Urol Clin N Am 29 (2002) 499–514
Physiology of female micturition Maryrose P. Sullivan, PhDa,*, and Subbarao V. Yalla, MDb a
VA Boston Healthcare System, 1400 VFW Parkway, Boston, MA 02132, USA Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
b
Micturition is a dynamic physiologic process consisting of alternating storage and expulsion phases and is accomplished by complex structural organization and functional characteristics of the bladder and its outlet. This seemingly elementary event in fact requires the remarkable ability of the related organs to perform dual and opposite functions in which the bladder serves as a reservoir during filling and a pump during voiding, while the urethra acts as a watertight sphincter throughout filling and a conduit during voiding. Although our current understanding of the anatomy and physiology of the lower urinary tract is far from complete, intensive research over the last decade has dramatically improved our appreciation of the neural, biomechanical, metabolic, and morphologic properties of the bladder and urethra. Most of our physiologic concepts related to bladder and outlet function are derived from clinical observations of voiding dysfunctions and neuropathology and from experimental studies in various animal species. These concepts continue to be refined and evolve. Aspects of micturition physiology that are gender related are caused primarily by anatomic differences in the bladder outlet and adjacent pelvic and perineal structures. To understand the pathophysiology of micturition in women, a coherent grasp of normal physiology is required, based on diverse disciplines, which include the neurophysiology and biomechanics related to the bladder and outlet, the unique pelvic and perineal anatomy of women, and interactions among all of these factors.
* Corresponding author. E-mail address: Sullymp@aol.com (M.P. Sullivan).
Lower urinary tract Anatomy The muscular body of the urinary bladder, the detrusor muscle, is composed of an interwoven network of smooth muscle bundles, criss-crossing in a random fashion in all directions and at all depths in the bladder wall without an arrangement as discrete layers [1]. These large diameter smooth muscle bundles are composed of compact groups of muscle cells. There are no convincing studies to suggest that gross anatomic differences in the bladder exist between the sexes. The smooth muscle of the trigone consists of two distinct layers. The deep muscle layer merges into the posteroinferior portion of the detrusor muscle, whereas the superficial trigonal muscle consists of small diameter muscle bundles that are morphologically distinct from the detrusor muscle. This layer is continuous proximally with the intramural ureters and distally with the smooth muscle of the proximal urethra. The stroma of the bladder consists of collagen, elastin, and fibroblasts in a proteoglycan matrix. Collagen (predominately types I, III, and IV) contributes to approximately one third of bladder dry weight and is mainly found in the connective tissue outside the muscle bundles. Elastin fibers are relatively sparse compared with collagen and are arranged parallel to the urothelial lining in the suburothelium and between smooth muscle bundles. The urothelium consists of at least three layers of specialized transitional epithelial cells joined by tight junctions. Proteoglycans and glycoproteins covering apical cells determine the permeability of the membrane and prevent bacterial colonization. Apical epithelial cells are impermeable to water, urea, and small molecules, but actively transport sodium and amino acids. The abundance
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of afferent fibers in this layer and the specialized sensory properties of the epithelial cells suggest that the urothelium may play an important role not only in regulation of the barrier function but also in modulation of storage and expulsive functions of the bladder [2]. The female bladder outlet is distinct from its male counterpart and consists of (1) an inner mucosal lining that is continuous with the bladder urothelium, (2) a muscular coat formed by an outer layer of striated muscle (rhabdosphincter), and (3) an inner layer of smooth muscle. The smooth muscle of the bladder neck is anatomically and pharmacologically distinct from the detrusor and is characterized by relatively small diameter bundles that extend obliquely or longitudinally into the urethral wall in females [3]. The urethral smooth muscle layer consists of a thick inner sheet of longitudinally oriented fibers and thin outer layer of circular fibers. These muscles are continuous proximally with the muscle of the bladder neck and terminate distally in the subcutaneous adipose tissue surrounding the external urethral meatus. The rhabdosphincter is an integral component of the urethral muscularis and is composed of both slow- and fast-twitch myofibers, with slow-twitch (relatively fatigue resistant) fibers predominating [4]. The rhabdosphincter is circularly arranged and is thickest in the middle third of the urethra, but relatively sparse in the posterior region between the urethra and vagina. Fibers of the