Metabolism Of Epinephrine Research Articles

Pathogenetic features of functional disorders in the remaining kidney during the early postoperative period of radical nephrectomy

Relevance. Despite the widespread introduction of organ-preserving operations into urological practice, the number of radical nephrectomies has continued to increase. The results of modern research show that the initial stages of diseases of the remaining kidney are already formed at the earliest possible time after radical nephrectomy; therefore, adequate management of the postoperative period is a key factor in the prevention of diseases of the single kidney. However, this approach should be based on a detailed understanding of the mechanisms of adaptive restructuring of the body, which have a key effect on the morphology and function of a single kidney.Objective. To study the features of adaptive body reactions and the dynamics of the functional state of a single kidney following radical nephrectomy.Materials and methods. In the early postoperative period, the clinical and laboratory parameters of 85 patients who underwent radical nephrectomy for renal cell carcinoma in the T2-T3N0M0 stage were studied. The control group comprised 25 patients who underwent similar operations for the same indications within a period of 1.5–12 months. The metabolism of adrenaline, histamine, and serotonin, indicators of psychological and emotional states, vegetative-vascular status, and nitrogen excretion and filtration functions of the remaining kidney were studied.Results. Radical nephrectomy, as well as the period of conscious expectation, is the cause of a stress syndrome that occurs due to an imbalance of the studied biogenic amines, accompanied by disorders of psychological and emotional health and vegetative-vascular disorders observed at least during the 2 weeks of the postoperative period. In addition, the filtration capacity of a single kidney is impaired, and it persists for 14 days at follow-up. Correlation analysis made it possible to establish reliable links between the imbalance of biogenic amine and anxiety levels and the severity of autonomic vascular disorders, which adversely affect kidney filtration.Conclusions. The results of this study indicate the need for pharmacological subsidies during the postoperative period of radical nephrectomy, which makes it possible to offset the negative impact of stress syndrome on the outcome of surgical treatment.

Cerebroprotective effects of D. triquetrum on sodium nitrite‐induced hypoxia and ethanol‐induced neurodegeneration in animal models relevant to dementia

AbstractBackgroundCognitive impairment is a multidimensional and complicated concept that subsumes the attention, concentration, learning, memory, problem‐solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency and manual dexterity.ObjectiveTo study the effects of aqueous extracts of roots of Desmodium triquetrum on cognitive deficit mice.MethodsAqueous extracts of Desmodium triquetrum (DTE) were screened for Sodium nitrite induced hypoxia and Ethanol induced neurodegeneration using behavioral models such as rotarod, Passive shock avoidance paradigm, special water bottle case model, elevated plus maze and Morris water maze. DTE (5, 2.5 and 1.25 mg/kg p.o.) were administered to the mice. Acquisition, retention, Transfer latency (TLT), Time spent in target quadrant (TSTQ), Step down latency (SDL) and Escape latency (ELT) and biochemical parameters such as AChE, MAOA, TBARS, epinephrine, 5 HT were determined. DNA fragmentation studies were conducted which were compared with Donepezil.ResultsDTE (5, 2.5 and 1.25 mg kg(‐1) p.o.) significantly (p < 0.001) protected the Sodium nitrite induced memory impairment by decreasing the time require to find the water bottle in special water bottle case model. DTE improved acquisition and retention memory significantly (p < 0.001) by decreasing the Transfer Latency Time (TLT), escape latency time, TSTQ and increased the Step Down Latency (SDL. DTE inhibited Acetylcholinestrase (p < 0.01) activity, increased GSH, decreased TBARS and inhibited MAOA activity. Reduced the metabolism of epinephrine, 5‐HT. DTE (5 mg kg‐1) protected the DNA fragmentation of frontotemporal cortex from hypoxic effects.ConclusionDesmodium triquetrum are beneficial in the management of Neurodegenerative disorders particularly for Alzheimer’s disease.

