Decrease muscarinic receptor levels

Neurochemical examination of biopsy and antopsy brain material from Alzheimer patients has revealed loss of the presynaptic marker enzymes acetyl coenzyme A (acetyl-CoA), chohne 6>-acetyltransferase and acetylcholinesterase (AChE), and of muscarinic receptor sites of the M2 subtype correlating with dementia score and severity of nenrohistopathology [8]. These alterations do, to some extent, reflect the well-documented neuronal cell loss in the nucleus of Meynert in presenile dementia and AD. Lesions of this brain nncleus in rats, a limited model for the cholinergic deficit of AD, resnlt in marked reductions in the levels of cholinergic en me markers in the neocortex accompanied by great decreases in the total muscarinic receptor levels [9,10]. 

Short-term memory tasks increase high-affinity uptake of acetylcholine, whereas long-term reference memory tasks cause an acute increase followed by a long-lasting decrease and inhibition (Decker et al. 1988). In contrast, the drug scopolamine creates amnestic effects by blocking muscarinic receptors and decreasing acetylcholine levels. Thus, at... 

The direct slowing of sinoatrial rate and atrioventricular conduction that is produced by muscarinic agonists is often opposed by reflex sympathetic discharge, elicited by the decrease in blood pressure (see Figure 6-7). The resultant sympathetic-parasympathetic interaction is complex because muscarinic modulation of sympathetic influences occurs by inhibition of norepinephrine release and by postjunctional cellular effects. Muscarinic receptors that are present on postganglionic parasympathetic nerve terminals allow neurally released acetylcholine to inhibit its own secretion. The neuronal muscarinic receptors need not be the same subtype as found on effector cells. Therefore, the net effect on heart rate depends on local concentrations of the agonist in the heart and in the vessels and on the level of reflex responsiveness. 

Mondry A, Bourgeois F, Carre F, Swynghedauw B, Moalic JM. 1995. Decrease in beta-1-adrenergic and M2 muscarinic receptor mRNA levels and unchanged accumulation of mRNAs coding for G-alpha i-2 and G alpha s proteins in rat cardiac hypertrophy. J Mol Cell Cardiol 27 2287-2294. 

In heart, muscarinic receptors inhibit adenylyl cyclase, via activation of PTX-sensitive G (35,80,81,136,137). However, K+ channel opening in response to muscarinic stimulation is not the result of decreased levels of cAMP [138,139], Evidence obtained using patch-clamped cells [160] argues against involvement of any second messenger at all [141-143] in regulation of the K+ channel. Moreover, experiments with inside-out patches demonstrate unequivocally that K+ channels couple directly to a receptor-regulated G protein [144,145], We call this functionally identified G protein Gk. 

Both drugs block reuptake of norepinephrine released from sympathetic nerve endings Imipramine inhibits the metabolism of diphenhydramine Both drugs block muscarinic receptors The drugs compete with each other for renal elimination 7. If phenelzine is administered to a patient taking fluoxetine, the most likely result is (A) Antagonism of the antidepressant action of fluoxetine A decrease in the plasma levels of fluoxetine Hypertensive crisis Priapism... 

Fig. 39.2 Suggested effects leading to neuroprotective activity of hupA in AD. HupA is considered to modulate the APP processing by inducing the activity of a-secretase. The increased activity of a-secretase causes enhancement of nutritional APP (sAPPa) and consequently inhibition the A[i pathway. These APP-modulating effects are mediated through Ml muscarinic receptor-mediated PKC-dependent cascade and Trk receptor-mediated ERK/MAPK-dependent cascade and caused by increased levels of ACh and NGF in the synaptic junction. Increased release of sAPPa and decreased A(3 release from APP followed by inhibition of A[i fibril formations affects the regulation of the expression of apoptotic proteins, attenuates oxidative stress, and allows the mitochondria, respiratory chain, and TCA cycle to function normally. APP amyloid precursor protein, PKC protein kinase C. ERK extracellular signal-regulating kinase, MAPK mitogen-activated protein kinase, TCA tricarboxylic acid cycle (citric acid cycle)...

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. 

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