Muscarinic agonists and antagonists: effects on the urinary bladder

Voiding of the bladder is the result of a parasympathetic muscarinic receptor activation of the detrusor smooth muscle. However, the maintenance of continence and a normal bladder micturition cycle involves a complex interaction of cholinergic, adrenergic, nitrergic and peptidergic systems that is currently little understood. The cholinergic component of bladder control involves two systems, acetylcholine (ACh) released from parasympathetic nerves and ACh from non-neuronal cells within the urothelium. The actions of ACh on the bladder depend on the presence of muscarinic receptors that are located on the detrusor smooth muscle, where they cause direct (M₃) and indirect (M₂) contraction; pre-junctional nerve terminals where they increase (M₁) or decrease (M₄) the release of ACh and noradrenaline (NA); sensory nerves where they influence afferent nerve activity; umbrella cells in the urothelium where they stimulate the release of ATP and NO; suburothelial interstitial cells with unknown function; and finally, other unidentified sites in the urothelium from where prostaglandins and inhibitory/relaxatory factors are released. Thus, the actions of muscarinic receptor agonists and antagonists on the bladder may be very complex even when considering only local muscarinic actions. Clinically, muscarinic antagonists remain the mainstay of treatment for the overactive bladder (OAB), while muscarinic agonists have been used to treat hypoactive bladder. The antagonists are effective in treating OAB, but their precise mechanisms and sites of action (detrusor, urothelium, and nerves) have yet to be established. Potentially more selective agents may be developed when the cholinergic systems within the bladder are more fully understood.