Adrenaline induces calcium signal in astrocytes and vasoconstriction via activation of monoamine oxidase

Adrenaline or epinephrine is a hormone playing an important role in physiology. It is produced de-novo in the brain in very small amounts compared to other catecholamines, including noradrenaline. Although the effects of adrenaline on neurons have been extensively studied, much less is known about the action of this hormone on astrocytes. Here, we studied the effects of adrenaline on astrocytes in primary co-culture of neurons and astrocytes. Application of adrenaline induced calcium signal in both neurons and astrocytes, but only in neurons this effect was dependent on α- and β-receptor antagonists. The effects of adrenaline on astrocytes were less dependent on adrenoreceptors: the antagonist carvedilol had only moderate effect on the calcium signal and the agonist of adrenoreceptors methoxamine induced a signal only in small proportion of the cells. We found that adrenaline in astrocytes activates phospholipase C and subsequent release of calcium from the endoplasmic reticulum. Calcium signal in astrocytes is initiated by the metabolism of adrenaline by the monoamine oxidase (MAO), which activates reactive oxygen species production and induces lipid peroxidation. Inhibitor of MAO selegiline inhibited both adrenaline-induced calcium signal in astrocytes and the vasoconstriction that indicates an important role for monoamine oxidase in adrenaline-induced signalling and function.

CEREBROPROTECTIVE EFFECTS OF GANGETIN ALKALOIDS ON SODIUM NITRITE-INDUCED HYPOXIA AND ETHANOL-INDUCED NEURODEGENERATION

Cognitive impairment is a multidimensional and complicated concept that subsumes the attention, concentration, learning, memory, problem-solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency and manual dexterity. Objective: To study the effects of Gangetin alkaloids from the seeds of Desmodium gangeticum on cognitive deficit mice. Gangetin alkaloids were screened for Sodium nitrite induced hypoxia and Ethanol induced neurodegeneration using behavioral models such as rotarod, Passive shock avoidance paradigm, special water bottle case model, elevated plus maze and Morris water maze. GA (5, 2.5 and 1.25 mg/kg p.o.) were administered to the mice. Acquisition, retention, Transfer latency (TLT), Time spent in target quadrant (TSTQ), Step down latency (SDL) and Escape latency (ELT) and biochemical parameters such as AChE, MAOA, TBARS, epinephrine, 5 HT were determined. DNA fragmentation studies were conducted which were compared with donepezil. GA (5, 2.5 and 1.25 mg kg(-1) p.o.) significantly (p < 0.001) protected the Sodium nitrite induced memory impairment by decreasing the time require to find the water bottle in special water bottle case model. GA improved acquisition and retention memory significantly (p < 0.001) by decreasing the Transfer Latency Time (TLT), escape latency time, TSTQ and increased the Step Down Latency (SDL. GA inhibited Acetylcholinestrase (p < 0.01) activity, increased GSH,decreased TBARS and inhibited MAOA activity. Reduced the metabolism of epinephrine, 5-HT. GA (5 mg kg(-1)) protected the DNA fragmentation of frontotemporal cortex from hypoxic effects. Gangetin alkaloids are beneficial in the management of neurodegenerative disorders particularly for Alzheimer’s disease.

Catechol-O-Methyltransferase and Genetic Variation Under Hemizygosity

Less than a decade after Julius Axelrod initially described catechol-O-methyltransferase (COMT) (1), an enzyme he had isolated from rat liver to elaborate epinephrine metabolism, Angelo DiGeorge first hinted at a congenital clinical syndrome of hypoparathyroidism and absence of the thymus (2). There is no reason to suspect that these contemporaries, ensconced in entirely different fields and approaches, would have made particular note of each other’s work, much less anticipated that their respective discoveries might inextricably converge half a century later in the modern era of psychiatric genetics.

Cerebroprotective Effect of Isolated Harmine Alkaloids Extracts of Seeds of Peganum harmala L. on Sodium Nitrite-induced Hypoxia and Ethanol-induced Neurodegeneration in Young Mice

