Adrenaline functions

The existence of a neuro-humoral mechanism or chemical agent intervening between nerve impulse and tissue response has been demonstrated chiefly by the work of Loewi (1921-1930) on the heart, Sherrington on the reflex-arc, and Lewis on the cutaneous capillaries. These chemical agents, or neurocrines as they may be termed, resemble the autacoids (Chapter XXIV), but the principal effect is local and more or less limited to the site of their origin. At the same time, two of the best known neurocrines, namely, acetyl choline and adrenaline, function as typical autacoids. 

Adrenaline functions as a hormone heing released from the adrenal gland in response to stress and acts most strongly at P receptors. Although noradrenaline (Fig. 10.3) has a very similar structure to adrenaline, its mcxle of release is... 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Adenosine triphosphate, coupled reactions and. 1128-1129 function of, 157, 1127-1128 reaction with glucose, 1129 structure of, 157, 1044 S-Adenosylmethionine, from methionine, 669 function of, 382-383 stereochemistry of, 315 structure of, 1045 Adipic acid, structure of, 753 ADP, sec Adenosine diphosphate Adrenaline, biosynthesis of, 382-383 molecular model of, 323 slructure of, 24... 

Cole et al. (1995) reported on knock-out mice with a germ line deletion of GR. They demonstrated that lack of GR leads to perinatal death, atelectasis of the lung, and lack of adrenalin synthesis. To circumvent perinatal lethality, Tranche et al. (1999) and Brewer et al. (2003) generated tissue-specific somatic deletions of GR. This allowed to characterize GR function in the CNS, the immune system, and the liver in more detail. In particular, these approaches revealed novel aspects of organ-specific glucocorticoid physiology such as anxiety-like behavior, growth control, and polyclonal T cell activation. 

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

In the preceding chapters, the synaptic pharmacology of those substances clearly established as NTs in the CNS, i.e. glutamate, GABA, ACh, NA, DA, 5-HT and certain peptides, has been discussed in some detail. There are other substances found in the CNS that could have a minor transmitter role, e.g. ATP, histamine and adrenaline, while still others that cannot claim such a property but clearly modify CNS function in some way, e.g. steroids, prostaglandins and nitric oxide. We will consider each of them in what we hope is appropriate detail. 

Adrenal gland A triangle-shaped organ positioned at the top of the kidney which functions as a double endocrine gland . The larger outer adrenal cortex secretes three classes of steroid hormones glucocorticoids (e.g., cortisol), minerlocorticoids (aldosterone) and small amounts of sex steroids (e.g., testosterone). The inner adrenal medulla secretes catecholamines (e.g., adrenaline and noradrenaline). 

Amine Molecules containing the atom nitrogen (N) and classified according to the nature of their functional group into monoamines (—NH2, e.g., dopamine) secondary amines (—NHR, e.g., adrenaline) tertiary amines (—NR2, e.g., imipramine) and quaternary amines (—N+R3, e.g., acetylcholine) (where R is a methyl group). 

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. 

The function of adrenaline is to mobilise all fuels that can be used by muscle to provide ATP to support physical activity in response to stress (i.e. fight or flight response). And to increase sensitivity of regulation of enzymes involved in control of the rate of processes that generate ATP. The biochemical effects in the heart increase cardiac output, in preparation for fight or flight . 

Noradrenaline is the main catecholamine in postganglionic sympathetic nerves and in the central nervous system it is also released from the adrenal gland together with adrenaline. Recently adrenaline has also been shown to be a transmitter in the hypothalamic region of the mammalian brain so, while the terms "noradrenergic" and "adrenergic" are presently used interchangeably, it is anticipated that they will be used with much more precision once the unique functions of adrenaline in the brain have been established. 

The central adrenergic system. It is only recently that immunohistochemical methods have been developed to show that adrenaline-containing cells occur in the brain. Some of these cells are located in the lateral tegmental area, while others are found in the dorsal medulla. Axons from these cells innervate the hypothalamus, the locus coeruleus and the dorsal motor nucleus of the vagus nerve. While the precise function of adrenergic system within the brain is uncertain, it may be surmized that adrenaline could play a role in endocrine regulation and in the central control of blood pressure. There is evidence that the concentration of this amine in cerebrospinal fluid... 

FIGURE 15.6 Retention factor for adrenaline as a function of the volume fraction of methanol (10%, 25%, and 40%) and the pairing ion (octylsulfonate) concentration. The theoretical line is obtained by combining Equations 15.38 and 15.39. Experimental data from Ref. [11]. (Reproduced with permission from Bartha, A. et al., J. Chromatogr., 506, 85, 1990.)... 

Noradrenaline is not only present in the sympathetic nerve endings but in the glandular cells of the adrenal medulla as well. The contents of noradrenaline in the medulla is dependent on the functional state of the gland and the species. Noradrenaline is always the precursor of adrenaline. In the central nervous system there are regions with a high noradrenaline content the hypothalamus and vegetative centers. 

Adrenaline is the main hormone released from the adrenal medulla. The glandular cells in this structure correspond to the second, postganglionic neuron of the sympathetic nervous system. Furthermore, adrenaline can be found in chromaffin cells in various tissues. For the better understanding of the function of noradrenaline it is important to realize that this substance, as a neuronal transmitter, affects only the innervated target structure, that is it acts mainly locally. Among these effects are the activation of the musculus dilatator to widen the pupillae in response to a reduced light intensity, an increase in heart rate as a response to a blood pressure drop due to a reduction of the peripheral resistance or constriction... 

Dopamine is an intermediate product in the biosynthesis of noradrenaline. Furthermore it is an active transmitter by itself in basal ganglia (caudate nucleus), the nucleus accumbens, the olfactory tubercle, the central nucleus of the amygdala, the median eminence and some areas in the frontal cortex. It is functionally important, for example in the extra-pyramidal system and the central regulation of emesis. In the periphery specific dopamine receptors (Di-receptors) can be found in the upper gastrointestinal tract, in which a reduction of motility is mediated, and on vascular smooth muscle cells of splanchnic and renal arteries. Beside its effect on specific D-receptors, dopamine activates, at higher concentrations, a- and -adrenoceptors as well. Since its clinical profile is different from adrenaline and noradrenaline there are particular indications for dopamine, like situations of circulatory shock with a reduced kidney perfusion. Dopamine can dose-dependently induce nausea, vomiting, tachyarrhythmia and peripheral vasoconstriction. Dopamine can worsen cardiac ischaemia. 

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