Nonadrenal epinephrine-forming enzymes in humans. Characteristics, distribution, regulation, and relationship to epinephrine levels.

Kennedy, Brian P.; Bigby, Timothy D.; Ziegler, Michael G.

doi:10.1172/jci117996

Cited by 44 publications

(31 citation statements)

References 32 publications

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“…Tryptamine N-methylating activity has been detected in a variety of tissues and species (Axelrod, 1961(Axelrod, , 1962Saavedra and Axelrod, 1972;Mandel et al, 1972;Narasimhachari et al, 1972;Saavedra et al, 1973;Wyatt et al, 1973;Mandell et al, 1974;Bhikharidas et al, 1975;Rä isä nen and Kä rkkä inen, 1978;Porta et al, 1979;Kennedy et al, 1995), but this activity has been best characterized biochemically in the rabbit lung. Therefore, a cDNA and gene encoding a rabbit tryptamine N-methyltransferase, INMT, were recently cloned and characterized (Thompson and Weinshilboum, 1998).…”

Section: Discussionmentioning

confidence: 99%

Human Indolethylamine N-Methyltransferase: cDNA Cloning and Expression, Gene Cloning, and Chromosomal Localization

et al. 1999

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Section: Discussionmentioning

confidence: 99%

Human Indolethylamine N-Methyltransferase: cDNA Cloning and Expression, Gene Cloning, and Chromosomal Localization

et al. 1999

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“…18 In fact, phenylethanolamine N-methyltransferase (the enzyme that transforms NE into epinephrine) has been demonstrated in human tissues other than the adrenal medulla, such as the lung, kidney, and liver, although in much lower concentrations. 18 Nevertheless, the concentrations of plasma epinephrine that we found in 3 of our patients at the peak of exercise are, in the mean, about 10-fold less than those we observed in normal subjects (1480Ϯ330 pmol/L after placebo and 2470Ϯ690 pmol/L after DMP) 9 ; they are not sufficient to stimulate presynaptic ␤2-adrenergic receptors. 19 The source of endogenous dopamine acting on the presynaptic D2-receptors is still unknown.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man

et al. 1999

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Abstract-Dopamine receptors type 2 (D2)-like receptor blockers cause an increase in the norepinephrine response to intense physical exercise. However, during intense physical exercise, D2-like antagonists also cause an increase in the epinephrine response, which itself might cause an increase in plasma norepinephrine through the activation of ␤2 presynaptic receptors. Therefore, we evaluated the effect of domperidone, a D2-like antagonist, on the norepinephrine response to physical exercise in 6 Addison patients (3 were adrenalectomized and 3 had adrenal tuberculosis). In these patients, the norepinephrine increase observed during exercise was significantly higher after the administration of domperidone than a placebo (Fϭ4,328; PϽ0.001). Because peripheral plasma norepinephrine does not reflect the sympathetic tone to the heart accurately, we evaluated the effect of domperidone administration (20 mg orally) on the sympathovagal balance, which was measured by the ratio between the high-and low-frequency components of heart rate variability, in 9 normal volunteers in the supine and sitting positions. When compared with placebo, domperidone caused a significant increase in the low/high frequency ratio (PϽ0.05) in the sitting position without modifying basal and stimulated norepinephrine plasma levels or blood pressure. These data support a role for endogenous dopamine in modulating norepinephrine release by human sympathetic nerves in vivo. (Hypertension. 1999;34:398-402.)Key Words: dopamine Ⅲ plasma Ⅲ norepinephrine Ⅲ heart N euronal dopamine receptors are widely distributed in the central 1 and the peripheral nervous system 2 at different levels. 3 In vitro 4,5 and in vivo 6,7 studies have clearly demonstrated that the activation of these receptors leads to a decrease in catecholamine release. Whether endogenous dopamine plays a modulatory role on sympathetic nerve terminals through these receptors was investigated with Dopamine receptors type 2 (D2)-like receptor antagonists.In previous studies, we demonstrated that D2-like antagonists do not modify plasma norepinephrine (NE) in humans when administered in conditions of rest or mild sympathetic stimulation, which is achieved by standing, a cold pressor test, or hand-grip. 8 During intense sympathetic activation, as induced by physical exercise performed up to 80% of maximal oxygen consumption (V O 2 max), D2-like antagonists cause a larger increase in plasma NE than placebo. 9 These data suggest that during a high degree of sympathetic stimulation, endogenous dopamine, which is coreleased by nerve endings, increases in the synaptic cleft to a level sufficient to modulate and inhibit NE release.However, during a high degree of sympathetic stimulation, the inhibition of D2-like receptors located in the chromaffin cells of the adrenal medulla also causes an increase in plasma epinephrine. 9 Therefore, the greater increase of plasma NE observed during intense physical exercise in subjects receiving domperidone (DMP), a D2-like receptor antagonist, could be due, at l...

