No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Hull KM, Maher TJ. Effects of L-tyrosine on mixed-acting sympathomimetic-induced pressor actions. Pharmacol Biochem Behav 43, 1047-1052
Abstract
We previously reported the ability of L-tyrosine (L-TYR) to potentiate the anorectic activity of various mixed-acting sympathomimetics including [R*S*]-(+/-)-norephedrine [phenylpropanolamine (PPA)], [1R,2S]-(-)-ephedrine (EPH), and [S]-(+)-amphetamine (AMPH) in hyperphagic rats. Included in those studies was the attenuation of L-TYR's effect when coadministered with L-valine, a large neutral amino acid that competes with L-TYR for uptake into the brain, suggesting a central locus for the action of L-TYR. Additional studies demonstrated the inability of L-TYR to alter the peripherally mediated PPA-, EPH-, and AMPH-induced increases in gastrointestinal transit time and retention and intrascapular brown adipose tissue thermogenesis. Because the mixed-acting sympathomimetics are known to increase blood pressure, these studies examined the ability of L-TYR to influence the pressor responses to PPA, EPH, and AMPH (0.03-1 mg/kg) in urethane-anesthetized rats. Each of the mixed-acting sympathomimetics significantly increased mean arterial, systolic, and diastolic blood pressures when administered alone, but no potentiation by L-TYR was observed. These results demonstrate the inability of L-TYR to potentiate the peripheral vasopressor effects of PPA, EPH, and AMPH. These data, in conjunction with our previous findings, suggest that the potentiation by L-TYR of the mixed-acting sympathomimetics is largely restricted to centrally mediated responses.
... The effect of caffeine on appetite and thermogenesis is measurable but rather weak [20][21][22][23][24]. Caffeine seems to be a potent thermogenic amplifier when given in conjunction with other SNS agonists such as ephedrine, catechins, or capsaicin [17,22,[25][26][27]. In addition, tyrosine supplementation together with other sympathomimetics increased temperature in the brown adipose tissue in rodents and decreased food intake in a synergistic fashion [28][29][30]. The rationale for combining the above ingredients is that the effects of the compounds may be potentiated in a synergistic fashion. ...
... The effects were probably strongly reduced, as the half-life of propranolol is 3 to 4 hours and the effect of caffeine appears to decrease 2 to 3 hours postintake [20,21,24]. Capsaicin has been observed to induce an anorectic effect in humans [14,15] and tyrosine in rats [28][29][30], whereas the effects of tea catechins on appetite and food intake are sparse and conflicting [19,[59][60][61]. In addition, the organoleptic quality of the present ad libitum meal was rated as a little higher than medium and may additionally have limited the ad libitum EI test. ...
A combination of tyrosine, capsaicin, catechins, and caffeine has been shown to possess a thermogenic effect in humans. The present objective was to investigate whether the thermogenic response to the bioactive combination (BC) could be diminished or abolished by propranolol. Twenty-two men (age, 29.0 +/- 7.1 years; body mass index, 26.0 +/- 3.6 kg/m(2); mean +/- SD) participated in a 4-way, randomized, double-blind, placebo-controlled crossover study. The effect of the following was tested: (1) placebo, (2) BC, (3) BC + 5 mg propranolol, and (4) BC + 10 mg propranolol. Resting metabolic rate, respiratory quotient, and the thermogenic response were measured for 5 hours postintake. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and appetite ratings were assessed every half hour. The BC increased resting metabolic rate by 5% (73 [36; 110] kJ/5 h, mean [95% confidence interval], P < .0001) compared with placebo. Both propranolol doses blunted the thermogenic response by 50% compared with placebo (P < .01). The BC increased SBP by 3% (4 +/- 1 mm Hg, P = .003) compared with placebo. The effect of BC on SBP was reduced by 25% by propranolol (P = .07). The BC (with or without propranolol) increased DBP by 6% (4 +/- 1 mm Hg, P </= .0002). Propranolol decreased heart rate by 5% (3 +/- 1 beats per minute, P < .0001) compared with placebo and BC. No effects were observed on appetite ratings. In conclusion, the study confirms the thermogenic properties of BC. The 50% reduction of the thermogenic response by propranolol indicates that beta-adrenergic pathways are partly responsible for the thermogenic response.
... In contrast, amino acid mixtures lacking tyrosine and phenylalanine increased plasma prolactin and decreased performance on a neurophysiological task sensitive to impaired dopaminergic function in humans (Gijsman et al., 2002). Giving tyrosine potentiated the brain‐mediated anorexic effect of sympathomimetic drugs (phenylpropanolamine; ephedrine; amphetamine ) (Hull and Maher, 1990), but not peripheral, sympathoadrenal‐mediated as changes in gastric transit, thermogenesis (Hull and Maher, 1991), or blood pressure (Hull and Maher, 1992). Tyrosine administration also prevented hypoxia‐induced decrements in learning and memory in rats (Shukitt‐ Hale et al., 1996). ...
