Cholinergic stimulants mechanism

FIGURE 19-1 T Mechanism of action of cholinergic stimulants. Direct-acting stimulants bind directly to the postsynaptic cholinergic receptor. Indirect-acting stimulants inhibit the cholinesterase enzyme, thus allowing acetylcholine to remain in the synaptic cleft. 

The parasympathetic division is the dominant portion of the pulmonary autonomic nervous system in all mammals. Airway smooth muscle is richly supplied with muscarinic receptors and stimulation of M3 receptors results in smooth muscle contraction and bronchoconstriction. Cholinergic stimulation is the primary mechanism of bronchospasm in horses with recurrent airway obstruction (Robinson et al 1996). Parasympathetic innervation can be demonstrated throughout the tracheobronchial tree of the horse but smooth muscle contraction evoked by stimulation of cholinergic nerves is more pronounced in the trachea than in the smaller bronchi. It is expected that parasympathetic blockade with a muscarinic antagonist will have the greatest effect in large, central airways. 

Dupuy, P. M., Winkler, M., Stanek, K., and Zapol, W. M. (1993b). Effect of methylene blue on airway mechanics during cholinergic stimulation. Am. Rev. Respir. Dis. 147(Suppl. 4), A286 (abstr.). 

The antispasmodic agents make use of the muscle relaxation effect of the antimuscarinic agents, but seem to depend on other additional mechanisms for success in obtaining the desired action, which is directly proportionate to the ability to relax the gut muscles in the absence, as well as the presence, of cholinergic stimulation. Examples of these types of dmgs are propantheline, hyoscine-N-butyl bromide and dicycloverine (Fig. 16.17). 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

Bronchial Asthma. Figure 2 Mechanisms of bronchial hyperresponsiveness. Toxic products from eosinophils [cationic peptides, reactive oxygen species (ROS)] cause epithelial injury. Nerve endings become easily accessible to mediators from mast cells, eosinophils [eosinophil-derived neurotoxin (EDN)], and neutrophils, and to airborne toxicants such as S02. Activation of nerve endings stimulates effector cells like mucosal glands and airway smooth muscle either directly or by cholinergic reflexes. 

Fig. 11.4. Model for cholinergic signalling in the intestinal mucosa, providing a possible rationale for AChE secretion by parasitic nematodes. ACh released from enteric cholinergic motor neurons stimulates chloride secretion, mucus secretion and Paneth cell exocytosis through muscarinic receptors. Secretory responses may be modulated by mast cell mediators, either directly or via the induction of neural reflex programmes. The role of muscarinic receptor-positive cells in the lamina propria of rats infected with N. brasiliensis is undetermined, as are potential mechanisms of trans-epithelial transport of the enzymes. Adapted from Cooke (1984).

HT4 receptors are also present in the pig and human hearts, primarily located in the atrium [9]. Experiments showed that stimulation of these receptors can result in tachycardia and can trigger positive inotropic effects. Moreover, it has been demonstrated that the 5-HT4 receptor is present in the human detrusor muscle and facilitates a cholinergic mechanism which may lead to increased bladder contractions [10]. Finally, acute (but not repeated) stimulation of 5-HT4 receptors present on the human adrenal cortex has been reported to trigger the release of corticosterone and aldosterone [11]. 

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