Of norepinephrine

FIGURE 27 5 Tyrosine is the biosynthetic precursor to a number of neurotransmit ters Each transformation IS enzyme catalyzed Hydroxy lation of the aromatic ring of tyrosine converts it to 3 4 dihyd roxyphenylalanine (l dopa) decarboxylation of which gives dopamine Hy droxylation of the benzylic carbon of dopamine con verts It to norepinephrine (noradrenaline) and methy lation of the ammo group of norepinephrine yields epi nephrine (adrenaline)... 

Histamine in the Cardiovascular System. It has been known for many years that histamine is present in sympathetic nerves and has a distribution within the heart that parallels that of norepinephrine (see Epinephrine and norepinephrine). A physiological role for cardiac histamine as a modulator of sympathetic responses is highly plausible (15). A pool of histamine in rat heart located neither in mast cells nor in sympathetic nerves has been demonstrated. The turnover of this metaboHcaHy active pool of histamine appears to be maintained by normal sympathetic activity. 

As of the mid-1990s, use of MAOIs for the treatment of depression is severely restricted because of potential side effects, the most serious of which is hypertensive crisis, which results primarily from the presence of dietary tyramine. Tyramine, a naturally occurring amine present in cheese, beer, wine, and other foods, is an indirecdy acting sympathomimetic, that is, it potently causes the release of norepinephrine from sympathetic neurons. The norepinephrine that is released interacts with adrenoceptors and, by interacting with a-adrenoceptors, causes a marked increase in blood pressure the resultant hypertension may be so severe as to cause death. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Desipramine [50-47-5] (35) and nortriptyline [72-69-5] (36) are demethylated derivatives and principal metaboHtes of (32) and (33), respectively. Both compounds possess less sedative and stronger psychomotor effects than the tertiary amine counterparts, probably because tricycHcs containing secondary amine groups generally show greater selectivity for inhibiting the reuptake of norepinephrine compared with the reuptake of serotonin. Protriptyline [438-60-8] (37), a stmctural isomer of nortriptyline, is another important secondary amine that displays a similar clinical profile. 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

The solubility of the resulting product may dictate the choice of solvent. Reductive alkylation of norepinephrine with a series of keto acids proceeded smoothly over platinum oxide in methanol-acetic acid mixtures. However, when n = 4 or 5, the product tended to precipitate from solution, making catalyst separation difficult. The problem was circumvented by using glacial acetic acid as solvent 38). 

Sclrild regression data for plientolamine blockade of norepinephrine responses in rat anococcygeus muscle (data shown in Figure 11.19). 

One group of antiadreneigic drugs inhibits the release of norepinephrine (a neurohormone of the sympathetic nervous system, see Chap. 22) from certain adrenergic... 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

All antiarrhythmic dra are used cautiously in patients with renal or hepatic disease. When renal or hepatic dysfunction is present, a dosage reduction may be necessary. All patients should be observed for renal and hepatic dysfunction. Quinidine and procainamide are used cautiously in patients with CHF. Disopyramide is used cautiously in patients with CHF, myasthenia gravis, or glaucoma, and in men with prostate enlargement. Bretylium is used cautiously in patients with digitalis toxicity because the initial release of norepinephrine with digitalis toxicity may exacerbate arrhythmias and symptoms of toxicity. Verapamil is used cautiously in patients with a history of serious ventricular arrhythmias or CHF. Electrolyte disturbances such as hypokalemia, hyperkalemia, or hypomagnesemia may alter the effects of the antiarrhythmic dru . Electrolytes are monitored frequently and imbalances corrected as soon as possible... 

Fbtentiates vasoconstrictor action of norepinephrine. Without glucocorticoids the vasoconstricting action is decreased, and blood pressure falls. 

Interactions with caffeine and aspirin can increase the effects of ephedrine. Norepinephrine works in part by increasing the levels of cyclic aminomethyl propanol (AMP) in cells. Caffeine inhibits the enzyme that breaks down cyclic AMP. Together, ephedrine makes more cyclic AMP, and caffeine prevents it from breaking down. Aspirin inhibits the receptors that turn off release of norepinephrine. 

It is appropriate at this juncture to illustrate the power of chemiluminescence in an analytical assay by comparing the limits of sensitivity of the fluorescence-based and the chemllumlnescence-based detection for analytes in a biological matrix. The quantitation of norepinephrine and dopamine in urine samples will serve as an illustrative example. Dopamine, norepinephrine, and 3,4-dihydroxybenzy-lamine (an internal standard) were derivatized with NDA/CN, and chemiluminescence was used to monitor the chromatography and determine a calibration curve (Figure 15). The limits of detection were determined to be less than 1 fmol injected. A typical chromatogram is shown in Figure 16. 

