System catecholamines

From the observation that tics were exacerbated by stress, and because cerebrospinal fluid flndings suggested possible alterations in central nervous system catecholamine metabolism, Cohen and colleagues (1979) used clonidine in the treatment of TS in what was among the first theory-based treatments for the disorder. 

Neurotensin. Neurotensia [39379-15-2] (NT),j )-Glu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Try-Ile-Leu-OH, is a tridecapeptide that is cleaved from the ribosomaHy synthesized precursor, proneurotensia. NT is distributed through the peripheral and central nervous systems as well as ia certain other cell types (3,67). NT is colocalized with catecholamines ia some neurons. 

The modern usage of P2" go Asts for the treatment of asthma dates to 1903 when the effect of injected epinephrine [51-43-4] (adrenaline) C2H23NO2, (1 R = CH3) was investigated (see Epinephrine and norepinephrine) (33). As in some other modem treatments, eg, xanthines and anticholinergics, the roots of P2" go Ast therapy for asthma can be found in historical records which document the use of herbal extracts containing ephedrine [299-42-3] C qH NO, (2) as bronchodilators. Epinephrine and ephedrine are stmcturaHy related to the catecholamine norepinephrine [51-41-2] CgH NO, (1, R = H), a neurotransmitter of the adrenergic nervous system (see Neuroregulators). 

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). 

Enhanced automaticity occurs in hypoxia, hypokalemia, hypercarbia, excessive sympathetic nervous system stimulation, or high concentrations of catecholamines. These conditions may lead to arrhythmias. Decreased automaticity may also lead to production of arrhythmias by enhancing ectopic activity in latent pacemakers (ectopic foci) or by altering conductivity and refractoriness in conduction pathways of myocardium. 

Halogenated hydrocarbons depress cardiac contractility, decrease heart rate, and inhibit conductivity in the cardiac conducting system. The cardiac-toxicity of these compounds is related to the number of halogen atoms it increases first as the number of halogen atoms increases, but decreases after achieving the maximum toxicity when four halogen atoms are present. Some of these compounds, e.g., chloroform, carbon tetrachloride, and trichloroethylene, sensitize the heart to catecholamines (adrenaline and noradrenaline) and thus increase the risk of cardiac arrhythmia. 

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. 

The distinction between a- and P-adrenergic receptors was first proposed by Ahlquist in 1948 based on experiments with various catecholamine derivatives to produce excitatory (a) or inhibitory (P) responses in isolated smooth muscle systems. Initially, a further subdivision into presynaptic a2- and postsynaptic oq-receptors was proposed. However, this anatomical classification of a-adrenergic recqrtor subtypes was later abandoned. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Pituitary Adenylyl Cyclase-activating Polypeptide (PACAP) is a 38-amino acid peptide (PACAP-38), which is widely expressed in the central nervous system. PACAP is most abundant in the hypothalamus. It is also found in the gastrointestinal tract, the adrenal gland and in testis. Its central nervous system functions are ill-defined. In the periphery, PACAP has been shown to stimulate catecholamine secretion from the adrenal medulla and to regulate secretion from the pancreas. Three G-protein coupled receptors have been shown to respond to PACAP, PAQ (PACAP type I) specifically binds PACAP, VPACi and VPAC2 also bind vasoactive intestinal peptide (VDP). Activation of PACAP receptors results in a Gs-mediated activation of adenylyl cyclase. 

Signs and symptoms of sympathetic nervous system activity are invariably found in MH. Levels of catecholamines are markedly increased in MH. Whether activation of the sympathetic nervous system is a primary or a secondary response in the syndrome has not been fully elucidated. Gronert reported that stress-induced sympathetic hyperactivity can initiate a malignant hyperthermic episode in susceptible swine without a triggering agent. Stress-induced MH in humans has been inferred because susceptible families have been shown to have an increased incidence of sudden death. Gronert s reasons that activation of the sympathetic... 

As the rate-limiting enzyme, tyrosine hydroxylase is regulated in a variety of ways. The most important mechanism involves feedback inhibition by the catecholamines, which compete with the enzyme for the pteridine cofactor. Catecholamines cannot cross the blood-brain barrier hence, in the brain they must be synthesized locally. In certain central nervous system diseases (eg, Parkinson s disease), there is a local deficiency of dopamine synthesis. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier and so is an important agent in the treatment of Parkinson s disease. 