rhabdosphincter extend cranially almost to the level of the bladder neck on the ventral urethral surface. Caudally, the rhabdosphincter is concavely arched across the ventral and lateral surface of the urethra, attaching to the lateral vaginal wall [46]. Although this discrete striated sphincter element is undoubtedly present around the female urethra and vagina, its muscle mass is relatively modest compared with the male striated sphincter. This difference can be attributed presumably to the predominant role of the male striated sphincter as a propulsive mechanism required to expel viscous fluid during ejaculation. The contents of the abdominopelvic cavity are supported primarily by the levator ani muscle group and fascia of the pelvic diaphragm [5]. The levator ani muscle group consists of the pubococcygeus, iliococcygeus, and ischiococcygeus muscles [6]. These muscles appear to provide a supportive layer, similar to a hammock, on which the bladder, proximal vagina, and intrapelvic rectum lie (Fig. 1) [7]. The presence of both slow- and fast-twitch fibers in these muscles suggests that they contribute to passive and active continence. The tonic activity
of these muscles provides an occlusive force on the urethral wall, whereas during increases in intraabdominal pressure, further contraction of these muscles stabilized by adjacent fascial structures forcefully constricts the urethra during coughing, laughing, or sneezing. The bladder, urethra, vagina, and uterus are suspended and supported within the bony pelvis by specialized condensations of the levator fascia composed of the endopelvic fascia and the perivesical fascia [8] in concert with the pelvic floor striated musculature. The pubourethral ligament is a dense meshwork of collagen fibers and smooth muscle bundles that anchors the anterior aspect of the urethra to the posteroinferior surface of the symphysis pubis and prevents downward and rotational displacement of the urethra. The urethropelvic ligaments provide support to the bladder neck and proximal urethra. This region of the levator fascia envelops the urethra and attaches to the tendinous arcs on both sides of the pelvis. The smooth muscle fibers of these ligaments receive rich presumptive cholinergic innervation [9], suggesting that these ligaments may play a role in maintaining urethral position during voiding. The most posterior condensation of the levator fascia is the cardinal ligaments, which provide indirect support of the bladder base [5]. The urethrovesical junction is supported by the pubocervical fascia located between the bladder and vagina. This fascia prevents herniation of the bladder and urethra into the vagina. Thus, the integral relationship between the endopelvic fascia and the levator ani muscle provides support to the vesical neck and allows elevation of the vesical neck during pelvic muscle contraction and descent during pelvic muscle relaxation [10]. Alterations in the type, quantity, and quality of collagen in these supportive structures have been implicated in the etiology of stress urinary incontinence [11,12]. The urogenital diaphragm is a complex threedimensional anatomic concept that has been inconsistently described for several decades. Mostwin and Burnett [13] have recently reinforced the description of the muscles of urogenital diaphragm as ascending from the vaginal introitus to the proximal urethra through the levator hiatus, encircling the urethra and vagina to varying degrees. Superiorly, these muscles completely surround the proximal urethra. Toward the lower portion of the vagina, the muscles insert progressively farther around the vagina until the urethra and vagina are completely encircled near the vaginal introitus. At this level, these muscles become confluent with
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Fig. 1. Schematic representation of pelvic floor muscles viewed from above. Levator ani muscles form a ‘‘hammock’’ to support and stabilize the bladder and urethra. The tendinous arc represents the insertion of the levator muscle on the obturator fascia. (From Raz S, Strothers L, Chopra A. Vaginal reconstructive surgery for incontinence and prolapse. In: Walsh PC, Retik AB, Vaughan ED (eds). Campbell’s Urology. Philadelphia, WB Saunders 1998, pp. 1059–94; with permission.)
the bulbospongiosus. Thus, the urogenital diaphragm is depicted as a tapered sleeve that is narrow at the apex and wider at the base where it is partially open posteriorly to accommodate the vagina. The deep transverse perineal muscles are located posteriorly between the perineal body and the ischial tuberosities (Fig. 2). These muscles, along with the levator group, contribute to active continence by reflex contraction during sudden changes in abdominal pressure.
Neuroanatomy Normal micturition depends on the complex interactions between the autonomic and somatic nervous systems and their coordination and integration by sensory innervation and various control centers in the brain and spinal cord. Significant differences in the neuroanatomy may not be expected between sexes; however, vesicourethral innervation may be influenced and functionally modified by hormones in women.
