[Study of the tachyphylactic action of ephedrine and tyramine on the isolated rat aorta].
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Animals↗
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Effects of benzene and other organic solvents on the decarboxylation of some brain aromatic-L-amino acids.
The intraperitoneal administration of benzene produced marked increases in mouse striatal concentrations of beta-phenylethylamine, p-tyramine and, to a lesser extent, m-tyramine. Similar increases were observed in rat striatal p- and m-tyramine. The subcutaneous administration of benzene dissolved in sesame oil increased mouse striatal p-tyramine but did not change m-tyramine. Benzene administration to mice pretreated with p-tyrosine produced marked increases in mouse striatal p-tyramine as well as in m-tyramine. The statistical analysis of the results indicated that the treatment produced an interaction that led to an increase in the concentration of both the p- and m-isomers of tyramine. The administration of benzene to m-tyrosine-pretreated mice increased striatal m-tyramine but p-tyramine was not increased. The treatment produced no potentiation in the formation of p- or m-tyramine. Of the other organic solvents given, pyridine produced the most marked effects. Its administration increased the concentration of both p- and m-tyramine in the mouse striatum. Treatment with toluene, chloroform, carbon tetrachloride or isoamylalcohol produced moderate increases in mouse striatal p-tyramine while toluene, dichloromethane or isobutylalcohol also increased m-tyramine. These increases in brain beta-phenylethylamine, p-tyramine and m-tyramine may play a contributory role in the human toxicity of benzene and some of these organic solvents; these toxic effects could be exacerbated after ingestion of foodstuffs containing the aminoacids phenylalanine or p-tyrosine or for those under treatment with a monoamine oxidase inhibitor.
Animals↗
Biochemical Basis of Resistance of Tobacco Callus Tissue Cultures to Hydroxyphenylethylamines.
It has been reported that hydroxyphenylethylamines, such as tyramine and octopamine, are toxic to tobacco (Nicotiana tabacum L.) callus cultures grown in the presence of auxins, whereas calli grown in the presence of cytokinins and crown gall cultures are resistant to these amines (P. Christou and K.A. Barton [1989] Plant Physiol 89: 564-568). In an attempt to understand the underlying mechanism of this resistance, we compared the fates of tyramine in tyramine-sensitive and tyramine-resistant tobacco tissue cultures (cv Xanthi nc). The very rapid formation of black-colored oxidation products from tyramine in sensitive tissues suggested that the toxicity might be caused by the oxidation of tyramine by phenol oxidases present in the tissues or released into the medium after subculture. This was confirmed through many indirect procedures (effect of exogenously added tyrosinase, induction of polyphenol oxidase [PPO] activity by auxin, etc.). The study of tyramine structure-activity relationships further suggested that the toxicity of tyramine might be due to the formation of indolequinones after oxidation by PPO. Subculture of calli grown on 2,4-dichlorophenoxyacetic acid in a medium containing benzyladenine triggered a slow decrease in PPO activity and dramatic increases in peroxidase and tyramine hydroxycinnamoyl transferase (THT) activities. THT was undetectable in calli grown on 2,4-dichlorophenoxyacetic acid but very active in tyramine-resistant crown gall cultures. Moreover, when [3H]tyramine was fed in vivo to tyramine-resistant tissues, it was rapidly integrated into cell walls in the wound periderm formed at the periphery of the calli. Both the conjugation of tyramine and its integration into cell walls could compete with the formation of toxic quinones and therefore play a part in the resistance. Thus, it seems likely that the control of the toxicity of hydroxyphenylethylamines by cytokinins results primarily from changes in the metabolism and the compartmentation of these amines.
Journal Article↗
The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain.
1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules.
Animals↗
Pharmacology of amezinium, a novel antihypotensive drug. III. Studies on the mechanism of action.
