The urinary bladder has several layers including the urothelium, lamina propria, and detrusor smooth muscle. The urothelium acts as a barrier between urine and the bladder wall. It transports ions and detects chemical and mechanical stimuli using various receptors. When activated, urothelial cells release substances that can signal nearby nerves or interstitial cells in the lamina propria. This signaling is believed to play a role in bladder sensation and function.

1. Anatomy and Physiology of
Urinary Bladder
Dr. Vivek. A
Urology PG
KMC / GRH

19. Lamina Propira and Vasculature
The lamina propria has been theorized to be the “functional center” for localized control of
the bladder, coordinating the activities of the urothelium and detrusor smooth muscle
Within the lamina propria, there is a diffuse plexus of unmyelinated nerve fibers making
contact with urothelium, blood vessels, and detrusor smooth muscle.
In addition to the nerve fibers, other important structures in the lamina propria include
interstitial cells (myofibroblasts) and microvasculature.
These myofibroblasts positioned in the lamina propria are primed to modulate physiologic
interactions between the urothelium and detrusor smooth muscle

21. Stroma
The main constituents of bladder wall stroma are collagen and elastin in a matrix composed of
proteoglycans.
The main cells are fibroblasts.
The passive mechanical properties of the bladder wall depend on the viscoelastic properties of the
stroma and of the relaxed detrusor muscle
The stroma has commonly been considered a passive low-metabolic tissue that fills out the space
among muscle bundles, vessels, and nerves
There has been increased appreciation for the role of the stroma in the adaptation of the bladder to
pathophysiologic conditions

22. Stroma
Bladder hypertrophy is likely
to involve an interaction of
stroma and smooth muscle.
In arteries, disruption of
elastin in the stroma can
stimulate proliferation of
smooth muscle
Although no such
mechanisms are yet known
in the bladder, it is possible
that there could be a more
intimate relationship
between changes in the
composition of the stroma
and muscle function and
growth than is appreciated at
present

23. Bladder Wall Collagen
Most of the bladder wall
collagen is found in the
connective tissue outside
the muscle bundles.
Changes in the relative
amounts of muscle and
nonmuscle tissue in the
bladder wall would
therefore influence collagen
concentration.
A number of different
collagen types have been
identified.
In the bladder, types I, III,
and IV are the most
common

24. Bladder Wall Collagen
• Morphometric and histochemical techniques to determine the
percentage volume of connective tissue in the bladder wall and to
measure the two major types (I and III) of collagen
• These methods quantitate three parameters of bladder
ultrastructure:
1.percentage volume of connective tissue,
2.ratio of connective tissue to smooth muscle, and
3.ratio of type III to type I collagen.
• These parameters have been shown to be abnormally elevated in
patients with bladder disease compared with normal patients.

25. Bladder Wall Collagen
The ratio of connective tissue to smooth muscle was significantly increased in
poorly compliant versus normal bladders.
The ratio of type III to type I collagen was also significantly elevated.
One can conclude that the poor storage function of poorly compliant bladders
is secondary to an alteration in the connective tissue content of the bladder
wall, especially increased collagen type III.

26. Bladder Wall Elastin and Matrix
Elastic fibers are amorphous structures composed of elastin and a microfibrillar component located mainly around the periphery of the
amorphous component
Elastin fibers are sparse in the bladder compared with collagen but are found in all layers of the bladder wall.
In spinal cord–injured rats, the elastin-to-collagen ratio increases over the first 6 weeks after injury.
During this 6 weeks, the bladder compliance increases and the bladder becomes overdistended.
Then the ratio is reduced as bladder compliance is decreased as a result of the emergence of DO 10 weeks after injury, suggesting a
potential role for elastin in the modulation of bladder compliance (Nagatomi et al., 2005; Toosi et al., 2008).
The nonfibrillar matrix in the stroma is largely composed of a gel of proteoglycans and water.
Proteoglycans are glycoproteins with glycosaminoglycans (GAGs) covalently attached.
The arrangement of the proteoglycans in the matrix creates a compartment of tissue water that has a viscous behavior when it is
subjected to deformation.

