Metabolism Of Epinephrine Research Articles

VANILLINSÄURE ALS ENDPRODUKT DES ABBAUES VON ADRENALIN UND NORADRENALIN

ABSTRACT In rat livers perfused with 3-methoxy-4-hydroxy-mandelic acid, formerly believed to be the endproduct of the metabolism of adrenaline and noradrenaline, three metabolites were detected by paper chromatography. After further purification by column chromatography, one of these substances was identified by melting point, shape of crystals, UV- and IR-spectra as vanillic acid. Perfusion with vanillic acid yielded only one metabolite in very small quantities. Because of its properties it is assumed to be a conjugate of vanillic acid. Hence vanillic acid, isolated in 1959 from human urine by Dirscherl & Schmidtmann, is the actual endproduct of the metabolism of adrenaline and noradrenaline.

The physiological and psychological effects of intravenously administered epinephrine and its metabolism in normal and schizophrenic men—II.: Psychiatric observations

Twelve “normal control” volunteers and twelve chronic schizophrenic patients received intravenous of isotopically labelled epinephrine in a complex experimental situation permitting simultaneous study of multiple biological and psychological variables. The major psychological changes accompanying epinephrine infusion were: (a) increased arousal, (b) narrowing of the field of attention, (c) change of direction of attention toward inner body experience, (d) resultant difficulty in communication and concentration and (e) subjective feelings of anxiety. Some “normal control” volunteer subjects distinguished these anxiety feelings from actual life-situation anxiety. There was no qualitative difference in the psychological response of the schizophrenic and the “normal control” groups to epinephrine infusion. In neither “normal control” volunteers, nor schizophrenic patients, did epinephrine cause the appearance or exacerbation of psychotic symptoms. There were two instances of increase of psychotic behavior during or after the epinephrine infusion in schizophrenic patients, but these could not be attributed to the epinephine per se; and seemed more clearly related to situational variables. This result fails to support hypotheses which attribute the origin of schizophrenic symptoms to an abnormality in the metabolism of epinephrine. Quantitative differences between the schizophrenic and “normal control” subjects showed that, as a group, the schizophrenic subjects were much less able to cope with the experimental situation (p = <0·002), showed more anxiety in response to the situation (p = <0·02) but less in response to epinephrine (p = <0·02), and ranked lower on involvement-communication (p = <0·02). It is believed that a major factor in the smaller anxiety response during epinephrine infusion in the schizophrenic patient group, compared to the “normal control” group, was its higher situational anxiety baseline. Differences between schizophrenic and “normal control” subjects in their ability to cope with an experimental situation, and in their resultant situational anxiety, are judged to be widely prevalent in research studies comparing schizophrenic and “normal control” subjects. Such differences must be given careful consideration before concluding that a particular hypothesis being investigated has or has not been validated.

Urine of children with sympathetic tumors. The excretion of 3-methoxy-4-hydroxy-mandelic acid.

Armstrong and co-workers 1 found, in 1956, while investigating the phenolic acids, a previously unknown constituent of human urine, which they identified one year later as 3-methoxy-4-hydroxymandelic acid (MHMA, vanillylmandelic acid). 2,3 At the same time they proved that the substance was a metabolite of norepinephrine. Shortly after this, several authors 4-13 published further work on the metabolism of epinephrine and norepinephrine which confirmed the fact that MHMA was the chief breakdown product. This is shown in Figure 1. Contrary to the labile catecholamines, this methylated pyrocatechinic acid is stabile. About 70 times as much appears in the urine as in the catecholamines. 14 This simplifies its quantitative determination. As the MHMA is excreted largely independently of nutritive factors, 3 it represents a measure of the turnover of the catecholamines. For this reason, its quantitative determination is of great theoretical and practical significance. During the test period, bananas should be

Metabolism of adrenaline after blockade of monoamine oxidase and catechol-O-methyltransferase.

Experiments in cats infused with 5 micromole of dl-adrenaline-2-C(14) showed that blockade of either monoamine oxidase or catechol-O-methyltransferase is largely compensated for by the activity of the intact enzyme system; combined blockade of both enzyme systems results in the formation of a new adrenaline catabolite and in the increased production of acidic, mainly conjugated, catabolites, the identity of which remains to be established.