Pharmacological studies on the mechanism of action of 4-amino-6-methoxy-1-phenyl-pyridazinim methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, are presented. 1. Amezinium increases the arterial blood pressure and heart rate of anaesthetized animals and of pithed rats by stimulating vascular alpha- and cardiac beta 1-adrenoceptors. The action was not modified by ganglionic blockade with hexamethonium. The alpha-adrenergic blocking drug phentolamine antagonized the blood pressure increasing effect and the beta-adrenergic blocking drug propranolol antagonized the heart rate increasing effect. 2. Noradrenaline depletion by pretreatment with reserpine reduced the pressor effect of amezinium to approximately the same extent as it reduced the effect of tyramine. It completely abolished the heart rate increasing effect. Under these conditions, high doses of amezinium reduced the heart rate. 3. Amezinium is taken up by adrenergic neurones. Inhibition of uptake 1 with desipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimsipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimsipramine reduced the pressor effect of amezinium and of tyramine. 4. Being a substrate of uptake 1, amezinium also inhibited noradrenaline and tyramine uptake. Consequently, it enhanced the pressor effect of exogenous noradrenaline and increased the contractions of the nictitating membrane following preganglionic stimulation (endogenous noradrenaline). It diminished the effect of indirectly acting sympathomimetic drugs (tyramine). It did not modify the action of the sympathomimetic drugs methoxamine and isoprenaline, which are not subject to uptake 1. 5. Amezinium inhibits monoamine oxidase (MAO). As a result of being concentrated in sympathetic neurones via uptake 1 amezinium causes specific inhibition of intraneuronal MAO; this was demontrated by enhanced restoration of the effects of tyramine and amezinium by noradrenaline infusion in reserpinized animals. The effective doses of amezinium here were lower than the doses necessary to inhibit tyramine and to exert a pressor effect. This is in accordance with the blood pressure increasing effect of amezinium itself by amezinium pretreatment and noradrenaline-infusion. 6. Pretreatment with a MAO inhibitor (nialamide) enhanced the pressor effect of amezinium, probably by also inhibiting extraneuronal MAO...
Animals↗
Mechanism of the indirect sympathomimetic effect of 5-hydroxytrypt-amine on the isolated heart of the rabbit.
1 Rabbit isolated hearts, perfused by the Langendorff technique, were used to investigate the indirect sympathomimetic effects of 5-hydroxytryptamine (5-HT). Comparisons were made with noradrenaline and with two indirectly acting sympathomimetic agents with entirely different mechanisms of action, tyramine and dimethylphenylpiperazinium (DMPP). 2 The cardiac stimulant effects of 5-HT, tyramine and DMPP were inhibited by propranolol and practolol and the pA2 values obtained were similar to those obtained with noradrenaline as the agonist. 3 Responses to 5-HT, tyramine and DMPP were greatly reduced on hearts from rabbits pretreated with 6-hydroxydopamine. Such hearts had less than 7% of their normal catecholamine concentration and no fluorescence characteristic of noradrenaline in the cardiac sympathetic nerves could be demonstrated. 4 Rapid, reversible and selective tachyphylaxis to 5-HT was demonstrated during perfusion with 5-HT. In hearts desensitized to DMPP by perfusion with DMPP, responses to 5-HT were also reduced. 5 Perfusion of hearts with colchicine inhibited stimulant responses to 5-HT and DMPP but had little effect on responses to noradrenaline or tyramine. 6 Desmethylimipramine enhanced cardiac stimulant responses to noradrenaline and to a lesser extent, those to 5-HT and DMPP. Responses to tyramine were consistently inhibited by desmethylimipramine. 7 Tetrodotoxin abolished responses of the heart to electrical nerve stimulation but left responses to noradrenaline, 5-HT and DMPP unaffected. 8 5-HT, tyramine and DMPP evoked 3H-release from hearts whose neuronal noradrenaline stores had been labelled by perfusion with [3H]-(-)-noradrenaline. The pattern of release evoked by 5-HT was similar to that of DMPP but differed from that of tyramine. 9 Reducing the calcium concentration in the Tyrode solution from 3.6 to 0.2 mEq/1 did not affect 3H-overflow after tyramine but greatly inhibited that evoked by 5-HT and DMPP. 10 The results confirm that the stimulatn effects of 5-HT on the rabbit isolated heart are the result of noradrenaline release. They further suggest that the site of the release is the terminal sympathetic nerve network. The mechanism of release shows more similarities to that of DMPP (calcium-dependent depolarization and exocytosis) than to that of tyramine (neuronal uptake and stoichiometric displacement).