This chapter describes the aromatic l-amino acids tryptophan and tyrosine and the effects on tyrosine metabolism of phenylalanine. Tryptophan and phenylalanine
are essential amino acids and must ultimately be derived from dietary proteins; tyrosine is obtained both from dietary proteins
and from the hydroxylation of phenylalanine by phenylalanine hydroxylase (PAH). The proportions of dietary tryptophan, tyrosine,
and phenylalanine that enter the systemic circulation are limited by three hepatic enzymes—tryptophan dioxygenase, tyrosine
aminotransferase, and phenylalanine hydroxylase—that destroy them. These enzymes all have high substrate K
m's, hence they have little effect on their amino acid substrates present in systemic blood but major, concentration-dependent
effects on the elevated concentrations, present postprandially, in portal venous blood.
All of the large, neutral amino acids (LNAA)—e.g., the three aromatic amino acids; the three branched-chain amino acids, leucine,
isoleucine, and valine—across from the brain's capillaries into its substance through the action of a single transport molecule,
LAT1. The kinetic properties of this molecule are such that it is saturated with LNAA at normal concentrations in systemic
blood so that the individual LNAA compete with each other for blood–brain barrier transport. Hence the effect of any treatment
on, for example, brain tryptophan, will depend not on plasma tryptophan, per se, but on the ratio of the plasma tryptophan
concentration to the summed concentrations of the other, competing LNAA. Small quantities of LNAA molecules also enter the
brain via choroid plexus transport into the cerebrospinal fluid.
The levels of tryptophan in the brain determine the substrate-saturation of tryptophan hydroxylase, and thus the rate at which
tryptophan is converted to 5-hydroxytryptophan and subsequently to serotonin or melatonin. Brain tyrosine levels may or may
not affect the rate at which tyrosine is hydroxylated, and converted to the catecholamines dopamine and norepinephrine, depending
on the firing frequency of the particular catecholaminergic neuron. If the neuron is firing with high frequency, the tyrosine
hydroxylase enzyme becomes multiply phosphorylated; this markedly increases its affinity for its otherwise-limiting cofactor
(tetrahydrobiopterin) so that local tyrosine concentrations become limiting (several groups of prefrontal dopaminergic neurons
normally fire unusually frequently, and are thus always susceptible to precursor control by available tyrosine levels). The
abilities of the precursor amino acids, tryptophan and tyrosine, to control the rates at which neurons can produce and release
their neurotransmitter products underlie a number of physiological processes, and also constitute a potential tool for amplifying
or decreasing synaptic neurotransmission.
... It has been shown that tyrosine supplementation together with other sympathomimetics decreased food intake in rats in a synergistic fashion. [18][19][20] Despite some inconsistencies 21 there is evidence to suggest that high-calcium intake given as a supplement, or in highcalcium diets, can produce weight loss. [22][23][24][25][26] The effects of these ingredients may be potentiated in a synergistic fashion when given in combination. ...
A combination of tyrosine, capsaicin, catechines and caffeine may stimulate the sympathetic nervous system and promote satiety, lipolysis and thermogenesis. In addition, dietary calcium may increase fecal fat excretion.
To investigate the acute and subchronic effect of a supplement containing the above mentioned agents or placebo taken t.i.d on thermogenesis, body fat loss and fecal fat excretion.
In total, 80 overweight-obese subjects ((body mass index) 31.2+/-2.5 kg/m(2), mean+/-s.d.) underwent an initial 4-week hypocaloric diet (3.4 MJ/day). Those who lost>4% body weight were instructed to consume a hypocaloric diet (-1.3 MJ/day) and were randomized to receive either placebo (n=23) or bioactive supplement (n=57) in a double-blind, 8-week intervention. The thermogenic effect of the compound was tested at the first and last day of intervention, and blood pressure, heart rate, body weight and composition were assessed.
Weight loss during the induction phase was 6.8+/-1.9 kg. At the first exposure the thermogenic effect of the bioactive supplement exceeded that of placebo by 87.3 kJ/4 h (95%CI: 50.9;123.7, P=0.005) and after 8 weeks this effect was sustained (85.5 kJ/4 h (47.6;123.4), P=0.03). Body fat mass decreased more in the supplement group by 0.9 kg (0.5; 1.3) compared with placebo (P<0.05). The bioactive supplement had no effect on fecal fat excretion, blood pressure or heart rate.
The bioactive supplement increased 4-h thermogenesis by 90 kJ more than placebo, and the effect was maintained after 8 weeks and accompanied by a slight reduction in fat mass. These bioactive components may support weight maintenance after a hypocaloric diet.
... Tyrosine has been reported to increase anorexia in rodents when combined with compounds that release endogeneous catacholamines. 6 ...
This study was designed to evaluate the efficacy and safety of a dietary herbal supplement containing citrus aurantium and phenylephrine in the treatment of obesity. Two pilot studies enrolled healthy subjects with body mass indexes 25-40 kg/m(2) to similar 8-week weight loss programs. Safety was assessed by physical examination and laboratory tests at screening and 8 weeks. The first pilot study randomized eight subjects to citrus aurantium (herbal phenylephrine) or placebo. Body composition by DEXA scan, waist circumference, and resting metabolic rate (RMR) were measured at baseline and 8 weeks. Food intake and appetite ratings were measured at baseline and week 2. The second pilot study randomized 20 subjects to two 2-hour RMR tests a week apart after phenylephrine (20 mg) or placebo followed by phenylephrine (20 mg) three times a day for 8 weeks. In the first pilot study, the citrus aurantium group gained 1.13 +/- 0.27 (mean +/- SEM) kg compared with 0.09 +/- 0.28 kg in the placebo group (P < .04). RMR at baseline rose more in the citrus aurantium group, 144.5 +/- 15.7 kcal/24 hours, than the placebo group, 23.8 +/- 28.3 kcal/24 hours (P < .002), but not at 8 weeks. DEXA, waist circumference, food intake, and hunger ratings were not different. In the second pilot study, the phenylephrine group lost 0.8 +/- 3.4 kg in 8 weeks (not significant), and RMR increased more in the phenylephrine group (111.5 +/- 32.6 vs. 37.4 +/- 22.7 kcal/24 hours, P = .02). There were no significant safety issues in either study. Although no toxicity was seen, these pilot studies suggest phenylephrine is not efficacious for weight loss.
