Epinephrine production

Corticosteroids also affect adrenomeduUary function by increasing epinephrine production the mechanism is exertion of a stimulatory action on two of the enzymes that regulate catecholamine synthesis, tyrosine hydroxylase, the rate-Umiting enzyme, and phenyl-ethanolamine Af-methyltransferase, which catalyzes the conversion of norepinephrine to epinephrine. Steroids also influence the metabolism of circulating catecholamines by inhibiting their uptake from the circulation by noimeuronal tissues (i.e., extraneuronal uptake see Chapter 9). This effect of corticoids may explain their permissive action in potentiating the hemodynamic effects of circulating catecholamines. 

The dopamine beta-hydroxylase (Dbh) gene is necessary for the production of NE and epinephrine. Disruption of this gene results in the absence of NE and epinephrine production and is therefore used in studies determining the roles of these neurotransmitters. This approach is favored over the knockout of adrenergic receptors because of the multiplicity of receptor types for NE and epinephrine. 

Some individual components of the injury experience have been studied separately in animal experiments. Pain, fear, hemorrhage, and tissue damage can all stimulate epinephrine production (Wl). Inhalational anesthesia stimulates the adrenal medulla but in deep anesthesia with intravenous barbiturates adrenomedullary secretion may be greatly diminished. 

Epinephrine production is catalyzed by PNMT, which is induced by glucocorticoids (cortisol). The venous drainage of the adrenal cortex, which contains very high concentrations of newly released cortisol, bathes the adrenal medulla before entering the general circulation. 

Use of the prodrug dipivefrin allows use of lower concentrations secondary to improved intraocular absorption (10- to 15-fold higher). The 0.1% dipivefrin produces equivalent lOP reduction to 1% to 2% epinephrine. Dipivefrin therefore may be tolerated by patients unable to tolerate epinephrine solutions, and it is often chosen over other epinephrine products when this class of drugs is indicated. 

Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

Many anodic oxidations involve an ECE pathway. For example, the neurotransmitter epinephrine can be oxidized to its quinone, which proceeds via cyclization to leukoadrenochrome. The latter can rapidly undergo electron transfer to form adrenochrome (5). The electrochemical oxidation of aniline is another classical example of an ECE pathway (6). The cation radical thus formed rapidly undergoes a dimerization reaction to yield an easily oxidized p-aminodiphenylamine product. Another example (of industrial relevance) is the reductive coupling of activated olefins to yield a radical anion, which reacts with the parent olefin to give a reducible dimer (7). If the chemical step is very fast (in comparison to the electron-transfer process), the system will behave as an EE mechanism (of two successive charge-transfer steps). Table 2-1 summarizes common electrochemical mechanisms involving coupled chemical reactions. Powerful cyclic voltammetric computational simulators, exploring the behavior of virtually any user-specific mechanism, have... 

Important products derived from amino acids include heme, purines, pyrimidines, hormones, neurotransmitters, and biologically active peptides. In addition, many proteins contain amino acids that have been modified for a specific function such as binding calcium or as intermediates that serve to stabilize proteins—generally structural proteins—by subsequent covalent cross-hnk-ing. The amino acid residues in those proteins serve as precursors for these modified residues. Small peptides or peptide-like molecules not synthesized on ribosomes fulfill specific functions in cells. Histamine plays a central role in many allergic reactions. Neurotransmitters derived from amino acids include y-aminobutyrate, 5-hydroxytryptamine (serotonin), dopamine, norepinephrine, and epinephrine. Many drugs used to treat neurologic and psychiatric conditions affect the metabolism of these neurotransmitters. 

Three amines—dopamine, norepinephrine, and epinephrine—are synthesized from tyrosine in the chromaffin cells of the adrenal medulla. The major product of the adrenal medulla is epinephrine. This compound constimtes about 80% of the catecholamines in the medulla, and it is not made in extramedullary tissue. In contrast, most of the norepinephrine present in organs innervated by sympathetic nerves is made in situ (about 80% of the total), and most of the rest is made in other nerve endings and reaches the target sites via the circu-... 

D. Phenylethanolamine-ZV-methyltransferase (PNMT) Catalyzes the Production OF Epinephrine ... 

The adrenal gland is located on the upper segment of the kidney (Fig. 42-1). It consists of an outer cortex and an inner medulla. The adrenal medulla secretes the catecholamines epinephrine (also called adrenaline) and norepineprhine (also called noradrenaline), which are involved in regulation of the sympathetic nervous system. The adrenal cortex consists of three histologically distinct zones zona glomerulosa, zona fasciculata, and an innermost layer called the zona reticularis. Each zone is responsible for production of different hormones (Fig. 42-2). 