Animals↗
Effects of molindone and fluphenazine on the brain concentration of some phenolic and catecholic amines in the mouse and the rat.
1 The concentrations of p- and m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homo-vanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m- or p-isomers of octopamine were also analysed. 2 Endogenous concentrations of p- and m-tyramine in the mouse striatum and p- and m-octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2 ng/g respectively. The rat striatum concentrations of p- and m-tyramine were 12.8 and 3.8 ng/g. 3 The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p-tyramine, an increase in m-tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors. 4 With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist. 5 The concentrations of hypothalamic p- and m-octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p-octopamine. These changes seem to depend on differences in the availability of p-tyramine to be converted into p-octopamine. 6 These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation.
3,4-Dihydroxyphenylacetic Acid↗
An investigation of alpha-methyl amino-acids and their derivatives on isolated tissue preparations.
1. The ability of alpha-methyl amino-acids and their corresponding amines to restore the sympathomimetic actions of tyramine, and the uptake of the amino-acids and the amines, were studied in isolated tissue preparations obtained from reserpine pretreated animals.2. Tyramine relaxed isolated rat ileum preparations from non-reserpinized rats but not from reserpine treated animals. alpha-Methyldopa, alpha-methylnoradrenaline and lower concentrations of metaraminol restored the responses of reserpinized preparations. alpha-Methyldopamine, alpha-methyl-m-tyrosine, alpha-methyl-p-tyrosine and higher concentrations of metaraminol did not do so. The restoring effect of alpha-methyldopa was blocked by disulphiram. alpha-Methyl-p-tyrosine or alpha-methyl-m-tyrosine blocked the restoring action of alpha-methyldopa but not of alpha-methylnoradrenaline. Cocaine blocked the restoration of responses to tyramine by alpha-methylnoradrenaline but not by alpha-methyldopa. alpha-Methyldopa and alpha-methylnoradrenaline failed to restore responses to tyramine in the presence of sodium-free Tyrode solution.3. Tyramine increased the perfusion pressure in isolated rabbit ear preparations obtained from non-reserpinized animals but was very much less active in preparations obtained from reserpine treated animals. alpha-Methyldopa, alpha-methyl-m-tyrosine, alpha-methylnoradrenaline, alpha-methyl-p-tyrosine and metaraminol restored the effects of tyramine. alpha-Methyldopamine did not do so. The restoring effect of alpha-methyldopa and alpha-methyl-m-tyrosine was blocked by disulfiram. alpha-Methyl-p-tyrosine blocked the restoring effect of alpha-methyl-m-tyrosine.4. Tyramine produced positive inotropic effects in isolated rabbit heart preparations. This was either reduced or absent in preparations obtained from reserpine pretreated animals. alpha-Methyldopa, alpha-methylnoradrenaline, alpha-methyl-m-tyrosine and metaraminol restored the responses to tyramine. alpha-Methyldopamine and alpha-methyl-p-tyrosine did not do so.
Amino Acids↗
Ontogenesis of enzyme systems deaminating different monoamines.
