PHYSIOLOGY AND PHARMACOLOGY

OF THE BLADDER AND URETHRA

Gregorio, Frances Mari

Mendoza, Alyanna
Cebu Institute of Medicine
 OUTLINE

• Lower Urinary Tract Anatomy

• Bladder Compartments
• Overview of the Urethra
• Urothelial Physiology
• Smooth Muscle Physiology
• Bladder Mechanics
• Neural control of the LUT
• Pharmacology
 LOWER URINARY TRACT ANATOMY

• BLADDER
Divisions:
1)body – above ureteral orifices
2)base – trigone + bladder neck
-closure of bladder neck in men facilitates antegrade ejaculation
-adrenergic innervation in the bladder neck in women is less than that in men

• URETHRA
-part of the bladder outlet along with the pelvic floor musculature
-smooth muscle + striated muscle (rhabdosphincter / EUS)
 BLADDER COMPARTMENTS

• Urothelium
-multilayered epithelium
-basal, intermediate and apical cells
-apical (umbrella) cells: in contact with urine and
microorganisms
-uroplakins: specialized class of proteins important in barrier
function

• Lamina Propria and Vasculature

-LP:“functional center” for localized control of the bladder
-contains nerve fibers, interstitial cells (myofibroblasts), and
microvasculature
-2 plexuses: mucosal plexus + subepithelial plexus
-intramural tension: principal determinant of blood flow in the bladder wall
-O2 deprivation of detrusor (ischemia)  decrease contractility
-ischemia and reperfusion  patchy denervation and altered SM function

• Stroma
-collagen + elastin +proteoglycan matrix
-main cells: fibroblasts
-passive mechanical properties: viscoelastic properties of stroma + relaxed detrusor muscle
• Bladder Wall Collagen
-most common: types 1,3,4
-two major types: 1,3
-poorly compliant bladders: CT:SM ratio increased, type3:1 collagen ratio increased
-poor storage function: alteration in CT content, especially increased type 3 collagen

• Bladder Wall Elastin and Matrix

-sparse in bladder compared with collagen
-found in all layers of the bladder wall
-stroma: proteoglycans + water

• Smooth Muscle
-myofibrils are arranged into fascicles (bundles)  connected together  syncitium
-motor innervation: postganglionic parasympathetic nerve fibers
 OVERVIEW OF THE URETHRA

 MALE URETHRA
-begins at the bladder neck and extends to the external
meatus
-composed of striated and smooth muscle
-development of the urethral sphincteric complex is
similar in both genders
- urethral complex is derived from musculature from
bladder detrusor, bladder trigone, and urethral muscles,
each of different embryonic origin
-the levator ani pelvic floor muscle does not surround the
ventral aspect of the urethra in either gender, and the
role of the levator ani in continence was questioned
4 SEGMENTS:
• Preprostatic
• Prostatic
• Membranous
• Bulbous and Penile
FEMALE URETHRA
-extends throughout the distal third of the
anterior vaginal wall from bladder neck to the
meatus
-network of subepithelial tissue: urtheral seal
effect; promotes continence
-EUS/ Rhabdosphincter (striated muscle):
under voluntary control and is part of the
pelvic floor musculature
-urinary continence results from the
combination of active muscle tone and
passive anatomic coaptation
 URETHRAL TONE

• Blocking striated sphincter activity with nicotinic neuromuscular blocking agents has variable effects and may
reduce urethral tone, but rarely by more than 40%, suggesting that the smooth muscles are important.
• Blocking sympathetic tone with α-adrenoceptor blockers may also reduce urethral pressure by about a third
• There is little evidence for the involvement of the cholinergic innervation in generating urethral pressure
• urethral pressure recording at the external sphincter during bladder filling increases uniformly along the entire
circumference
• Norepinephrine or hypogastric nerve stimulation augments this pressure, suggesting a role for adrenergic
receptors and sympathetic nerves in the function of the EUS
• Estrogen is known to increase the urethral blood flow, result ing in increased distention of the lamina propria
blood vessels
• Impaired arterial blood supply to the urethra decreases the intra luminal pressure but at present it is not
known whether it is the decrease in vascular filling or the urethral hypoxia that mediates the decrease in
urethral pressure.
 FIBER TYPES OF URETHRAL
STRIATED MUSCLE

• Twitch-type myofibrils
-can be further classified as slow and fast on the basis of functional and metabolic characteristics
-slow-twitch fibers : ideally suited to maintaining sphincter tone for prolonged periods
-fast-twitch fibers : add to sphincter tone rapidly to maintain continence when intra-abdominal pressure is
abruptly increased
-periurethral striated muscle of the pelvic floor contains both fast-twitch and slow-twitch fibers
-striated muscle of the distal sphincter mechanism contains predominantly slow-twitch fibers and provides more
than 50% of the static resistance
-the distal urethra is composed primarily of slow-twitch myofibrils in contrast to the periurethral striated
muscles of the pelvic floor, which contain fast-twitch and slow-twitch fibers
-in the male, the rhabdosphincter consists of 35% fast-twitch and 65% slow-twitch fibers
-in the female, the ratio of slow-twitch to fast-twitch fibers is 87% slow-twitch and 13% fast-twitch fibers
 UROTHELIAL PHYSIOLOGY

