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The 2-step synthesis of [1- 14 C]tyramine hydrochloride is described with the product being characterized by TLC, HPLC, and UV spectroscopy. Several methods are provided to purify [1- 14 C]tyramine hydrochloride, and its storage and stability are also discussed., (© 2018 John Wiley & Sons, Ltd.)

N-methyltyramine (NMT) is a protoalkaloid isolated from various plant species. It is assumed that NMT is an adrenergic agonist with pharmacological properties similar to other structurally related biogenic amines. Current research studies indicate that NMT is an α-adrenoreceptor antagonist, and exhibits modest inhibitory (antagonistic) activity with respect to the breakdown of fats (lipolysis). Furthermore, NMT has been shown to enhance appetite and digestion of foods through its stimulatory effects on gastrin and pancreatic secretions. As a consequence, NMT is not an ingredient that should be used in dietary supplements designed to promote weight loss. It may result in an increase in perceived energy by promoting appetite and the digestion and absorption of nutrients while inhibiting the breakdown to fats to energy., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background and Purpose: Type 1 diabetes is a multifactorial inflammatory disease that develops as a result of deregulated immune responses, causing progressive autoimmune destruction of insulin-producing beta cells of pancreas. 2-((4-acetoxyphenyl)-2-chloro-N-methyl) ethylammonium chloride, compound A (CpdA), is a selective glucocorticoid receptor (GR) agonist that displays strong anti-inflammatory and immunomodulatory activities. We investigated the therapeutic effectiveness of CpdA in a pharmacological model of type 1 diabetes in mice., Experimental Approach: The utility of CpdA in diabetes prevention was evaluated in vivo through its prophylactic administration to male C57BL/6 mice that received multiple low doses of streptozotocin for immunoinflammatory diabetes induction. The effect of CpdA on disease development was studied by measuring blood glucose and insulin level, histopathological examination, determination of the nature of infiltrating cells, pro- and anti-inflammatory cytokine production, and signalling pathways., Key Results: Prophylactic in vivo therapy with CpdA conferred protection against development of immunoinflammatory diabetes in mice by dampening the M1/Th1/Th17 immune response and switching it towards an anti-inflammatory M2/Th2/Treg profile, thus preserving beta cell function., Conclusions and Implications: Anti-diabetic properties of CpdA are mediated through modulation of immune cell-mediated pathways, but without triggering adverse events. These findings provide basic information for the therapeutic use of selective GR agonists in the amelioration of islet-directed autoimmunity., (© 2014 The British Pharmacological Society.)

Aims: The trace amine-associated receptor (Taar) family displays high species- and subtype-specific pharmacology. Several trace amines such as β-phenylethylamine (β-PEA), p-tyramine and tryptamine are agonists at TA(1) but poorly activate rat and mouse Taar4., Principal Results: Using rat TA(1) and Taar4 chimera, we identified determinants in transmembrane helices 3 and 6, which, when replaced by the corresponding portion of rat TA(1) , can rescue cell surface expression of rat Taar4. When expressed at the cell surface, rat Taar4 pharmacology was very similar to that of TA(1) and coupled to the Gα(s) -protein/AC pathway. Our data suggest that binding pockets of Taar for surrogate agonists overlap between paralogs., Conclusions: This implicates that the repertoire of Taar ensures functional redundancy, tissue- and cell-specific expression and/or different downstream signalling rather than different agonist specificity., (© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Background and Purpose: Tryptamine increases blood pressure by vasoconstriction, but little is known about its actions on the mesentery, in particular the resistance arteries. Tryptamine interacts with trace amine-associated receptors (TAARs) and because of its structural similarity to 5-HT, it may also interact with 5-HT receptors. Our hypothesis is therefore that the rat mesenteric arterial bed will exhibit vasopressor and vasodepressor responses to tryptamine via both 5-HT and TAARs., Experimental Approach: Tryptamine-evoked responses were assayed from pressure changes of the rat-isolated mesenteric vasculature perfused at constant flow rate in the absence and presence of adrenoceptor and 5-HT receptor antagonists., Key Results: Tryptamine caused dose-dependent vasoconstriction of the mesenteric arterial bed as increases in perfusion pressure. These were unaffected by the α(1) -adrenoceptor antagonist, prazosin, but were attenuated by the non-selective α-adrenoceptor antagonist, phentolamine. The 5-HT(2A) receptor antagonists, ketanserin and ritanserin, abolished the tryptamine-induced pressure increases to reveal vasodilator responses in mesenteric beds preconstricted with phenylephrine. These tryptamine-induced vasodilator responses were unaffected by the 5-HT(7) receptor antagonist, SB269970, but were eliminated by the NOS inhibitor, N(ω) -nitro-L-arginine methyl ester (L-NAME). Tyramine and β-phenylethylamine also caused vasodilatation in pre-constricted vasculature, which was also abolished by L-NAME., Conclusions and Implications: Tryptamine causes vasoconstriction of the mesenteric vasculature via 5-HT(2A) receptors, which when inhibited exposed vasorelaxant effects in pre-constricted tissues. The vasodilatation was independent of 5-HT(2A) and 5-HT(7) receptors but like that for tyramine and β-phenylethylamine was due to NO release. Potency orders suggest TAAR involvement in the vasodilatation by these trace amines., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background and Purpose: Although trace amines (TAs) are historically considered 'false neurotransmitters' on the basis of their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors, ligand-gated receptor channels and/or sigma receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and beta-phenylethylamine (beta-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to the D(2) receptor agonist, quinpirole., Experimental Approach: Electrophysiological recordings of D(2) receptor-activated G-protein-gated inward rectifier K(+) channel (GIRK) currents were performed on dopaminergic cells from midbrain slices of mice and on Xenopus oocytes expressing D(2) receptors and GIRK channels., Key Results: TYR and beta-PEA reversibly reduced D(2) receptor-activated GIRK currents in a concentration-dependent manner on SNpc neurones. The inhibitory effect of TAs was still present in transgenic mice with genetically deleted TA(1) receptors and they could not be reproduced by the selective TA(1) agonist, o-phenyl-3-iodotyramine (O-PIT). Pretreatment with antagonists of sigma1 and sigma2 receptors did not block TA-induced effects. In GTPgammaS-loaded neurones, the irreversibly-activated GIRK-current was still reversibly reduced by beta-PEA. Moreover, beta-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes., Conclusions and Implications: TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from TA(1), sigma-receptors, D(2) receptors or GIRK channels. Although their precise mechanism of action remains to be identified, TAs, by antagonizing the inhibitory effects of dopamine, may render dopaminergic neurones less sensitive to autoreceptor feedback inhibition and hence enhance their sensitivity to stimulation.

