Mechanisms of the antilipolytic response of human adipocytes to tyramine, a trace amine present in food

Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions. Lipolytic activity was determined in adipocytes from human subcutaneous abdominal adipose tissue. Glycerol release was increased by a fourfold factor with classical lipolytic agents (1 μM isoprenaline, 1 mM isobutylmethylxanthine) while the amine was ineffective from 0.01 to 100 μM and hardly stimulatory at 1 mM. Tyramine exhibited a partial antilipolytic effect at 100 μM and 1 mM, which was similar to that of insulin but weaker than that obtained with agonists at purinergic A1 receptors, α2-adrenoceptors, or nicotinic acid receptors. Gi-protein blockade by Pertussis toxin abolished all these antilipolytic responses save that of tyramine. Indeed, tyramine antilipolytic effect was impaired by MAO-A inhibition. Tyramine inhibited protein tyrosine phosphatase activities in a manner sensitive to ascorbic acid and amine oxidase inhibitors. Thus, millimolar tyramine restrained lipolysis via the hydrogen peroxide it generates when oxidized by MAO. Since tyramine plasma levels have been reported to reach 0.2 μM after ingestion of 200 mg tyramine in healthy individuals, the direct effects we observed in vitro on adipocytes could be nutritionally relevant only when the MAO-dependent hepato-intestinal detoxifying system is overpassed

Mechanisms of the antilipolytic response of human adipocytes to tyramine, a trace amine present in food.

Tyramine is found in foodstuffs, the richest being cheeses, sausages, and wines. Tyramine has been recognized to release catecholamines from nerve endings and to trigger hypertensive reaction. Thereby, tyramine-free diet is recommended for depressed patients treated with irreversible inhibitors of monoamine oxidases (MAO) to limit the risk of hypertension. Tyramine is a substrate of amine oxidases and also an agonist at trace amine-associated receptors. Our aim was to characterize the dose-dependent effects of tyramine on human adipocyte metabolic functions. Lipolytic activity was determined in adipocytes from human subcutaneous abdominal adipose tissue. Glycerol release was increased by a fourfold factor with classical lipolytic agents (1 µM isoprenaline, 1 mM isobutylmethylxanthine) while the amine was ineffective from 0.01 to 100 µM and hardly stimulatory at 1 mM. Tyramine exhibited a partial antilipolytic effect at 100 µM and 1 mM, which was similar to that of insulin but weaker than that obtained with agonists at purinergic A1 receptors, α2-adrenoceptors, or nicotinic acid receptors. Gi-protein blockade by Pertussis toxin abolished all these antilipolytic responses save that of tyramine. Indeed, tyramine antilipolytic effect was impaired by MAO-A inhibition. Tyramine inhibited protein tyrosine phosphatase activities in a manner sensitive to ascorbic acid and amine oxidase inhibitors. Thus, millimolar tyramine restrained lipolysis via the hydrogen peroxide it generates when oxidized by MAO. Since tyramine plasma levels have been reported to reach 0.2 µM after ingestion of 200 mg tyramine in healthy individuals, the direct effects we observed in vitro on adipocytes could be nutritionally relevant only when the MAO-dependent hepato-intestinal detoxifying system is overpassed.

Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine.

PURPOSE: The inhibitory effects of antidepressants, such as imipramine, desipramine, and fluvoxamine, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with those on dopamine formation catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: Inhibition constants (Ki) of the antidepressants toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10, which were expressed in recombinant Escherichia coli, were compared. RESULTS: Imipramine and desipramine competitively or non-competitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 3.9-4.9, 5.9-9.6, and 26.7-37.5 µM, respectively. The maximal velocity (Vmax) values for dopamine formation by all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations up to 40-100 µM, indicating that fluvoxamine stimulated dopamine formation. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6-mediated dopamine formation by these antidepressants would be affected by CYP2D6 polymorphism in the brain. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Direct and indirect cardiovascular actions of cathinone and MDMA in the anaesthetized rat.