Technique for the Study of Alternate Metabolic Pathways; Epinephrine Metabolism in Man

A general method of determining the relative magnitudes of different pathways of formation of a urinary metabolite from a single precursor substance is described. The method requires the administration of the precursor and an intermediate labeled with different isotopes, and the determination of the ratio of the isotopes in the metabolites. A preliminary application to epinephrine metabolism in man is presented.

Activation and Inhibition of Adrenaline Metabolism

MANY drugs enhance or block the actions of adrenaline; but little is known as to whether they act by modifying the metabolism of the catecholamine. In this work the effects of a variety of drugs on the rate of disappearance of radioactive adrenaline in the whole mouse were examined. Details of drug dosage are given in Table 1. Mice were treated with drug and then adrenaline (3 µgm.) labelled with H-3 was administered intravenously. Ten minutes after the adrenaline injection the animals were killed, homogenized in a Waring blendor, and an aliquot of the homogenate assayed for labelled adrenaline remaining1. Control animals, untreated with drug, were given adrenaline labelled with H-3 at a similar time.

Metabolism of epinephrine and other sympathomimetic amines.

HE PHYSIOLOGICAL ACTIONS of epinephrine and other sympathomimetic amines are well established, yet the metabolism of these compounds is poorly understood. Although several enzymes have been shown to transform these amines in vitro, the part that they play in the intact organism has been conjectural. In the past few years considerable information concerning the fate of sympathomimetic amines has become available. Many new enzymes have been found that are of importance in the transformation of these amines. This review will describe these newer developments in the metabolism and physiological disposition of catecholamine hormones and related compounds of therapeutic interest.

The influence of amine oxidase inhibitors on epinephrine metabolism in man.

Annals of the New York Academy of SciencesVolume 80, Issue 3 p. 726-733 THE INFLUENCE OF AMINE OXIDASE INHIBITORS ON EPINEPHRINE METABOLISM IN MAN* Oscar Resnick, Oscar Resnick Worcester Foundation for Experimental Biology, Shrewsbury, Mass.Search for more papers by this author Oscar Resnick, Oscar Resnick Worcester Foundation for Experimental Biology, Shrewsbury, Mass.Search for more papers by this author First published: September 1959 https://doi.org/10.1111/j.1749-6632.1959.tb49249.xCitations: 11 * The work reported in this paper was supported in part by Contract No. DA-49-007-MD-438 with the Army Research and Development Board, Department of the Army, Washington, D. C.; by a grant from The Ford Foundation, New York, N. Y.; and by a grant from Hoffmann-La Roche Inc., Nutley, N. J. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume80, Issue3Amine Oxidase InhibitorsSeptember 1959Pages 726-733 RelatedInformation

Disappearance rates of infused epinephrine and norepinephrine from plasma: a comparison of normal and schizophrenic subjects.

<h3>Introduction</h3> Recently, in the course of experiments dealing with intravenous infusions of epinephrine and norepinephrine in man,¹occasion presented itself to perform infusions on a group of normal subjects and on a group of schizophrenic patients. It appeared that data concerning plasma concentrations of epinephrine and norepinephrine during infusions had bearing on recent suggestions that schizophrenia might be related to a faulty metabolism of either of these two substances. Hoffer and co-workers,^2,3for instance, had presented evidence suggestive that certain oxidized derivatives of epinephrine, namely, adrenochrome (3-hydroxy-2,3dihydro-1-methylindole-5,6-quinone) and adrenolutin (3,5,6-trihydroxy-1-methylindole) were capable of producing transient psychoses and other mental aberrations in man when administered intravenously or orally. Thus, the view was advanced³that a defect in epinephrine metabolism resulting in the formation of excessive quantities of adrenochrome or adrenolutin might be an etiologic factor in schizophrenia. In support of this

Schizophrenia: a new approach.

In the April, 1952 issue of this journal, Osmond and Smythies (47) suggested that schizophrenia might be caused by a defect in adrenaline metabolism. They called this hypothetical adrenaline derivative “M-substance” because they endowed it with mescaline-like psychotomimetic qualities but with an effective potency nearer that of adrenaline or even the hugely powerful LSD-25. They showed that mescaline and adrenaline were sufficiently alike chemically for such an intermediate to be at least imaginable. In addition, they emphasized that the mescaline experience and the more acute and dramatic forms of schizophrenia have many similarities. They hoped that researchers would hunt diligently for our M-substance.