27. Smooth Muscle
Histologic examination of the bladder body reveals that myofibrils are arranged into fascicles (bundles) in random directions
The individual cells within a bundle are connected to form a functional syncytium.
This architecture differs from the discrete circular and longitudinal smooth muscle layers in the ureter or gastrointestinal (GI)
tract.
Bladder smooth muscles have no cross striations visible under the microscope.
Each detrusor smooth muscle cell contains a single nucleus.
The individual smooth muscle cells in the bladder wall are small spindle-shaped cells with a central nucleus; fully relaxed,
they are several hundred micrometers long with a 5- to 6-µm maximum diameter
The cell membranes of smooth muscle contain caveolae—flask-shaped invaginations of the membrane—and elements of
the intracellular sarcoplasmic reticulum (SR) are often associated with caveolae

28. The motor innervation of the bladder smooth muscle is from the postganglionic parasympathetic
nerve fibers, although intramural ganglia can exist within the bladder wall.
Varicosities can release a variety of neurotransmitters including acetylcholine (ACh) and adenosine
triphosphate (ATP).
It is unlikely that every smooth muscle cell receives direct synaptic contact; the presence of gap
junctions allows excitation to propagate throughout the smooth muscle syncytium.
Postjunctional receptors, such as muscarinic and purinergic receptors, are present on the smooth
muscle cell.
When activated by their respective agonists, these receptors initiate the excitation-contraction
events of the smooth muscle.
The detrusor smooth muscle has afferent innervation that could mediate afferent signals related to
smooth muscle activity

30. Fiber Types of Urethral Striated Muscle
Striated muscles are characterized as slow type and twitch type.
Twitch-type myofibrils can be further classified as slow and fast on the basis of functional and
metabolic characteristics
Slow-twitch fibers seem ideally suited to maintaining sphincter tone for prolonged periods, whereas
fast-twitch fibers may be needed to add to sphincter tone rapidly to maintain continence when
intra-abdominal pressure is abruptly increased.
Similar to smooth muscle, contraction of striated muscle fibers is governed by intracellular calcium,
through interactions with troponin.

31. The fast-twitch fibers can be recruited rapidly but also fatigue rapidly and perform
predominantly anaerobic metabolism
Fast-twitch fibers exhibit rapid bursts of contractile force and are rich in myosin
ATPase that catalyzes the actin-myosin interaction.
The speed of contraction may be correlated with the histochemical reaction of this
ATPase and alkaline pH.
In addition, fast-twitch muscles are supplied with a fast isoform of the Ca2+ -ATPase,
which translocates the cytosolic calcium into the abundant SR to allow rapid relaxation

32. In contrast, slow-twitch fibers are found in greater percentage in muscles that
require sustained tension, such as the pelvic levators and urethral sphincter
These muscle fibers are recruited and fatigue slowly and can perform high rates of
oxidative metabolism because they possess less of the myosin ATPase activity and
contain an increased expression of a slow isoform of the Ca2+ -ATPase
These fibers give rise to the background electromyographic activity seen during a
urodynamic evaluation

33. External Urethral Sphincter (EUS)
Rhabdosphincter
Skeletal muscle that is
present in the walls of the
urethra and is separate from
the periurethral skeletal
muscle of the pelvic floor.
The muscle cells are smaller
than ordinary skeletal
muscle: 15 to 20 µm in
diameter.

34. External Urethral Sphincter (EUS)
• The EUS is composed of two parts.
1. Peri urethral striated muscle component
2. Smooth muscle component

35. External Urethral Sphincter (EUS)
• The periurethral striated muscle of the pelvic floor contains fast-
twitch and slow-twitch fibers.
• The striated muscle of the distal sphincter mechanism contains
predominantly slow-twitch fibers) and provides more than 50% of the
static resistance
• In the male, the rhabdosphincter consists of 35% fast-twitch and 65%
slow-twitch fiber
• In the female, the ratio is 87% slow-twitch and 13% fast-twitch fibers