The stimulants cathinone (from Khat leaves) and methylenedioxymeth-amphetamine (MDMA) produce adrenoceptor mediated tachycardia and vasopressor actions that may be the result of direct receptor stimulation, actions on the noradrenaline transporter, and/or displacement of noradrenaline from nerve terminals. Effects of cathinone or MDMA were compared with those of the indirect sympathomimetic tyramine. Male Wistar rats were anaesthetized with pentobarbitone for blood pressure and heart rate recording. Some rats were sympathectomised by treatment with 6-hydroxydopamine. In the anaesthetised rat, cathinone, MDMA and tyramine (all 0.001-1 mg/kg) produced marked tachycardia, tyramine produced marked pressor responses and MDMA produced small pressor responses. The tachycardia to cathinone and MDMA was almost abolished by propranolol (1mg/kg). Pretreatment with cocaine (1mg/kg) did not significantly affect the tachycardia to cathinone or MDMA, but reduced the response to tyramine. However, in sympathectomised rats, the tachycardia to cathinone or MDMA was markedly attenuated, but the tachycardia to tyramine was only partially reduced. Blood pressure effects of tyramine and MDMA were also markedly attenuated by sympathectomy. The results demonstrate firstly that cocaine may not be the most suitable agent for assessing direct versus indirect agonism in cardiovascular studies. Secondly, the use of chemical sympathectomy achieved the desired goal of demonstrating that cardiac ß-adrenoceptor mediated actions of cathinone and MDMA are probably largely indirect.

Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1.

Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC's physiological actions begin with its stimulation of ß1- and ß2-adrenergic receptor-mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC's psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for intracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse trace amine-associated receptor 1 (mTAAR1), which was completely reversed by the trace amine-associated receptor 1 (TAAR1)-selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human ß2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human ß2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug.

Evidence for a possible neurotransmitter/neuromodulator role of tyramine on the locust oviducts.

Visualization of the tyraminergic innervation of the oviducts was demonstrated by immunohistochemistry, and the presence of tyramine was confirmed using high-performance liquid chromatography coupled to electrochemical detection. Oviducts incubated in high-potassium saline released tyramine in a calcium-dependent manner. Stimulation of the oviducal nerves also resulted in tyramine release, suggesting that tyramine might function as a neurotransmitter/neuromodulator at the locust oviducts. Tyramine decreased the basal tension, and also attenuated proctolin-induced contractions in a dose-dependent manner over a range of doses between 10(-7) and 10(-4) M. Low concentrations of tyramine attenuated forskolin-stimulated cyclic AMP levels in a dose-dependent manner. This effect was not blocked by yohimbine. High concentrations of tyramine increased basal cyclic AMP levels of locust oviducts in a dose-dependent manner; however, the increases in cyclic AMP were only evident at the highest concentrations tested, 5 x 10(-5) and 10(-4) M tyramine. The tyramine-induced increase in cyclic AMP shared a similar pharmacological profile with the octopamine-induced increase in cyclic AMP. Tyramine increased the amplitude of excitatory junction potentials at low concentrations while hyperpolarizing the membrane potential by 2-5 mV. A further increase in the amplitude of the excitatory junction potentials and the occurrence of an active response was seen upon washing tyramine from the preparation. These results suggest that tyramine can activate at least three different endogenous receptors on the locust oviducts a putative tyramine receptor at low concentrations, a different tyramine receptor to inhibit muscle contraction, and an octopamine receptor at high concentrations.

(-)-Deprenyl inhibits tyramine-induced noradrenaline release, but not tyramine-induced dopamine release or potassium-induced noradrenaline release, from rat brain synaptosomes.

The effect of (-)-deprenyl (selegiline), a therapeutic agent for Parkinson's disease, on the tyramine-induced release of catecholamine from rat brain synaptosomes was studied using a superfusion system. Tyramine (10(-7) to 10(-5)M) enhanced the release of [3H]noradrenaline (NA) and [3H]dopamine (DA) from forebrain and striatal synaptosomes in a dose-dependent manner. (-)-Deprenyl (5x10(-5)M) had no effect on spontaneous catecholamine release, suggesting that it has no tyramine-like catecholamine releasing effect. Pretreatment with (-)- or (+)-deprenyl (5x10(-5)M) significantly prevented the tyramine (10(-6)M)-induced NA release, but not DA release. The inhibitory action of (-)-deprenyl was not observed on potassium (15mM)-induced NA release. (-)-Desmethyldeprenyl (5x10(-5)M), a metabolite of (-)-deprenyl, and a monoamine oxidase-A (MAO-A) inhibitor, clorgyline (5x10(-5)M), failed to block the tyramine-induced NA and DA release. Although (+)-deprenyl, a potent DA uptake inhibitor, did not inhibit tyramine-induced DA release, a catecholamine uptake inhibitor nomifensine (5x10(-5)M) did. In summary, (-)-deprenyl at a dose inhibiting tyramine-induced NA release did not have any effect on tyramine-induced DA release or potassium-induced NA release.

Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs.

Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.

B96Bom encodes a Bombyx mori tyramine receptor negatively coupled to adenylate cyclase.

