Treatment-resistant detrusor overactivity--underlying pharmacology and potential mechanisms.
Bladder function during filling and micturition is regulated by peripheral and central nervous and hormonal control systems. Micturition occurs in response to afferent signals from the lower urinary tract, and distention of the bladder wall is the primary stimulus. In the animal and human bladder, efferent adrenergic, cholinergic and nonadrenergic, noncholinergic (NANC) neurotransmission has been demonstrated. The most important receptors for activation of contraction are muscarinic (M3) and purinergic receptors (P2X1), however, the contribution of these receptors to contraction may differ between species, and may be changed in bladder dysfunction associated with detrusor overactivity (DO) and/or the overactive bladder (OAB) syndrome, such as outflow obstruction, neurogenic bladders, idiopathic DO and diabetes. The NANC component of the nerve-induced response in such disorders may be responsible for up to 40-50% of the total bladder contraction. Whether this in vitro'atropine-resistance' corresponds to DO/OAB seen in patients not responding to antimuscarinic treatment is not known. Afferent signalling from the urothelium may be involved in both normal bladder function and in DO/OAB, but its role in antimuscarinic-refractory patients remains to be established. Several central nervous system (CNS) transmitters/transmitter systems, including gamma aminobutyric acid (GABA), opioid, serotonin, noradrenaline, dopamine or glutamatergic receptors and mechanisms are known to be involved in micturition control. The contribution of these receptors and mechanisms in DO/OAB resistant to treatment with antimuscarinics is not known, but drugs acting at these sites may offer future treatment possibilities.
Andersson
K-E
KE
Department of Clinical and Experimental Pharmacology, Lund University Hospital, Lund, Sweden. karl-erik.andersson@klinfarm.lu.se
D000818:Animals; D002490:Central Nervous System / Q000503:physiopathology; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000502:physiology; D015398:Signal Transduction; D017211:Treatment Failure; D001743:Urinary Bladder / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000503:physiopathology*; D019459:Urothelium / Q000503:physiopathology
D018727:Muscarinic Antagonists; D017981:Receptors, Neurotransmitter