Clinical Science (1986)7 0 (Suppl.14), 3s-6s
3s
The distribution of noradrenergic nerves in the human lower
urinary tract
JOHN A. GOSLING
Medical School, University ofManchester, U.K.
The following account reviews some of our work on
the distribution of sympathetic nerves in the human
urinary tract. As an initial comment it is important
to stress that considerable species variation occurs
in the innervation of the lower urinary tract. As
examples, the rat bladder does not possess intramural ganglion cells although neurones can be
readily demonstrated amongst human detrusor
muscle; in the cat a rich distribution of
noradrenergic nerves occurs in the body of the
bladder, whereas in the human, nerves of this type
are rarely observed amongst detrusor muscle cells.
In obtaining human samples acknQwledgment is
made to clinical colleagues who have provided the
material which has enabled the present histochemical and fine structural study to be completed.
Gross anatomy of the sympathetic input to the
pelvis
The superior hypogastric plexus, often called the
presacral nerve, is formed by sympathetic nerve
fibres which descend into the pelvis and receives
contributions from the lower two thoracic and
upper two lumbar segments of the spinal cord.
These fibres cross the pelvic brim and continue as
the inferior hypogastric plexus. Parasympathetic
fibres from the second, third and fourth sacral
nerves join with these sympathetic fibres to form
the pelvic plexus. Additional sympathetic fibres
derived from the lumbar and pelvic parts of the
sympathetic ganglia also contribute to the pelvic
piexus.
Key words: bladder, cholinergic nerve fibres, ganglia, noradrenergic nerve fibres, rhabdosphincter,
urethra.
Correspondence: Professor J. A. Gosling, Department
of Anatomy, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9FT, U.K.
Distribution of catecholamine-containing nerves
in the bladder and the urethra
Catecholamine-containing nerves in relation to
autonomic neurones
The vesical plexus lies close to the bladder wall
and contains groups of ganglion cells which extend
into the adventitia of the bladder. These neurones
are uniform in size and structure and are rich in
acetylcholinesterase but devoid of cytoplasmic
catecholamine.
It is assumed that these non-cholinergic cell
bodies are ‘cholinergic’in type. These ‘presumptive
cholinergic’ neurones which lie within the vesical
plexus are closely related to beaded noradrenergic
terminals. Similar noradrenergic neurones occur in
small groups throughout the human detrusor.
Recent fine structural studies have demonstrated
nerve terminal regions containing small dense cored
vesicles lying in close proximity to these intramural
ganglion cells. Nerve terminals containing 40-60
nm diameter electron dense vesicles are thought to
characterize noradrenergic nerves. Hence these
structural observations lend support to the view
that those autonomic neurones which supply the
bladder are influenced by sympathetic nerves.
Catecholamine-containing nerves and bladder
smooth muscle
As previously noted noradrenergic nerves are
rarely observed amongst bladder smooth muscle
cells. Unfortunately, in adult human material the
presence of abundant autofluorescent connective
tissue makes identification of catecholaminecontaining terminals particularly difficult with the
light microscope. Nevertheless, with the electron
microscope, terminals containing vesicles with
small dense cores have not been observed.
Trigonal smooth muscle lies immediately deep to
the epithelium of the region and forms a thin layer
on the inner aspect of the detrusor muscle. Cate-
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J. A . Gosling
cholamine-containing nerves are evident amongst
this type of muscle with both light and electron microscope techniques. These findings are compatible
with the visual observations of Learmonth, namely
that direct electrical stimulation of the inferior
hypogastric plexus causes the smooth muscle of the
trigone to kontract.
These regional differences in the distribution of
noradrenergic nerves are of importance when
studies of detrusor muscle in vitro are to be undertaken. With regard to biochemical studies on bladder biopsy samples it is also of importance to note
that trigonal epithelium (unlike urothelium elsewhere in the bladder) is characterized by the
occurrence of 5-hydroxydopamine-containing
enterochromaffin cells.
Catecholamine-containing nerves and the male
bladder neck and urethra
Important sex differences in the distribution of
sympathetic nerves occur in the region of the bladder neck. Embedded in the posterior aspect of the
capsule of the prostate are small catecholaminecontaining neurones. This type of nerve cell corresponds in the human to the so-called short
noradrenergic neurone, which has been described
in other species and is believed to be involved in the
sympathetic innervation of the male genital tract.
