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Practical Urology: EssEntial PrinciPlEs and PracticE

variables, mirabegron was significantly superior

potent for excitation.106 Possibly, both capsaicin

to placebo concerning mean volume voided per

and RTX can have effects on Ad-fibers. It is also

micturition, mean number of incontinence epi-

possible that capsaicin at high concentrations

sodes, nocturia episodes, urgency incontinence

(mM) has additional, non-specific effects.107

episodes, and urgency episodes per 24 h. The

Experimental and clinical evidence suggest

drug was well tolerated, and the most commonly

that capsaicin-sensitive afferents can be involved

reported side effects were headache and gastro-

in a number of urological disorders, including

intestinal adverse effects. The results of this

neurogenic and idiopathic DO, painful bladder

proof of concept study showed that the principle

syndrome/interstitial cystitis, and hemorrhagic

of b3-AR agonism may be useful for treatment

cystitis.102 Both capsaicin and resiniferatoxin

of patients with OAB/DO.

have been used successfully to treat bladder

function disturbances.4 However, the difficulties

Transient Receptor Potential (TRP) Receptors

with the handling of resiniferatoxin (e.g., the

drug may adhere to the administration device),

Appropriate bladder function is dependent on an

has limit the use of this therapeutic approach.

intact afferent signaling from the bladder to the

CNS. This signaling conveys information about

bladder filling and the status of the tissue, e.g.,

Phosphodiesterases (PDEs)

presence of infectious agents etc. As mentioned

Drugs stimulating the generation of cAMP are

previously, the afferent nerves comprise small,

slowly conducting myelinated Ad-fibers and

known to relax smooth muscles, including the

slowly conducting, unmyelinated C-fibers. The

detrusor.1,89 It is also well established that drugs

former are excited by mechanoreceptors and con-

acting through the NO/cGMP system can relax

vey information about bladder filling, while

the smooth muscle of the bladder outflow region.1

C-fibers mediate painful sensations recognized by

Use of PDE inhibitors to enhance the cAMPand

chemoreceptors. Among these are the TRP recep-

cGMP-mediated relaxation of LUT smooth mus-

tors.102,103 The mammalian TRP family consists of

cles (detrusor prostate, urethra) should then be a

28 channels that can be subdivided into six differ-

logical approach to treat OAB/DO.108

ent classes. TRP channels are activated by a diver-

Studies with the PDE1 inhibitor, vinpocetine

sity of physical (voltage, heat, cold, mechanical

(reducing the break-down of cAMP), showed

stress) or chemical (pH, osmolality) stimuli and

relaxant effects in vitro, but poor clinical effi-

by binding of specific ligands, enabling them to

cacy in OAB/DO patients.109 PDE 4 (which also

act as multifunctional sensors at the cellular level.

preferably hydrolyses cAMP) has been impli-

Among the many TRP channels demon-

cated in the control of bladder smooth muscle

strated in the LUT, so far only the TRPV1 chan-

tone. PDE 4 inhibitors reduced the in vitro con-

nel has been the target of clinical interventions.

tractile responses of guinea pig110 and rat111,112;

By means of capsaicin, a subpopulation of pri-

bladder strips, and also suppressed rhyth-

mary afferent neurons innervating the bladder

mic bladder contractions of the isolated guinea

and urethra, the “capsaicin-sensitive nerves,”

pig bladder.30 There seems to be no published

has been identified. It is believed that capsaicin

experience of the effects of PDE 4 inhibition in

exerts its effects by binding to and activating

the treatment of OAB/DO. However, previous

TRPV1 receptors on these nerves. Capsaicin

experiences with selective PDE 4 inhibitors,

exerts a biphasic effect: initial excitation is fol-

used for other indications, showed emesis to be

lowed by a long-lasting blockade, which renders

a dose-limiting effect.113 If this adverse effect

sensitive primary afferents (C-fibers) resistant

can be avoided, the preclinical information sug-

to activation by natural stimuli. In sufficiently

gests that PDE 4 inhibition may be a promising

high concentrations, capsaicin is believed to

approach.

cause “desensitization” initially by releasing

Treatment with sildenafil (PDE 5 inhibitor,

and emptying the stores of neuropeptides, and

preventing break-down of cGMP) improved uri-

then by blocking further release.Resiniferatoxin

nary symptom scores in men with erectile dys-

is an analogue of capsaicin, approximately 1,000

function and LUT symptoms (LUTS114), and this

times more potent for desensitization than cap-

observation has been confirmed in randomized,

saicin,104,105 but only a few hundred times more

controlled clinical trials.115–117