... Pseudoephedrine (PSE) and phenylpropanolamine (PPA) are mixed-acting sympathomimetic amines that have been used commonly as decongestants in the treatment of coughs and colds. [10][11][12][13][14] The effectiveness of PSE and PPA as decongestants is specifically related to the activation of α-adrenergic receptors in the nasal mucosa, resulting in vasoconstriction, reduced blood flow, decreased mucosal edema, and, ultimately, improved nasal patency. 15,16 At mucosal sympathetic nerve endings, these agents directly stimulate adrenergic receptors (direct action) and displace norepinephrine from neuronal storage sites (indirect action). ...
Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.
The complex 2{[Ni(l-Tyr)2(bpy)]}·3H2O·CH3OH [1, where l-Tyr = l-tyrosine; bpy = 2,2'-bipyridine (2,2'-bpy)] was obtained in crystalline form and characterized by X-ray and spectroscopic (FT-IR, NIR-vis-UV, and HFEPR) and magnetic methods. The complex crystallized in the hexagonal system with a = b = 12.8116(18) Å, c = 30.035(6) Å, and space group P3221. The six-coordination sphere around the Ni(2+) ion is formed by two N and two O l-tyrosinato atoms and completed by two N atoms of the 2,2'-bpy molecule. Neighboring [Ni(l-Tyr)2(bpy)] units are joined via weak hydrogen bonds, which create a helical polymeric chain. The coordinated atoms form a strongly distorted cis-NiN2N2'O2 octahedral chromophore. The solid-state electronic spectrum of complex 1 was analyzed assuming D2h symmetry, and the observed bands were assigned to (3)B1g → (3)Ag, (3)B1g → (3)B3g, (3)B1g → (3)B2g, (3)B1g → (3)B3g, (3)B1g → (3)B1g, and (3)B1g → (3)B2g transitions for the I and II d-d bands, respectively. The crystal-field parameters found for D2h symmetry are Dq = 1066 cm(-1), Ds = 617 cm(-1), Dt = -93 cm(-1), B22 = 7000 cm(-1), and Racah B = 812 cm(-1). Magnetic studies revealed the occurrence of hydrogen-bonded metal pairs. The spin Hamiltonian parameters D = -3.262 cm(-1) and E = -0.1094 cm(-1), determined from high-field, high-frequency electron paramagnetic resonance spectra, together with a weak antiferromagnetic exchange parameter J = -0.477 cm(-1), allowed us to reproduce the powder magnetic susceptibility and field-dependent magnetization of the complex. The biological activity of 1 has been tested by using the Fusarium solani, Penicillium verrucosum, and Aspergillus flavus fungi strains and Escherichia coli, Pseudomonas fluorescens, Serratia marcescens, and Bacillus subtilis bacterial strains.
Narcolepsy-cataplexy is a disabling neurological disorder that affects 1/2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafmil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming.
To investigate the effect of three different food ingredients tyrosine, green tea extract (GTE) and caffeine on resting metabolic rate and haemodynamics, and on ad libitum energy intake (EI) and appetite.
Twelve healthy, normal weight men (age: 23.7 +/- 2.6 years, mean +/- s.d.) participated in a four-way crossover, randomized, placebo-controlled, double-blind study. Treatments were administered as tablets of 500 mg GTE, 400 mg tyrosine, 50 mg caffeine, or placebo, and were separated by >3-day washout. The acute thermogenic response was measured in a ventilated hood system for 4 h following ingestion. Blood pressure, heart rate (HR), and subjective appetite sensations were assessed hourly and ad libitum EI 4 h post-dose.
Caffeine induced a thermogenic response of 6% above baseline value (72 +/- 25 kJ per 4 h, mean +/- s.e.) compared to placebo (P<0.0001). The thermogenic responses to GTE and tyrosine were not significantly different from placebo. Tyrosine tended to increase 4-h respiratory quotient by 1% compared to placebo (0.01 +/- 0.005, P=0.05). Ad libitum EI was not significantly different between treatments but was reduced by 8% (-403 +/- 183 kJ), 8% (-400 +/- 335 kJ) and 3% (-151 +/- 377 kJ) compared to placebo after intake of tyrosine, GTE and caffeine, respectively. No significant difference in haemodynamics was observed between treatments.
Only caffeine was thermogenic in the given dose and caused no haemodynamic side effects. The sample size was probably too small to detect any appetite suppressant properties of the treatments. Further investigations are required.