36. The majority of the fast-twitch fibers and about a fourth of the slow-twitch
fibers in the intramural striated muscle of the human membranous urethral
sphincter show positive staining for nitric oxide (NO) synthase (NOS) in the
sarcolemma
Moreover, the striated periurethral muscles of the pelvic floor are adapted for
the rapid recruitment of motor units required during increases in abdominal
pressure.
It has been speculated that the successful treatment of stress incontinence
by pelvic floor exercises or electrostimulation is caused by the conversion of
fast-twitch to slow-twitch striated muscle fibers

37. SMOOTH MUSCLE COMPONENT, which receives noradrenergic
innervation.
Stimulation of the hypogastric nerve elicits myogenic potentials in
the EUS
Whether this activity is the result of smooth or striated muscle is
unclear
Because these potentials persist after α-adrenergic blockade,
investigators postulate that the activity arises from striated muscle

39. UROTHELIAL PHYSIOLOGY

40. FUNCTIONS OF BLADDER
BARRIER FUNCTION
IONIC TRANSPORT
SENSOR – TRANSDUCER FUNCTION OF UROTHELIUM

41. BARRIER FUNCTION
Epithelial permeability, including that of the urothelium, depends on a number
of factors.
These are passive diffusion, osmotically driven diffusion, active transport, and
inertness of the membrane to the solutes to which it is exposed.
The human bladder urothelium is also permeable to water because of
expression of the water transport protein aquaporin.
A direct measurement of urothelial diffusive permeability in the human has not
yet been made

42. BARRIER FUNCTION
Breakdown of the apical (umbrella) cells in animal models of cystitis has shown increased water and urea permeability.
Presumably, leakage of urinary solutes into the lamina propria is also responsible for the symptoms of cystitis
This increase in urothelial permeability with cystitis is increased further by distention of the bladder.
The hypothesis is that with distention of the bladder, the weakened urothelium with denuded apical umbrella cells and no
real barrier in the intermediate or basal cells is further disrupted, thus allowing further egress of urine constituents into
the detrusor.
Similar breakdown of the apical cells is thought to occur in most forms of infectious cystitis and also in radiation cystitis.

43. BARRIER FUNCTION
Tight junction (TJ) proteins also contribute to the impermeability of the bladder urothelium.
TJ proteins include zona occludens-1 (ZO-1), occludin, claudin-4, claudin-8, and claudin-12
TJs are present between cells to prevent paracellular (between the cell)
These TJ proteins adapt to stretch of the urothelium during filling and voiding without affecting
permeability (of small molecules biotin, fluorescein, and ruthenium red), although there was a 10-fold
drop in transepithelial resistance (TER) during urothelial stretch

44. BARRIER FUNCTION
The GAG layer, which
has been described to
be located on the
luminal surface of the
apical urothelial cell,
has been a
controversial subject
of research into
urothelial barrier
function.

46. The GAG layer may have
importance in bacterial
antiadherence and in prevention
of urothelial damage by large
macromolecules.
However, there is no definite
evidence that the GAG layer acts
as the primary impermeability
barrier between urine and plasma
in the human urothelium.

47. Ionic Transport
The apical membrane of the
urothelium has a high electrical
resistance , whereas the
basolateral membrane resistance
is approximately 10-fold lower
Active sodium transport across
the urothelium has been
demonstrated

48. IONINC TRANSPORT
Sodium that is transported into the cell is removed at the basolateral
membrane by an Na+ -K+ exchanger.
This leaves the cell with a negative intracellular charge. The basolateral
membrane contains K+ and Cl− channels, Na+ -H+ exchangers, and Cl− -HCO3 −
exchangers.
These channels and exchangers are important in recovery of cell volume during
an increase in serosal osmolality

49. Sensor-Transducer Function of the Urothelium
• Whereas the urothelium has historically been viewed primarily as a barrier, there is
increasing evidence that urothelial cells display a number of properties similar to
sensory neurons (nociceptors and mechanoreceptors) and that both types of cells
use diverse signal-transduction mechanisms to detect physiologic stimuli.
• Examples of “sensor molecules” (i.e., receptors and ion channels) associated with
neurons that have been identified in urothelium include receptors for :
• Bradykinin
• Neurotrophins
• Purines
• Norepinephrine (α and β)
• Ach
• Protease-activated receptors
• Amiloride-mechanosensitive
• Na+ channels such as ENaC, and
• A number of transient receptor potential (TRP) channels (TRPV1, TRPV2, TRPV4, TRPM8)