Central mechanisms The brain stem center in the pontine reticular formation, which receives input from the cerebellum, basal ganglia, hypothalamus, and cerebral cortex, is considered the origin of the common pathway of efferent impulses and exerts both facilitatory and inhibitory effects on the spinal cord centers [14]. This pontine micturition center is responsible for sustaining detrusor contraction and for promoting striated sphincter relaxation for the efficient emptying of the bladder during micturition. The cerebellum receives sensory input from the bladder and pelvic floor muscles and is thought to coordinate bladder contraction with striated sphincter relaxation and to maintain tone of the pelvic floor musculature [14,15]. Conscious inhibition of the micturition reflex is controlled by part of the medial wall of the anterior frontal cortex and the anterior cingulate gyrus. Although micturition can occur in the absence of cortical control, cortical involvement is essential for inhibition of the lower centers until volitional voiding can be appropriately executed.
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Fig. 2. Perineal view of urogenital and perianal musculature. (From Raz S, Strothers L, Chopra A. Vaginal reconstructive surgery for incontinence and Prolapse. In: Walsh PC, Rett K, Vaughan ED (eds): Campbell’s Urology. Philadelphia, WB Saunders 1998, pp. 1059–94; with permission.)
Autonomic pathways Parasympathetic innervation of the lower urinary tract is conveyed by the pelvic nerve. Motor signals transmitted by the lateral corticospinal tract relay in the intermediolateral gray matter of the parasympathetic nucleus in the second, third, and fourth segments of the sacral cord and emerge as preganglionic axonal projections in the ventral roots of the sacral spinal nerves. The pelvic nerves, which are derived from this preganglionic supply, arise from deep in the pelvis on each side of the rectum to meet the hypogastric nerves, branch repeatedly, and eventually form the pelvic plexus. Most of the preganglionic fibers synapse with postganglionic fibers in or near the wall of the bladder and urethra. The sympathetic autonomic nucleus is located in the intermediolateral gray matter column of the lowest thoracic and upper two lumbar segments. Peripheral axonal projection of neurons of the sympathetic spinal nucleus, which are conveyed by ventral roots of spinal nerves, enter the corresponding ganglia of the lumbar sympathetic chain. Centrifugal fibers of these ganglia join to form a lumbosacral preaortic plexiform nerve arrangement (superior hypogastric plexus). The left and right hypogastric nerves arise from this plexus and relay, along with the pelvic nerve, in the pelvic plexus. Here, sympathetic postgan-
glionic and parasympathetic nerves form a network of interconnected nerve strands in the pelvic fascia located lateral to the rectum, internal genitalia, and lower urinary organs. Branches from the pelvic plexus pass laterally to the bladder and trigone and to the upper third of the vagina (Fig. 3). Given the anatomic proximity of these branches to the uterine ligaments, especially the cardinal ligament, and to the upper aspect of the vagina, varying degrees of voiding dysfunction can result from surgical disruption of autonomic innervation and fascial support to the bladder and urethra during radical hysterectomy [16,17].
Sacral somatic pathway Somatomotor innervation of the rhabdosphincter and striated muscles of the pelvic floor is conveyed by the pudendal nerve [18]. Cell bodies of the pudendal nerve lie in the anterior horn of the second through fourth segments of the sacral cord in Onuf’s nucleus. In addition, triple innervation (somatomotor and dual autonomic) of the rhabdosphincter has been proposed based on ultrastructural and histochemical studies in the cat [19,20]. Although evidence of an autonomic contribution from cholinergic fibers in the human rhabdosphincter is unresolved, a sympathetic component has been shown in humans [21,22].