1 A detailed investigation into the postnatal development of the activity of the enzyme monoamine oxidase (MAO) in the rat and domestic pig was carried out. 2 MAO activity was measured in littermate male rats aged between 3 and 122 days belonging to six breeding colonies. The tissues studied were three brain regions in which monoamines may play a role in neuronal transmission (septum, hypothalamus, corpus striatum) and, for comparison, in the cerebellum. Liver, heart and adrenal glands were the peripheral organs studied. The following substrates were used to measure MAO activity in each tissue homogenate: kynuramine, tyramine, dopamine, tryptamine and 5-hydroxytryptamine (5-HT). 3 MAO activity towards kynuramine, tyramine and dopamine increased after birth in all brain regions and also in the liver, to reach maximal values between days 40 and 80. In the heart and the adrenal glands enzyme activity remained low up to 30-40 days and then increased steeply. This was the case in all litters examined. 4 All tissues deaminated more tyramine than dopamine. In the liver, the ratio of the quantities of tyramine deaminated/dopamine deaminated was approx. 2 at all ages. In the homogenates of whole brains (including or excluding the hypothalamus and striatum) this ratio was also 2 at all ages. In contrast in the isolated striatum and hypothalamus it was first much higher and reached a value of 2 only at an age of about 20 days. This may indicate an independent development of a dopamine and a tyramine deaminating enzyme system in discrete brain regions. It was suggested, that the low ability to deaminate dopamine in discrete brain regions may be due to the local presence of an enzyme inhibitor which becomes too diluted to be active in homogenates of whole brain. 5 Deamination of tryptamine in the striatum decreased between day 5 and 20 in 3 out of 4 colonies tested. There was a large fall in the deamination of 5-HT in all tissues of one group of rats, but in another 4 groups the tissues of the 5 day old rats deaminated smaller amounts of 5-HT than those of the older rats. 6 Purified hypothalamic mitochondria from 40 day old rats deaminated more tyramine and dopamine but not tryptamine per mg protein than those from 5 day old rats. 7 In the domestic pig there was a significant rise in the values in hippocampal MAO activity towards dopamine and tyramine from the foetus (55 day gestation) to the 1 week old piglet. A further steady rise up to week 6 was indicated, but this rise was not statistically significant. The difference between rat and pig probably reflected the much higher degree of maturity of the latter at birth. 8 In the hippocampus of the pig the ratio between the amount of tyramine deaminated/dopamine deaminated decreased from greater than 10 (foetus) to 4.8 in the 6 week old pig and 2 in the adult.
Age Factors↗
Inhibition of post-ganglionic motor transmission in vas deferens by indirectly acting sympathomimetic drugs.
1. Using field stimulation with short trains of pulses (< 10 per train), the post-ganglionic motor transmission in the mammalian vas deferens has been further analysed pharmacologically.2. In preparations taken from guinea-pigs, rats and rabbits the effects of the indirectly sympathomimetic drugs, tyramine and cocaine, could be explained entirely on the basis of the actions of released, endogenous noradrenaline.3. Tyramine produced a contraction in vasa taken from normal rats but not from normal guinea-pigs. The tyramine contraction was due to release of endogenous noradrenaline because it was not seen in preparations taken from reserpinized rats and because it was abolished in normal vasa by phenoxybenzamine or phentolamine, thus denying the supposed inaccessibility, to alpha-blockers, of the motor alpha-adrenoceptors activated by endogenous noradrenaline.4. Phenoxybenzamine or phentolamine failed to block post-ganglionic motor transmission in rat and in guinea-pig vasa.5. Tyramine strongly inhibited motor transmission in vasa taken from normal but not from reserpinized guinea-pigs.6. Tyramine produced inhibition of motor transmission in phenoxybenzamine-treated preparations taken from normal but not from reserpinized rats.7. Cocaine inhibited motor transmission in guinea-pig and in rat vasa. This effect was not due to a local anaesthetic or to a smooth-muscle depressant action because it did not occur in preparations taken from reserpinized animals.8. The inhibitory effect of tyramine or cocaine was not abolished by beta-adrenoceptor blockade with propranolol.9. Whereas reserpinization abolished the tyramine- and cocaine-inhibitions, it did not affect the inhibitory actions of noradrenaline or of PGE(2).10. Indomethacin and sodium meclofenamate, which suppress prostaglandin synthesis, did not affect the twitch-inhibiting actions of noradrenaline, tyramine or cocaine.11. These results provide further support for the conclusion that post-ganglionic motor transmission to the vas deferens is non-adrenergic in these species and assign to endogenously released noradrenaline an inhibitory role upon motor transmission.