The aim of the study was to isolate the harmine alkaloids from the seeds of Peganum harmala (TAPH) and its cerebroprotective effect on cognitive deficit mice. The tested doses of TAPH were screened for Sodium nitrite induced hypoxia and Ethanol induced neurodegeneration using behavioral models. The TAPH was found to be non-neurotoxic and Psychoactive by preventing the motor impairment and increasing the locomotion activity of animals in Rota rod and Actophotometer respectively. TAPH (5, 2.5 and 1.25 mg kg(-1) p.o.) significantly (p < 0.001) protected the Sodium nitrite induced memory impairment by decreasing the time require to find the water bottle in special water bottle case model. In Elevated Plus Maze (EPM) and Passive Shock Avoidance paradigm (PSA) the TAPH shown improved acquisition and retention memory significantly (p < 0.001) by decreasing the Transverse Latency Time (TLT) and increasing the Step Down Latency (SDL), respectively in dose dependent manner. The results were well supported by biochemical parameters, by inhibiting the Acetylcholinestrase (p < 0.01) activity, increasing the GSH (p < 0.001) level and decreasing the TBARS (p < 0.001) level of whole brain. Moreover TAPH has shown the significant Monoamine oxidase-A (MAO-A) inhibition action (p < 0.001), hence it reduces the metabolism of epinephrine, 5-HT and other monoamines and enhances the action of these neurotransmitters indirectly; this adrenergic system plays an important role in learning and memory. Further, TAPH (5 mg kg(-1)) protect the DNA fragmentation of frontotemporal cortex of the brain from hypoxic effect induced by Sodium nitrite in Gel Electrophoresis studies. The results were comparable to their respective standards. Hence, harmine alkaloids are potential enough to utilize in the management of Neurodegenerative disorders of the type Alzheimer's diseases.

Renalase Lowers Ambulatory Blood Pressure by Metabolizing Circulating Adrenaline

BackgroundBlood pressure is acutely regulated by the sympathetic nervous system through the action of vasoactive hormones such as epinephrine, norepinephrine, and dopamine. Renalase, a recently described, secreted flavoprotein, acutely decreases systemic pressure when administered in vivo. Single‐nucleotide polymorphisms present in the gene are associated with hypertension, cardiac disease, and diabetes. Although renalase's crystal structure was recently solved, its natural substrate(s) remains undefined.Methods and ResultsUsing in vitro enzymatic assays and in vivo administration of recombinant renalase, we show that the protein functions as a flavin adenine dinucleotide– and nicotinamide adenine dinucleotide–dependent oxidase that lowers blood pressure by degrading plasma epinephrine. The enzyme also metabolizes the dopamine precursor l‐3,4‐dihydroxyphenylalanine but has low activity against dopamine and does not metabolize norepinephrine. To test if epinephrine and l‐3,4‐dihydroxyphenylalanine were renalase's only substrates, 17 246 unique small molecules were screened. Although the search revealed no additional, naturally occurring compounds, it identified dobutamine, isoproterenol, and α‐methyldopa as substrates of renalase. Mutational analysis was used to test if renalase's hypotensive effect correlated with its enzymatic activity. Single–amino acid mutations that decrease its enzymatic activity to varying degrees comparably reduce its hypotensive effect.ConclusionsRenalase metabolizes circulating epinephrine and l‐3,4‐dihydroxyphenylalanine, and its capacity to decrease blood pressure is directly correlated to its enzymatic activity. These findings highlight a previously unrecognized mechanism for epinephrine metabolism and blood pressure regulation, expand our understanding of the sympathetic nervous system, and could lead to the development of novel therapeutic modalities for the treatment of hypertension. (J Am Heart Assoc. 2012;1:e002634 doi: 10.1161/JAHA.112.002634.)

A novel approach to study the reaction of adrenaline autooxidation: A possibility for polarographic determination of superoxide dismutase activity and antioxidant properties of various preparations

The reaction of adrenaline autooxidation in an alkaline carbonate buffer followed by formation of superoxide radicals and the product of its oxidation, adrenochrome, which models the quinone pathway of adrenaline metabolism in the body, is accompanied by oxygen consumption. A study of this process by the polarographic method enabled one to apply this reaction to determine the activity of superoxide dismutase and antioxidant properties of biological and chemical compounds; it is based on evaluation of a latent period and the rate of oxygen consumption, which are measured in the presence of examined compounds. It was suggested that known neuroand cardiotoxicity of the quinone products of adrenaline oxidation may be associated not only to their intrinsic properties and reactive oxygen species formed but also local hypoxia of those regions of the cell and tissue where the quinone oxidation of adrenaline occurs.

