for the insensitivity to tyramine stimulation on incubation day 5. Although the level of cAMP could not be stimulated above basal level on incubation day 5, beta-antagonists caused a decrease in the level of cAMP, with no decrease in heart rate. These observations indicate that the beta-receptor is coupled to adenylate cyclase on incubation day 5 but it is questionable whether adenylate cyclase is effectively coupled to heart rate. Isoproterenol and tyramine caused a significant elevation in cardiac cAMP and heart rate on incubation day 17 following intravenous in ovo injection. Hearts made sympathetically aneural by removal of premigratory neural crest responded to isoproterenol but not tyramine on incubation day 17 which demonstrates that the morphologically aneural hearts are also functionally aneural.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

Effect of noradrenaline on retinal blood flow in healthy subjects.

PURPOSE: To gain insight into the role of circulating catecholamines on retinal blood flow in vivo. DESIGN: Nonrandomized, open, crossover design. PARTICIPANTS: In 10 healthy male subjects, tyramine and noradrenaline were administered in stepwise increasing doses. These doses were selected to induce comparable changes in systemic blood pressure. METHODS: During each infusion step, retinal vessel diameter and retinal venous blood speed were measured with the Zeiss retinal vessel analyzer (Zeiss, Jena, Germany) and laser Doppler velocimetry, respectively. MAIN OUTCOME MEASURES: Retinal blood flow through a major temporal vein was calculated. RESULTS: As expected, tyramine and noradrenaline induced a systemic hypertensive response. Tyramine caused a moderate increase in noradrenaline plasma levels, whereas exogenous noradrenaline increased noradrenaline plasma levels more than 10-fold. Nevertheless, neither tyramine nor noradrenaline induced any effect on retinal hemodynamic parameters. CONCLUSIONS: These data indicate that even high levels of circulating noradrenaline have little impact on retinal vascular tone and retinal blood flow. Hence, the adrenergic system appears not to play a major role in retinal blood flow regulation.

Adrenergic Uptake Inhibitors↗

Screening of biogenic amine production by lactic acid bacteria isolated from grape must and wine.

The potential to produce the biogenic amines tyramine, histamine and putrescine, was investigated for lactic acid bacteria (LAB) of various origin, including commercial malolactic starter cultures, type strains and 78 strains isolated from Spanish grape must and wine. The presence of biogenic amines in a decarboxylase synthetic broth was determined by reverse-phase high performance liquid chromatography (RP-HPLC). Tyramine was the main amine formed by the LAB strains investigated. Leuconostoc strains were the most intensive tyramine formers. No potential to form biogenic amines was observed in Oenococcus oeni strains. Two strains of Latobacillus buchneri were associated with putrescine formation. None of the lactic acid bacteria produced histamine. According to these in vitro results, the commercial starter bacteria analyzed did not produce histamine, tyramine and putrescine.

Biogenic Amines↗