The Michaelis-Menten kinetics of blood-brain barrier transport of fourteen amino acids was investigated with a tissue-sampling, single-injection technique in the anesthetized rat. Tracer quantities of 14C-labelled amino acids and 3H2O, used as a freely diffusible internal reference, were mixed in 0.2 ml of buffered Ringer's solution and injected rapidly into a common carotid artery. Circulation was terminated by decapitation at 15s following injection. A brain uptake index (Ib) was determined from the ratio of 14C dpm in the brain tissue and the injection mixture divided by the same ratio for the 3H2O reference. Brain clearance of tracer concentration of amino acid was saturable when various concentrations of unlabeled amino acid were added to the injection solution. Double reciprocal plots of the saturation data yielded Km (mM) values that ranged from a low of 0.09 mM for arginine to a high of 0.75 mM for cycloleucine. Transport V values were determined from the relationship P = V/Km where P is the blood-brain barrier permeability constant (ml/g per min): P was calculated from the Ib for each amino acid based on a cerebral blood flow of 0.56 ml/g per min and a fractional extraction of 0.75 for the 3H2O reference 15s following carotid injection. The V values ranged from a low of 6.2 nmol/g per min for lysine to a high of 64 nmol/g per min for l-DOPA. Efflux of the tracer amino acid during the 15-s period after injection was assumed to be slow, since the rate constant of cycloleucine from brain to blood was low, 0.11 min-1.
The tyrosine concentration of fasted rats was measured in plasma, brain and tissues receiving sympathetic innervation after L-tyrosine (200 mg/kg) was administered alone or in the presence of an equimolar cocktail containing isoleucine, leucine and valine. In the samples taken at 15, 30, 45, 60, 120 or 180 minutes, the highest concentrations of L-tyrosine were observed in plasma, heart, adrenal gland and kidney at 15 minutes, but in interscapular brown adipose tissue at 15 and 30 minutes and in brain at 15-60 minutes. The decline from peak concentrations was slower in brain, kidney and interscapular brown adipose tissue than in plasma, but in all tissues examined, control levels of free tyrosine were attained by 180 minutes postadministration . Competing large neutral amino acids reduced the maximal uptake of tyrosine in the brain by 48% but had no effect in the other tissues examined.
Phenylpropanolamine (PPA) produces weight loss that may result, in part, from an excitatory action of PPA on brown adipose tissue (BAT) thermogenesis. Adult male and female rats were anesthetized with 1.2 g/kg urethane and treated (ip) with either 0.9% saline or 5, 10, 20, or 40 mg/kg dl-PPA. Interscapular BAT (IBAT) and rectal temperatures were recorded every minute for 10 min prior to and 60 min following drug injection. Control rats exhibited stable IBAT and rectal temperatures prior to and after saline injection, whereas PPA-treated rats exhibited in-creases in IBAT temperature and, after a 10-15-min lag, in rectal temperature. There were no differences between male and female rats with regard to the effect of PPA on IBAT and rectal temperature. The implications of these data for an explanation of the weight-reducing effect of PPA are discussed.
The sympathomimetic properties of PPA and its individual component enantiomers d- and l-norephedrine (NOR) were examined in isolated perfused/superfused caudal arteries from Sprague-Dawley (SD) rats. Segments of caudal artery were cannulated, mounted in a tissue bath, and perfused with a modified Kreb's solution. PPA, d- and I-NOR were alternately injected into the perfusion stream, and vasoconstriction was measured as the rise in perfusion pressure. Various drugs were added to the perfusion buffer to determine the activity of PPA, d-, and I-NOR at specific adrenoceptor subtypes and to determine whether the actions of these vasoconstrictors were influenced by calcium channel antagonists, cocaine, or reserpine. The results demonstrated that the norephedrines acted as partial agonists primarily via direct stimulation of postjunctional alpha1-adrenoceptors with relatively low potency; however, I-NOR did have significant activity at beta-adrenoceptors with relatively low potency; however, I-NOR did have significant activity at beta-adrenoceptors as well. When the enantiomers of PPA were compared, d-NOR had only minor vasoconstrictor activity, relative to I-NOR, which was well over 100 times less potent than the endogenous.
The effects of agents, which are known to induce release of catecholamines from synaptosomes, were assessed on the synthesis of dopamine from tyrosine, as reflected in the evolution of 14CO2 from L-[1-14C]-tyrosine, in intact rat striatal synaptosomes. At a time when release had occured, whereas reserpine inhibited the synthesis of dopamine from tyrosine, with an ED50 of , tyramine (ED50 of ) and (+)-amphetamine (ED50 of ) enhanced the rate of synthesis. The presence of nialamide (10−4M) or pargyline (10−3M) had no effect on synaptosomal dopamine synthesis in the absence or presence of amphetamine, tyramine, or reserpine. Neither reserpine, tyramine, nor amphetamine effected the activity of tyrosine hydroxylase or DOPA decarboxylase in the absence of synaptosomal structural integrity. Nor did these drugs effect the accumulation of [3H]-tyrosine into synaptosomes. The data are consistent with the existence of at least two pools of synaptosomal dopamine, one of which can interact with tyrosine hydroxylase. Two hours after pretreatment of rats with 5 mg/kg (+)-amphetamine, the level of synaptosomal dopamine biosynthesis was decreased by 39%. The rate of dopamine synthesis in synaptosomes from amphetamine-pretreated rats was assessed in the presence of reserpine and tyramine. The data are not consistent with alterations in pool size being the only mechanism affecting synaptosomal dopamine synthesis. A mechanism is discussed involving an equilibrium of tyrosine hydroxylase between active and inactive conformers in the presence of an inhibitory pool of dopamine.