A cDNA encoding a biogenic amine receptor (B96Bom) was isolated from silkworm (Bombyx mori) larvae, and the ligand response of the receptor stably expressed in HEK-293 cells was examined. Tyramine (TA) at 0.1-100 micro m reduced forskolin (10 micro m)-stimulated intracellular cAMP levels by approximately 40%. The inhibitory effect of TA at 1 micro m was abolished by yohimbine and chlorpromazine (each 10 micro m). Although octopamine (OA) also reduced the cAMP levels, the potency was at least two orders of magnitude lower than that of TA. Furthermore, unlabelled TA (IC50 = 5.2 nm) inhibited specific [3H]TA binding to the membranes of B96Bom-transfected HEK-293 cells more potently than did OA (IC50 = 1.4 micro m) and dopamine (IC50 = 1.7 micro m). Taken together with the result of phylogenetic analysis, these findings indicate that the B96Bom receptor is a B. mori TA receptor, which is negatively coupled to adenylate cyclase. The use of this expression system should facilitate physiological studies of TA receptors as well as structure-activity studies of TA receptor ligands.

Tyramine and benzylamine partially but selectively mimic insulin action on adipose differentiation in 3T3-L1 cells.

Biogenic amines like tyramine, methylamine and the non-naturally occuring amine, benzylamine, have been described to promote adipose conversion of murine 3T3 preadipocytes. To further investigate these novel effects of amines, we studied whether they selectively mimic the long-term adipogenic action of insulin. To this aim, we decided to use the 3T3-L1 cell line since this model needs a complex combination of inducers to trigger the differentiation programme: insulin, isobutylmethylxanthine (IBMX, an activator of cAMP-signal transduction pathway) and the synthetic glucocorticoid, dexamethasone. A cell culture protocol was designed, by which each component of the differentiation cocktail was replaced with either benzylamine or tyramine, in order to determine whether these amine oxidase substrates could substitute any of the differentiation inducers in 3T3-L1 cells. The incomplete lipid accumulation found in cells grown under IBMX- or dexamethasone-free conditions was not improved by the daily addition of amines to the culture medium. Insulin was the only component of adipose differentiation cocktail of 3T3-L1 that could be replaced, although partially, by tyramine or benzylamine. When used at 0.5 mM, these amines resulted in a significant increase of triacylglycerol accumulated eight days after confluence, when compared to cells kept without insulin. This partial insulin replacement was totally abolished by SSAO-inhibitors, while MAO-blockade did not reduce lipid accumulation. As previously reported for other insulin-sensitive processes, such as stimulation of glucose transport or lipolysis inhibition in mature adipocytes, the stimulation of adipogenesis by tyramine and benzylamine was an SSAO-dependent mechanism that apparently shared common signaling pathways with insulin.

Regulation of chloride permeability by endogenously produced tyramine in the Drosophila Malpighian tubule.

The Malpighian (renal) tubule of Drosophila melanogaster is a useful model for studying epithelial transport. The purpose of this study was to identify factors responsible for modulating transepithelial chloride conductance in isolated tubules. I have found that tyrosine and several of its metabolites cause an increase in chloride conductance. The most potent of these agonists is tyramine, which is active at low nanomolar concentrations; the pharmacology of this response matches that of the previously published cloned insect tyramine receptor. In addition, the tubule appears capable of synthesizing tyramine from applied tyrosine, as shown by direct measurement of tyrosine decarboxylase activity. Immunohistochemical staining of tubules with an antibody against tyramine indicates that the principal cells are the sites of tyramine production, whereas previous characterization of the regulation of chloride conductance suggests that tyramine acts on the stellate cells. This is the first demonstration of a physiological role for an insect tyramine receptor.

Reserpine attenuates interstitial adenosine-mediated activation of ecto-5'-nucleotidase in rat hearts in vivo.

