Catecholamines release

Inhibition of acetylcholine stimulated medullary catecholamine release... 

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals 216... 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals. Catecholamines diffuse from the site of release, interact with receptors and are transported back into the nerve terminal. Some of the catecholamine molecules may be catabolized by MAO and COMT. The cate-cholamine-reuptake process was originally described by Axelrod [18]. He observed that, when radioactive norepinephrine was injected intravenously, it accumulated in tissues in direct proportion to the density of the sympathetic innervation in the tissue. The amine taken up into the tissues was protected from catabolic degradation, and studies of the subcellular distribution of catecholamines showed that they were localized to synaptic vesicles. Ablation of the sympathetic input to organs abolished the ability of vesicles to accumulate and store radioactive norepinephrine. Subsequent studies demonstrated that this Na+- and Cl -dependent uptake process is a characteristic feature of catecholamine-containing neurons in both the periphery and the brain (Table 12-2). 

Alousi, A. and Weiner, N. The regulation of norepinephrine synthesis in sympathetic nerves effect of nerve stimulation, cocaine, and catecholamine-releasing agents. Proc. Natl Acad. Sci. U.S.A. 56 1491-1496,1966. 

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

The catecholamine-releasing agent beta-phenylethylamine (PEA) also produces the 5-HT syndrome (156) by direct activation of 5-HT receptors. The 5-HT antagonists methysergide and mianserin blocked the syndrome-producing effects of PEA, while depletion of 5-HT by PCPA or 5,7-DHT treatments was not effective. A possible role of catecholamines in the syndrome-producing effects of PEA cannot presently be discounted. 

Mercuric chloride may induce catecholamine release from adrenals. The initial phase may be due to amine displacement by the mercury ion but the secondary phase probably involves alteration of membrane structures [95]. Mercury compounds have also been shown to increase the efflux of monoamines from mouse striated slices [96] and from adrenergic nerve fibre terminals [97], the effect being attributed to inhibition of Na /K+-ATPase activity and(or) disruption of intracellular Ca2+ regulatory mechanisms [96]. 

Borowitz JL, Bom GS, Isom GE. 1988. Potentiation of evoked adrenal catecholamine release by cyanide Possible role of calcium. Toxicology 50 37-45. 

Kanthasamy AG, Maduh EU, Peoples RW, et al. 1991a. Calcium mediation of cyanide-induced catecholamine release Implications for neurotoxicity. Toxicol Appl Pharmacol 110 275-282. 

Kalix P. (1982). The amphetamine-like releasing effect of the alkaloid (-)cathinone on rat nucleus accumbens and rabbit caudate nucleus. Prog Neuropsychopharmacol Biol Psychiatry. 6(1) 43-49. Kalix P. (1983). A comparison of the catecholamine releasing effect of the khat alkaloids (-)-cathinone and (+)-norpseudoephedrine. Drug Alcohol Depend. 11(3-4) 395-401. 

Schneider AS, Nagel JE, Mah SJ. (1996). Ibogaine selectively inhibits nicotinic receptor-mediated catecholamine release. Eur J Pharmacol. 317(2-3) Rl-2. 

Responses in the dopamine system are more complex (see chapter by Balfour, this volume). Repeated nicotine injections resulted in enhanced extracellular DA levels in the NAc (Benwell and Balfour 1992, 1997), but not in the striatum (Benwell and Balfour 1997). Analysis of the precise placement of dialysis probes has revealed differential responses to drugs of abuse, including nicotine, between the NAc core (ventral striatum) and shell (Di Chiara 2002 Balfour 2004 Wonnacott et al. 2005 see chapter by Balfour, this volume). Moreover, the sensitised neurotransmitter responses observed in the hippocampus and NAc were markedly attenuated if rats received a constant infusion of a low level of nicotine (Benwell and Balfour 1997). Thus, transient peaks of nicotine appear capable of sensitising some brain pathways with respect to catecholamine release, but the responses may be mitigated by lower sustained plasma concentrations, possibly due to desensitisation. The extent that presynaptic nAChRs contribute to this process in vivo is unclear presynaptic a7 nAChRs on glutamatergic afferents to the VTA merit attention as potential mediators of sensitisation (see Sect. 2.2.2). 

Becker JB, Ramirez VD (1980) Dynamics of endogenous catecholamine release from brain fragments of male and female rats. Neuroendocrinology 31(1) 18-25 Beckett AH, Gorrod JW, et al (1971) The effect of smoking on nicotine metabolism in vivo in man. 1 Pharm Pharmacol 23 62S-67S... 

