Acetylcholine in humans

Frolich L, Dirr A, Gotz ME, GseU W, Reichmann H, et al. 1998. Acetylcholine in human CSF methodological considerations and levels in dementia of Alzheimer type. J Neural Transm 105 961... 

The primary cardiovascular effects of muscarinic agonists are reduction in peripheral vascular resistance and changes in heart rate. The direct effects listed in Table 7-3 are modified by important homeostatic reflexes, as described in Chapter 6 and depicted in Figure 6-7. Intravenous infusions of minimally effective doses of acetylcholine in humans (eg, 20-50 mcg/min) cause vasodilation, resulting in a reduction in blood pressure, often accompanied by a reflex increase in heart rate. Larger doses of acetylcholine produce bradycardia and decrease atrioventricular node conduction velocity in addition to hypotension. 

Watanabe et al. used a pyrolysis gas chromatography-mass spectro-metric method for the determination of acetylcholine in human blood... 

Sastry, B. V. R, Olubadewo. J. O., and Schmidt. D. E. (1973). Placental cholinergic. system and occurrence of acetylcholine in human placenta. Fed. Proc. 32, 742A. 

Welsch, F., and Wenger, W. C. (1980). Acetylcholine in human placenta Identification by pyrolysis gas chromatography/ mass spectrometry and tissue levels following dilTerent modes of delivery. Naunyn-Schmiedherg s Arch. Pharmacol 311, 113-118. 

Primarily hydrolyses esters with short acyl moiety, such as acetylcholine (ACh). It is the major ChE in human blood, muscle and brain cells. AChE mRNA is 20-fold more abundant than BChE mRNA. 

Pharmacological experiments have strongly implicated acetylcholine in the control of REM sleep. In humans, intravenous infusion of the AChE inhibitor... 

Mitsis, E.M., van Dyck, C.H., Krantzler, E. et al. Prolonged occupancy of nicotinic acetylcholine receptors by nicotine in human brain a preliminary study. Paper presented at the Annual Meeting of the Society for Research on Nicotine and Tobacco, Orlando, FL, 2006. 

Wang, F., Nelson, M., Kuryatov, A. et al. Chronic nicotine treatment upregulates human a3 32 but not a3P4 acetylcholine receptors stably transfected in human embryonic kidney cells. J. Biol. Chem. 1998 28721, 1998. 

Perhaps the largest gap in the evidence surrounds the primary site of action of nicotine in the brain - the acetylcholine receptor itself. Studies on links with tobacco dependence in humans will await closer definition of the complex interaction between nicotine and its receptor and the identification of the receptor sub-types that are important in addiction pathways (see Section 22.4). 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

Hiemke, C. et al., Expression of alpha subunit genes of nicotinic acetylcholine receptors in human lymphocytes, Neurosci. Lett., 214,171, 1996. 

Thus a distinction was provided between simple esterases, such as fiver esterase, which catalysed the hydrolysis of simple aliphatic esters but were ineffective towards choline esters. The term 1 cholinesterase was extended to other enzymes, present in blood sera and erythrocytes of other animals, including man, and in nervous tissue, which catalysed the hydrolysis of acetylcholine. It was assumed that only one enzyme was involved until Alles and Hawes2 found that the enzyme present in human erythrocytes readily catalysed the hydrolysis of acetylcholine, but was inactive towards butyrylcholine. Human-serum enzyme, on the other hand, hydrolyses butyrylcholine more rapidly than acetylcholine. The erythrocyte enzyme is sometimes called true cholinesterase, whereas the serum enzyme is sometimes called pseudo-cholinesterase. Stedman,3 however, prefers the names a-cholinesterase for the enzyme more active towards acetylcholine, and / -cholinesterase for the one preferentially hydrolysing butyrylcholine. Enzymes of the first type play a fundamental part in acetylcholine metabolism in vivo. The function of the second type in vivo is obscure. Not everyone agrees with the designation suggested by Stedman. It must also be stressed that enzymes of one type from different species are not always identical in every respect.4 Furthermore,... 

The cholinesterase-inhibiting activity of the phosphorofluoridates was compared quantitatively with that of eserine sulphate thus. To 0-2 ml. of heparinized human plasma was added 05 ml. of a solution containing either eserine or the phosphorofluoridate in varying concentrations then the mixture was kept at room temperature for 10 min. before 1 /tg. of acetylcholine in 1 c.c. saline solution was added. After 5 min. at room temperature, the mixture was made up to 10 ml. with frog saline containing eserine 1/100,000, which at once stopped the action of any cholinesterase not yet inactivated. The solution was then assayed for acetylcholine on the frog rectus-muscle preparation. 

Behavioral and motor effects Mescaline and its analogs inhibit cholinergic neuromuscular transmission by blocking release of acetylcholine and reducing end-plate potentials in the micromolar range (Ghansah et al. 1993). This effect has not been investigated in humans, but it could reduce the force of muscle contractions and motor control. 

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