We examined whether reserpine-induced norepinephrine (NE) depletion attenuated the products of adenosine in rat heart. A flexibly mounted microdialysis technique was used to measure the concentration of interstitial adenosine and to assess the activity of ecto-5'-nucleotidase in rat hearts in situ. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and perfused with Tyrode solution containing adenosine 5'-monophosphate (AMP) at rate of 1.0 microliter/min. The baseline level of dialysate adenosine was 0.51 +/- 0.09 microM. The introduction of AMP (100 microM) through the probe increased markedly the dialysate adenosine to 8.95 +/- 0.86 microM, and this increase was inhibited by ecto-5'-nucleotidase inhibitor, alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP, 100 microM), to 0.66 +/- 0.38 microM. Thus, the level of dialysate adenosine is a measure of the ecto-5'-nucleotidase activity in the tissue in situ. AMP concentration for the half-maximal effect of adenosine release (EC(50)) was 107.3 microM. The maximum attainable concentration of dialysate adenosine (E(max)) by AMP was 21.1 microM. However, the EC(50) and E(max) values with reserpinized animals were 106.9 and 7.1 microM, respectively. Electrical stimulation of the left stellate ganglion increased significantly dialysate adenosine concentration, from the control level of 8.66 +/- 0.96 microM to 12.38 +/- 1.11 microM. After stimulation, dialysate adenosine returned to near the prestimulation level. When corresponding experiments were performed with reserpinized animals, the effect of electrical stimulation was abolished. Tyramine (endogenous catecholamine trigger) increased the adenosine concentration in a concentration-dependent manner. However, the elevation of adenosine concentration with reserpinized animals was not observed. These results suggest that reserpine attenuates NE-induced adenosine via stimulation of alpha(1)-adrenoceptor and protein kinase C mediated activation of ecto-5'-nucleotidase in rat heart.

The effects of T-588, a novel cognitive enhancer, on noradrenaline uptake and release in rat cerebral cortical slices.

Previously, we reported that (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)-ethoxy]e thanol hydrochloride (T-588), a novel cognitive enhancer, stimulated noradrenaline (NA) release from rat cerebral cortical slices. In this study, we investigated the effects of T-588 on NA uptake and release, compared to the effects of desipramine, a blocker of the NA carrier on the plasma membrane. Both T-588 and desipramine caused dose-dependent inhibition of [3H]NA uptake into the slices. Addition of 3 mM T-588 stimulated [3H]NA release from the prelabeled slices even in the presence of 10 microM desipramine, which inhibited NA uptake completely. Tyramine, which accelerates NA carrier-mediated release, also stimulated [3H]NA release, and tyramine-stimulated release was inhibited by desipramine. These findings indicated that T-588-stimulated NA release was not mediated by 1) inhibition of reuptake or 2) reverse transport mediated by NA carriers. Reserpine, which interacts with the intracellular vesicular transport system, increased [3H]NA efflux from slices. High K+-, not T-588-, stimulated [3H]NA release was shifted upward by reserpine. These findings suggest that T-588 evokes NA release by a mechanism similar to that induced by reserpine. T-588 might act as a cognitive enhancer via neurotransmitter release in the brain.

Reboxetine prevents the tranylcypromine-induced increase in tyramine levels in rat heart.

This study aimed to examine whether the increase in heart radioactivity levels after intravenous injection of 14C-tyramine to rats pretreated with the irreversible MAO inhibitor tranylcypromine could be antagonized by reboxetine, a potent and selective noradrenaline uptake blocker. Reboxetine was found totally to abolish the effect of tranylcypromine. Heart radioactivity levels after reboxetine and tranylcypromine were very similar to those found when tyramine was injected after reboxetine only. These results suggest that reboxetine might be advantageously combined with tranylcypromine, or any MAO inhibitor, in depressed patients unresponsive of either treatment given alone.

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.

The effects of tyramine on salivary flow rate and protein secretion by rat submandibular glands.

The effects of different doses of p-tyramine injected i.v. and i.p. on salivary flow rates and proteins secreted by the submandibular glands of rats were studied with and without various types of autonomic blockers and two enzyme inhibitors. The salivary flow rates and the amounts of protein secreted progressively increased with increasing doses injected both i.v. and i.p., whereas they were dramatically reduced with all autonomic blockers except the lowest doses of beta-blockers, atropine, and yohimbine. Salivation in response to p-tyramine injected i.v. and i.p. was completely abolished by simultaneous injections of both prazosin and propranolol. The concentration of protein was not dose-dependent and was not reduced by yohimbine and phenoxybenzamine at almost all doses used. However, prazosin significantly increased the protein concentration. Protease activities were dose-dependent but were significantly reduced with alpha-blockers other than yohimbine, and with most beta-blockers. The proteins secreted in response to p-tyramine at all doses injected i.v. and i.p. were of the alpha-type except with the lowest dose injected i.p. However, the alpha-type was completely replaced by the beta-type in the presence of all alpha-blockers except yohimbine, but not with beta-blockers, atropine, or two enzyme inhibitors. Pargyline, a monoamine-oxidase inhibitor, but not disulfiram, a dopamine-beta-hydroxylase inhibitor, affected all parameters except the type of protein. Thus, p-tyramine may activate both the alpha 1- and beta 1-adrenoceptors in the submandibular glands of rats directly or indirectly.

