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Practical Urology: EssEntial PrinciPlEs and PracticE

PAG and the medial part of the PMC (the

many of them are less useful in the clinical situ-

M-region), which also control the descending

ation due to the lack of selectivity for the LUT,

pathways in the micturition reflex. Thus, PMC

which may result in intolerable side effects. For

can be seen as a switch in the micturition reflex,

example, calcium antagonists and potassium

inhibiting parasympathetic activity in the

channel openers should theoretically be good

descending pathways when there is low activity

targets for drugs aimed for bladder control.

in the afferent fibers, and activating the para-

However, no such drugs have been developed

sympathetic pathways when the afferent activity

with sufficient selectivity for the LUT.

reaches a certain threshold.10 The threshold is

Detailed discussions of possible targets and

believed to be set by the inputs from more ros-

of the basis for therapeutic interventions, as

tral regions in the brain. In cats, lesioning of

well as assessments of current therapeutic prin-

regions above the inferior colliculus usually

ciples can be found in recent comprehensive

facilitates micturition by elimination of inhibi-

reviews.4,13,16

tory inputs from more rostral areas of the brain.

On the other hand, transactions at a lower level

Afferent Signaling Mechanisms

inhibit micturition. Thus, the PMC seems to be

under a tonic inhibitory control. A variation of

Urothelium

the inhibitory input to PMC results in a varia-

tion of bladder capacity. Experiments on rats

Recent evidence suggests that the urothelium

have shown that the micturition threshold is

may serve as a mechanosensor which, by pro-

regulated by, e.g., GABA-ergic inhibitory mech-

ducing NO, ATP, ACh and other mediators, can

anisms in the PMC neurones.

control the activity in afferent nerves, and

thereby the initiation of the micturition reflex.17

Vesico-Spinal-Vesical Micturition Reflex

Low pH, high K+, increased osmolality, and low

temperatures can all influence afferent nerves,

Spinal lesion rostral to the lumbo-sacral level

possibly via effects on the “vanilloid” (TRPV1)

interrupt the vesico-bulbo-vesical pathway and

receptor, which is expressed both in afferent

abolish the supraspinal and voluntary control of

nerve terminals and in the epithelial cells that

micturition. This results initially in an areflexic

line the bladder lumen.18,19 A network of inter-

bladder accompanied by urinary retention.10 An

stitial cells (Interstitial Cells of Cajal; ICC),

automatic vesico-spinal-vesical micturition reflex

extensively linked by Cx43-containing gap junc-

develops slowly, although voiding is generally

tions, was found to be located beneath the

insufficient due to bladder-sphincter dyssyner-

urothelium in the human bladder.20,21 This inter-

gia, i.e., simultaneous contraction of bladder and

stitial cellular network was suggested to operate

urethra. It has been demonstrated in chronic spi-

as a functional syncytium, integrating signals

nal cats that the afferent limb of this reflex is con-

and responses in the bladder wall. The firing of

veyed through unmyelinated C-fibers which

suburothelial afferent nerves and the threshold

usually do not respond to bladder distension,11

for bladder activation may be modified by both

suggesting changed properties of the afferent

inhibitory (e.g., NO) and stimulatory (e.g., ATP,

receptors in the bladder. Accordingly, the mictu-

ACh, tachykinins, prostanoids) mediators. ATP,

rition reflex in chronic spinal cats is blocked by

generated by the urothelium,has been suggested

capsaicin, a neurotoxin which blocks C-fiber

as an important mediator of urothelial signal-

mediated neurotransmission (see below).

ing.22 Supporting such a view, intravesical ATP

induces detrusor overactivity in conscious

rats.23 Furthermore, mice lacking the P2X

Targets for Pharmacologic

3

receptor were shown to have hypoactive

Intervention

bladders.24,25

There seem to be other, thus far unidentified,

factors in the urothelium that could influence

Peripheral Targets

bladder function.13 Fovaeus et al.26 found a pre-

viously unrecognized nonadrenergic, non-

Although there are many drugs acting on peri-

nitrergic, non-prostanoid inhibitory mediator

pheral targets involved in micturition control

is released from the rat urinary bladder by