Adrenalin - Epinephrine

Adrenaline (epinephrine) is a catecholamine, which is released as a neurotransmitter from neurons in the central nervous system and as a hormone from chromaffin cells of the adrenal gland. Adrenaline is required for increased metabolic and cardiovascular demand during stress. Its cellular actions are mediated via plasma membrane bound G-protein-coupled receptors. 

Catecholamines are biogenic amines with a catechol (o-dihydroxy-benzol) structure. They are synthesized in nerve endings from tyrosine and include dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine). 

FIGURE 1.23 Effect of a 10-min exposure to two concentrations of a phenoxybenzamine-like compound, dibenamine (DB), on the contractile response of a strip of rabbit aorta to adrenaline (epinephrine). (From Furchgott, R. F., Adv. Drug Res., 3, 21-55, 1966.)... 

Various hydroxyl and amino derivatives of aromatic compounds are oxidized by peroxidases in the presence of hydrogen peroxide, yielding neutral or cation free radicals. Thus the phenacetin metabolites p-phenetidine (4-ethoxyaniline) and acetaminophen (TV-acetyl-p-aminophenol) were oxidized by LPO or HRP into the 4-ethoxyaniline cation radical and neutral V-acetyl-4-aminophenoxyl radical, respectively [198,199]. In both cases free radicals were detected by using fast-flow ESR spectroscopy. Catechols, Dopa methyl ester (dihydrox-yphenylalanine methyl ester), and 6-hydroxy-Dopa (trihydroxyphenylalanine) were oxidized by LPO mainly to o-semiquinone free radicals [200]. Another catechol derivative adrenaline (epinephrine) was oxidized into adrenochrome in the reaction catalyzed by HRP [201], This reaction can proceed in the absence of hydrogen peroxide and accompanied by oxygen consumption. It was proposed that the oxidation of adrenaline was mediated by superoxide. HRP and LPO catalyzed the oxidation of Trolox C (an analog of a-tocopherol) into phenoxyl radical [202]. The formation of phenoxyl radicals was monitored by ESR spectroscopy, and the rate constants for the reaction of Compounds II with Trolox C were determined (Table 22.1). 

Amino acid derivatives include the thyroid hormones, catecholamines (e.g. adrenaline (epinephrine)) and dopamine, neurotransmitters such as y-aminobutyric acid (GABA) and noradrenaline (norepinephrine). All of these signalling molecules retain... 

Two amino acids, tyrosine and arginine are of particular importance as precursors of signalling molecules. As outlined in Figure 4.3, tyrosine is the amino acid precursor of thyroid hormones tri-iodothyronine (T3) and tetra-iodothyronine (T4) and also of catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). 

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

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). 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

Serotonin (5-hydroxytrptamine, 5-HT) synthesis involves an hydroxylation reaction (catalysed by tryptophan mono-oxygenase) and a decarboxylation step, similar to that in adrenaline (epinephrine) synthesis. 

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. 

Adrenaline (epinephrine)-producing (adrenergic) and acetylcholine secreting (cholinergic) neurones of the autonomic nervous system have direct and complimentary effects on the tone of blood vessels. 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

Furthermore, as well as CaCM-induced phosphorylation, MLCK is also subject to control via a cAMP-dependent protein kinase, PKA. Phosphorylated MLCK binds CaCM only weakly, thus contraction is impaired. This explains the relaxation of smooth muscle when challenged with adrenaline (epinephrine), a hormone whose receptor is functionally linked with adenylyl cyclase (AC), the enzyme that generates cAMP from ATP. 

Biosynthesis and degradation of glycosaminoglycans biosynthesis of collagen, mineralization and demineralization of bone. Fatty acid synthesis and triglyceride storage in adipocytes promoted by insulin and triglyceride hydrolysis and fatty acid release stimulated by glucagon and adrenaline (epinephrine). 

Adrenaline (epinephrine) is a sympathomimetic agent that causes bronchodilatation. It is used to relieve bronchospasm in anaphylactic shock reactions. Histamine, kinins and prostaglandins, such as prostaglandin E2, are inflammatory mediators. In response to allergic stimuli, inflammatory mediators may cause bronchoconstrictions. Guaifenesin is an expectorant preparation that increases bronchial secretions to promote the expulsion of the mucus coughed up. 

Note that in nature, these are all enzyme-catalysed reactions. This makes the reactions totally specific. It means possible competing Sn2 reactions involving attack at either of the two methylene carbons in SAM are not encountered. It also means that where the substrate contains two or more potential nucleophiles, reaction occurs at only one site, dictated by the enzyme. The enzymes are usually termed methyltransferases. Thus, in animals an A-methyltransferase is responsible for SAM-dependent A-methylation of noradrenaline (norepinephrine) to adrenaline (epinephrine), whereas an O-methyltransferase in plants catalyses esterification of salicylic acid to methyl salicylate. 

Epinephrine, and endogenic catecholamine, is better known by its official English name adrenaline. Epinephrine is a powerful agonist of both a- and j8-adrenergic receptors. Its action is very complex and depends not only on the relative distribution of adrenergic receptors in... 

As was already mentioned (Chapter 12), the characteristic uniqueness of a-adrenoblock-ers is their ability to reduce the pressor effect of adrenaline (epinephrine). In particular. 

---