The bicyclic amidoximes (LXIV) and (LXV) cause a reduction in blood pressure in various animal species, but apparently they are not adrenergic neurone blocking agents [270]. The activity of (LXIV)i thought to be mainly due to catecholamine release and subsequent depletion, whilst the action of (LXV) involves blockade at a-receptors [270]. 

These drugs selectively reduce cardiostimulatory, vasodilating, broncholytic, and metabolic (glycogenolytic and lipolytic) action of catecholamines released from adrenergic nerve endings and adrenal glands. 

The examined drugs reversibly bind with 8-adrenergic receptive regions and competitively prevent activation of these receptors by catecholamines released by the sympathetic nervous system, or externally introduced sympathomimetics. 

Deficiency of adrenal medullary catecholamines appears to give no ill effects, and replacement therapy is therefore not used, but adrenal medullary tumours, phaeochromocytomas, secrete excess catecholamines often causing hypertension with dramatic episodes of headache, palpitations, pallor, sweating and anxiety. This condition is normally treated surgically, but preoperative preparation is mandatory to avoid catastrophic effects of surges of catecholamine release. A combination of alpha- and beta-adrenergic receptor blockade is normally used, with drugs such as phenoxybenzamine or doxazosin as alpha-blockers, and propranolol as a non-selective beta-blocker. 

Metabolic Effects. The hyperglycemic effect of nickel is discussed under endocrine effects because it appears to be secondary to the effects on catecholamine release from the adrenal gland and central nervous system and to the effects on insulin release by the pancreas. 

Kirby LG, Chou-Green JM, Davis K, Lucki I (1997) The effects of different stressors on extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Brain Res 760 218-230 Kirby LG, Rice KC, Valentino RJ (2000) Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology 22 148-162 Kozicz T, Yanaihara H, Arimura A (1998) Distribution of urocortin-like immunoreactivity in the central nervous system of the rat. J Comp Neurol 391 1-10 Lavicky J, Dunn AJ (1993) Corticotropin-releasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freely moving rats as assessedby microdialysis. J Neurochem 60 602-612... 

SA node and A-V fibers become dominant. Activation of M2 receptors increases the potassium permeability and reduces cAMP levels, slowing the rate of depolarization and decreasing the excitability of SA node and A-V fiber cells. This results in marked bradycardia and a slowing of A-V conduction that can override the stimulation of the heart by catecholamines released during sympathetic stimulation. In fact, very high doses of a muscarinic agonist can produce lethal bradycardia and A-V block. Choline esters have relatively minor direct effects on ventricular function, but they can produce negative inotropy of the atria. 

Bretylium administration produces an initial brief increase in sinus node automaticity that is probably the result of a drug-induced release of catecholamines from sympathetic nerve terminals. No change or a slight decrease in sinus heart rate is observed after the initial phase of catecholamine release. 

Moderate doses increase conduction velocity and decrease the A-V nodal refractory period this effect may result from the initial drug-induced catecholamine release. The net effect of bretylium on A-V transmission during chronic therapy is unknown. 

A unique property of bretylium as an antiarrhythmic agent is its positive inotropic action. This effect, related to its actions on the sympathetic nervous system, includes an initial release of neuronal stores of norepinephrine followed shortly by a prolonged period of inhibition of direct or reflex-associated neuronal norepinephrine release. The onset of bretylium-induced hypotension is delayed 1 to 2 hours because the initial catecholamine release maintains arterial pressure before this time. 

These data and findings from serotonin depletion studies show that, in patients treated successfully, NA and serotonin systems are involved in maintenance of drug-induced remission. However, the absence of an increased severity in depressive symptoms in drug-free patients with depression suggests that alterations in serotonin and catecholamine release may not be causally involved in the pathophysiology of mood disorders. 

Taken together with the results obtained by DlPalma s group,117,118 the finding by Barnes et al.H 0f the particularly large effect of prior treatment with reserplne on the response of the arterial pressure to I seems to confirm the Involvement of catecholamine release In this hypertensive response. It Is clear, however, that X also has a direct Inotropic effect on the heart, In that the increase In stroke volume was blocked only partially by any of the three possible antagonists used by Barnes et al. Xn view of the fact that none of the possible antagonists was able to prevent more than about 68.52 of the increase In peripheral resistance Induced by X, this oxime may well have direct stimulant effects on vascular smooth muscle. 

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