Background and Purpose: The dietary trace amines tyramine and beta-phenylethylamine (beta-PEA) can increase blood pressure. However, the mechanisms involved in the vascular effect of trace amines have not been fully established. The purpose of this study was to evaluate whether trace amine-dependent vasoconstriction was brought about by tyramine and beta-PEA acting as indirect sympathomimetic agents, as previously assumed, or whether trace amine-dependent vasoconstriction could be mediated by recently discovered trace amine-associated (TAA) receptors., Experimental Approach: The responses to p-tyramine and beta-PEA were investigated in vitro in rings of the left anterior descending coronary arteries of pigs., Key Results: p-Tyramine induced a concentration-dependent (0.1-3 mM) vasoconstriction. The maximum response and pD(2) value for p-tyramine was unaffected by endothelium removal or pre-treatment with antagonists for adrenoceptors, histamine, dopamine or 5-HT receptors. beta-PEA also produced a concentration-dependent (0.3-10 mM) vasoconstriction which was unaffected by endothelium removal, beta-adrenoceptor or 5-HT receptor antagonists. A substantial, but reduced, response to beta-PEA was obtained in the presence of prazosin (alpha(1)-adrenoceptor antagonist), haloperidol (D(2)/D(3) dopamine receptor antagonist) or mepyramine (H(1) histamine receptor antagonist). The pD(2) value for beta-PEA was unaffected by any of the antagonists tested., Conclusions and Implications: Vasoconstriction induced by p-tyramine does not involve an indirect sympathomimetic effect, although vasoconstriction caused by beta-PEA may occur, in part, by this mechanism. We therefore propose that trace amine-dependent vasoconstriction is mediated by phenylethylamine-specific receptors, which are closely related to or identical to TAA receptors. These receptors could provide a target for new antihypertensive therapies.

Background and Purpose: Ephedrine and amphetamine can cause substantial increases in systemic arterial pressure. However, the role of endogenous noradrenaline release in mediating the pressor response to ephedrine is controversial. Studies using pharmacologic agents to decrease the synthesis, storage, and release of catecholamines have supported both a direct and an indirect mechanism of action for ephedrine. The purpose of the present study was to determine if endogenous noradrenaline release is required for cardiovascular responses to ephedrine and amphetamine using a genetic mouse model., Experimental Approach: Increases in systemic arterial pressure and heart rate in response to ephedrine and amphetamine were investigated and compared in dopamine beta-hydroxylase knockout (Dbh -/-) mice that cannot synthesize noradrenaline. Dbh +/- littermates have normal noradrenaline and adrenaline tissue levels, and served as controls in all experiments., Key Results: In Dbh -/- mice the increases in systemic arterial pressure and heart rate in response to i.v. injections of ephedrine were not impaired whereas responses to amphetamine were markedly reduced, when compared with responses in Dbh +/- mice. The pressor response to tyramine was abolished whereas pressor responses to noradrenaline, phenylephrine, dopamine, and angiotensin II were similar in Dbh -/- and Dbh +/- mice., Conclusions and Implications: The present results in Dbh -/- mice provide support for the hypothesis that pressor responses to ephedrine are directly mediated whereas responses to amphetamine are dependent on the release of noradrenaline and suggest that Dbh +/- and Dbh -/- mice are useful for the study of direct and indirect mechanisms.

This work presents the behavioral effects of riparin I (methyl ether of N-benzoyl tyramine) from unripe fruit of Aniba riparia (Lauraceae) on the elevated plus maze, open field, rota rod and hole board tests in mice. Riparin I was administered acutely by intraperitoneal (i.p.) and oral routes to male mice at doses of 25 and 50 mg/kg. The results showed that riparin I (25 and 50 mg/kg, i.p. and per os) increased the number of entries and the time of permanence in the open arms in the plus maze test. Similarly, in the hole board test, riparin I in both routes increased the number of head dips. Riparin I with both doses and routes had no effects on spontaneous motor activity in mice or in the rota rod test, but decreased the number of groomings. These results showed that riparin I by both administration routes has effects on the central nervous system with antianxiety effects on the plus maze and hole board tests. The substance is devoid of myorelaxant effects., (Copyright 2005 John Wiley & Sons, Ltd.)

The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a >30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD>30 index (pretreatment/treatment ratio of PD>30) of > or = 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine-containing foods are not warranted when taking linezolid.

1. The effects of the alpha(1)-adrenoceptor antagonists doxazosin (0.1 -- 2 mg kg(-1)), RS-100329 (alpha(1A); 0.01 -- 1 mg kg(-1)), RS-513815 (Ro 151-3815, alpha(1B); 0.3 -- 3 mg kg(-1)) and BMY 7378 (alpha(1D); 0.1 -- 1 mg kg(-1)), the 5-HT(1A) receptor agonist, 8-OH-DPAT (0.03 -- 0.3 mg kg(-1)) and antagonist WAY-100635 (0.03 -- 0.3 mg kg(-1)) were investigated (i.v.) on the 'micturition reflex' in the urethane anaesthetized male rat. 2. Reflex-evoked urethra contractions were most sensitive to the inhibitory action of RS-100329, followed by doxazosin, BMY 7378 and WAY-100635 and then RS-513815. The maximum inhibition was 66, 63, 54, 46 and 22% at doses of 0.3, 0.5, 0.3, 0.3 and 3 mg kg(-1) respectively. 3. BMY 7378 and 8-OH-DPAT decreased, while WAY-100635 increased, the pressure threshold to induce bladder contraction. WAY-100635 (0.01 mg kg(-1)) blocked the effects of BMY 7378 (1 mg kg(-1)) on bladder pressure and volume threshold. 4. Doxazosin, RS-100329 and BMY 7378 had a similar potency in inducing a fall in arterial blood pressure while WAY-100635 only caused a fall at the highest dose. 5. Therefore, reflex-evoked urethral contraction involves the activation of alpha(1A/1D)-adrenoceptors, as BMY 7378 and RS-100329 are similarly potent in attenuating this effect. The ability of WAY-100635 to attenuate this contraction may suggest that 5-HT(1A) receptors are also involved. However, as this inhibition occurred at the highest dose of WAY-100635, which also caused a fall in arterial blood pressure; this effect is considered to be due to blockade of alpha(1)-adrenoceptors not 5-HT(1A) receptors. Nevertheless the initiation of the 'micturition reflex' involves the activation of 5-HT(1A) receptors.

1. P2X-Purinoceptors and alpha1-adrenoceptors have previously been shown to involve in the double peaked vasoconstrictor responses to periarterial electrical nerve stimulation in the isolated and perfused canine splenic artery. The present study made an attempt to investigate effects of prolonged cold storage (7 days at 4 degrees C) on vasoconstrictor responses to periarterial electrical nerve stimulation, tyramine, noradrenaline and adenosine 5'-triphosphate (ATP) in the isolated canine splenic artery. 2. The periarterial nerve stimulation (1-10 Hz) readily causes a double peaked vasoconstriction in the non-stored preparations. After cold stored for 7 days, the double peaked vasoconstriction was still recognized, although the response became significantly smaller. The first phase was decreased relatively greater than the second phase by the cold storage. 3. In the cold stored preparations, the dose-response curve for tyramine was shifted to the right in a parallel manner. Prazosin almost completely inhibited tyramine-induced vasoconstriction but alpha,beta-methylene ATP failed to influence the response to tyramine. 4. The vasoconstrictor responses to noradrenaline and ATP were not significantly modified by the prolonged cold storage. 5. From these results, it is concluded that the functions of sympathetic co-transmission of purinergic components might be influenced more than that of adrenergic components in the cold storage canine splenic artery.