COMT inhibition with nitecapone does not affect the tyramine pressor response.

Nitecapone (OR-462) is a new selective COMT inhibitor with gastroprotective properties. The aim of the present study was to determine whether nitecapone potentiates the haemodynamic effects of a tyramine-induced increase in catecholamine release. The systolic blood pressure response to tyramine was studied in 11 healthy male volunteers (age 20-32 years). Tyramine was given i.v. as rapid bolus injections in increasing doses without drug intake and after oral intake of single doses of 25 mg and 100 mg of nitecapone. The tyramine dose required to increase systolic blood pressure by 30 mm Hg ('pressor dose') was 4.98 mg, 5.04 mg and 4.88 mg after no medication, and with 25 mg and 100 mg of nitecapone, respectively. There were also no differences in the systolic blood pressure response vs time curves between the three regimens. COMT inhibition with nitecapone did not potentiate the haemodynamic responses to tyramine-induced catecholamine release.

Methoxyphenamine inhibits basal and histamine-induced nasal congestion in anaesthetized rats.

1. Nasal resistance in anaesthetized rats was assessed by measuring air overflow during ventilation of the nasal passages at constant pressure. Nasal basal resistance was reduced in a dose-dependent manner by methoxyphenamine hydrochloride (0.01-30 mg kg-1, i.v.), pseudoephedrine hydrochloride (0.03-3 mg kg-1, i.v.) and adrenaline bitartrate (0.01-3 micrograms kg-1, i.v.). Both methoxyphenamine and pseudoephedrine were less potent and less efficacious than adrenaline but caused longer-lasting responses. 2. Nasal congestion induced by histamine (0.2% nebulised solution passed into the nasal passages for 15 s) was inhibited by i.v. administration of methoxyphenamine, pseudoephedrine, adrenaline, methoxamine or tyramine: the ID50s against 0.2% histamine-induced nasal congestion were 1.16 (95% confidence limits; 0.5, 1.8) mg kg-1, 0.25 (0.19, 0.33) mg kg-1, 0.037 (0.018, 0.06) micrograms kg-1, 8.12 (6.74, 9.65) micrograms kg-1 and 30.6 (26.1, 35.8) micrograms kg-1 respectively. 3. The inhibitory effects of both methoxyphenamine and tyramine on histamine-induced nasal congestion were reduced after administration of desmethylimipramine (0.1 and 1 mg kg-1, i.v.) or prazosin (0.1 and 0.3 mg kg-1, i.v.). Similarly, the inhibitory effects of methoxamine were reduced after prazosin (0.1 and 0.3 mg kg-1). 4. These results indicate that methoxyphenamine (1 mg kg-1, i.v.) inhibits histamine-induced nasal congestion in the rat. This action, at least in part, is probably indirect being mediated by release of neuronal noradrenaline which then acts on alpha 1-adrenoceptors.

Evidence that endogenous catecholamines are involved in alpha 2-adrenoceptor-mediated modulation of the aortic baroreceptor reflex in the nucleus tractus solitarii of the rat.

Microinjections of alpha-methylnoradrenaline and tyramine into the rat nucleus tractus solitarii (NTS) potentiated the depressor and bradycardiac responses to aortic nerve stimulation whereas yohimbine injected similarly inhibited them. NTS pretreatment with yohimbine inhibited the baroreflex potentiation effects of alpha-methylnoradrenaline and tyramine whereas intraventricular pretreatment with 6-hydroxydopamine inhibited only that of tyramine. These results provide evidence that endogenous catecholamines in the rat NTS are involved in alpha 2 adrenoceptor-mediated modulation of the aortic baroreceptor reflex.

Beta-blockade antagonism of tyramine-induced rise in blood pressure.

The effect beta-adrenoceptor blockade on the pressor response to tyramine has been investigated in 6 healthy volunteers, each submitted to an i.v. tyramine pressor test before and after 7 days of propranolol 40 mg b.d. or indenolol 60 mg o.d. Tyramine was given as i.v. boluses of 1-6 mg, alternating with saline, in a randomized, single blind fashion. Prior to treatment tyramine caused a temporary, dose-dependent increase in systolic and diastolic blood pressure, whilst the heart rate remained unaffected. Both propranolol and indenolol reduced the pressor response to tyramine, as shown by a significant increase in ED15, i.e. the dose of tyramine required to increase systolic blood pressure by 15%.