• the primary role of the urothelium is to form a relatively

impermeable barrier to protect the underlying stroma of the
bladder
• other roles of the bladder urothelium include sentinel defense
against uropathogenic bacterial infections, afferent signaling, and
modulation of detrusor smooth muscle contractility
 BARRIER FUNCTION
• Epithelial permeability, including that of the urothelium, depends on a number of factors:
-passive diffusion
-osmotically driven diffusion
-active transport
-inertness of the membrane to the solutes to which it is exposed

 IONIC TRANSPORT
• the apical membrane of the urothelium has a high electrical resistance
• the basolateral membrane resistance is approximately 10-fold lower
• 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  important in recovery of cell volume during an increase in serosal osmolality
 Sensor-Transducer Function of the Urothelium
• 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
• 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  these agents are
known to have excitatory and inhibitory actions
on afferent nerves that are close to or in the
urothelium
• chemicals released from urothelial cells may act
directly on afferent nerves or indirectly through
an action on suburothelial interstitial cells
• NO released locally in the bladder
appears to have an inhibitory effect on
afferent activity in the bladder
• ATP released from urothelial cells
during stretch can activate a population
of suburothelial bladder afferents
expressing P2X3 receptors, signaling
changes in bladder fullness and pain
• prostaglandins: regulation of detrusor
muscle activity and cytoprotection of the
urothelium
• Urothelium derived inhibitory factors,
which decrease the force of detrusor
muscle contraction in response to
muscarinic stimulation
 KEY POINTS: UROTHELIUM
 Uroplakin proteins and TJ proteins play key parts in urothelial barrier function.
 Uroplakins have also been shown to act as the primary attachment site of type
1 piliated uropathogenic E. coli.
 The GAG layer may have importance in bacterial antiadherence, but there is no
definite evidence that the GAG layer serves impermeability function.
 Urothelial cells can release and respond to neurotransmitters.
 Myofibroblasts mediate interaction between urothelial cells and afferent nerves.
SMOOTH MUSCLE PHYSIOLOGY
 DETRUSOR 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
 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
• Recent evidence suggests that the “normal” bladder may be spontaneously active and that exaggerated
spontaneous con tractions could contribute to the development of an OAB
• A population of cells within the detrusor layer, known as interstitial cells or myofibroblasts, has been
proposed to have a pacemaking role in spontaneous activity of the bladder.
BLADDER MECHANICS
 URINARY STORAGE (FILLING)
• In addition to smooth muscle, the human bladder is composed of roughly 50% collagen and 2%
elastin. With injury, obstruction, or denervation, collagen content increases
• When contractile protein content exceeds collagen, greater distensibility is achieved (compliance).
Conversely, when collagen levels increase, compliance falls.
• Bladder compliance (C) is defined as the change in volume (V) relative to the corresponding
change in intravesical pressure (P): C = V / P

 VOIDING MECHANICS
• Intravesical pressure reflects the combined factors of abdominal (Pabd) and detrusor (Pdet)
pressures. Therefore, Pdet = Pves – Pabd
• Micturition relies on a neurally mediated detrusor contraction, causing Pdet to rise without a
significant change in Pabd.
• To assess the strength of a detrusor contraction, Pdet alone is an insufficient measure
 NEURAL CONTROL OF THE LOWER
URINARY TRACT

 Peripheral Nervous System

• The LUT is innervated by three sets of peripheral nerves involving the parasympathetic,
sympathetic, and somatic nervous systems
• Pelvic parasympathetic nerves arise at the sacral level of the spinal cord, excite the bladder,
and relax the urethra.
• Lumbar sympathetic nerves inhibit the bladder body and excite the bladder base and urethra.
• Pudendal nerves excite the EUS.
 SPINAL CIRCUITRY
AFFERENT PATHWAYS
NEUROTRANSMITTERS
• tension receptors, volume receptors, and
silent afferents (including nociceptors) are • Glutamate plays an important role in the
present spinal efferent circuitry supporting micturition.
• Intravesical irritant chemicals reduce the • The spinal noradrenergic system, mediated by
pressure thresholds of most of these α1 adrenocep tors, has a modulatory role in
endings, including the highthreshold controlling micturition by inhibiting afferent
receptors. inputs from the bladder and facilitating the
• A substantial proportion of the C-fiber descending limb of the spinal micturition
afferent population is silent (i.e., reflex to increase bladder contractility.
insensitive to normal distention).
However, these fibers become • Transmitters such as 5HT, purines, glycine,
mechanosensitive after the action of and GABA appear to selectively modulate the
various chemical mediators. volume threshold by actions in the sacral
spinal cord.
• During inflammation and possibly other
pathologic conditions there is • Glutamate appears to be involved as an
recruitment of mechanosensitive C excitatory transmit ter in the supraspinal
fibers that form a new functional circuitry controlling micturition.
afferent pathway. This is the rationale for
intravesical Cfiber neurotoxin capsaicin • Glutamate may also be a mediator of DO
and RTX therapy after neural injury.
 PHARMACOLOGY