Two sisters with cluster headache were studied with respect to the pupillary responses to instillation into the conjunctival sac of a single drop of a 1% solution of phenylephrine and a 2% solution of tyramine. The changes in pupillary diameters were documented by photographic pupillometry prior to and at 15, 30, 60, and 90 minutes after the instillations. Of the two sisters, one (case A) was examined during a symptom-free interval, when she had been free from cluster headache attacks for 2 1/2 years. When the cluster headaches recurred, retesting was performed. The other sister (case B) had been free from cluster headaches for 9 years, when she was examined. The findings indicate hypofunction within the postganglionic sympathetic nerve fibers during a cluster headache period. The hypofunction is bilateral, and thus, can not be a consequence of the unilateral cluster headache attacks. During remissions, tyramine induces a marked mydriasis, particularly on the symptomatic side, tentatively indicating an excessive release of stored monoamines.

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase-A (MAO-A) inhibitor, was studied in a single-blind, parallel-group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run-in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600-1800 mg) during placebo to 290 mg (range, 150-500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100-300) during befloxatone 10 mg twice daily, and 155 mg (range, 100-250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2-, 6.5-, and 7.9-fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20-mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO-A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20-mg once daily after meals.

1. Coronary vascular responses to bilateral carotid occlusion (BCO) and the intravenous infusion of tyramine (Tyr, 20 micrograms kg-1 min-1) and noradrenaline (NA, 0.5 microgram kg-1 min-1) were examined after bilateral vagotomy and antagonism of beta-adrenoceptors. BCO, Tyr and NA decreased large coronary artery diameter and increased mean coronary resistance and systemic arterial pressure without affecting heart rate. 2. Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA, 5 and 15 mg kg-1) significantly increased mean arterial pressure and decreased heart rate and large coronary artery diameter. Mean coronary resistance was unaffected by either dose of L-NNA. L-NNA significantly reduced depressor and coronary vasodilator responses to the endothelium-dependent vasodilator acetylcholine (ACh, 10 micrograms kg-1, i.v.). Systemic and coronary vasodilator responses to sodium nitroprusside (SNP, 5 micrograms kg-1) were unaffected by L-NNA with the exception that the dilatation of the large coronary artery was significantly enhanced by the higher dose. 3. L-NNA significantly enhanced constriction of the large coronary arteries caused by BCO, Tyr and NA but did not affect the increases in mean coronary resistance or systemic arterial pressure. 4. Inhibition of NO synthesis enhances adrenergic constriction of large coronary arteries caused by both neuronally released and exogenous noradrenaline. In contrast, L-NNA did not affect adrenergic constriction of coronary or systemic resistance vessels. Endothelium-derived NO may play an important role in the modulation of noradrenergic vasoconstriction in coronary conductance arteries.

1. Neuropathy is a frequently diagnosed complication of diabetes mellitus. Effective pharmacotherapy is not available. 2. The spontaneously diabetic BB/Wor rats develop secondary complications like neuropathy as do human diabetic patients. 3. BB/Wor rats treated with insulin via a subcutaneous implant show a significant impairment of sensory and motor nerve conduction velocity 6 weeks after the onset of diabetes mellitus. 4. Intraperitoneal treatment of diabetic BB/Wor rats with the Ca2+ antagonist, nimodipine (20 mg kg-1), from week 6 onwards every 48 h for a period of 6 weeks resulted in a significant increase of sensory and motor nerve conduction velocity. 5. Twelve weeks after the onset of diabetes mellitus BB/Wor rats show a 40% impairment of sciatic nerve blood flow as compared to the non-diabetic age-matched controls. Treatment with nimodipine (20 mg kg-1) from week 6 onwards significantly increased the sciatic nerve blood flow as compared to placebo-treated diabetic BB/Wor rats. 6. The adrenergic responsiveness of the vasa nervorum of the sciatic nerve to tyramine and phenylephrine was investigated as a parameter for autonomic neuropathy. 7. The fact that nimodipine treatment restored the reduced response to tyramine independently of the reduced postsynaptic phenylephrine responsiveness indicates that nimodipine improves adrenergic responsiveness mainly at the presynaptic level.

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.

1. Functional alterations of the sympathetic neuroeffector junction of the left atria were studied in rats with streptozotocin-induced diabetes. 2. Eight to 12 weeks of diabetes resulted in a marked decrease in the positive inotropic response of left atria to electrical field stimulation (EFS). 3. The overflow of [3H]-noradrenaline from diabetic left atria caused by EFS was much less than that from control preparations. 4. The concentration-response curves showed no change in sensitivities of the left atria to exogenous noradrenaline and tyramine in diabetic rats. The maximum positive inotropic response to these agents were similar in diabetic and control animals. 5. The left atrial content of noradrenaline was not significantly changed in diabetic rats. The cocaine-sensitive uptake of [3H]-noradrenaline was also unaltered. 6. Atropine enhanced the positive inotropic response and [3H]-noradrenaline overflow induced by EFS in control left atria. Similarly, yohimbine caused an enhancement of EFS-evoked inotropic response in control atria. However, these effects of the antagonists were not observed in diabetic left atria. 7. It is concluded that the decrease in the positive inotropic response of the left atria to EFS in diabetic rats is caused by an impairment of noradrenaline release from the sympathetic nerve terminals through a calcium-dependent exocytotic mechanism. The present results also indicate that presynaptic alpha 2-adrenoceptors and muscarinic receptors that are linked to inhibition of the noradrenaline release during nerve stimulation may be functionally impaired in diabetic animals.

1. The rat vas deferens was excised, stored at 4-6 degrees C and tested after 24, 48, 72 or 96 h for its contractile activity and for the presence of innervation. 2. The maximal contractile capacity of the vas, tested through cumulative concentrations of barium chloride (3 x 10(-2) M) was progressively reduced from about 110 mm to about 63 mm after 72 h, without further decay after 96 h. Spontaneous rhythmic contractions were practically absent. 3. A loss of endogenous pools of catecholamines was indicated by four parameters: (a) a decline of about 80% after 24 h and of more than 95% after 48 h of the contractile effect of the indirect sympathomimetic agonist tyramine; (b) a fall of about 20%, 50% and 85% on the concentration of noradrenaline, respectively after 24, 48 and 72 h; (c) a fall of about 25% and 90% after respectively 24 and 48 h, of the activity of dopamine-beta-hydroxylase (DBH); (d) a decline of noradrenaline-induced histofluorescence on cross sections of the vas. 4. A loss of neuronal uptake capacity was indicated by: (a) a progressive variation of the apparent affinity for adrenaline, expressed as pD2 values, that increased by about 1.5 log units (corresponding to a 30 fold potentiation) after 72 h, and (b) a reduction of the ability of cocaine to potentiate the contractile effects of adrenaline. 5. The pD2 values for barium chloride, 5-hydroxytryptamine (5-HT) and histamine were not significantly changed, while the corresponding value for acetylcholine was slightly but significantly reduced by about 0.8 log units. 6. The maximal heights of concentration-response curves for noradrenaline, acetylcholine, histamine and 5-HT were reduced by 42-66% in relation to controls. However, when this reduction was measured in relation to the corresponding barium effect, by means of the relative responsiveness ratio (p), a small though significant increase was observed for noradrenaline, and a fall for the other drugs.7. It is concluded that: (1) the values for the various biochemical and pharmacological parameters decline at different rates, though revealing altogether that denervation is completed by at least 85% after 72 h of hypothermic storage; (2) two of the results, i.e., the lack of spontaneous rhythmic contractions and the lack of increased contractile effects for acetylcholine, 5-HT and histamine, indicate that in these conditions the vas is devoid of the so-called nonspecific signs of denervation.