Administration of L-tyrosine to normotensive or spontaneously hypertensive rats reduces blood pressure. The effect is maximal within 2 hr of injection. In spontaneously hypertensive rats, a dose of 50 mg/kg, intraperitoneally, reduces blood pressure by about 12 mm Hg (1 mm Hg = 1.33 x 10(2) pascals); a dose of 200 mg/kg produces the maximal effect, a reduction of about 40 mm Hg. Tryptophan injection (225 mg/kg) also lowers blood pressure in spontaneously hypertensive rats, but only by about half as much as an equivalent dose of tyrosine. Other amino acids tested (leucine, isoleucine, valine, alanine, arginine, and aspartate) do not affect blood pressure. Tyrosine injection appears to reduce blood pressure via an action within the central nervous system, since the effect can be blocked by co-administering other large neutral amino acids that reduce tyrosine's uptake into the brain. That tyrosine's antihypertensive action is mediated by an acceleration in norepinephrine or epinephrine release within the central nervous system is suggested by the concurrent increase that its injection produces in brain levels of methoxyhydroxyphenylethylglycol sulfate.
To elucidate a possible role of tyrosine supply as a factor modulating catecholamine biosynthesis in the adrenergic cell, the transport of [14C]tyrosine into cultured bovine adrenal chromaffin cells was first examined, and the relationship between [14C]tyrosine transport and [14C]catecholamine formation was then investigated. Under the conditions which were routinely employed to determine the rate of catecholamine biosynthesis, tyrosine was taken up into the cells in a manner independent of extracellular Na+ and Ca2+, and this uptake was also insensitive to ouabain and various metabolic inhibitors. The stimulation of these cells with high K+ and other secretagogues caused no significant alteration in the uptake. While, tyrosine transport was markedly inhibited by tyrosine analogues and other L-aromatic amino acids, and this inhibition was accompanied by the reduction of [14C]catecholamine formation. In contrast, tyrosine transport was markedly enhanced by flavone, and this enhancement was also accompanied by the augmentation of catecholamine production under the same experimental conditions. These results seem to indicate that the transport of tyrosine into the cells may be closely related to catecholamine formation within the cells, thus providing an evidence for a possible role of tyrosine supply as one of the factors affecting catecholamine production in the adrenal chromaffin cell.
We have recently reported the ability of L-tyrosine (L-TYR) to potentiate the anorectic activity of various mixed-acting sympathomimetics including phenylpropanolamine (PPA), l-ephedrine (EPH) and d-amphetamine (AMP). Included in those studies was the attenuation of L-TYR's effect when coadministered with L-valine, a large neutral amino acid which competes with L-TYR for uptake into the brain, suggesting a central locus for the action of L-TYR. To determine to what extent L-TYR can potentiate peripheral actions, we investigated the effects of L-TYR with either PPA (20 mg/kg), EPH (20 mg/kg) or AMP (1.75 mg/kg) on gastric transit, gastric retention and intrascapular brown adipose tissue thermogenesis. In each of the paradigms studied, PPA, EPH and AMP significantly increased the expected sympathomimetic-mediated response, but no potentiation of L-TYR was observed. These results are consistent with the hypothesis that L-TYR potentiates the anorectic activity of the mixed-acting sympathomimetics largely via an action at a central locus.
Phenylpropanolamine (PPA, d,l-norephedrine), available in many over-the-counter nasal decongestants and appetite suppressants, is a racemic mixture of the enantiomers d- and l-norephedrine. The present study evaluates the effects of the individual PPA enantiomers on a variety of nondrug (food deprivation) and drug-induced hyperphagias (2-deoxyglucose and insulin). Racemic PPA has been shown to significantly suppress food intake in these hyperphagic models. Both l-norephedrine (5-50 mg/kg) and d-norephedrine (5-150 mg/kg), administered intraperitoneally, significantly suppressed feeding after a 4-hr fast during the dark cycle. During the light period, l-norephedrine (7.5, 10, 15 mg/kg) and d-norephedrine (75, 100, 150 mg/kg) significantly reduced food intake at the 1-hr and 3-hr time intervals in the 24-hr food deprivation-, insulin- and 2-deoxyglucose-induced hyperphagic models. Only 7.5 mg/kg l-norephedrine in the insulin-induced hyperphagia at 3 hr failed to significantly suppress feeding. These results indicate that each individual PPA enantiomer possesses the ability to suppress food intake in rats made hyperphagic by various stimuli.