Dopamine (5-hydroxylase is a copper-containing enzyme involved in the synthesis of the catecholamines norepinephrine and epinephrine from tyrosine in the adrenal medulla and central nervous system. During hy-droxylation, the Cu+ is oxidized to Cu " reduction back... 

The general picture of muscle contraction in the heart resembles that of skeletal muscle. Cardiac muscle, like skeletal muscle, is striated and uses the actin-myosin-tropomyosin-troponin system described above. Unlike skeletal muscle, cardiac muscle exhibits intrinsic rhyth-micity, and individual myocytes communicate with each other because of its syncytial nature. The T tubular system is more developed in cardiac muscle, whereas the sarcoplasmic reticulum is less extensive and consequently the intracellular supply of Ca for contraction is less. Cardiac muscle thus relies on extracellular Ca for contraction if isolated cardiac muscle is deprived of Ca, it ceases to beat within approximately 1 minute, whereas skeletal muscle can continue to contract without an extraceUular source of Ca +. Cyclic AMP plays a more prominent role in cardiac than in skeletal muscle. It modulates intracellular levels of Ca through the activation of protein kinases these enzymes phosphorylate various transport proteins in the sarcolemma and sarcoplasmic reticulum and also in the troponin-tropomyosin regulatory complex, affecting intracellular levels of Ca or responses to it. There is a rough correlation between the phosphorylation of Tpl and the increased contraction of cardiac muscle induced by catecholamines. This may account for the inotropic effects (increased contractility) of P-adrenergic compounds on the heart. Some differences among skeletal, cardiac, and smooth muscle are summarized in... 

In stroke patients presenting to the ED, the first goal of treatment is immediate cardiac and respiratory stabilization. The systemic blood pressure is most often elevated in the setting of an acute stroke as the result of a catecholamine surge, and if the patient is hypotensive, the clinician should consider a concomitant cardiac process, such as myocardial infarction (MI), congestive heart failure (CHF), or pulmonary embolism (PE). 

Attempts to diminish the overall metabolism of trichloroethylene might be useful (e.g., hypothermia, mixed-function oxidase inhibitors, competitive inhibitors of trichloroethylene metabolism [i.e., P-450 substrates]), if instituted soon enough after trichloroethylene exposure. Catecholamines (especially beta agonists) act in concert with trichloroethylene, increasing the risk of cardiac arrhythmias. Hence, catecholamines should be administered to patients only in the lowest efficacious doses and for certain limited presentations of trichloroethylene poisoning. Ethanol should also be avoided because concurrent exposure to trichloroethylene and ethanol can cause vasodilation and malaise and may potentiate central nervous system depression at high dosage levels of either compound. 

If a series of related chemicals, say noradrenaline, adrenaline, methyladrenaline and isoprenaline, are studied on a range of test responses (e.g. blood pressure, heart rate, pupil size, intestinal motility, etc.) and retain exactly the same order of potency in each test system, then it is likely that there is only one type of receptor for all four of these catecholamines. On the other hand, if, as Ahlquist first found in the 1940s, these compounds give a distinct order of potency in some of the tests, but the reverse (or just a different) order in others, then there must be more than one type of receptor for these agonists. 

Lindvall, O and Bjorkland, A (1978) Organisation of catecholamine neurons in the rat central nervous system. In Handbook of Psychopharmacology, Vol. 9 (Eds Iversen, LL, Iversen, SD and Snyder, SH), Plenum, New York, pp. 139-231. 

Moore, RY and Bloom, FE (1978) Central catecholamine neuron systems, anatomy and physiology of the dopamine system. Ann. Rev. Neurosci. 1 129-169. 

Certainly, such a complex system for metabolism of noradrenaline (which is shared with the other catecholamines) strongly suggests that its function extends beyond that of merely destroying transmitter sequestered from the synapse. However, as yet, little is known about the regulation of this pathway and any influence it might have on noradrenergic transmission. One crucial, additional role for MAO appears to be the... 

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