We examined the influence of toloxatone, a new reversible monoamine oxidase-A inhibitor used in the treatment of depression, on tyramine-induced pressor effect in healthy volunteers. The maximum increase in systolic blood pressure produced by four single oral doses of tyramine administered during a meal and ranging from 100 mg to 800 mg was compared during repeated (3 to 5 days) administration of placebo, 200 mg toloxatone three times a day and 400 mg toloxatone three times a day in a single-blind, three-period crossover study. Toloxatone by itself had no significant influence on blood pressure. During administration of toloxatone, no significant increase in tyramine-induced increase in systolic blood pressure was observed for tyramine doses of 200 mg or less that are consistently higher than those associated with normal food intake. However, toloxatone increased the tyramine-induced increase in blood pressure after 400 mg tyramine (400 mg toloxatone three times a day) and 800 mg tyramine (200 mg toloxatone three times a day and 400 mg toloxatone three times a day). This pharmacodynamic interaction could be explained by an increase in tyramine systemic bioavailability in the presence of toloxatone. It is concluded that interaction between tyramine in meals and toloxatone is unlikely to occur in patients after long-term administration of the drug at therapeutic dosages.

This study was conducted to establish the safety, tolerability, side effects, and pressor effects of tyramine on subjects treated with moclobemide, a short-acting reversible and preferential monoamine oxidase inhibitor, and to compare these responses with the responses of subjects treated with phenelzine. Twelve healthy male volunteers participated. An oral tyramine sensitivity test was performed on all subjects 24 hours before the start of a 28-day open-label treatment with phenelzine or moclobemide. A tyramine challenge was performed on day 28 on four subjects treated with phenelzine. The mean dose of oral tyramine required to increase systolic blood pressure by 30 mm Hg was 15 mg. The mean dose of tyramine that produced a clinical response (day 28) in subjects treated with moclobemide was 240 mg. No subject receiving moclobemide responded clinically on day 31 after receiving hourly doses of 20, 40, 80, 160, and 320 mg, respectively. These findings suggest that moclobemide may be used without stringent dietary precautions.

1. The effects of neuropeptide Y (NPY) were examined on adrenergic and non-adrenergic, non-cholinergic (NANC) neurotransmission in the rat anococcygeus muscle. 2. NPY (0.1-0.3 microM) greatly potentiated the contractile responses induced by field stimulation. Prazosin (0.1 microM) completely abolished the stimulation-induced responses either in the absence or presence of NPY. 3. NPY (0.1-0.3 microM) enhanced only the contractile responses to low doses of noradrenaline (NA, 0.003-0.01 microM). Responses to tyramine were unaffected by the same concentrations of NPY. 4. In superfused anococcygeus, previously loaded with [3H]-NA, NPY (0.1-0.3 microM) failed to modify the basal, as well as the stimulation-evoked, release of tritium at 2 and 4 Hz. 5. NANC relaxations induced by electrical stimulation were significantly reduced, in a concentration-related manner, by 0.1-0.3 microM NPY. 6. L-NG-nitro-arginine (L-NOARG, 30 microM) enhanced the stimulation (0.25-1 Hz)-induced motor responses. In the presence of L-NOARG (30 microM), NPY (0.1 microM) did not modify the motor responses induced by field stimulation (0.25-0.5 Hz). L-Arginine did not reverse the NPY-induced potentiation of stimulation-induced motor responses. 7. The relaxations of anococcygeus muscle induced by sodium nitroprusside (SNP, 0.01-0.3 microM) were diminished by NPY (0.1-0.3 microM). 8. Our study suggests that NPY, at concentrations devoid of contractile effect, potentiates the motor responses of rat anococcygeus muscle as a consequence, at least in part, of the inhibition of NANC relaxing responses by a different mechanism from L-NOARG.

The mydriatic action of sympathomimetic eyedrops after a therapeutic dose of ergotamine was measured in migraine patients with and without histories of long-term ergotamine abuse. Mydriasis induced by the postsynaptic alpha 1-agonist phenylephrine was similar in both groups of patients tested, whereas pupillary dilation caused by the release of noradrenaline tyramine was markedly greater in patients with histories of ergotamine abuse. The enhanced response to tyramine disappeared after drug withdrawal. These findings indicate that continuous ergotamine medication causes a reversible alterations in iris sympathetic transmission. This manifestation may reflect a central inhibition of pupillary sympathetic activity.

1. Using a number of agonist and antagonist compounds, we have attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the rabbit isolated renal artery. 2. In vessel segments precontracted with the thromboxane-mimetic agent, U46619 (100 nM), neither 5-HT (10(-8) to 10(-4) M) nor 5-carboxamidotryptamine (5-CT; 10(-8) to 3 x 10(-4) M) caused relaxations like those observed with methacholine. Both 5-HT and 5-CT further increased the tone of the vessels, with pD2 values of 7.1 and 7.9, respectively. 3. In the absence of U46619, both 5-HT (10(-7) to 3 x 10(-3) M) and 5-CT (10(-7) to 10(-3) M) contracted the rabbit renal artery, but with reduced potencies. The contractions to 5-HT were reproducible and the rank order of potency (pD2) of the agonists was: alpha-methyl-5-HT (5.7), sumatriptan (5.3), 5-HT (5.1), 8-hydroxy-2(di-n-propylamino)tetralin (5.0), 5-CT (4.7) and 5-methoxytryptamine (4.3). 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, flesinoxan and RU 24969 elicited either only small contractions or none at all. 4. The contractile effect of 5-HT was unaffected by MDL 72222 (10(-6) M) and metergoline (10(-8) and 10(-7) M), was weakly antagonized by ketanserin and phentolamine (pKB: 6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pKB: 8.6). Responses to 5-CT and sumatriptan were affected by ketanserin, phentolamine and methiothepin similarly to 5-HT-induced responses. 5. Ketanserin was ineffective against noradrenaline-induced contractions, which were antagonized by phentolamine with a pKB of 7.3. The pKB values of phentolamine against 5-HT, 5-CT or sumatriptan were about half a log unit lower than against noradrenaline.6. In vascular preparations treated with cocaine (3 x 10- I M), the potency (pKB) of phentolamine as an antagonist of the responses to noradrenaline (7.6) and 5-HT (6.7) did not differ significantly from the values in untreated preparations. However, the difference between the pKB values of phentolamine against the two agonists was now about one log unit.7. Pretreatment of the vascular strips with 6-hydroxydopamine (1.5 x 10- 3M) did not significantly affect responses to 5-HT or 5-CT, but almost eliminated those to tyramine. Cocaine (3 x 10- 5M) slightly potentiated noradrenaline-induced contractions, but did not significantly affect those induced by 5-HT.8. These data suggest that: (i) 5-HT receptors mediating vasodilatation are not present in the rabbit renal artery smooth muscle or endothelium; (ii) the contractile effect of 5-HT does not involve the release of noradrenaline from sympathetic nerve stores; (iii) the 5-HT receptor in the rabbit renal artery is not of the 5-HT2, 5-HT3 or 5-HT4 type. The pharmacological properties of this receptor most closely resemble those described for the heterogeneous 5-HT1-like category.

