Editing Functional: Pharmacological Management of LUTS (section)

=== Background ===

* '''<span style="color:#ff0000">Detrusor muscle contracts in response to stimulation of muscarinic receptors by acetylcholine</span>''' and by electric stimulation of intrinsic cholinergic nerves.
** Pre-ganglionic parasympathetic nerves release acetylcholine (Ach)
** This Ach acts on nicotinic receptors on post-ganglionic parasympathetic neurons on the bladder
** In response to this Ach, '''post-ganglionic parasympathetic neurons release Ach which stimulates muscarinic receptors on the bladder smooth muscle, resulting in bladder contraction'''
** Contractile responses can be completely abolished by atropine
* '''<span style="color:#ff0000">Muscarinic receptors</span>'''
** '''Coupled to G proteins,''' but the signal transduction systems may vary.
*** In general, M1, M3, and M5 receptors are considered to couple preferentially to Gq/11, activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium.
*** M2 and M4 receptors couple to pertussis toxin–sensitive Gi/o, resulting in inhibition of adenylate cyclase activity.
** '''<span style="color:#ff0000">5 different subtypes</span>''' based on molecular cloning and (4 different receptor subtypes based on pharmacology)
*** '''M1: thought to be involved in cognition.'''
*** '''M2: primary cholinergic receptor in the heart causing bradycardia when activated and tachycardia when blocked.'''
*** '''M3: primary role in salivation, bowel motility, and visual accommodation.'''
*** '''M4/M5 subtypes are not associated with dry mouth, constipation, tachycardia, drowsiness, blurred vision'''
*** '''<span style="color:#ff0000">M1 to M5 are all found in the bladder</span>'''
**** '''<span style="color:#ff0000">M2 and M3 are the most common type of muscarinic receptors in the bladder, with M2 predominating at least 3:1 over M3 receptors</span>'''
**** '''<span style="color:#ff0000">M3 receptors are the most important for contraction</span>'''
***** '''Stimulation of M3 receptors by ACh induces calcium influx through L-type Ca2+ channels''', as well as IP3 hydrolysis as a result of phospholipase C activation, resulting in the release of intracellular calcium, both of which '''contribute to a smooth muscle contraction'''
***** '''The functional role for M2 receptors is unknown.'''
****** M2 receptor stimulation may oppose sympathetically induced smooth muscle relaxation, mediated by β-ARs via inhibition of adenylyl cyclase
***** Muscarinic receptor subtype-mediated detrusor contractions shift from M3 to M2 receptor subtype in certain pathologic conditions, such as obstructed or neurogenic bladders