50. When urothelial cells
are activated through
these receptors and
ion channels in
response to
mechanical as well as
chemical stimuli, they
can, in turn, release
chemical mediators
such as NO, ATP, ACh,
and substance P (SP)
These agents are
known to have
excitatory and
inhibitory actions on
afferent nerves that
are close to or in the
urothelium

51. Chemicals released from urothelial cells may act directly on afferent nerves
or indirectly through an action on suburothelial interstitial cells (also
referred to as myofibroblasts) that lie in close proximity to afferent nerves.
Myofibroblasts are extensively linked by gap junctions and can respond to
chemicals that in turn modulate afferent nerves
Thus it is believed that urothelial cells and myofibroblasts can participate in
sensory mechanisms in the urinary tract by chemical coupling to the
adjacent sensory nerves.

52. Prostaglandins are also released from the urothelium. These are assigned two possible functions: regulation of
detrusor muscle activity and cytoprotection of the urothelium
The predominant forms found in human urothelium from biopsy specimens are 6-oxo PFE2 more than PGF2α
more than thromboxane B2.
PGI2 (prostacyclin) is also produced.
The production of prostaglandins also increased greatly with inflammation
Prostaglandin synthesis also occurs in the ureter, where it is speculated to be important in the regulation of
ureteral peristalsis and also in reducing the development of blood clots in the lumen of the ureter–
prostaglandin F2α (PGF2α) more than

53. The urothelium also releases substances called urotheliumderived inhibitory factors,
which decrease the force of detrusor muscle contraction in response to muscarinic
stimulation
The molecular identity of this factor is not known; however, pharmacologic studies
suggest that it is not NO, a prostaglandin, prostacyclin, adenosine, catecholamine, γ-
aminobutyric acid (GABA), or a factor that acts through apamine sensitive, small-
conductance K+ channels.
It has been shown that an inhibitory response through this factor is attenuated in a
fetal model of bladder outlet obstruction (BOO)

54. Suburothelial Interstitial Cells
Subepithelial interstitial cells, which are also called myofibroblasts, are located just below the basal
layer of the urothelium. These myofibroblasts stain for vimentin and α-smooth muscle actin but not
for desmin
These cells are linked by gap junctions consisting of connexin 43 (Cx43) proteins and make close
appositions with C-fiber nerve endings in the submucosal layer of the bladder, suggesting that
there is a network of functionally connected interstitial cells immediately below the urothelium
that may be modulated by other nerve fibers
ATP can induce inward currents associated with elevated intracellular Ca2+ in isolated suburothelial
interstitial cells

56. SMOOTH MUSCLE MECHANICS
Muscarinic receptors induce detrusor contraction in response to ACh released from
parasympathetic nerve terminals by calcium entry through Ca2+ channels
Although calcium serves the same triggering role in all muscle types, the mechanism of
activation is different in smooth muscle
The contractile response is slower and longer lasting than that of skeletal and cardiac
muscle
Evidence suggests that the “normal” bladder may be spontaneously active and that
exaggerated spontaneous contractions could contribute to the development of an OAB

57. Detrusor Smooth Muscle Contraction Sequence
Ca2+ binds to
calmodulin (CaM),
activating it
CaM activates the
kinase enzyme (myosin
light chain kinase)
The kinase enzyme
catalyzes phosphate
transfer from adenosine
triphosphate to myosin,
allowing myosin to
interact with actin of the
thin filaments
Smooth muscle relaxes
with intracellular
decrease in Ca2+ levels