CBs, like OPs, can cause a variety of sublethal neurotoxic and behavioral effects. In one study with goldfish Carrasius auratus), Bretaud et al. (2002) showed effects of carbofuran on behavioral end points after prolonged exposure to 5 pg/L of the insecticide. At higher levels of exposure (50 or 500 pg/L), biochemical effects were also recorded, including increases in the levels of norepinephrine and dopamine in the brain. The behavioral endpoints related to both swimming pattern and social interactions. Effects of CBs on the behavior of fish will be discussed further in Chapter 16, Section 16.6.1. 

Silver RB, Mackins CJ, Smith NCE, Koritchneva IL, Lefkowitz K, Lovenberg TW> Levi R Coupling of histamine H3 receptors to neuronal Na+/H+ exchange a novel protective mechanism in myocardial ischemia, Proc Natl Acad Sci USA 2001 98 2855. Silver RB, Poonwasi KS, Seyedi N, Wilson SJ, Lovenberg TW, Levi R Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. Proc Natl Acad Sci USA 2002 99 501. 

The sympathetic nervous system, through hberation of norepinephrine in adipose tissue, plays a central role in the mobilization of free fatty acids. Thus, the increased hpolysis caused by many of the factors described above can be reduced or abolished by denervation of adipose tissue or by ganglionic blockade. 

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31—5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase, a pyridoxai phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A -methyltransferase uti-hzes S-adenosyhnethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42). 

PNMT catalyzes the N-methylation of norepinephrine to form epinephrine in the epinephrine-forming cells of the adrenal medulla. Since PNMT is soluble, it is assumed that norepinephrine-to-epinephrine conversion occurs in the cytoplasm. The synthesis of PNMT is induced by glucocorticoid hormones that reach the medulla via the intra-adrenal portal system. This special system provides for a 100-fold steroid concentration gradient over systemic arterial blood, and this high intra-adrenal concentration appears to be necessary for the induction of PNMT. 

Evidence from a number of systems suggests that ion flux plays a role in palytoxin action. In a wide range of systems, palytoxin effects are accompanied by a change in intracellular cation levels. For example, the influx of Na and/or Ca is associated with palytoxin-stimulated contraction of cardiac and smooth muscle, the release of norepinephrine by rat pheochromocytoma (PC12) cells, and the depolarization of excitable membranes 12—15). Palytoxin also induces K efflux from erythrocytes and thus alters ion flux in a nonexcitable membrane system as well 16-19). In both excitable and nonexcitable membranes, the ultimate action of palytoxin has been shown to be dependent on extracellular cations. The palytoxin-induced effects on smooth muscle and erythroctyes can be inhibited by removing Ca from the media, and the palytoxin-induced release of norephinephrine from PC12 cells can be blocked in Na" free media (ii, 14y 18, 20, 21)... 

PTX caused a dose-dependent release of norepinephrine (NE). The NE release induced by lower concentrations of PTX increased proportionately with increasing Na concentrations, but was not modified by tetrodotoxin. However, the NE-releasing action of higher concentrations of PTX was dependent on external Ca, but not Na . Thus our experimental results suggest that in adrenergic neurons the PTX-induced release of NE by lower concentrations of PTX is brought about by tetrodotoxin-insensitive Na permeability, whereas that induced by higher concentrations is mainly caused by a direct increase of Ca influx into smooth muscle cells. 

Marzan AS, Hungerbuhler HJ, Studer A, Baumgartner RW, Georgiadis D. Feasibility and safety of norepinephrine-induced arterial hypertension in acute ischemic stroke. Neurology 2004 62(7) 1193-1195. 

McCormick, DA, Pape, HC and Williamson, A (1991) Actions of norepinephrine in the cerebral cortex and thalamus implications for function of the central noradrenergic system. Prog. Brain Res. 88 293-305. 

Povlock, SL and Amara, SG (1997) The structure and function of norepinephrine, dopamine and serotonin transporters. In Neurotransmitter Transporters Structure, Function, and Regulation (Ed. Reith, MEA), Humana Press, Totowa, NJ, pp. 1-28. 

Matsumura, Y., Miyawaki, N., Sasaki, Y. and Morimoto, S. (1985). Inhibitory effects of norepinephrine, methoxamine and phenylephrine on renin release from rat kidney cortical slices. J. Pharmacol. Exp. Ther. 233, 782-787. 

Based on the modest ability of the (+)-isomers of MDMA and MBDB to inhibit the reuptake of norepinephrine (NE) into hypothalamic synaptosomes (Steele et al. 1987). it seemed possible that noradrenergic pathways might be involved in the eue. In ano er series of drug discrimination experiments designed to test this hypothesis, the specific NE uptake inhibitor (-)-tomoxctine was tested for stimulus transfer in doses up to 10 mg/kg in MDMA-trained rats. At 5 mg/kg, 67 percent of the animals responded on, the drug lever. However, pretreatment with tomoxetine in six rats trained to discriminate MDMA from saline had no effect on the discrimination of a subsequent dose of MDMA. 

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