Norepinephrine inhibition

Compared to a,-receptors, a2-receptors have only moderate distribution on the effector tissues however, they have important presynaptic effects. Alpha-one receptors are found on effector tissue cells at the neuroeffector junction the a2-receptors are found on the varicosities of the postganglionic neuron. Norepinephrine released from this neuron not only binds to the a.j-receptors on the effector tissue to cause some physiological effect but also binds to the a2-receptors on the neuron. Alpha-two receptor stimulation results in presynaptic inhibition" or in a decrease in the release of norepinephrine. In this way, norepinephrine inhibits its own release from the sympathetic postganglionic neuron and controls its own activity. Both ar and a2-receptors have equal affinity for norepinephrine released directly from sympathetic neurons as well as circulating epinephrine released from the adrenal medulla. 

Frohman EM, Vayuvegula B, Gupta S, van den Noort S (1988) Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (la) antigen expression on cultured astrocytes via beta-2-adrenergic signal transduction mechanisms. Proc. Natl. AcadSci. USA 85 1292-1296. 

Trombley PQ. 1992. Norepinephrine inhibits calcium currents and EPSPs via a G-protein-coupled mechanism in olfactory bulb neurons. J Neurosci 12 3992-3998. 

Reuptake of norepinephrine inhibited by TCAs, amoxapine, maprotiline, atomoxetine... 

Venlafaxine is a potent reuptake inhibitor of serotonin, with a less potent effect on norepinephrine and dopamine, and does not interact with other neurotransmitter receptors. The lower affinity for norepinephrine transport requires dose elevation in order to achieve both serotonin and norepinephrine inhibition. Emerging evidence indicates that higher doses of venlafaxine (200-375 mg/day) may have a faster onset of action, observed as early as 4 days to 1 week following treatment initiation. 

Reserpine (e.g., Serpasil) Partially depletes catecholamine stores in peripheral nervous system and perhaps in the CNS. Decreases total peripheral resistance, heart rate, and cardiac output. Seldom used for mild to moderate hypertension. No longer recommended for psychiatric disorders. "Parasympathetic predominence" (bradycardia, diarrhea, bronchoconstriction, increased secretions), decreased cardiac contractility and output, postural hypotension (depletes norepinephrine inhibiting vasoconstriction), peptic ulcers, sedation and suicidal depression, impaired ejaculation, gynecomastia. Low risk of rebound hypertension because of long duration of action. 

X,-Adrenoceptors occur on noradrenergic nerve terminals. Their activation by norepinephrine inhibits adeny lyl cyclase. The consequent fall in cAMP doses Ca channels and diminishes further transmitter release. 

Glucagon is believed to stimulate insulin secretion in man. Secretin, pancreozymin, and gastrin have all been found to stimulate insulin release. Acetylcholine and carbamylcholine stimulate insulin secretion in vitro in contrast, epinephrine and norepinephrine inhibit it. Thus, in pheochromocytoma, acute insulin responses are inhibited. 

The serotonin and norepinephrine reuptake inhibitors, or SNRIs, have both serotonin and norepinephrine inhibition, and are less selective than the SSRls. They also have nausea as a common adverse event on initiation, and can have dizziness, drowsiness, sweating, and dry mouth, as well as sexual dysfunction, as occur with the SSRI and have been associated with serotonin syndrome. 

Overholt JL, Prahhakar NR. Norepinephrine inhibits a toxin resistant Ca current in carotid body glomus cells evidence for a direct G protein mechanism. J Neurophysiol 1999 81 225-233. 

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. 

The Class I agents decrease excitability, slow conduction velocity, inhibit diastoHc depolarization (decrease automaticity), and prolong the refractory period of cardiac tissues (1,2). These agents have anticholinergic effects that may contribute to the observed electrophysiologic effects. Heart rates may become faster by increasing phase 4 diastoHc depolarization in SA and AV nodal cells. This results from inhibition of the action of vagaHy released acetylcholine [S1-84-3] which, allows sympathetically released norepinephrine [51-41-2] (NE) to act on these stmctures (1,2). 

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. 

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. 

The small molecular transmitter characteristic of the sympathetic nervous system is norepinephrine. However, epinephrine from the adrenal medulla is an important partner in systemic sympathetic actions. The actions of the sympathetic system are unique because in different smooth muscles responses are diametrically opposed they may be either by contraction or inhibition of contraction and... 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

Imamura M, Lander HM, Levi R Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine Aj-receptors and a2-adrenoceptors. Circ Res 1996 78 475. 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

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)... 

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