The effects of L-tyrosine (L-TYR) on the anorectic activity of several mixed-acting sympathomimetics were determined during the dark cycle in rats made hyperphagic by food deprivation. L-TYR (200 mg/kg) significantly potentiated the anorectic activity of phenylpropanolamine, (-)-ephedrine and (+)-amphetamine by 48, 50 and 37%, respectively. When the dose of L-TYR was varied (25-400 mg/kg), a significant dose-dependent relationship was noted. The observed potentiation was positively correlated with increases in brain TYR concentrations; blockade of L-TYR uptake into the brain by the coadministration of L-valine prevented this potentiation. Various other L-amino acids, as well as D-TYR, failed to mimic the potentiating action of L-TYR. As determined by alpha-methyl-p-TYR pretreatment, the L-TYR-induced potentiation was dependent upon increased catecholamine synthesis. Although various other mixed-acting sympathomimetic anorexiants were similarly potentiated by L-TYR, the direct-acting beta-2 adrenoceptor anorexiants, salbutamol and methoxyphenamine, were not. These results indicate that L-TYR specifically potentiates the anorectic activity of the studied mixed-acting sympathomimetics and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response. The possibility that the effect of mixed-acting sympathomimetics is normally limited by the availability of L-TYR is suggested.
Previous studies have demonstrated the ability of tyrosine (TYR), the amino acid precursor of catecholamines, to increase blood pressure in rats made hypotensive by haemorrhage. Other studies have shown that supplementation of the diet with TYR can reverse certain neurochemical and behavioural consequences associated with acute stress. Such studies demonstrate that during conditions of enhanced neuronal firing catecholamine synthesis is accelerated when additional precursor TYR is made available. In these situations the rate-limiting enzyme of catecholamine synthesis, tyrosine hydroxylase, activated via phosphorylation, becomes responsive to additional TYR. Our experiments were designed to study the ability of dietary TYR (3.7%, or 4X the normal amount), to prevent the rapid fall in blood pressure observed during acute haemorrhage. Rats consuming the high TYR diet (5 days) maintained arterial blood pressure (systolic, diastolic and mean) at significantly greater values during the period of acute haemorrhagic insult than animals maintained on a control diet. Rats fed the high TYR diet had significantly greater levels of the amino acid in the heart, adrenal glands, liver, kidney, brainstem, spleen and semimembranosus pars caudalis muscle. We conclude that TYR can be stored and most likely utilized in the synthesis of catecholamines for the maintenance of arterial blood pressure during acute haemorrhage. These results are of particular importance in light of the fact that most total parenteral nutrition solutions contain very little if any TYR.
The mechanisms of tyrosine hydroxylase (TH) activation by depolarization or exposure of dopaminergic terminals to cyclic AMP have been compared using rat striatal slices. Tissues were incubated with veratridine or 60 mM K+ (depolarizing conditions), on the one hand, and forskolin or dibutyryl cyclic AMP, on the other. K+-(or veratridine-)induced depolarization triggered an activation of TH (+75%) that persisted in soluble extracts of incubated tissues. This effect disappeared when drugs (EGTA, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, Gallopamil) preventing Ca2+- and calmodulin-dependent processes were included in the incubating medium. In contrast, prior in vivo reserpine treatment or in vitro addition of benztropine did not affect the depolarization-induced activation of TH. In vitro studies of soluble TH extracted from depolarized tissues indicated that activation was associated with a marked increase in the enzyme Vmax but with no change in its apparent affinity for the pteridin cofactor 6-methyl-5,6,7,8-tetrahydropterin (6-MPH4) or tyrosine. Furthermore, the activated enzyme from depolarized tissues exhibited the same optimal pH (5.8) as native TH extracted from control striatal slices. In contrast, TH activation resulting from tissue incubation in the presence of forskolin or dibutyryl cyclic AMP was associated with a selective increase in the apparent affinity for 6-MPH4 and a shift in the optimal pH from 5.8 to 7.0-7.2. Clear distinction between the two activating processes was further confirmed by the facts that heparin- and cyclic AMP-dependent phosphorylation stimulated TH activity from K+-exposed (and control) tissues but not that from striatal slices incubated with forskolin (or dibutyryl cyclic AMP). In contrast, the latter enzyme but not that from depolarized tissues could be activated by Ca2+-dependent phosphorylation. These data strongly support the concept that Ca2+- but not cyclic AMP-dependent phosphorylation is responsible for TH activation in depolarized dopaminergic terminals.
The ability of (+/-)-norephedrine (phenylpropanolamine) and its component isomers, (+)-and (-)-norephedrine, to activate adrenergic receptor subtypes in the cardiovascular system of the urethane/chloralose-anaesthetized pithed rat has been investigated. At all adrenoceptor subtypes, (-)-norephedrine was the most potent agonist followed by (+/-)- then (+)-norephedrine. The greatest activity was observed at the alpha 1-receptor, with little activity observed at either beta 1 or beta 2-adrenoceptors. Reserpinization shifted the (-)-norephedrine dose-response curve slightly to the right, indicating that only a minor portion of its activity is due to the release of stored endogenous catecholamines. These results suggest that most of the cardiovascular activity of the compounds is through the direct activation of alpha 1-adrenoceptors.