The neurotoxin MPP+ potently inhibited the striatal binding of [3H]-tyramine, a putative marker for the vesicular transporter of dopamine, and provoked a massive in vivo release of striatal dopamine. Tetrabenazine, an established ligand for the vesicular catecholamine carrier, potently inhibited [3H]-tyramine binding, tyramine-provoked striatal efflux of dopamine and the fast component of MPP(+)-induced dopamine release. It is concluded that MPP+ in the striatum, besides interacting with additional intracellular targets, avidly binds at a vesicular site functionally involved with the outward transport of dopamine.

Pupil diameter was measured during the headache-free interval in 38 migraine sufferers selected from the general community. In each case, at least 70 percent of attacks recurred on the same side. Anisocoria was greater than in 40 control subjects, but miosis was not consistently greater on the usual side of headache. Average pupil diameter was similar in migraine sufferers and controls. In patients with pupillary dilation lag on the usual side of headache, miosis persisted after 4% cocaine eyedrops. These findings suggest that cervical sympathetic outflow was lower on the usual side of headache in a subgroup of migraine sufferers. Pupillary dilatation to tyramine eyedrops was greater in control subjects than in migraine sufferers, consistent with decreased function of post-ganglionic cervical sympathetic fibres. Pupillary dilatation to 1% phenylephrine eyedrops did not differ consistently between the headache and headache-free sides, and was similar in migraine sufferers and controls. Thus, adrenergic supersensitivity of the pupils was not evident in this community sample of migraine sufferers. Vasodilatation or swelling of the arterial wall in the carotid canal could cause minor cervical sympathetic deficit in patients with frequent or severe attacks of migraine. Loss of sympathetic vascular tone could increase vasodilatation and pain during attacks.

This study compared the effects of moclobemide (Ro11-1163), a selective and reversible inhibitor of monoamine-oxidase (MAOI) type A and phenelzine, an irreversible non-selective MAOI, on the pressor responses to IV tyramine and norepinephrine. Because of the reversibility of this inhibition, the pressor effect of tyramine was expected to be minimal. Twelve healthy men participated in this randomized double-blind, placebo-controlled, crossover study. Volunteers began with oral treatment of moclobemide (100 mg TID) or phenelzine (15 mg TID) for 1 week followed by placebo treatment for 2 weeks and then moclobemide or phenelzine treatment for another week. The tyramine and norepinephrine challenge tests were conducted at baseline and then at weekly intervals, for a total of five challenges. The average tyramine dose that was required to increase systolic blood pressure by 25 mm Hg (PD25) was 1.6 +/- 0.2 mg after moclobemide treatment, which was lower (P less than .01) than the baseline value of 3.6 +/- 0.7 mg and that after phenelzine (3.0 +/- 0.5 mg) treatment. Moclobemide did not influence norepinephrine sensitivity. In conclusion, moclobemide mildly decreased the sensitivity to IV tyramine as compared with placebo and phenelzine.

1. Focal extracellular recording techniques were used to study the effects of clonidine, yohimbine and tyramine on the intermittent transmitter release mechanism in the guinea-pig vas deferens in vitro. Drugs were applied locally to the varicosities located within the recording electrode. Statistical methods were used to determine whether noradrenaline (NA) acts locally to inhibit secretion from the same or a closely related release site (local regulation) on an impulse-to-impulse basis. 2. The alpha-adrenoceptor agonist, clonidine, inhibited transmitter release, an effect reversed by the alpha-adrenoceptor antagonist, yohimbine. Yohimbine alone increased action potential-evoked transmitter release, findings consistent with the idea that transmitter release is regulated through prejunctional alpha-adrenoceptors. 3. The indirectly acting sympathomimetic, tyramine, powerfully inhibited evoked transmitter release, an effect reversed by both yohimbine and phentolamine. The inhibitory effects of tyramine were greatly reduced in tissues taken from animals pretreated with reserpine. Clonidine powerfully inhibited transmitter release in reserpinized tissues showing that prejunctional alpha-adrenoceptors were functionally intact. The inhibitory effects of tyramine on transmitter release are therefore mediated indirectly through the release of endogenous NA. 4. Paradoxically, when transmitter release from a small population of variscosities on a single nerve fibre was studied in the absence of alpha-adrenoceptor antagonists, no evidence was found for local regulation of transmitter release. 5. The intermittent character of the transmitter release process makes it difficult to envisage how impulse-to-impulse regulation could occur. Furthermore, it is unlikely that NA will accumulate to any appreciable extent in the vicinity of the secreting varicosity. 6. The pharmacological evidence clearly supports the view that NA released from sympathetic nerve terminals by nerve impulses modulates subsequent transmitter release. However, the evidence does not support the view that released NA acts locally to inhibit secretion from recently activated varicosities.

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.

1. FPL 63012AR is a D1-receptor agonist in the dog kidney, 10 times as potent as dopamine, reducing renal vascular resistance by 20% with an intra-arterial dose of 0.42 nmol kg-1. 2. No prejunctional inhibitory D2-receptor agonist activity was detected in either the isolated ear artery of the rabbit or in the conscious dog as D2-receptor-mediated emesis. 3. Unlike dopamine, FPL 63012AR had no significant agonist activity at alpha 1-, alpha 2-, beta 1- or beta 2-adrenoceptors. 4. FPL 63012AR is a potent inhibitor of [3H]-noradrenaline uptake (Uptake1) into brain synaptosomes, with an IC50 of 29.5 nM, i.e. 9.2 times more potent than dopamine. 5. The ability to block Uptake1, in the anaesthetised dog was confirmed by inhibition of the tyramine-induced pressor and inotropic responses. 6. Intravenous infusion of FPL 63012AR in anaesthetized and conscious dogs (0.3 to 3 nmol kg-1 min-1) reduced vascular resistance and increased blood flow to the kidney which was accompanied by hypotension and tachycardia. 7. It is concluded that FPL 63012AR is an example of a novel class of potent agonists at the D-receptor. Such compounds may have the potential for use clinically in improving renal perfusion and reducing afterload.

