TRP channels in lower urinary tract dysfunction

Abstract

Lower urinary tract dysfunction (LUTd) represents a major healthcare problem. Although it is mostly not lethal, associated social disturbance, medical costs, loss of productivity and especially diminished quality of life should not be underestimated. Although more than 15% of people suffer from a form of LUTd to some extent, pathophysiology often remains obscure. In the past 20 years, transient receptor potential (TRP) channels have become increasingly important in this field of research. These intriguing ion channels are believed to be the main molecular sensors that generate bladder sensation. Therefore, they are intensely pursued as new drug targets for both curative and symptomatic treatment of different forms of LUTd. TRPV1 was the first of its class to be investigated. Actually, even before this channel was cloned, it had already been targeted in the bladder, with clinical trials of intravesical capsaicin instillations. Several other polymodally gated TRP channels, particularly TRPM8, TRPA1 and TRPV4, also appear to play a prominent role in bladder (patho)physiology. With this review, we provide a brief overview of current knowledge on the role of these TRP channels in LUTd and their potential as molecular targets for treatment.

Figure 1

Schematic traces of video-urodynamic recordings, as seen in patients with different types of LUTd. LUTd can often be objectively measured by video-urodynamic recording. Although P_detrusor, a measure of the force generated by the bladder muscle, cannot be measured directly, it can be calculated by subtracting abdominal pressure (measured by a rectal catheter) from intravesical pressure (measured by an intravesical catheter). Q_flow visualizes the flow of urine through the urethra. In the EMG trace, activity of the urethral sphincter is measured. Top figure: Normal filling and voiding, as one would expect to see in a healthy person. Second: In patients with neurogenic detrusor overactivity (NDO), the bladder often has an altered shape, desire to void is less prominent due to the loss of afferent input and the detrusor muscle is overactive. Third: NDO is often accompanied by detrusor sphincter dyssynergia (DSD). The same features of NDO are present, but during voiding, the sphincter fails to relax, causing high intravesical pressure and reduced emptying of the bladder. Fourth: In patients with overactive bladder syndrome (OAB), bladder pressure, urine output, bladder shape and EMG recording are all normal, but patients report a strong desire to void at much lower volumes than normal controls. Maximal bladder volume is often also lower. Last: In contrast to OAB, idiopathic detrusor overactivity (IDO) does not cause earlier desire to void, but the detrusor is more active during the filling phase. OAB and IDO are often present simultaneously in patients.

Figure 2

TRP channels in LUTd. Overview of all forms of LUTd that are discussed in this review, with their respective links to TRP channels that have been implicated in their treatment or pathogenesis.