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Fig. 3. Innervation of female urogenital organs. (From the Ciba Collection of Medical Illustrations)
Afferent pathways Ramifications of the pelvic plexus contain afferent pathways from the bladder and urethra. These fibers reach the dorsal root ganglia through the pelvic and hypogastric nerves. Afferent fibers of the rhabdosphincter and striated muscles of the pelvic floor are conveyed by the pudendal nerve. Thus, sensory information from the lower urinary tract is relayed to the lumbar and sacral segments of the spinal cord or to the peripheral ganglia constituting the infraspinal reflex arcs. Afferent nerves are found within the urothelium, in the subepithelium and muscle layers, and around blood vessels and intramural ganglion cells of the bladder and urethra. Mucosal sensory nerves respond to distension, to chemicals released from urothelial cells, and to changes in the chemical composition of urine [23]. Thin myelinated delta fibers in the bladder function as slowly adapting tension receptors, whereas unmyelinated C-fibers function as nociceptors responding to cold, inflammatory
mediators, and ischemia [3]. Presumptive sensory fibers contain calcitonin gene-related peptide (CGRP) [24]. A small subpopulation of CGRPcontaining sensory nerves also contain tachykinins, such as substance P and neurokinin A [24]. C-fiber afferents may also contain pituitary adenylate cyclase-activating peptide [25]. Peptides released from sensory nerves can modulate smooth muscle contraction, facilitate neurotransmitter release from nerves, increase plasma permeability, and produce vasodilation [26,27]. Recent studies suggest that a purinergic mechanism is involved in mechanosensory transduction because ATP released from epithelial cells in response to distension activates purinergic receptors on subepithelial sensory nerve terminals—a response that is attenuated in mice lacking these receptors [28,29]. Peripheral neurophysiology Intrinsic innervation of the lower urinary tract is derived from postganglionic neurons of the
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urogenital short neuron system, which are designated by their emanation from peripheral ganglia that are a short distance from, adjacent to, or within the effector organ [30]. These ganglia contain varying proportions of cholinergic and adrenergic principle neurons and small intensely fluorescent cells (modulators of interganglionic vasomotor function and ganglionic transmission), as well as a complex intraganglionic network of cholinergic and adrenergic fibers that either pass uninterrupted through the ganglia or synapse with one or more ganglionic cells. This arrangement, in which ganglion cells are innervated by pre- and postganglionic nerves originating within the ganglia, provides a morphologic substrate for coordination and modulation of sympathetic and parasympathetic neural components at the organ level [1]. Small autonomic ganglia occur throughout the adventitia, muscularis, and suburothelium of the bladder and urethra and typically consist of 5 to 20 nerve cell bodies. Inherent properties of postganglionic parasympathetic neurons allow the responses to preganglionic input to be filtered or potentiated at the effector site [31]. Postganglionic neurons within peripheral ganglia are modulated by various peptides. In the intramural ganglia of the detrusor, for example, vasoactive intestinal peptide (VIP), nitric oxide (NO) synthase, neuropeptide Y (NPY), and galanin have been detected along with classic neurotransmitters [32]. Although the dual autonomic innervation of the bladder and urethra by cholinergic and adrenergic axons has been ultrastructurally confirmed [1], the density and distribution of intrinsic nerves is not entirely clear. Cholinergic innervation is abundant in the bladder body; however, the density is less in the bladder neck region and urethra. In contrast, adrenergic innervation is thought to be sparse in the body but more abundant in the urethra. The terminal regions of autonomic nerve fibers in the bladder have extensive vesicle-filled varicosities found adjacent to smooth muscle cells that release neurotransmitters ‘‘en passage’’ [31]. Ultrastructural studies indicate that bladder smooth muscle cells can have cholinergic, adrenergic, or both types of neuroeffector junctions. Postganglionic axoaxonal synapses have also been described in intrinsic vesicourethral innervation [1]. Postjunctional muscarinic receptors consist of both M2 and M3 subtypes in human bladder, with a predominance of M2 receptor subtype. Although bladder contraction is directly mediated by activation of M3 receptors, M2 receptor activation may
inhibit b-adrenoceptor–mediated relaxation and thus indirectly induce bladder contraction. Despite the greater abundance of M2 receptors, the M3 receptor subtype represents the dominant functional subtype. This finding is supported by the recent demonstration that mice lacking the M3 subtype showed marked bladder distension and a 95% reduction in the response to carbachol [33]. Prejunctional M1 receptors have been shown to facilitate cholinergic transmission, whereas M2 and M4 receptors appear to be inhibitory [34]. Pregnancy and pathology may alter cholinergically mediated responses because muscarinic receptor density is reduced in the bladders of pregnant rabbits and with experimentally induced detrusor instability [35]. a-Adrenergic receptors have been identified in pre- and postjunctional locations. Prejunctional a1-adrenergic receptors enhance acetylcholine release, whereas a2-adrenoceptors on adrenergic and cholinergic nerve terminals inhibit neurotransmitter release [36]. Activation of postjunctional aadrenoceptors mediates contraction of the trigone and bladder neck and thus promotes closure of the bladder outlet. Stimulation of b-adrenergic receptors causes smooth muscle relaxation by enhanced adenylate cyclase activity. In addition to the classic autonomic neurotransmitters acetylcholine and norepinephrine, other transmitters can also modulate neurotransmitter release or effects. These cotransmitters can be stored and released along with a classic neurotransmitter or stored in separate vesicles and differentially released depending on the frequency or pattern of stimulation, thus providing exquisite neural control of organ function. Because nerveinduced contractile responses in the bladder are only partially inhibited by anticholinergic agents and unaffected by a- and b-adrenergic agents [37], a nonadrenergic, noncholinergic component has been proposed. Several studies suggest that this atropine-resistant portion of the contractile response is partly mediated by purine nucleotides [38,39]. An important functional contribution, however, of this component under normal conditions in humans has not been fully established. Nevertheless, the presence of purinergic receptors in parasympathetic ganglia, afferent nerve terminals, urothelial cells, dorsal root ganglia, suburothelial afferent plexus, and bladder smooth muscle cells suggests that purinergic nerves may be involved in diverse processes, including smooth muscle contraction, mechanosensory signaling, and epithelial barrier functions [36].