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“…The N-methylation of tryptamine has been detected in a variety of species and tissues (2,8,9,(31)(32)(33)(34), but it has remained unclear whether those activities were catalyzed by a single enzyme with broad substrate specificity or by members of a family of related N-MTs. Since the rabbit lung was the tissue in which INMT had been studied most intensively, we set out to purify rabbit lung INMT, to clone and express its cDNA and to clone its gene as steps toward understanding the function and regulation of this enzyme as well as those of possible orthologues in other species and paralogues in the rabbit.…”

Section: Discussionmentioning

confidence: 99%

Rabbit Lung Indolethylamine N-Methyltransferase

Thompson

Weinshilboum

1998

Journal of Biological Chemistry

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Indolethylamine N-methyltransferase (INMT) catalyzes the N-methylation of tryptamine and structurally related compounds. This reaction has been studied because of its possible role in the in vivo synthesis of psychoactive compounds or neurotoxins and has been characterized biochemically in preparations of rabbit lung. Therefore, we set out to purify rabbit lung INMT, to clone and express its cDNA, and to clone and structurally characterize its gene as steps toward understanding the function and regulation of this enzyme. Rabbit lung INMT was purified and partial amino acid sequence was obtained. A polymerase chain reaction-based approach was then used to clone a rabbit lung INMT cDNA with a 792-base pair open reading frame that encoded a 263-amino acid protein with a predicted molecular mass of 29 kDa. When the cDNA was expressed in COS-1 cells, the encoded protein catalyzed the methylation of tryptamine and structurally related compounds, and was inhibited by two products of the reaction, S-adenosyl-L-homocysteine Methylation is an important reaction in the metabolism of many drugs, other xenobiotics, and endogenous molecules (1). The methylation of tryptamine and structurally related compounds by a cytosolic S-adenosyl-L-methionine (AdoMet) 1 -dependent methyltransferase (MT) was first described in the rabbit lung over 30 years ago (2). That reaction, with tryptamine as a substrate, is shown in Fig. 1. Interest in this reaction originally focused on the possible role of N-methylation in the metabolism of biogenic amines to form psychoactive agents such as N, N-dimethyltryptamine and N,N-dimethyl-5-hydroxytryptamine (2). Subsequently, there was also interest in the possibility that the N-methylation of compounds such as the ␤-carbolines and the isoquinolines might generate neurotoxins (3-7). As a result, a series of enzymes capable of methylating tryptamine have been characterized biochemically (2, 8 -12), and at least two tryptamine N-MT isoforms have been described in both rabbit lung (9) and rabbit liver (10, 12). Although these activities have been referred to by a variety of names including rabbit lung MT (2), nonspecific MT (2), aromatic alkylamine N-MT (13), indolamine N-MT (9, 14), arylamine N-MT (10), and amine N-MT (12), we will refer to the enzyme that we have studied as indolethylamine N-MT (INMT) (11). No cDNA for any of these activities or enzymes has been cloned and expressed to make it possible to associate the activity being studied with a single protein. Therefore, it has remained controversial whether tryptamine methylation is catalyzed by a single gene product with a broad substrate specificity or by a series of related enzymes.We set out to purify rabbit lung INMT, clone its cDNA, and clone and structurally characterize its gene to make it possible to study the function of this enzyme and to search for orthologues in other species, including humans. Since tryptamine had been used as a "prototypic" methyl acceptor substrate for most of the original biochemical studies of this activity, tryp...

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Nonadrenal epinephrine-forming enzymes in humans. Characteristics, distribution, regulation, and relationship to epinephrine levels.

Cited by 44 publications

References 32 publications

Human Indolethylamine N-Methyltransferase: cDNA Cloning and Expression, Gene Cloning, and Chromosomal Localization

Human Indolethylamine N-Methyltransferase: cDNA Cloning and Expression, Gene Cloning, and Chromosomal Localization

In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man

Rabbit Lung Indolethylamine N-Methyltransferase

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