 MUSCARINIC MECHANISMS
• There are at least five muscarinic receptor subtypes. Pharmcologically, M1, M2, and M3 receptor subtypes
have been found in the human bladder.
• Stimulation of M3 receptors by ACh induces calcium influx through Ltype Ca2+ channels, as well as IP3
hydrolysis as a result of PLC activation, resulting in the release of intracel lular calcium, both of which
contribute to a smooth muscle contraction.
• Muscarinic receptor subtype–mediated detrusor contraction shift from M3 to M2 receptor subtype has been
reported in bladder muscle specimens from neurogenic bladder dysfunction patients.
 ADRENERGIC MECHANISMS
• βAdrenergic–stimulated relaxation is mediated through the activation of adenylate cyclase and the
accumulation of cAMP.
• The β3adrenergic receptor is the most highly expressed subtype among α and βadrenoceptor subtypes, and
β3 receptor agonists are in clinical trials for treatment of DO.
• In the human, there is a predominant expression of α1D receptors present in the normal bladder, and the
level of expression of αadrenoceptor mRNA, which is considerably low compared with β 3 adrenoceptors in
normal bladders, was not increased in the bladder with outflow obstruction.
• Urethral tone and intraurethral pressure are influenced by αadrenergic receptors. The α1A adrenoceptor is
the major subtype in the prostate and urethra, and all three α1 adrenoceptor subtypes (α1A, α1B, α1D) are
present in blood vessels.
 NEUROGENIC BLADDER

• Normal micturition is associated with a spinobulbospinal reflex mediated

by lightly myelinated Aδ afferents.
• Unmyelinated C fibers are normally relatively insensitive to gradual
distention of the urinary bladder.
• After spinal cord injury, a capsaicin sensitive C fiber mediated spinal
reflex develops and may play a role in the development of DO.
• Treatment of neurogenic DO patients with intravesical capsaicin or
another Cfiber neurotoxin, RTX, produces symptomatic improvement in a
subpopulation of these patients and reduces the density of TRPV1
immunoreactivity in nerve fibersand urothelium.
• The bladder icewater urodynamic test has been suggested as a research
method to assess the C fiber–mediated micturitionreflex but is not
practiced clinically.
 BLADDER OUTLET OBSTRUCTION

• Obstruction induced DO with irritative voiding symptoms has been

attributed to denervation supersensitivity, because increased contractile
responses of the bladder smooth muscle to cholinergic agonists have
been observed. Altera tions in detrusor contractility may also result
from changes in contractile proteins.
• Increases in receptormediated muscle contractility and interaction among
smooth muscle cells have been observed with BOO.
• BOO in rats causes enhancement of a spinal reflex.
• Bladder tissue and urine NGF content is increased in obstructed
bladders in animals.
 BLADDER PAIN SYNDROME
AND INTERSTITIAL CYSTITIS
• Histologic analysis of bladders from patients with BPS/IC often revealed
marked edema, vasodilation, proliferation of nerve fibers, and infiltration of
mast cells.
• NGF appears to be a key player in the link between inflammation and
altered pain signaling. NGF is expressed widely in various cells, including
urothelial cells, smooth muscle cells, and mast cells, and can activate mast
cells to degranu late and proliferate.
• Application of NGF sequestering molecules can reduce bladder overactivity
elicited by cyclophosphamide induced cystitis.
• Direct evidence linking chronic bladder inflammation with functional changes
in Cfiber afferents has been obtained in rat chronic cystitis models. Chronic
bladder inflammation can also induce changes in functional properties of
chemo sensitive receptors, such as TRPV1 in sensory neurons.
 AGING

• Bladder sensation and urethral pressure decline with age, and a

reduction in bladder capacity associated with age may be related to
DO rather than to aging itself, because bladder capacity was not
seen to decrease with age but was smaller in subjects with DO.
Thus aging appears to induce hypo function of the bladder and
urethra in humans.
• In contrast to altered nerve activity, there appears to be no
significant change in detrusor contractile responses to cho linergic or
electric stimulation between young and old animals.
• Most studies have shown that detrusor contractile responses to
αadrenergic stimulation increase and that detrusor relaxing responses
to βadrenergic stimulation decrease in old rats.
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