These neurones probably supply sympathetic
fibres to the prostate, vas deferens, seminal vesicle
and the bladder neck. In addition some fibres may
extend into the vesicle plexus and there intluence
the presumed parasympathetic neurones which
supply the bladder muscle. From a functional viewpoint, although the sympathetic innervation of the
male genital tract is widely acknowledged, it is not
known whether the ‘short’ noradrenergic cell bodies
represent the sole source of nerves of this type.
T h e role played by the sympathetic innervation
of the bladder neck also remains unresolved.
Although stimulation of these nerves at the time of
ejaculation is very effective in preventing reflux of
semen into the bladder, it is not known whether
they maintain resting tone of the smooth muscle
cells of the bladder neck.
Catecholamine-containing nerves and the female
bladder neck and urethra
Physiological and pharmacological evidence
has
demonstrated
sympathetically
induced
responses of the smooth muscle of the female
urethra. However, morphological studies have
failed to demonstrate a significant population of
catecholamine-containing nerve fibres. Hence the
influence of sympathetic nerves on the smooth
muscle of the female bladder neck and urethra is
unresolved.
Catecholamine-containing nerves and the rhabdosphincter
In both sexes the intramural striated muscle of
the urethra (the rhabdosphincter) lies on the outer
aspect of the smooth muscle coat. Amongst the
striated cells of the rhabdosphincter occasional noradrenergic nerves are observed which are unrelated
to the vascular supply of the region. A similar
arrangement has been observed in other striated
muscles, namely the diaphragm and the pelvic floor.
Hence, although the sympathetic nervous system
may modify the activity of the rhabdosphincter, this
influence is not unique to this particular sphincter
(as claimed by other workers) and may be of widespread occurrence.
Summary
Noradrenergic nerves have been demonstrated
amongst the ganglion cells of the vesical plexus and
of the bladder. Trigonal smooth muscle receives a
supply of noradrenergic fibres although similar
nerves are rarely observed in relation to the smooth
muscle of the detrusor. In the male numerous noradrenergic nerves occur in the walls of the bladder
neck, prostate, seminal vesicles and vas deferens;
nerves of this type are scarce in the smooth muscle
coat of the female bladder neck and urethra. The
striated muscle of the rhabdosphincter in both sexes
receives a scant (but significant) supply of noradrenergic nerve fibres.
DISCUSSION
Mundy: In relation to the ganglia, could you
relate what you have been saying to the presence of
so-called SIF cells (small intensely fluorescent cells)
in ganglia? Secondly, could you tell us whether you
think that the morphological di€ferences between
extramural and intramural ganglia reflect in any
way functional differences? And finally, could you
comment on whether you think there might be a difference between the thoracolumbar input through
the recognized hypogastric nerves and other nerve
filaments you mentioned from the lumbar and
sacral segments of the cord?
Gosling: Concerning SIF cells, we have demonstrated their presence in cats but have been unable
Noradrenergic nerves in the urinary tract
to do so in human material. In fetal and infant
human species, we have observed masses of adrenaline-containing paraganglia associated with developing autonomic nerves. However, in these
specimens SIF cells were also absent.
With regard to possible differences between
intravesical or extravesical ganglia - I would
speculate that since the cell bodies are rich in
acetylcholinesterase, and that in both locations they
are associated with noradrenergic nerves (probably
inhibitory in function), they should be regarded as
being functionally similar.
I am uncertain as to what the contribution made
from the lower lumbar and pelvic sympathetic ganglia might be to the general functional signhcance of
the vesical plexus.
Burnstock: You mentioned how difficult it often
is in human tissue to distinguish specific fluorescence from the background autofluorescence. Tim
Cowan in our laboratory has recently developed a
beautiful way of distinguishing these two kinds of
fluorescence by using pontamine sky blue. This
makes the background a kind of nice orange colour
and the green fluorescence then shines up above it.
This is good not only for catecholamines but for all
the immunofluorescent techniques.
My question concerns your discussion of the
noradrenergic fibres in the striated muscle. You
made the point that one cannot base a decision
about whether they are innervating striated muscle
on morphology alone. One needs physiology. You
mentioned some evidence for striated muscle of the
diaphragm and pelvic floor having noradrenergic
innervation. Did this show that noradrenergic
stimulation changed membrane potential in striated
muscle or did it interfere with motor cholinergic
nerve transmission acting presynaptically? What
was it actually doing? What was the evidence?
Gosling: The evidence (not so much physiological as neuroanatomical) was based on serial thin
sections tracing noradrenergic fibres into the
muscle, to show synaptic relationships with the
striated cells. As far as they could determine these
nerves were not related to any other recognized
sympathetic target site (e.g. vessels). They assumed,
and quoted other evidence, that striated muscle was
influenced by the noradrenergic terminals they
demonstrated in close relation with the striated
muscle. For physiological support they were relying
on other workers who demonstrated a response of
striated muscle to noradrenergic stimulation, with
the details of which I am unfamiliar.