Establishment of a paediatric age-related reference interval for the measurement of urinary total fractionated metanephrines

Normetanephrine and metanephrine are intermediate metabolites of noradrenaline and adrenaline metabolism. To assess whether normetanephrine and metanephrine analysis may aid in the diagnosis of Neuroblastoma, a reference interval for these metabolites must first be established. The overall aim of this study was to establish a paediatric age-related reference interval for the measurement of total fractionated metanephrines. A total of 267 urine samples were analysed following acid hydrolysis. This releases the metanephrines from their sulphate-bound metabolites. The samples were analysed using reverse phase high-performance liquid chromatography with electro-chemical detection on a Gilson automated sequential trace enrichment of dialysate sample system. Data were analysed using Minitab Release version 14. Outliers were removed using the Dixon/Reed one-third rule. Partitioning of the age groups was achieved using Harris and Boyd's standard normal deviate test. Non-parametric analysis of the data was performed, followed by the establishment of the 2.5th and the 97.5th reference limits. The established reference intervals are described in Table 2.

Flavonoids can be Potent Inhibitors of Human Phenylethanolamine N-Methyltransferase (hPNMT)

Inhibition of human phenylethanolamine N-methyltransferase (hPNMT) has been proposed as a method for the treatment of several mental processes which related on adrenaline metabolism. We performed in silico screening to identify flavonoid inhibitors of hPNMT using automated docking method and selected 9 inhibitor candidates based on ligand score (LigScore) and binding free energy (∆Gbind) estimation. Among 9 flavonoid candidates, 7 flavonoids belong to flavones while the rest of them belong to flavanone. All candidates have common chemical features; two hydrogen bond interactions with side chain of Lys75 and backbone carbonyl oxygen of Asn39, and two hydrophobic interactions. One hydrophobic site is formed by Val53, Leu262, and Met258 and the other is made up of Phe182, Ala186, Tyr222, and Val269. This study can be helpful to understand the structural features for inhibition of PNMT and showed flavonoids as promising inhibitor candidates for hPNMT.

Ascorbic acid inhibits spinal meningeal catechol-o-methyl transferase in vitro, markedly increasing epinephrine bioavailability.

The spinal menings have previously been shown to contain catechol-o-methyl transferase (COMT), the enzyme that metabolizes epinephrine to the inactive metabolite metanephrine. The authors of this study aimed to quantitate the metabolism of epinephrine traversing the spinal meninges and to determine if that metabolism could be inhibited. In addition, they tried to determine the meningeal permeability of epinephrine. Macca nemestrina spinal meninges were mounted in a diffusion cell and epinephrine was added to the donor reservoir at time 0. Three hundred minutes later, all buffer in the recipient reservoir was collected and analyzed for epinephrine metabolites. The experiments were conducted with either ascorbic acid (1 mM) or sodium metabisulfite (5.3 mM) added as antioxidants. In the presence of sodium metabisulfite, 60 +/- 6% of the epinephrine traversing the meningeal specimens was metabolized by COMT. In contrast, in the presence of ascorbic acid, less than 3% of the epinephrine traversing the spinal meninges was metabolized by COMT (P = 0.0001). The meningeal permeability coefficient for epinephrine was 0.38 +/- 0.08 cm/min x 10(-3). Epinephrine permeability through the spinal meninges is low, and meningeal COMT markedly reduces the bioavailability of what little epinephrine can traverse the meninges. However, a clinically relevant concentration of ascorbic acid, a competitive inhibitor of COMT, almost completely blocks epinephrine metabolism and increases the bioavailability of epinephrine.