Chlorpromazine (CPZ) and pentoxifylline (PTX) were shown to inhibit TNF release and improve survival during murine endotoxemia (Gl). CPZ (M25) and epinephrine (PI6) pretreatment markedly up-regulated IL-10 production induced by LPS, a phenomenon also observed with cyclosporine (Dl). PTX pretreatment did not affect LPS-induced IL-10 release. Thus, TNF and IL-10 can be differentially regulated during murine endotoxemia. The sustained or even increased production of IL-10 could play a role in the protective effects of these drugs against LPS toxicity in vivo. 

P16. van der Poll, T., Coyle, S. M., Barbosa, K., Braxton, C. C., and Lowry, S. F., Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin-10 production during human en-dotoxemia. J. Clin. Invest. 97,713-719 (1996). 

Adrenal medulla. Derived from neural crest tissue, the adrenal medulla forms the inner portion of the adrenal gland. It is the site of production of the catecholamines, epinephrine and norepinephrine, which serve as a circulating counterpart to the sympathetic neurotransmitter, norepinephrine, released directly from sympathetic neurons to the tissues. As such, the adrenal medulla and its hormonal products play an important role in the activity of the sympathetic nervous system. This is fully discussed in Chapter 9, which deals with the autonomic nervous system. 

The 02, radical can act as an oxidant as well as a reductant and chemical estimates of its production can also be based on its ability to oxidize epinephrine to adren-ochrome [62], These chemical methods have the additional advantage of not requiring highly specialized equipments. Also based on its redox property, the 02 radical can be determined by chemiluminescence methods through the measurement of the intensity of the fluorescence radiation emitted after chemical oxidation of 02 by, e.g., lucigenin [63-67], These methods, however, are limited by the poor selectivity and lack of capability for in-vivo performance. 

Superoxide generation was detected via the NADPH-dependent SOD-inhibitable epinephrine oxidation and spin trapping [15,16], Grover and Piette [17] proposed that superoxide is produced equally by both FAD and FMN of cytochrome P-450 reductase. However, from comparison of the reduction potentials of FAD (-328 mV) and FMN (190 mV) one might expect FAD to be the most efficient superoxide producer. Recently, the importance of the microsomal cytochrome h558 reductase-catalyzed superoxide production has been shown in bovine cardiac myocytes [18]. 

Nitroblue tetrazolium (NBT, 3,3 -(3,3,-dimethoxy-l,l,-biphenyl-4,4 -diyl)bis-2-(4-nitrophe-nyl)-5-phenyl-2H-tetrazolium dichloride) is reduced by superoxide to formazan as a final product, which can be measured spectrophotometrically [73]. Although the rate constant for NBT reduction by superoxide is moderately high 5.88+0.12x 104 1 mol 1 s 1 [74], the formation of formazan is not a simple one-electron transfer process, and the final product is formed as a result of disproportionation of intermediate free radicals. Similar to cytochrome c, NBT is easily reduced by the other reductants that confines its application for superoxide detection. Moreover, similar to epinephrine, NBT free radical is apparently... 

The sympathetic nervous system (SNS) and the hypothalamic-pituitary axis work together as important modulators of the immune system after exposure to stressors. Norepinephrine (NE) and epinephrine (EPI) (catecholamines from the SNS) and neuroendocrine hormones modulate a range of immune cell activities, including cell proliferation, cytokine and antibody production, lytic activity, and migration. This chapter will focus on these two major pathways of brain-immune signaling, briefly summarizing the evidence for SNS and hypothalamic-pituitary-adrenal (HPA) modulation of immune function, their influence on immune-mediated diseases, immune modulation in aging, and early life influences on these pathways. 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

The liver is richly endowed with COMT and MAO it therefore contributes significantly to the degradation of circulating norepinephrine and epinephrine. The end product of the combined actions of MAO and COMT is van-illylmandelic acid. 

Cardiostimulation. By stimulating Pi-receptors, hence activation of ade-nylatcyclase (Ad-cyclase) and cAMP production, catecholamines augment all heart functions, including systolic force (positive inotropism), velocity of shortening (p. clinotropism), sinoatrial rate (p. chronotropism), conduction velocity (p. dromotropism), and excitability (p. bathmotropism). In pacemaker fibers, diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostim-ulant effect of p-sympathomimetics such as epinephrine is exploited in the treatment of cardiac arrest Use of p-sympathomimetics in heart failure carries the risk of cardiac arrhythmias. 

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