Clorgyline (1 and 10 microM) and (+)-deprenyl (10 microM) both significantly potentiated the tyramine (100 microM)-induced release of [3H]-noradrenaline from rat cerebral cortex slices. (-)-Deprenyl (50 microM) significantly reduced it, while lower concentrations had no effect on noradrenaline release. However, in combination, 1 microM (-)-deprenyl blocked the release-facilitating action of 1 microM clorgyline, and 10 microM (-)-deprenyl that of 10 microM (+)-deprenyl. Low concentrations of (+)- and (-)-deprenyl (1 and 10 microM), both selectively inhibited phenylethylamine oxidation by monoamine oxidase B. Higher concentrations of (-)-deprenyl (20 and 50 microM) also inhibited 5-hydroxytryptamine oxidation by monoamine oxidase A. Clorgyline (1 and 10 microM) inhibited both enzymes. Thus, the effects of these drugs on noradrenaline-release cannot be explained solely in terms of irreversible inhibition of monoamine oxidase A and B, and other possible mechanisms are discussed. If the brain-slice model faithfully mirrors the sequence of events manifesting peripherally as the tyramine hypertensive response ('cheese effect'), then it is possible that low doses of (-)-deprenyl, administered with antidepressant monoamine oxidase inhibitors, can prevent this adverse reaction.

LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) (10, 20 and 50 mg kg-1) had no significant effect on pressor responses to noradrenaline or tyramine in rats anaesthetized with urethane. Desmethylimipramine (1 mg kg-1) blocked the response to tyramine but chlorimipramine (5 mg kg-1) had no significant effect on responses to noradrenaline or tyramine. In the rabbit, anaesthetized with chloralose, LM 5008 (5 mg kg-1) had no effect on pressor responses to noradrenaline, tyramine or angiotensin II, while desmethylimipramine (0.25 mg kg-1) inhibited responses to tyramine and potentiated those to noradrenaline. LM 5008 (10 mg kg-1) had no effect on resting blood pressure of conscious normotensive or DOCA-saline hypertensive rats. Tranylcypromine (5 mg kg-1) produced a fall in blood pressure in conscious normotensive and in DOCA hypertensive rats. Treatment with a combination of LM 5008 (10 mg kg-1) and tranylcypromine (5 mg kg-1) resulted in the appearance of a behavioural hyperactivity syndrome, but blood pressure was not different from that of animals treated with tranylcypromine alone. These results further demonstrate the selectivity of LM 5008 for 5-hydroxytryptamine as opposed to catecholamine uptake.

The relative efficacy of epinephrine and norepinephrine on vascular alpha 1- and alpha 2-adrenoceptors and also the difference in vasoconstriction induced by exogenous norepinephrine as opposed to neuronally released norepinephrine were studied in the forearm of healthy volunteers. Intra-arterial cumulative dose infusions of epinephrine and norepinephrine (0.6, 1.6 and 4.0 ng kg-1 min-1) were given in the presence of saline, the selective alpha 1-antagonist doxazosin (0.1 microgram kg min-1) the selective alpha 2-antagonist yohimbine (1.0 microgram kg min-1) and the combination of both antagonists. beta-Adrenoceptor-mediated effects were prevented by a concomitant i.a. infusion of propranolol (1.0 microgram kg-1 min-1). Forearm blood flow (FBF) was measured before each infusion and at the end of each dose step. Neuronal norepinephrine was released by i.a. infusion of tyramine in three cumulative doses (0.25, 0.50 and 1.25 micrograms kg-1 min-1) and by lower body negative pressure (LBNP, -40 mmHg for 5 min). Changes in FBF were measured without and with concomitant i.a. infusions of the aforementioned doses of doxazosin and yohimbine. In the LBNP experiment the opposite arm was used as a control. Forearm blood flow was measured by plethysmography. Epinephrine and norepinephrine induced an equal and dose-dependent vasoconstriction, which was significantly inhibited by doxazosin as well as yohimbine and to a greater extent by the combination of the antagonists. No differences were found between epinephrine and norepinephrine in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether small changes in sympathetic activity would cause detectable changes in plasma norepinephrine (NE) levels, and whether the effects of endogenously released and exogenous NE differ, we injected tyramine infusions and l-norepinephrine (l-NE), into six healthy subjects, and the changes in blood pressure (BP) and plasma NE were related. The mean increase in systolic BP was approximately 17 mm Hg with both infusions; diastolic BP increased with l-NE but did not rise significantly with tyramine. Heart rate fell more with l-NE than with tyramine infusions. The maximum increase in plasma NE levels was more than 500% during l-NE infusions but less than 200% with tyramine. There was no correlation between plasma NE and absolute levels of systolic BP when individual data were plotted for tyramine infusions, whereas mean group changes in systolic BP correlated strongly with mean group plasma NE, both during tyramine and l-NE infusions. The slope of the relationship was much steeper for tyramine than for l-NE. We conclude that the use of plasma NE to measure small differences in sympathetic activity among individuals is limited by interindividual variability, whereas changes in sympathetic activity within groups are more likely to be detected.

1. The effect of compound 48/80 on the rat femoral vasculature was examined by means of a cross-circulation technique. 2. Intra-arterial injection of increasing doses (1.5 to 15 microgram) of compound 48/80 caused dose-dependent vasoconstriction preceded by transient vasodilatation. The vasoconstriction was significantly reduced in reserpine-treated preparations and converted to vasodilatation by methysergide. 3. When the vasoconstrictor response to a large dose (300 microgram) of adenosine was abolished by repeated administration, the response to compound 48/80 remained unaltered. 4. The present results indicate that the femoral arterial vasoconstriction by compound 48/80 in the rat is mediated by the release of 5-hydroxytryptamine (5-HT); this 5-HT may be liberated from a different storage site from that released by adenosine.

[14C]-beta-phenethylamine [( 14C]-PEA) was instilled intragastrically, intraduodenally (i.d.) or infused into the portal vein or femoral artery of cats, anaesthetized with chloralose, to investigate its distribution in the body. [14C]-PEA and phenylacetic acid (PAA) accounted for approximately 85% of radioactivity recovered in blood from control cats or those pretreated with deprenyl or mebanazine. Progressively greater portal venous (PV), cranial mesenteric arterial (CMA) and PV-CMA concentrations of PEA and PAA were observed with increase in amount of PEA instilled intraduodenally (i.d.); PAA predominated over PEA, more so in CMA than PV blood. Radioactivity was not recovered from blood following intragastric instillation of PEA. When histamine 1.7 mumol kg-1, i.d., was combined with PEA 1.7 mumol kg-1, i.d., or tyramine 8.5 mumol kg-1, i.d., was combined with PEA 8.5 mumol kg-1, i.d., PV-CMA values for PEA were significantly augmented. Arterial concentrations of PEA were increased 3.5 to 5 fold compared to controls by pretreatment with mebanazine or deprenyl plus clorgyline; arterial concentrations of PAA were reduced. PEA blood concentrations were not significantly altered by clorgyline or deprenyl pretreatment. Infusion of PEA 680, 1020 or 1360 nmol kg-1 min-1 for 20 min into the portal vein raised blood pressure 60 to 100 mmHg (at a PEA concentration of ca, 2 nmol ml-1) but lacked effect on the nictitating membrane despite peak arterial PEA concentrations of 20 nmol ml-1; in cats pretreated with mebanazine or clorgyline plus deprenyl, half-maximum contraction of the nictitating membrane occurred with arterial PEA concentrations of 4.8 to 9 nmol ml-1. In cats pretreated with mebanazine or deprenyl plus clorgyline, half maximum contraction of the nictitating membrane was elicited also by intraduodenal PEA 8.5 mumol kg-1 at arterial PEA concentrations of ca. 2 nmol ml-1, despite lack of effect of PEA 17 mumol kg-1, i.d., in control cats with a peak arterial PEA concentration of 1.8 nmol ml-1. [14C]-PEA and PAA were recovered from liver, kidney, distal small intestine, lung, arterial vessel walls, skeletal muscle, brain, foetus and amniotic liquor, after PEA instilled i.d., overall concentration of PEA exceeding that of PAA except in the kidney. The combined amount of PEA and PAA in kidney was 7 to 20 fold that in other tissues. PEA content of tissues was significantly elevated and that of PAA diminished by pretreatment with deprenyl plus clorgyline, and to a lesser extent after mebanazine.