Animals↗
Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation.
BACKGROUND: In the majority of humans > or = 1 year after cardiac transplantation, cardiac norepinephrine (NE) stores reappear, suggesting late sympathetic reinnervation. METHODS AND RESULTS: To determine whether there are regional differences in reinnervation, we measured markers of sympathetic reinnervation of the sinus node (SN) and left ventricle (LV) in five early transplant recipients (< or = 4 months after cardiac transplantation), 45 late transplant recipients (> or = 1 year after cardiac transplantation), and seven normally innervated control patients. SN reinnervation was defined as an increase in heart rate by more than five beats per minute after injection of tyramine into the artery supplying the SN. LV reinnervation was defined as a measurable LV NE release after left main coronary injection of 8 micrograms/kg tyramine. In 13 patients with previously known LV reinnervation, regional LV reinnervation was assessed by NE release after subselective injection of tyramine (4 micrograms/kg) into the proximal left anterior descending and circumflex arteries. Five of five patients < or = 4 months after cardiac transplantation had no change in heart rate and no LV NE release, confirming early, total denervation. In contrast, > or = 1 year after cardiac transplantation, tyramine caused a heart rate increase (eight to 49 beats per minute) in 32 of 45 patients and LV NE release in 33 of 45. Although LV NE release was correlated with the change in heart rate in late cardiac transplantation recipients (r = .61), eight of 45 had only heart rate response, nine had only LV NE release, and four had neither. In late cardiac transplantation recipients with LV reinnervation, tyramine caused NE release from both the anterior descending and circumflex perfusion fields in 10 of 14, but one of 14 patients released NE only after circumflex tyramine and three of 14 only after left anterior descending tyramine stimulation. Tyramine caused a marked heart rate increase and LV NE release in all control patients. CONCLUSIONS: Sympathetic reinnervation after cardiac transplantation is regionally heterogeneous. SN reinnervation is not associated necessarily with LV reinnervation, and LV reinnervation can involve the anterior and posterior walls together or separately.
Cardiac Catheterization↗
Studies on human placental monoamine oxidase using mixed substrates.
The activity of mitochondrial monoamine oxidase (MAO) from human placenta was measured with mixtures of labelled and unlabelled tyramine, serotonin (5-HT), benzylamine and beta-phenylethylamine (PEA). Tyramine deamination was inhibited by benzylamine and PEA but not by 5-HT, while benzylamine deamination was inhibited by tyramine and PEA, but not by 5-HT, 5-HT deamination was inhibited by tyramine, benzylamine and PEA and PEA deamination was inhibited by tyramine, benzylamine and 5-HT. These results suggest that MAO in human placenta has multiple catalytic sites or consists of different enzymes. Probably, tyramine, benzylamine and PEA are deaminated oxidatively at a common catalytic site while 5-HT is deaminated at another catalytic site. Benzylamine deamination was inhibited in a mixed noncompetitive fashion by tyramine and PEA in air, but benzylamine deamination was competitively inhibited by PEA at higher concentrations of oxygen. The deaminations of other substrates were inhibited competitively by other substrates, in air. Reciprocal plots of PEA deamination with benzylamine, 5-HT and tyramine gave hyperbolic curves.
Benzylamines↗
Hypertensive episode associated with phenelzine and tap beer--a reanalysis of the role of pressor amines in beer.