O-Methylation, the principal route of metabolism of epinephrine in man.

Evidence is presented which indicates that the principal pathway of metabolism of epinephrine in man is O-methylation to metanephrine. The extent of the conLversion to metanephrine, a physiologically inactive compound, indicates that the enzyme responsible for this reaction, catechol-O-methyl transferase, is the enzyme mainly involved in the termination of action of epinephrine in man.

O-methylation, the principal pathway for the metabolism of epinephrine and norepinephrine in the rat

O-methylation, the principal pathway for the metabolism of epinephrine and norepinephrine in the rat

Serum Copper and Oxidase Activity in Schizophrenic Patients

The possibility that the metabolism of epinephrine and of other amines may be altered in schizophrenia, the observation that plasma copper is increased during chlorpromazine therapy,1and the knowledge that ceruloplasmin, a copper-protein in serum which varies with stress situations, can oxidize epinephrine have stimulated research on copper in serum of mental patients. A recent claim by Akerfeldt2that the fresh blood serum from mental patients had the capacity to oxidize N, N-dimethyl-p-phenylenediamine more rapidly than fresh serum from healthy control subjects, and that this increased oxidizing activity of serum from mental cases was probably due to an increase in ceruloplasmin in the serum of mental patients makes it pertinent to review the factors which affect this and related reactions. Except for a marked decrease in ceruloplasmin in serum of patients with hepatolenticular degeneration and in some patients with the nephrotic syndrome, the blood levels of

Glutathione levels in mental and physical illness.

Several authors * have reported lower levels of reduced glutathione (GSH) in the blood of patients with endogenous psychosis. Recently, in our search for possible biochemical correlates of schizophrenia, we found evidence that these patients oxidized adrenaline more rapidly than normal persons without systemic disease.† Our data indicated that the increased speed of adrenaline breakdown was not specific for schizophrenia, and we therefore have been searching for a more basic substance which might shed light on this observation. Since lower glutathione levels seem to be a quite consistent finding, we were interested in exploring this phenomenon further to determine if it might be related to our findings with adrenaline metabolism. In the present study, we have compared the glutathione levels of hospitalized schizophrenic patients and outpatient, so-called pseudoneurotic, schizophrenics with levels obtained from normals and patients without evidence of psychosis, but with a variety of systemic diseases. We compared these findings

The in vitro oxidation of epinephrine in plasma.

<h3>Introduction</h3> Several reports have recently appeared in the literature which speculate on the possibility that faulty epinephrine metabolism might underlie the psychological aberrations that one sees in schizophrenic patients. Lindemann¹reported aggravation of psychotic symptoms in schizophrenic patients following injections of epinephrine. Hoffer * and Osmond,³in several articles, mention this possibility and describe the appearance of psychotic-like symptoms in normal persons following the administration of adrenochrome and adrenolutin (3,5,6-trihydroxy-1-methylindole), two oxidation products of epinephrine metabolism. Rinkel and associates⁴speculate upon the possibility that adrenoxine, another oxidation product of epinephrine metabolism of yet unknown structure, may be the responsible agent in the production of psychotic symptoms. In the monograph, "Studies in Schizophrenia,"⁵we described aberrations on physiological recordings in the septal region and hippocampus which occur consistently in schizophrenic patients. Stimulation of the septal region produced autonomic changes similar to those seen with the administration of epinephrine.

Experimental psychotic states.

The use of drugs such as mescaline and lysergic acid diethylamide for the experimental production of temporary psychotic states continues to offer unique opportunities for further research. The discovery that a metabolite of adrenaline induces an experimental psychosis suggests the possibility that an error in adrenaline metabolism may be an etiological factor in some naturally occurring psychoses. Experimental psychoses, however, are not identical in form with any naturally occurring ones although there is resemblance to delirium and, to a lesser extent, to schizophrenia. Lysergic acid does not possess therapeutic value sufficient to justify its use in psychiatric practice other than on an experimental basis. As a means of releasing repressed material, it is less effective than intravenous sodium amytal. Self-administration of an hallucinogen by the psychiatrist permits subjective experience of psychotic symptoms.