Burnstock: But they have not actually shown it in
the bladder, so we still do not have any direct evidence for a noradrenergic input.
Gosling:That is correct, this was not in the bladder.
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Burnstock: These days one can localize receptors with autoradiography and it would be worth
seeing whether there are noradrenergic receptors
on the striated muscle cells, too. Those together
might make a more convincing picture.
Hindmarsh: Have you noticed any difference in
the terminals within the ganglia of a male and
female? Have you actually made any differentiation
between the two?
Gosling:No.
Hindmarsh: Do you think that there might be a
difference between the two?
Gosling:If one regards the sympathetic terminals
on vesical ganglia as having an inhibitory influence
upon bladder activity in the male, bladder contractions would be inhibited by noradrenergic terminals acting on vesical gangha to prevent detrusor
contraction at the time of ejaculation. I do not know
whether bladder inhibition at the time of arousal
occurs in the female.
Hindmarsh: I think that John Malvern has been
looking at people who have urgency at the point of
excitement or climax in the female.
Milroy: You showed a beautiful slide of the trigone with a very rich innervation of presumed noradrenergic endings. Was that from a male bladder?
Are male and female the same?
Gosling:The same. There is no difference, as far
as we can judge, in the distribution of noradrenergic
nerves in the trigone.
Milroy: Does that innervation continue into the
bladder neck?
Gosling: It does through the bladder neck and
into the preprostatic region in the male. It becomes
a continuation of the urethral smooth muscle in the
female.
Milroy: So the female bladder neck is no
different in its innervation?
Gosling: In the female innervation decreases in
the urethral smooth muscle. This result may be a
technical failure. So it may be that it relates to our
failure to demonstrate a continuation of noradrenergic nerves from the trigone down h t o the
female urethra.
Mundy: There have been various bits of pharmacological evidence to suggest that cholinergic
innervation of the urethra is somewhat less than in
the bladder. Could you comment on the distribution of cholinergic neurones in the urethra as compared with the bladder?
Gosling: We have never found enzyme-positive
ganghon cells within the wall of the urethra. However, the distribution of enzyme-positive nerves is
surprisingly rich in both sexes. Numerous enzymepositive nerves ramify in the prostatic substance
and in the smooth muscle component of the female
urethra. Interestingly, pharmacological evidence
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J. A. Gosling
exists to show that acetylcholine seems to be
singularly ineffective at causing contraction of
female urethral smooth muscle.
Brown: What is the significance of the sympathetic nerve fibres in the trigone?
Gosling: T h e terminal ureter has a rich sympathetic innervation in comparison with the upper
ureter. It may be that sympathetic fibres are in some
way important in controlling the lower ureter, trigone and ureterovesical orifice.
Cuine: As the question of cholinergic innervation
was mentioned, could I ask if you have noticed any
difference in the cholinergic innervation of the anterior as opposed to the posterior prostatic capsule? Because pharmacologically we have found
quite a difference.
Gosling:No, I cannot say I have noticed that.
Andersson: Noradrenergic nerves are not necessarily synonymous with sympathetic nerves. Do you
have any indication of nerves being within the sympathetic nervous system which d o not contain noradrenaline as a transmitter? I think we shall discuss
this later on, but is there a morphological basis for
it?
Gosling: There are well-recognized cholinergic
sympathetic nerves: for example, those that con-
trol sweating. I use the classification of sympathetic
and parasympathetic very loosely. T h e presence of
cell bodies in the capsule of the prostate is counter
to traditional teaching, where sympathetic nerves
are supposed to have their cell bodies located central to the target site. Would one then include them
as sympathetic or parasympathetic? They could be
classified as parasympathetic noradrenergics. So
you are dealing, I think, with semantics.
Andersson: I did not mean that. I mean that even
if you have noradrenaline within sympathetic
nerves, it does not mean that it is the only transmitter you can find. If you stimulate the hypogastric
nerve you clearly have effects on both the bladder
and the urethra. If you look at the pictures you
showed and the amounts of noradrenaline coming
out, it is difficult to conceive that noradrenaline is
the transmitter doing all these things in the bladder
and the urethra. It might be that there are two
operations, co-transmitters. That was what I meant.
Gosling:I see. We are using as a marker for this
particular type of nerve noradrenaline, a catecholamine. Within the same terminal there may be other
substances about which we have little knowledge
which are being released as co-transmitters.