Phenylpropanolamine (PPA, (+/-)-norephedrine) is commonly found in appetite suppressants and nasal decongestants. Within the cardiovascular system of the pithed rat, the drug and its two component enantiomers ((-)- and (+)-norephedrine) are largely direct-acting agonists. The interaction between simultaneous alpha 1-, alpha 2- and beta 2-adrenoceptor mediated effects of the drug and its two enantiomers have been examined using the cardiovascular system of the pithed rat. On all adrenoceptors tested the potency was (-)- greater than (+/-)-, greater than (+)-norphedrine. The alpha 1- and alpha 2-mediated pressor responses of each were enhanced in the presence of the beta 2-adrenoceptor antagonist, ICI 118,551, and diminished in the presence of the selective beta 2-adrenoceptor agonist salbutamol. It is concluded that each form of the drug possesses the intrinsic ability to interact with the alpha 1-, alpha 2- and beta 2-adrenoceptors in the system used and that the interaction with those adrenoceptors determines the net increase in diastolic blood pressure that follows the intravenous administration of the compounds. These findings have a bearing on the recent controversy regarding the use of beta-blocking agents in the treatment of overdosage of the drug.
Various studies have confused the norephedrine and norpseudoephedrine isomers with phenylpropanolamine (PPA, d,l-norephedrine). This confusion has led us to investigate the pharmacological activity of the norephedrine (NOR) and norpseudoephedrine (NORP) isomers in the cardiovascular system of the urethane:chloralose anesthetized rat. Following intravenous administration, in a cumulative-dose fashion, l-NOR and PPA were the most potent compounds at increasing arterial blood pressure, while d-NOR, d-NORP, and l-NORP were relatively inactive at the doses tested (0.31-10 mg/kg). Prior reserpinization did not significantly shift the cumulative dose-response curves for l-NOR and PPA. Repetitive injections of PPA and l-NOR (1 mg/kg, 4 doses at 5-min intervals) failed to produce tachyphylaxis to the pressor response. On the other hand, when d-NORP was administered in a similar fashion, tachyphylaxis to the second and subsequent doses was observed. These studies demonstrate that significant mechanistic differences exist between these norephedrine isomers.
d,l-Norephedrine (PPA) is available as an over-the-counter appetite suppressant and nasal decongestant in the U.S.A. The pseudoisomer d-norpseudoephedrine, is available as an appetite suppressant in Europe, and has been isolated as one of the stimulatory components (cathine) of the Khat plant. Some authors have misidentified cathine as PPA and this confusion in the literature has resulted. PPA and d-norpseudoephedrine possess significantly different pharmacological properties despite having identical structural formulae. Anorectic activity was determined in a food-deprived rat model. PPA and d-norpseudoephedrine were approximately one-tenth as potent as d-amphetamine with all compounds producing a dose-dependent decrease in food intake. Locomotor activity in an open-field apparatus was determined as an index of CNS stimulation. Male Sprague-Dawley rats treated with d-norpseudoephedrine, in doses between 10 and 50 mg/kg, exhibited significantly increased locomotor scores compared to saline (control) treated animals, an increase similar to that caused by 2 mg/kg d-amphetamine. PPA (5-50 mg/kg) failed to increase locomotion significantly. These results indicate that although each compound tested decreased food intake in a dose-dependent fashion, significant differences in open-field locomotion do exist between PPA, d-norpseudoephedrine, and d-amphetamine. Stereoisomeric compounds, although structurally similar, frequently have different pharmacological effects. Thus extreme care must be taken to properly identify these compounds in the literature.
Phenylpropanolamine (PPA) induces anorexia and weight loss via an as yet unidentified mechanism. In the present study, we evaluated the inhibitory action of PPA on gastric emptying. Adult female Sprague-Dawley rats consumed a wet-mash test meal and were then treated (IP) with either saline or 5, 10, 20 or 40 mg/kg PPA. Gastric retention (ratio of weight of gastric content to weight of mash consumed) was evaluated immediately after the meal in a group of saline-treated rats or 3 hours after the meal in the drug groups and another saline-treated group. Rats treated with saline exhibited minimal retention (0.21) over a 3 hour period whereas rats treated with 5, 10, 20 or 40 mg/kg dl-PPA exhibited increased gastric retention ratios of 0.29, 0.66, 0.63, and 1.38, respectively. These data demonstrate that PPA has a marked inhibitory action on gastric emptying and suggest that further studies are warranted to evaluate the possible contribution of gastric retention to the anorexic action of PPA.
In vitro studies of rat brain tyrosine hydroxylase and tryptophan hydroxylase activities have demonstrated nonlinearities in both time course and substrate velocity curves that were sensitive to small changes in tetrahydrobiopterin (BH4) concentrations when studied within a range speculated to approximate the in vivo condition. High-performance liquid chromatographic determinations of rat striatal BH4 levels reported here are consistent with such a nonlinear relationship of BH4 and brain monoamine synthesis under four in vivo conditions: 1-day s.c. amphetamine infusion, L-tryptophan loads, i.v.t. administration of corticotropin releasing factor and the diurnal rhythms of the dopaminergic nigrostriatal and serotonergic raphe hippocampal systems. Only the results of continuous 10-day amphetamine infusion were consistent with a simple stoichiometric relationship between the (postulated) rate limiting concentrations of BH4 and regional levels of brain monoamines. Although some of the statistically significant changes in regional brain BH4 levels are small, previous reports of the failure of biopterin to change in response to more than 30 other central nervous system drugs, including such stimulants as methylphenidate and cocaine, makes them noteworthy.