A case report of a hypertensive crisis resulting from the ingestion of tap beer in a patient on an irreversible monamine oxidase inhibitor (MAOI; phenelzine) stimulated the investigation of different kinds of beer for tyramine concentration. The objective was to determine the tyramine concentration in tap and bottled beers. A total of 98 beer samples (79 different brands of beer) were analyzed by high-performance liquid chromatography for tyramine. Of these 98 beers, 49 were bottled or canned beers and 49 were beers on tap. All of the bottled beers analyzed had safe tyramine concentrations (< or = 10 mg/liter; range, 0 to 3.16 mg/liter) and, thus, do not require restriction in patients receiving MAOIs. Therefore, the consumption of canned or bottled beer, including dealcoholized beer, in moderation (fewer than four bottles or cans; 1.5 liters within a 4-hour period) appears to be safe and does not require restriction in patients receiving MAOIs. Only 4 of 98 beer samples studied were found to have a dangerous (> 10 mg/liter) tyramine concentration, one of which was the index beer. The tyramine concentration in these four beers ranged from 26.34 to 112.91 mg/liter. All four of these beers were tap beers produced by bottom fermentation (lagers) and brewed by a secondary fermentation process. Although we did not find any visible bacterial growth in the tap beers with high tyramine content, this finding does not preclude the possibility that bacterial contamination, bacterial growth, production of tyramine, and eventually bacterial death occurred at some earlier time. Therefore, to err on the side of caution, it is recommended that patients on irreversible MAOIs avoid beers on tap.
Adult↗
Catabolite repression and derepression of arylsulfatase synthesis in Klebsiella aerogenes.
When a mutant (Mao(-)) of Klebsiella aerogenes lacking an enzyme for tyramine degradation (monoamine oxidase) was grown with d-xylose as a carbon source, arylsulfatase was repressed by inorganic sulfate and repression was relieved by tyramine. When the cells were grown on glucose, tyramine failed to derepress the arylsulfatase synthesis. When grown with methionine as the sole sulfur source, the enzyme was synthesized irrespective of the carbon source used. Addition of cyclic adenosine monophosphate overcame the catabolite repression of synthesis of the derepressed enzyme caused by tyramine. Uptake of tyramine was not affected by the carbon source. We isolated a mutant strain in which derepression of arylsulfatase synthesis by tyramine occurred even in the presence of glucose and inorganic sulfate. This strain also produced beta-galactosidase in the presence of an inducer and glucose. These results, and those on other mutant strains in which tyramine cannot derepress enzyme synthesis, strongly suggest that a protein factor regulated by catabolite repression is involved in the derepression of arylsulfatase synthesis by tyramine.
Culture Media↗
Clinical pharmacology of moclobemide during chronic administration of high doses to healthy subjects.
The objectives of this study were to assess the tolerability, safety, pharmacodynamics and pharmacokinetics of high-dose moclobemide in healthy subjects. Two sequential groups of six male and six female subjects (eight on active treatment, four on placebo) received for 8 days moclobemide 450 mg b.i.d. and 600 mg b.i.d., respectively. Intravenous tyramine pressor tests were conducted at baseline, at the beginning of treatment and at steady state. Oral tyramine pressor tests with 50, 100 and 150 mg tyramine were conducted under steady-state conditions. Pharmacokinetic parameters of moclobemide and two of its metabolites in plasma and urine were determined after the first and last dose of moclobemide. The incidence and intensity of adverse events was dose-dependent. The most frequently reported adverse events were insomnia, headache, dizziness and dry mouth. The i.v. tyramine pressor sensitivity during both moclobemide dosing regimens was enhanced 3 to 4-fold. Intake of tyramine 50 mg did not result in systolic blood pressure increases greater than 30 mmHg. With regard to blood pressure increases, tyramine 100 mg is still compatible with moclobemide 450 mg b.i.d. but not with 600 mg b.i.d. The clearance of moclobemide decreased by about 60% on multiple dosing, but no differences were found between both dosing regimens. The urinary excretion of the N-oxide metabolite doubled during multiple dosing. In conclusion, the maximum tolerated dose of moclobemide in healthy subjects is 600 mg b.i.d. provided the tyramine content in a meal is not higher than 50 mg.
Adult↗
Hypertyraminemia in cirrhotic patients.