ON THE MECHANISM OF ADRENALINE POTENTIATING ACTION OF COCAINE

It is widely known that cocaine potentiates the responses of sympathetically innervated organs to adrenaline, sympathin, and to sympathetic nerve stimulation. Adrenaline potentiating action of cocaine was first observed by Froehlich and Loewi (1) in 1910. But the mode of this action has not yet been clearly established, though many experiments have since been carried out in order to account for the phenomenon. It has been suggested that cocaine enhances the sensitivity of adrenergic effector systems, or protects the autoxidation of adrenaline or increases the permeability of sympathetically innervated cells, , thus favoring the entrance of stimulating agents. Recently, with the advance in the study of metabolism of adrenaline, it has been suggested that the potentiating action of cocaine is due to inhibition of the enzymatic systems which inactivate adrenaline in vivo. On the other hand, the fate of adrenaline Is still unknown, in spite of many experiments that have been done on this problem. Hynal (2) and many others reported that liver destroys adrenaline in vivo, while Markowitz (3) and others obtained the negative results. Even in vitro experiments, Embden (4) and others observed the destruction of adrenaline in blood but Machii (5) and others observed the fact that adrenaline is inactivated by perfusion through the isolated liver or other organs, or by addition o:f various tissue extracts. On the contrary, Oliver and Schaefer (6) found that small amount of suprarenal extract or adrenaline retained its activity much longer in blood than in aqueous solution, and this observation has many times been confirmed by Wiltshire (7) and many other investigators who suggested that in blood and tissues is present an inhibitor of autoxidation of adrenaline such as protein, amino acids, ascorbic acid or glutathion. More recently, various enzymes inactivating adrenaline were discovered from animal and plant tissues and one of them is called amine oxidase. It is considered that amine oxidase is contained abundantly in liver and intestine, the inactivating power of which is much stronger than that in other organs. It is not yet clear, however, how much important part these enzymes play in the inactivation of adrenaline in the animal body. Richter (8) reported that the rapid inactivation of adrenaline in vivo is rather due to sulfoconjugation than to amine oxidase. Bacq (9) has also expressed doubts on the deamination of adrenaline due to amineoxidase in vivo. Okamura (10) described that the rapid disappearance of the biological action of adrenaline in vivo is mainly due to the adsorption of adrenaline by red blood-corpuscles but not due to the oxidative destruction. Since Gaddum (11) has explained the ephedrine potentiation to adrenaline by inhibition of amine oxidase, MacGregor (12), Tripot (13) and Philpot (14) have extended Gaddum's hypothesis, and have proved that not only ephedrine but also cocaine and other local anesthetics inhibit the action of enzymes which inactivate adrenaline. Philpot (14) pointed out that amine oxidase is much more strongly affected by these local anesthetics than other enzymes, but Bain et al. (15) described that cocaine cannot diminish the adrenaline inactivating power of liver in vitro. As above mentioned, the fate of adrenaline in vivo is very complicated, and the experimental evidences are not yet sufficient to show how cocaine prevents adrenaline from inactivation. It was, therefore, intended to study the effects of cocaine and other local anesthetics on the action of adrenaline, on the detoxication of adrenaline in liver in vivo and in vitro and also the correlation between blood and tissues (especially liver extract) which may possibly be connected with the inactivation of adrenaline. Furthermore, the influence of local anesthetics (especially cocaine) on the adrenaline inactivation in vitro was investigated.