Cianopramine, a new tricyclic antidepressant, is a potent inhibitor of neuronal serotonin (5-HT) uptake in animals. We studied the effect of cianopramine on 5-HT uptake (ex vivo) in platelets and on peripheral neuronal adrenergic function in catecholamine pressure response tests in normal subjects. The inhibition of 14C-labeled 5-HT uptake into platelets was 57% +/- 12% 2 hr after 0.5 mg (after 24 hr: 27% +/- 13%), 59% +/- 10% 2 hr after 1 mg (24 hr: 41% +/- 13%), and 80% +/- 2% 2 hr after 2 mg cianopramine (24 hr: 52% +/- 10%). Systolic blood pressure response to intravenous tyramine and norepinephrine was unchanged after 2 mg cianopramine. The phenylephrine dose required for an increase of 40 mm Hg in systolic blood pressure was 67 +/- 25 micrograms/min before cianopramine and 86 +/- 32 micrograms/min 2 hr after 2 mg cianopramine, which suggests weak alpha-receptor antagonism of cianopramine. Our results in man are consistent with potent, specific 5-HT uptake inhibition by cianopramine without a clinically relevant effect on peripheral neuronal norepinephrine reuptake.

1 The effect of a series of antidepressant drugs on noradrenaline accumulation was studied in the isolated anococcygeus muscle of the rat. 2 The most potent inhibitors of noradrenaline accumulation were nortriptyline, desipramine and protriptyline. Opipramol, trimipramine and iprindole were active only in high concentrations. 3 Contractions of the anococcygeus muscle produced by noradrenaline were strongly potentiated by nortriptyline, desipramine and protriptyline. Other uptake inhibitors were less active in potentiating the noradrenaline response. 4 Nortriptyline, in concentrations that potentiated the action of noradrenaline, reduced or abolished the response to tyramine.

1. The mechanism of efflux of (-)-[(3)H]-noradrenaline was examined in rabbit atria, which were pretreated with reserpine and pargyline.2. Between 40 and 100 min, efflux occurred predominantly from a single intraneuronal compartment.3. Efflux was rapidy increased by (-)- and (+)-noradrenaline, tyramine and (+/-)-metaraminol, but not by (+/-)-isopropylnoradrenaline or (+/-)-normetanephrine. The increase in efflux produced by (-)-noradrenaline was inhibited by cocaine and desipramine but not by lidocaine.4. Spontaneous effluxes, and those accelerated by (-)-noradrenaline, were temperature-sensitive.5. Efflux was increased by ouabain, omission of K(+), metabolic inhibition and lowering of the external Na(+) concentration. These effects were significantly reduced by cocaine and desipramine but not by lidocaine.6. These findings provide evidence that the efflux of [(3)H]-noradrenaline from adrenergic nerves occurs by a cocaine-sensitive, carrier-mediated process. The characteristics of the efflux process are compatible with, but not conclusive proof for, the Na(+)-gradient hypothesis.

1 Guanidine increased noradrenaline (NA) output at 5 Hz by 3 to 6 fold, and doubled it at 30 Hz. Onset of maximum activity was slow, and reversal was also slow. Output of NA induced by potassium, sodium deprivation, or tyramine was not affected. 2 NA output was doubled at low concentrations (1 to 2 mM) of guanidine, but maximal effect was obtained at 4 mM. At 10 mM, spontaneous release was occasionally observed. 3 The effect of guanidine on NA release was related to the external calcium concentration. Outputs which previously have been shown to be insignificant at 5 Hz in 0.25 and 0.75 mM calcium-Krebs solution were markedly enhanced by guanidine. Guanidine enhanced release at all calcium concentrations up to 7.5 mM, but maximum output was obtained at 2.5 mM. 4 Guanidine had no effect on the recovery of intra-arterially infused NA. 5 The effects of guanidine and tetraethyl-ammonium (TEA) on NA release at 5 Hz were additive. 6 Guanidine reversed the inhibition of NA release by guanethidine during nerve stimulation at 5 and 10 Hz, and the NA output increased nearly 2.5 fold after repeated stimulation of the nerves. Guanidine was less effective in reversing the inhibitory effects of guanethidine on NA release at 30 Hz. 7 Guanidine did not affect release of catecholamines (CA) from the perfused cat adrenal gland by splanchnic nerve stimulation. 8 It is suggested that guanidine enhances NA release partly by increasing the influx of calcium into the neurone during an action potential, and also by interfering with intracellular binding of calcium.

Monoamine oxidase inhibitors can elicit increases in systolic blood pressure after tyramine ingestion (cheese effect). Moclobemide is a new, reversible, preferential monoamine oxidase A inhibitor with antidepressant properties. Its potentiation of the tyramine pressor effect during 200 mg t.i.d. chronic treatment was compared with tranylcypromine, 10 mg b.i.d., in a double-blind, parallel-group, placebo-controlled study (n = 16). Tyramine was mixed with food and ingested in increasing daily doses, during a normal meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (tyramine 30). When compared with the usual fasting oral tyramine tests performed in the same subjects, the mean tyramine 30 dose with a meal was 2.8 times higher. The mean tyramine 30 dose with a meal decreased from 1450 mg (range, 800 to 2000 mg) during placebo to 306 mg (range, 150 to 500 mg) during moclobemide (factor, 5.0) and from 1200 mg (range, 1000 to 1600 mg) during placebo to 35 mg (range, 20 to 50 mg) during tranylcypromine (factor, 38.2). The duration of the systolic blood pressure increase was longer with tranylcypromine (126 minutes) than with moclobemide (69 minutes) (p less than 0.01).

1 The cat anococcygeus muscle is shown to possess a dual innervation similar to the rat anococcygeus, with a motor adrenergic innervation and an inhibitory innervation whose transmitter is unknown. The pharmacological properties of the cat muscle were investigated and compared with those of the rat muscle.2 The cat muscle contracts to noradrenaline, 5-hydroxytryptamine, tyramine, amphetamine, guanethidine, cocaine and lysergic acid diethylamide (LSD). The effects of noradrenaline and 5-hydroxytryptamine are blocked by phentolamine and methysergide respectively.3 The cat anococcygeus is relaxed by acetylcholine, carbachol, isoprenaline, ATP, prostaglandins E(1), E(2) and F(2alpha) and vasopressin, all of which contract the rat muscle. The effects of acetylcholine and carbachol are blocked by atropine and those of isoprenaline by propranolol.4 Field stimulation produces contraction of the cat anococcygeus, which is blocked by phentolamine and guanethidine but unaffected by hexamethonium, atropine or neostigmine.5 In the presence of guanethidine (10(-5)M), the tone of the muscle is raised and field stimulation produces relaxation of the muscle. These inhibitory responses are unaffected by phentolamine, hexamethonium, atropine or neostigmine.6 Neostigmine potentiates the effects of acetylcholine, but not of carbachol in relaxing the cat anococcygeus and in contracting the rat anococcygeus, but has no effect on either motor or inhibitory responses to field stimulation.7 Cold storage for up to eight days had little effect on either the motor response to noradrenaline or the motor or inhibitory response to field stimulation of the cat anococcygeus. Beyond eight days, the response to field stimulation diminishes more rapidly than the response to noradrenaline.