59. NEURAL CONTROL TO THE
LOWER URINARY TRACT

60. PERIPHERAL NERVOUS SYSTEM
• PARASYMPATHETIC
• SYMPATHETIC
• SOMATIC

61. PARASYMPATHETIC
Parasympathetic preganglionic neurons innervating the LUT are located in the lateral part of
the sacral intermediate gray matter in a region termed the sacral parasympathetic nucleus
Parasympathetic preganglionic neurons send axons through the ventral roots to peripheral
ganglia, where they release the excitatory transmitter ACh
Parasympathetic postganglionic neurons in humans are located in the detrusor wall layer as
well as in the pelvic plexus
This is an important fact to remember because patients with cauda equina or pelvic plexus
injury are neurologically decentralized but may not be completely denervated

62. SYMPATHETIC
Sympathetic outflow from the rostral lumbar spinal cord provides a
noradrenergic excitatory and inhibitory input to the bladder and urethra
Activation of sympathetic nerves induces relaxation of the bladder body and
contraction of the bladder outlet and urethra, which contribute to urine storage
in the bladder.
The peripheral sympathetic pathways follow a complex route that passes
through the sympathetic chain ganglia to the inferior mesenteric ganglia and
then through the hypogastric nerves to the pelvic ganglia

63. SOMATIC
The EUS motoneurons are located along the lateral border of the
ventral horn, commonly referred to as the Onuf nucleus
Sphincter motoneurons also exhibit transversely oriented
dendritic bundles that project laterally into the lateral funiculus,
dorsally into the intermediate gray matter, and dorsomedially
toward the central canal.

66. BLADDER AFFERENT PROPERTIES :
FIBRE TYPE LOCATION NORMAL FUNCTION INFLAMMATION EFFECT
A delta Smooth muscle Sense bladder fullness
(Wall Tension)
Increase discharge at low pressure threshold
C fibre Mucosa Respond to stretch
(Bladder Volume
Receptors)
Increase discharge at lower threshold
C fibre Muscle Nociception to
overdistention
(Silent afferent)
Sensitive to irritants
Become mechanosensitive and unmask new
afferent pathway during inflammation
STRETCH-SENSITIVE MUSCULAR MECHANORECEPTORS
TENSION RECEPTORS

69. Modulators of Afferent Sensitivity:

70. Efferent pathways to bladder
• Mechanism of storage and voiding reflexes

71. Spinal cord interneurons relay information
about the bladder to the pontine micturition
center (PMC), Barrington nucleus, and PAG.
The PMC also gets input from the PAG, lateral
hypothalamus, and medial preoptic nucleus.
PMC neurons project to the locus ceruleus
(LC) and preganglionic parasympathetic
neurons of the lumbosacral spinal cord that
innervate the detrusor.
There are also projections to premotor
neurons in the dorsal gray commissure that
innervate Onuf nucleus, which projects to the
urethral sphincter.
A pontine continence center (PCC) has been
proposed in the cat and is localized to the L-
region of the pons. Neurons here project to
the Onuf nucleus.

72. Storage reflexes
During the storage of urine, distention of the bladder
produces low-level bladder afferent firing.
Afferent firing, in turn, stimulates the sympathetic
outflow to the bladder outlet (base and urethra) and
pudendal outflow to the external urethral sphincter.
These responses occur by spinal reflex pathways and
represent “guarding reflexes,” which promote
continence.
Sympathetic firing also inhibits detrusor muscle and
transmission in bladder ganglia.

73. Voiding Reflex
At the initiation of micturition, intense vesical afferent
activity activates the brainstem micturition center,
which inhibits the spinal guarding reflexes
(sympathetic and pudendal outflow to the urethra).
The pontine micturition center also stimulates the
parasympathetic outflow to the bladder and internal
sphincter smooth muscle.
Maintenance of the voiding reflex is through ascending
afferent input from the spinal cord, which may pass
through the periaqueductal gray matter (PAG) before
reaching the pontine micturition center.

74. The thalamus, the insula, the
prefrontal cortex, the anterior
cingulate, the periaqueductal gray
(PAG), the pons, the medulla, and the
supplementary motor area (SMA) are
activated during urinary storage
A scheme of connections among
various forebrain and brainstem
structures are involved in the control
of the bladder and the sphincter in
humans