To evaluate the role of tyramine in hepatic disorders, we used a radioimmunoassay to study plasma concentration of tyramine in eight healthy subjects, 20 hospitalized patients without liver disease, and 13 cirrhotic patients of whom seven had hepatic encephalopathy. The effect of increasing dietary protein on tyramine level of cirrhotic patients was also assessed. No significant difference in plasma tyramine concentration was seen between normal subjects, 1.3 +/- 0.1 ng per milliliter (average +/- S.E.), hospitalized patients without hepatic disease (1.4 +/- 0.1 ng per milliliter) and cirrhotic patients without encephalopathy (2.7 +/- 0.5 ng per milliliter). However, the tyramine level in cirrhotic patients with encephalopathy, 6.4 +/- 0.1 ng per milliliter, was significantly (P less than 0.001) higher than in normal subjects or in cirrhotic patients without encephalopathy. Increasing dietary protein from 40 to 80 g per day raised fasting tyramine concentration by 30 to 70 per cent within three days in both encephalopathic and non-encephalopathic cirrhotic patients. Concentration of plasma tyramine in cirrhotic subjects was significantly correlated with that of plasma tyrosine (P less than 0.001).
Adult↗
Induction by endogenous noradrenaline of an alpha 1-adrenoceptor-mediated positive inotropic effect in rabbit papillary muscles.
1. The possible involvement of alpha 1-adrenoceptors in the inotropic and electrophysiological responses to endogenous noradrenaline released by tyramine was examined in rabbit papillary muscles. 2. A concentration-dependent positive inotropic effect was produced by tyramine. This effect of tyramine was not observed in muscles from rabbits pretreated with reserpine. 3. The positive inotropic effect of tyramine was greatly inhibited by propranolol, but not altered by prazosin. However, when beta-adrenoceptors were blocked by pretreatment with propranolol, tyramine still produced a positive inotropic effect, an effect which was antagonized by prazosin. 4. Tyramine caused a decrease in action potential duration (APD) and an increase in action potential amplitude in a concentration-dependent manner. Isoprenaline also produced the same electrophysiological effects. These electrophysiological effects of both agents were inhibited by propranolol. 5. When beta-adrenoceptors were blocked by propranolol, the observed prazosin-sensitive positive inotropic effect of tyramine was not accompanied by any change in APD. In contrast, APD was markedly prolonged by alpha 1-adrenoceptor stimulation with phenylephrine in the presence of propranolol, in association with the positive inotropic effect. 6. It is concluded that in rabbit papillary muscles, endogenous noradrenaline causes a positive inotropic effect predominantly mediated by beta-adrenoceptors, but can still evoke a positive inotropic effect through alpha 1-adrenoceptors when beta-adrenoceptor stimulation is eliminated. This suggests that the alpha 1-adrenoceptor-mediated positive intropic mechanism(s) may be masked by simultaneous activation of beta-adrenoceptors. In addition, this study indicates that APD prolongation is not involved in the alpha 1-adrenoceptor-mediated inotropic responses to endogenous noradrenaline.
Action Potentials↗
Sequencing of the tyrosine decarboxylase cluster of Lactococcus lactis IPLA 655 and the development of a PCR method for detecting tyrosine decarboxylating lactic acid bacteria.
The enzymatic decarboxylation of tyrosine produces tyramine, the most abundant biogenic amine in dairy products-especially in cheeses. The screening of lactic acid bacteria isolated from different artisanal cheeses and a number of microbial collections identified 22 tyramine-producing strains belonging to different genera. The Lactococcus lactis strain IPLA 655 was selected, and the genes encoding a putative tyrosyl tRNA synthetase, a tyrosine decarboxylase (tdcA), and a tyrosine-tyramine antiporter, found together as a cluster, were sequenced. The disruption of tdcA yielded a strain unable to produce tyramine. Comparison of the L. lactis IPLA 655 tdcA gene with database tdcA sequences led to the design of two primers for use in a PCR method that identified potential tyramine-producing strains. The proposed method can use purified DNA, isolated colonies, milk, curd, and even cheese as a template. Molecular tools for the rapid detection of tyramine-producing bacteria at any time during the fermentation process could help prevent tyramine accumulation in fermented foods. The proposed technique could be of great use to the food industry.
Amino Acid Sequence↗