Relation between Blood Lead and Urinary Biogenic Amines in Community-exposed Men

The cross-sectional relation between levels of urinary biogenic amines (dopamine, epinephrine, norepinephrine, and serotonin) and levels of blood lead was examined in a study of 645 male participants from a longitudinal study of aging. This stable population of men had initially been recruited from communities in and around Boston, Massachusetts, and had not been selected with regard to lead exposure. Blood lead samples and 24-hour and 2-hour urine specimens were collected during regularly scheduled clinic visits. In multivariate linear regression step-forward models, 24-hour epinephrine excretion was significantly and positively associated with blood lead (beta = 0.101 microgram(microgram/dl)-1 blood lead, SE (standard error) (beta) = 0.045, p = 0.026). Twenty-four-hour norepinephrine excretion was positively associated with blood lead (beta = 0.023 microgram(microgram/dl)-1 blood lead, SE(beta) = 0.029, p = 0.425), and both 24-hour dopamine (beta = -4.35 microgram(microgram/dl)-1 blood lead, SE(beta) = 6.90, p = 0.529) and 2-hour serotonin (beta = -0.348 microgram(microgram/dl)-1 blood lead, SE(beta) = 0.277, p = 0.210) excretion were negatively associated with blood lead; however, these relations did not achieve statistical significance. An increase of 10 micrograms/dl in blood lead was associated with an increase in epinephrine excretion of 11 micrograms/24 hours. These results support the hypothesis that epinephrine metabolism is influenced by low levels of lead exposure.

Biochemical evidence that brainstem adrenaline-containing neurons are activated during clonidine withdrawal in the spontaneously hypertensive rat.

We have investigated the effects of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.1 mg/kg/day for 7 or 10 days) and of withdrawal of such treatment on brainstem noradrenaline and adrenaline metabolism in the adult spontaneously hypertensive rat (SHR). After a seven day treatment with clonidine, noradrenaline and adrenaline turnovers were unchanged both in the A2-C2 and A1-C1 regions. During withdrawal, the noradrenaline turnover was also unchanged in these regions. However, the adrenaline turnover was significantly increased 16 h after withdrawal (p less than 0.01) in the A2-C2 region and 16 h (p less than 0.01) and 40 h (p less than 0.05) after withdrawal in the A1-C1 region. These results show that noradrenaline metabolism is unchanged both during clonidine treatment and during its withdrawal in the brainstem catecholaminergic regions analyzed. In contrast, the increases in adrenaline turnover found in the A2-C2 and A1-C1 regions suggest that the adrenergic neurons of the brainstem could be activated during clonidine withdrawal. As the adrenergic C1 neurons are a key element of the sympathetic vasopressor system, the increase in adrenaline turnover observed during withdrawal could be at the origin of the sympathetic hyperactivity found after cessation of prolonged treatment with clonidine.

Age Differences in the Plasma Clearance Mechanisms for Epinephrine and Norepinephrine in Humans*

There is an age-related increase in plasma norepinephrine (NE) in humans that is due to both an increase in NE appearance into plasma and a decrease in plasma NE clearance. However, previous studies demonstrated no difference in plasma epinephrine (EPI) in young and old subjects, and the effect of aging on plasma EPI appearance and clearance is unclear. To study age differences in basal NE and EPI metabolism we infused eight young (aged 19-26 yr) and eight old (aged 64-74 yr) normal subjects with [3H]NE or [3H]EPI (15 microCi/m2 bolus dose plus 0.35 microCi/m2/min for 50 min) to achieve steady state conditions on separate days. The old subjects had higher arterialized plasma NE levels [mean, 217 +/- 13 (+/- SE) vs. 149 +/- 12 pg/mL; P less than 0.005] and plasma NE appearance. In contrast, neither plasma EPI levels (98 +/- 8 vs. 104 +/- 10 pg/mL; P = NS) nor EPI appearance rates were different in the old and young subjects. The plasma clearance rates of EPI and NE were nearly identical in the young subjects (1.63 +/- 0.14 vs. 166 +/- 0.09 L/min X m2; P = NS). Plasma NE clearance was lower in the old compared to the young subjects (1.38 +/- 0.06 vs. 1.64 +/- 0.10 L/min X m2; P less than 0.05) and was lower than EPI plasma clearance in the same subjects. Although NE and EPI can be removed by both neuronal and nonneuronal uptake mechanisms, and mean plasma clearance values for NE and EPI are the same in the young, the age-related decline in catecholamine clearance is specific for NE. This finding implies a differential effect of age on a catecholamine removal mechanism that is specific for NE.

Capsaicin-induced beta-adrenergic action on energy metabolism in rats: influence of capsaicin on oxygen consumption, the respiratory quotient, and substrate utilization.