1 The effects of cocaine and sodium on bretylium uptake into sympathetic nerve terminals were investigated in the reserpine-treated guinea-pig left atrium. The ability of bretylium pretreatment to increase the retention of noradrenaline was used as an index of bretylium uptake. Such increased retention has been assessed both by direct measurement and by the ability of tyramine to produce an inotropic response. 2 The restoration of the response to tyramine after incubation with noradrenaline was abolished when the atrium was pretreated with bretylium in the presence of cocaine. When bretylium was added before cocaine, or when alpha-methyl-noradrenaline (not a substrate for monoamine oxidase) was used for incubation, the responses to tyramine were restored in the normal way. 3 Bretylium greatly enhanced the retention of [3-H]-noradrenaline; when bretylium was added in the presence of cocaine, [3-H]-noradrenaline retention was severely impaired. 4 Pretreatment with bretylium in a low-sodium (25 mM) or sodium-free medium significantly decreased the retention of [3-H]-noradrenaline, as compared with the control. 5 Potassium deprivation did not modify the enhanced retention of [3-H]-noradrenaline induced by bretylium pretreatment. 6 Bretylium was released from the nerve terminals by exposure of the preparation to a sodium-free medium or to a solution containing calcium 50 mM, leading to a considerable decrease in [3-H]-noradrenaline retention. 7 The results are consistent with the view that both cocaine and sodium deprivation block the uptake of bretylium by the adrenergic nerve terminals, and that bretylium is probably taken up by a mechanism similar to or identical with the uptake system for noradrenaline and other amines.

1 Platelet-rich plasma (PRP) of guinea-pigs with or without reserpine was preincubated either with [(14)C]-5-hydroxytryptamine ([(14)C]-5-HT) plus [(3)H]-dopamine or with [(14)C]-5-HT plus [(3)H]-noradrenaline ([(3)H]-NA). After isolation on two successive dextran gradients the double-labelled platelets were incubated in Tris-buffer in the presence or absence of various drugs. The decrease in radioactivity in the platelets was measured in order to determine the amount of the amine that had been liberated.2 Spontaneous liberation of the labelled amines was more marked in reserpine-treated platelets than in normal ones and somewhat more pronounced for the (3)H-catecholamines than for [(14)C]-5-HT.3 The reserpine-like benzoquinolizine, Ro 4-1284, caused liberation of all three labelled amines in normal but not in reserpine-treated platelets. More [(3)H]-dopamine was liberated than [(14)C]-5-HT and less [(3)H]-NA.4 The arylalkylamines, tyramine and p-chloromethamphetamine (PCMA), liberated all three labelled amines from normal platelets, and [(14)C]-5-HT and [(3)H]-dopamine, but not [(3)H]-NA from reserpine-treated ones. In normal platelets dopamine was reduced to a greater extent than [(14)C]-5-HT and [(3)H]-NA to a smaller extent, whereas in reserpine-treated platelets [(14)C]-5-HT was more markedly diminished than [(3)H]-dopamine.5 The 5-HT uptake inhibitor, imipramine, had little influence on the spontaneous and drug-induced liberation of [(14)C]-5-HT and [(3)H]-dopamine.6 It is concluded that (3)H-catecholamines like [(14)C]-5-HT are mostly localized in the granular pool of platelets; the three drugs tested liberate [(3)H]-dopamine [(3)H]-NA and [(14)C]-5-HT from the granular pool. Ro 4-1284 does not liberate (3)H-catecholamines and [(14)C]-5-HT from extragranular sites whereas tyramine and PCMA also act on the extragranular pool of [(3)H]-dopamine and [(14)C]-5-HT but not [(3)H]-NA.7 The liberation of catecholamines from platelets differs from that of 5-HT in several respects and platelets are only partly comparable to neurones as far as drug-induced liberation of biogenic amines is concerned.

It is not known whether in depressed patients antidepressant treatment increases or reduces monoaminergic neurotransmission. Clinical studies are therefore reviewed that investigate adaptive changes at adrenoceptors in depressed patients treated with desipramine, and the net effect of these changes upon neurotransmission. Although in animals chronic desipramine treatment enhances the responsiveness of alpha 1-adrenoceptors to phenylephrine, no such effect could be demonstrated in patients upon the responsiveness of pupil diameter to phenylephrine. However, in keeping with animal studies, clinical evidence of altered responsiveness of alpha 2-adrenoceptors could be demonstrated after chronic desipramine treatment. The alpha 2-mediated growth hormone response to clonidine was increased after one week's treatment with desipramine and then reduced during the second and third weeks of treatment. No clinical measure of the responsiveness of central beta-adrenoceptors is available. However, the secretion of melatonin is a measure of neurotransmission at noradrenergic terminals in the pineal with alpha 1-, alpha 2- and beta 1-adrenoceptors. In normal volunteers the secretion of melatonin was increased by the noradrenaline uptake inhibitors desipramine and (+)-oxaprotiline; (-)-oxaprotiline had no effect. In depressed patients melatonin secretion was increased after three weeks' treatment with desipramine. These and other clinical studies suggest that antidepressant treatments increase noradrenergic neurotransmission in depressed patients.

1 The degree of selective monoamine oxidase (MAO) inhibition produced by (-)-deprenyl, clorgyline, LY51641 and tranylcypromine was examined in relation to modification of tyramine and noradrenaline contractile responses of the rat isolated vas deferens. 2 All inhibitors possessed reversible alpha-adrenoceptor blocking activity, determined against noradrenaline on the denervated vas deferens. For LY51641 and tranylcypromine, antagonism was competitive, with pA2 values of 6.17 and 5.16. 3 Clorgyline, LY51641 and (-)-deprenyl (10(-5) M) inhibited the tyramine response while present in the organ bath: LY51641, which was the most potent as an alpha-adrenoceptor blocker, produced this effect at 10(-6) M. Responses to tyramine and noradrenaline were potentiated on wishing out the inhibitors, but noradrenaline potentiation was seen only when tyramine had been present in the system. 4 Tranylcypromine (10(-6) M) potentiated responses to noradrenaline and tyramine while present in the organ bath. 5 Potentiation of tyramine responses by clorgyline and LY51641 occurred at 91% and 64% inhibition of MAO type A respectively, although full potentiation of the tyramine response was elicited only when substantial inhibition of both enzyme types occurred. Selective inhibition of MAO type B by 67% (with deprenyl) was not associated with tyramine potentiation.