Tyrosine, the amino acid precursor of catecholamines, increases blood pressure (BP) in rats made hypotensive by hemorrhage. Since this amino acid also accelerates catecholamine synthesis in and release from frequently-firing neurons, we tested the hypothesis that tyrosine's pressor action resulted from this mechanism. Male Sprague-Dawley rats (500 g) were anesthetized with chloralose (50 mg/kg) and urethane (500 mg/kg) and tracheostomized. The carotid artery was cannulated allowing BP to be recorded continuously. Blood was removed until systolic BP fell to half of each animal's starting value; 45 min later, animals received tyrosine or other treatments in volumes of 1 ml/kg. Tyrosine (100 mg/kg) increased BP by 58%, while saline caused an insignificant increase. Pretreatment with carbidopa, which inhibits tyrosine's conversion to catecholamines, blocked the amino acid's effect. Tyrosine also failed to increase BP in rats made hypotensive with phentolamine, suggesting that it acts via catecholamine receptors. Adrenal epinephrine significantly (P less than 0.02) and splenic norepinephrine slightly (P less than 0.07) increased in rats receiving tyrosine after 1 h of hypotension when compared with tissue-catecholamine contents in similar rats. These observations show that tyrosine increases BP during hemorrhagic hypotension by accelerating catecholamine synthesis.
The hydroxylase cofactor, tetrahydrobiopterin, and its biosynthetic system are localized in dopaminergic nerve terminals in
the striatum. This conclusion is based on the nearly equivalent loss of tyrosine hydroxylase and tetrahydrobiopterin and its
initial biosynthetic enzyme, guanosine triphosphate cyclohydrolase, after injection of 6-hydroxydopamine into the substantia
nigra. The role of the hydroxylase cofactor in the regulation of dopamine synthesis is reassessed.
Tyrosine, the amino acid precursor of catecholamines, increases blood pressure (BP) in hemorrhaged hypotensive rats. Since tyrosine may also be decarboxylated to form tyramine, which releases norepinephrine from sympathetic terminals, we tested the hypothesis that tyramine formation might mediate tyrosine's ability to increase BP. Three lines of evidence indicate that tyrosine does not act via this mechanism: pretreatment with reserpine blocked tyramine's but not tyrosine's pressor activity; pretreatment with hexamethonium left tyramine's effect intact but blocked the pressor response to tyrosine; and plasma tyramine did not increase after an hemodynamically-active dose of tyrosine (100 mg/kg).
Rats fasted overnight were allowed to consume single meals containing 0, 18, or 40% protein or continued to fast; after 2 h, brains and sera were taken and assayed for various amino acids. In general, serum levels of most amino acids were reduced by the 0% protein meal and elevated by the high-protein meal when compared with those associated with fasting conditions. Exceptions were those not diminished by the 0% protein meal (tryptophan, methionine, proline) and those increased (alanine) or decreased (glycine) by all of the test meals. Amino acids exhibiting the broadest normal ranges (estimated by comparing their serum levels after 40% protein with those after 0% protein) were tyrosine, leucine, valine, isoleucine, and proline; serum lysine and histidine, two basic amino acids, also varied more than threefold. Brain levels of lysine, histidine, and some of the large neutral amino acids (LNAAs) also exhibited clear relationships to the protein content of the test meal: those of valine, leucine, and isoleucine were depressed by the 0% protein but increased (compared with 0% protein) when protein was added to the meal: brain tyrosine was increased by all of the test meals in proportion to their protein contents; tryptophan, phenylalanine, and glutamate were increased after the 0% protein meal but not by protein-containing meals; brain lysine, histidine, and methionine were increased after the high-protein meal, and brain alanine was increased slightly by all of the meals.(ABSTRACT TRUNCATED AT 250 WORDS)
Intraventricular injection of 15 microgram L-tyrosine results in a significant reduction in blood pressure in the spontaneously hypertensive rat. An increase in the turnover of norepinephrine as indexed by MOPEG-SO4 is observed concurrently. The data are consistent with the previously suggested depressor role of certain central noradrenergic neurons.
Recent climate talks in Bali have made progress toward action on deforestation and forest degradation in developing countries,
within the anticipated post-Kyoto emissions reduction agreements. As a result of such action, many forests will be better
protected, but some land-use change will be displaced to other locations. The demonstration phase launched at Bali offers
an opportunity to examine potential outcomes for biodiversity and ecosystem services. Research will be needed into selection
of priority areas for reducing emissions from deforestation and forest degradation to deliver multiple benefits, on-the-ground
methods to best ensure these benefits, and minimization of displaced land-use change into nontarget countries and ecosystems,
including through revised conservation investments.
Norephedrine and norpseudoephedrine: Pharma-cologically and clinically distinct isomers of phenylpropanola-mine Phenyl-propanolamine: Risks, benefits, and controversies
- J P Morgan
Morgan, J. P. Norephedrine and norpseudoephedrine: Pharma-cologically and clinically distinct isomers of phenylpropanola-mine. In: Morgan, J. P.; Kagan, D. V.; Brody, J. S., eds. Phenyl-propanolamine: Risks, benefits, and controversies. New York: Praeger; 1985:180-194.
Norephedrine and norpseudoephedrine: Pharmacologically and clinically distinct isomers of phenylpropanolamine
- Morgan