ON THE MECHANISM OF ADRENALINE POTENTIATING ACTION OF COCAINE

It is widely known that cocaine potentiates the responses of sympathetically innervated organs to adrenaline, sympathin, and to sympathetic nerve stimulation. Adrenaline potentiating action of cocaine was first observed by Froehlich and Loewi (1) in 1910. But the mode of this action has not yet been clearly established, though many experiments have since been carried out in order to account for the phenomenon. It has been suggested that cocaine enhances the sensitivity of adrenergic effector systems, or protects the autoxidation of adrenaline or increases the permeability of sympathetically innervated cells, thus favoring the entrance of stimulating agents. Recently, with the advance in the study of metabolism of adrenaline, it has been suggested that the potentiating action of cocaine is due to inhibition of the enzymatic systems which inactivate adrenaline in vivo. On the other hand, the fate of adrenaline is still unknown, in spite of many experiments that have been done on this problem. Hynal (2) and many others reported that liver destroys adrenaline in vivo, while Markowitz (3) and others obtained the negative results. Even in vitro experiments, Embden (4) and others observed the destruction of adrenaline in blood but Machii (5) and others observed the fact that adrenaline is inactivated by perfusion through the isolated liver or other organs, or by addition of various tissue extracts. On the contrary, Oliver and Schaefer (6) found that small amount of suprarenal extract or adrenaline retained its activity much longer in blood than in aqueous solution, and this observation has many times been confirmed by Wiltshire (7) and many other investigators who suggested that in blood and tissues is present an inhibitor of autoxidation of adrenaline such as protein, amino acids, ascorbic acid or glutathion. More recently, various enzymes inactivating adrenaline were discovered from animal and plant tissues and one of them is called amine oxidase. It is considered that amine oxidase is contained abundantly in liver and intestine, the inactivating power of which is much stronger than that in other organs. It is not yet clear, however, how much important part these enzymes play in the inactivation of adrenaline in the animal body. Richter (8) reported that the rapid inactivation of adrenaline in vivo is rather due to sulfoconjugation than to amine oxidase. Bacq (9) has also expressed doubts on the deamination of adrenaline due to amine oxidase in vivo. Okamura (10) described that the rapid disappearance of the biological action of adrenaline in vivo is mainly due to the adsorption of adrenaline by red blood-corpuscles but not due to the oxidative destruction. Since Gaddum (11) has explained the ephedrine potentiation to adrenaline by inhibition of amine oxidase, MacGregor (12), Tripot (13) and Philpot (14) have extended Gaddum's hypothesis, and have proved that not only ephedrine but also cocaine and other local anesthetics inhibit the action of enzymes which inactivate adrenaline. Philpot (14) pointed out that amine oxidase is much more strongly affected by these local anesthetics than other enzymes, but Bain et al. (15) described that cocaine cannot diminish the adrenaline inactivating power of liver in vitro. As above mentioned, the fate of adrenaline in vivo is very complicated, and the experimental evidences are not yet sufficient to show how cocaine prevents adrenaline from inactivation. It was, therefore, intended to study the effects of cocaine and other local anesthetics on the action or adrenaline, on the detoxication of adrenaline in liver in vivo and in vitro and also the correlation between blood and tissues (especially liver extract) which may possibly be connected with the inactivation of adrenaline. Furthermore, the influence of local anesthetics (especially cocaine) on the adrenaline inactivation in vitro was investigated.

The nature of pressor substances in pheochromocytomas.

The actions of aqueous extracts of two pheochromocytomas are compared before and after the administration of the adrenergic blocking agent, Dibenamine. One tumor contained predominantly a substance which, like norepinephrine, had pressor actions after Dibenamine. The other tumor contained chiefly an epinephrine-like substance. The significance of the presence of norepinephrine in pheochromocytomas and its role in epinephrine metabolism are discussed.

Physiology at the London Hospital Medical College : Dr. John L. D‘Silva

DR. JOHN L. D‘SILVA, reader in physiology at St. Bartholomew‘s Hospital Medical College, who has been appointed to the chair of physiology at the London Hospital Medical College, was born and educated in southern India. He graduated with first-class honours in chemistry at King‘s College, London, in 1929, and remained there for a further three years doing research on the chemistry of disulphides. In 1932 he went over to physiology, still at King‘s College, carrying out investigations on the effect of adrenaline on the metabolism of potassium. After a short period with Messrs. British Drug Houses, Ltd., spent on research into the molecular distillation of fish oils in connexion with the study of vitamin A, he went in 1936 to St. Bartholomew‘s Hospital Medical College, where he was demonstrator in physiology and in biochemistry, and continued his Work on the metabolism of adrenaline and potassium. He Was awarded the degree of D.Sc. for his published work. During the Second World War, Dr. D‘Silva qualified as a medical practitioner and also continued teaching. After work at St. Bartholomew‘s Hospital, in 1944 Dr. D‘Silva was appointed to the Medical College again and has remained there since, lecturing and carrying out research on the physiology of the visual process.