The mode of action of capsaicin on energy metabolism was investigated in rats. The oxygen consumption was higher when capsaicin (6.0 mg/kg) was intraperitoneally injected than when it was not injected. The respiratory quotient (R.Q.) increased and then decreased after the administration of capsaicin. The levels of serum glucose and immunoreactive insulin rapidly increased after the administration of capsaicin. Also, liver glycogen rapidly decreased, in contrast to the serum glucose concentration which rapidly increased. The serum-free fatty acid level gradually increased after the administration of capsaicin. These alterations in energy metabolism on the administration of capsaicin were similar to those in the metabolism of epinephrine, and were specifically inhibited by various beta-adrenergic blockers. On the other hand, the alterations were not affected by pretreatment with alpha-adrenergic or ganglion blockers. These results suggest that the mode of action of capsaicin on the enhancement of energy metabolism in rats comprises a direct (as an agonist) and/or an indirect (via catecholamine) beta-adrenergic action. Therefore, it was speculated that the adrenergic action of capsaicin resulted, at least in part, in a decrease in the perirenal adipose tissue weight and serum triglyceride concentration in rats fed a high fat diet supplemented with capsaicin (T. Kawada et al., J Nutr 116:1272-1278, 1986).

Vitamins in psychiatry. Do they have a role?

Deficiencies of specific vitamins produce consistent symptoms of psychiatric disorder. Thiamine deficiency, which is common in alcoholism, can produce confusion and psychotic symptoms, in addition to neurological signs. Vitamin B12 and folate deficiency may contribute symptoms of disorientation, depression or psychosis; their measurement is a part of routine dementia work-ups. Pyridoxine deficiency results in seizures, although the effects of exogenously administered pyridoxine are not clearly understood in depression and anxiety - the disorders in which it is most frequently used clinically. The use of vitamins has been most prominent in psychiatry in the treatment of schizophrenia, where large doses of nicotinic acid were initially given alone and later combined with other vitamins and minerals. Several theoretical models were described to support the use of vitamins in schizophrenia. These included: the parallels of schizophrenia to the psychiatric symptoms of pellagra; hypotheses of a defect in adrenaline metabolism; and the accumulation of psychotoxic substances which produce psychotic symptoms. Initially, positive results were reported over 30 years ago, but have not been replicated by thorough investigations. An extensive series of comprehensive placebo-controlled trials failed to show efficacy for any of the vitamin therapies tested. Although clearly less effective than antipsychotic drug treatment, vitamin therapy is not without risks - adverse effects have been reported with nicotinic acid, pyridoxine and vitamin C.(ABSTRACT TRUNCATED AT 250 WORDS)

Ocular distribution of topically applied adrenaline in albino and pigmented rabbits.

Systemic absorption, ocular distribution and ocular metabolism in albino and pigmented rabbit of topically applied 1% [3H]l-adrenaline eye drops was studied by liquid scintillation counting and thin layer chromatography. The effect of adrenaline on the pupillary diameter was also registered. The peak plasma level of adrenaline was reached at 150 min. The corneal adrenaline metabolism was substantial, but did not vary with the rabbit strain. At 30 min after instillation, the total adrenaline concentration of pigmented iris and ciliary body exceeded that of corresponding albino tissues. At 180 min the drug concentration of the iris and ciliary body did not differ between the rabbit strains. The time course of adrenaline induced mydriasis was equal in both rabbit strains. Since neither total adrenaline concentration at 180 min nor the time course of adrenaline induced mydriasis differed between the rabbit strains, the higher initial adrenaline uptake by pigmented tissues is not explained by pigment binding. It is proposed that the increased initial binding of adrenaline by pigmented tissues is caused by a difference between pigmented and albino tissues in the number of adrenergic neurones; this is also supported by the literature.

