Therapeutic Modulation of Urinary Bladder Function: Multiple Targets at Multiple Levels

Abstract

Storage dysfunction of the urinary bladder, specifically overactive bladder syndrome, is a condition that occurs frequently in the general population. Historically, pathophysiological and treatment concepts related to overactive bladder have focused on smooth muscle cells. Although these are the central effector, numerous anatomic structures are involved in their regulation, including the urothelium, afferent and efferent nerves, and the central nervous system. Each of these structures involves receptors for—and the urothelium itself also releases—many mediators. Moreover, hypoperfusion, hypertrophy, and fibrosis can affect bladder function. Established treatments such as muscarinic antagonists, β-adrenoceptor agonists, and onabotulinumtoxinA each work in part through their effects on the urothelium and afferent nerves, as do α1-adrenoceptor antagonists in the treatment of voiding dysfunction associated with benign prostatic hyperplasia; however, none of these treatments are specifically targeted to the urothelium and afferent nerves. It remains to be explored whether future treatments that specifically act at one of these structures will provide a therapeutic advantage.

Epigallocatechin-3-gallate alleviates bladder overactivity in a rat model with metabolic syndrome and ovarian hormone deficiency through mitochondria apoptosis pathways

“…In current clinical treatment for OAB, anti-muscarinic agents, β3-adrenoceptor agonists, and botulinum toxins intravesical injection have been reported to be helpful 41 . But these agents suppress the OAB symptoms without alleviating the underlying etiology; therefore, additional treatment modalities are needed.…”

Biased Agonism in Drug Discovery—Is It Too Soon to Choose a Path?

“…Thus, while such drugs were already in clinical development, it became clear that cAMP generation plays a minor role (if any role at all) in mediating detrusor smooth muscle relaxation by b-adrenoceptor agonists (Frazier et al, 2005;Uchida et al, 2005). Perhaps even more importantly, it is now increasingly being questioned whether the detrusor smooth muscle cell is indeed the cellular target of this drug class or rather is indirectly modulated via the urothelium, afferent nerves, or other structures (Michel, 2015). Therefore, even with today's knowledge it is difficult to say which cell type (system bias) and which signaling pathway (ligand bias) would be the optimal target for the treatment of OAB syndrome.…”

Are blood vessels a target to treat lower urinary tract dysfunction?

“…More recently, it became clear that several other types of cells and organs contribute to regulating detrusor smooth muscle function. These include the urothelium (Andersson and McCloskey 2014;Michel 2015), afferent nerves (Michel and Igawa 2015;Yoshimura et al 2014b), and the central and autonomic nervous systems (Fowler and Griffiths 2010;Yoshimura et al 2014a). Alterations in any of these may at least partly be responsible for detrusor dysfunction and, accordingly, be potential targets for the treatment of bladder dysfunction.…”