Muscarinic action of ACh

In view of the preponderance of muscarinic receptors in the CNS and the conceived need to augment the muscarinic actions of ACh in the treatment of Alzheimer s disease, much attention has been given recently to the synthesis of agonists that penetrate the blood-brain barrier, especially those that act specifically on M] receptors. 

VII. Muscarinic Action of ACh Appears to Regulate the Release of Catecholamines in Hypoxia-Challenged Carotid Bodies... 

Acetylcholine—the acetic ester of choline—has very strong and multiple biological actions. It excites or inhibits many organs and tissues in concentrations as low as 10" -10 ° even much higher sensitivity to ACh has been described. Dale divided the diverse effects of ACh into two large groups muscarinic and nicotinic effects. The muscarinic effects of ACh include its action on smooth muscle, for example its capacity to stimulate intestinal muscles or to cause a fall in blood pressure its inhibitory action on the cardiac pace-maker and muscles its action on the glands, the ability to induce salivary secretion, for instance. The muscarinic action of ACh resembles the effects of parasympathetic nerves it is reproduced by muscarine and blocked by atropine. 

Chapter 1 which showed that since muscarine mimicked some of the actions of ACh (but not all) while nicotine mimicked the other actions of ACh, then ACh probably acted on two distinct types of receptors. The fact that atropine antagonised the muscarinic effects of ACh but not the nicotinic effects, while tubocurarine blocked the nicotinic effects provided firm evidence for this concept. These simple qualitative observations by Langley and others at the beginning of the twentieth century led to the development of more quantitative pharmacological methods that were subsequently used to identify and classify receptors. These methods were based on the use of both (1) agonist and (2) antagonist drugs ... 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

Activation of endothelial cell muscarinic receptors by acetylcholine (Ach) releases endothelium-derived relaxing factor (nitric oxide), which causes relaxation of vascular smooth muscle precontracted with norepinephrine, 10-8M. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of Ach on vascular smooth muscle. (NA, noradrenaline [norepinephrine]. Numbers indicate the log concentration applied at the time indicated.)... 

Muscarinic receptors play an essential role in regulating the functions of organs innervated by the autonomic nervous system to maintain homeostasis of the organi.sm. The action of ACh on muscarinic receptors con re.sull in. stimulation or inhibition of the organ system affected. ACh stimulates secretions from salivary and sweat glands, secretions and contraction of the gut. and constriction of the airways of the respiratory tract. It inhibits contraction of the heart and relaxes smooth muscle of blood vc.ssels. 

Hasselmo and Bower (1992a,b) have examined the actions of ACh on PC neurons excitability. In PC slices, ACh and muscarinic cholinergic agonists cause a suppression... 

Atropine competes with ACh and other muscarinic agonists for a common binding site on the muscarinic receptor, thus effectively antagonizing the actions of ACh at muscarinic receptor sites, which would otherwise lead to increased tracheobronchial and salivary secretions, bronchoconstriction and bradycardia. The... 

Stimulation or inhibition of autonomic effector cells by ACh results from interaction of ACh with muscarinic ACh receptors. In this case, the effector is coupled to the receptor by a G protein (see Chapter 1). In contrast to skeletal muscle and neurons, smooth muscle and the cardiac conduction system (sinoatrial [SA] node, atrium, atrioventricular [AV] node, and the His-Purkinje system) normally exhibit intrinsic activity, both electrical and mechanical, that is modulated but not initiated by nerve impulses. At some smooth muscle, ACh causes a decrease in the resting potential (i.e., the membrane potential becomes less negative) and an increase in the frequency of spike production, accompanied by a rise in tension. A primary action of ACh in initiating these effects through muscarinic receptors is probably partial depolarization of the cell membrane brought about by an increase in Na and, in some instances, Ca conductance activation of muscarinic receptors can also activate the G -PLC-IP pathway leading to the mobilization of stored Ccf. Hence, ACh stimulates ion fluxes across membranes and/or mobilizes intracellular Ca to cause contraction. 

Muscarinic agonists mimic the muscarinic effects of ACh and typically are longer-acting congeners of ACh or natural alkaloids that display httle selectivity for the various subtypes of muscarinic receptors. The muscarinic, or parasympathomimetic, actions of the drugs considered in this chapter are practically equivalent to the effects of postganglionic parasympathetic nerve impulses hsted in Table 6-1. AH of the actions of ACh and its congeners at muscarinic receptors can be blocked by atropine. 

Ipratropium bromide (ATROVENT, others) is a quaternary ammonium derivative of atropine. Oxitropium bromide is a quaternary derivative of scopolamine. Ipratropium blocks all subtypes of muscarinic receptors and thus blocks presynaptic muscarinic inhibition of ACh release. The most recently developed and bronchoselective member of this family, tiotropium bromide (spiriva), has a longer duration of action and shows some selectivity for Mj and M3 receptors, with lower affinity for receptors, and thus less presynaptic effect on ACh release. 

---