Effects of β-adrenergic inhibitors on noradrenaline and adrenaline metabolism in brain regions of the rat

Chloranolol (5 mg/kg i.p.) retarted the disappearance of noradrenaline induced by the dopamine-β-hydroxylase (DBH) inhibitor FLA 63, in the hypothalamus, nucleus of the solitary tract (A-2/C-2 area), and lateral reticular nucleus (A-1/C-1 area) regions, while propranolol (20 mg/kg i.p.) was effective only in the hypothalamus and in the lateral reticular nucleus. The DBH inhibitor-caused accumulation of dopamine was also inhibited by chloranolol in the solitary tract nucleus. Chloranolol and propranolol were able to antagonize the fall in adrenaline concentration due to the phenylethanolamine-N-methyltransferase (PNMT) inhibitor, Lilly 87130, only in the region of the solitary tract nucleus. The data suggest that β-adrenergic inhibitors reduce nonadrenaline and adrenaline turnover in the central nervous system, most characteristically in the solitary tract nucleus and that this effect is possibly related to their antihypertensive effectiveness.

Hormone mediated changes in monoamine stores and regulation of enzymes of biosynthesis and metabolism in the rat adrenal gland. Influence of progesterone, estradiol, ACTH and testosterone administration

The influence of daily injections, for 7 days, of 17-hydroxyprogesterone caproate (8 mg/100 g body weight pro die ), of estradiol-17β 17-undecylate (1.2 mg/100 g body weight pro die ) of testosterone enanthate (2 mg/100 g body weight pro die ) and of ACTH (4 IU/ 100 g body weight pro die ) to male wistar rats, weighing 200 g, were investigated. Monoamine storage and regulation of enzymes phenylethanolamine N-methyl transferase (PNMT), monoamine oxidase (MAO)and catechol-O-methyl transferase (COMT) were studied in the adrenal glands. Results from testosterone treated rats were especially significant: the hormone administration decreased the stores of dopamine and norepinephrlne (epinephrine precursors), stimulated PNMT and decreased metabolism of epinephrine by MAO and COMT. However, the adrenal content of epinephrlne remained in the normal range. These findings suggest that uptake of epinephrine is accelerated in peripheral tissues by testosterone.

The effect of tryptolines (1, 2, 3, 4-tetrahydro-β-carbolines) on monoamine metabolism and the platelet aggregation response in human platelets

Tryptolines (1, 2, 3, 4-tetrahydro-β-carbolines) are structurally related to 5-hydroxytryptamine. Using the human platelet preparation as a model of central serotoninergic neurons the action of various tryptolines on 5-hydroxytryptamine and epinephrine metabolism have been examined. All these compounds are competitive selective inhibitors of monoamine oxidase ‘type A’, 5-hydroxytryptamine being ‘type A’ substrate. 5-hydroxytryptoline and 5-methoxytryptoline are the most active monoamine oxidase inhibitors with IC 50 0.5 μ m and 1.5 μ m respectively using 5-hydroxytryptamine as substrate. Tetrahydro-β-carbolines are also potent uptake inhibitors of 5-hydroxytryptamine and epinephrine; a significantly greater uptake inhibitory selectivity being shown for 5-hydroxytryptamine than epinephrine. Platelet aggregation response induced by 5-hydroxytryptamine, epinephrine and adenosine 5'-diphosphate are mediated by specific receptors on the platelet. Tetrahydro-β-carbolines by themselves do not induce platelet aggregation but are potent inhibitors of 5-hydroxytryptamine and epinephrineinduced aggregation. However, they are ineffective on aggregation induced by adenosine 5'-diphosphate. The comparison of the inhibition kinetics of tetrahydro-β-carbolines for 5-hydroxytryptamine and epinephrine uptake with that of the platelet aggregation response to these amines have shown that 5-hydroxymethtryptoline, methtryptoline, and tryptolin are poor inhibitors of uptake. However, 5-hydroxymethtryptoline and tryptoline are potent inhibitors of the aggregation response. It is suggested that tryptoline derivatives can distinguish between receptors for uptake and the platelet aggregation response to 5-hydroxytryptamine. In all respects 5-hydroxytryptoline and 5-methoxytryptoline showed greater pharmacological activity than the tryptoline and methtryptoline. Although the in vivo formation of tryptolines has been a matter of controversy, they have profound pharmacological activity. This is reflected in their actions described above. The results confirm what has been observed using rat brain preparations and would suggest that human platelets can be used as a model to study the action of these compounds on central serotoinergic neurons.