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Although many other neuropeptides or modulators have been described in the lower urinary tract, including VIP, NPY, 5-hydroxytryptamine, histamine, galanin, and NO, their specific contribution to normal bladder function is unclear. Despite gaps in knowledge related to neuromodulation, the presence of these and other putative transmitters and neuromodulators represents an opportunity to identify new targets for future drug discoveries that may impact the treatment of various lower urinary tract dysfunctions. VIP and NO synthase are colocalized in cholinergic nerves [40,41], suggesting that these substances may interact cooperatively during the initiation and maintenance of voiding. NPY has been shown to colocalize with nitric oxide synthase in adrenergic neurons of the pelvic ganglia [42] and with cholinergic nerves [41]. In the urethra, a nonadrenergic noncholinergic contribution to urethral smooth muscle relaxation has been described. NO has subsequently been identified as the mediator of this response. NO synthase-containing nerves colocalize with cholinergic, adrenergic, VIP, NPY, and CGRP immunoreactive nerve fibers in the urethra of the female rat, suggesting that NO is an important transmitter in the urethra with functions including direct smooth muscle inhibition, sensory neurotransmission, and modulation of the effects of other transmitters [43].
Micturition reflexes The considerable number of reflexes that have been described over the last hundred years clearly reflects the complexity of the micturition processes. More than 32 reflexes have been assigned to the storage and/or voiding phases of micturition. Barrington initially described seven micturition reflexes. The more functional description by Bradley of the neural control of micturition was summarized in four loops. The first loop described the cerebral inhibitory control of the pontine micturition center, which is responsible for inactivating the micturition reflex. The second loop is the micturition reflex pathway represented by afferent pathways from the lower urinary tract to the pons and efferent pathways to the bladder and urethra. The coordination of the detrusor, urethra, and pelvic floor during filling and emptying of the bladder is illustrated by the third loop. Finally, the fourth loop describes the voluntary control of urethral sphincter function.
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During bladder filling, the first sensation to void typically occurs at approximately 150 mL, and a strong desire can be sensed at approximately 400 mL or more. Several neurologic mechanisms contribute to progressive urine storage until afferent activity reaches a critical level (Fig. 4). This is achieved by inhibition of preganglionic neurons by inhibitory spinal interneurons, a filtering effect by parasympathetic ganglia that prevents transmission of low preganglionic activity, and sympathetic inhibition of parasympathetic ganglionic transmission mediated by a2-adrenoceptors [44]. Sympathetic stimulation of b-adrenergic receptors located in bladder smooth muscle also promotes bladder accommodation, whereas sympathetic stimulation of a-adrenergic receptors causes urethral contraction and an increase in urethral closure forces. A negative feedback mechanism involving a vesicosympathetic reflex allows an increase in bladder pressure during bladder filling to trigger an increase in inhibitory sympathetic input to the bladder. Vesical afferent input during bladder filling also activates pudendal motoneurons, thus triggering sphincter contraction and contributing to urethral closure through a spinal pathway known as the guarding reflex. Stimulation of somatic afferent pathways in the pudendal nerve from activation of external urethral sphincter or pelvic floor striated muscles can inhibit the parasympathetic excitatory pathway to the bladder [45]. The voiding reflex is mediated by a spinobulbospinal circuit that passes through the pons and involves both activation of the parasympathetic input to the bladder and inhibition of sympathetic and somatic inputs to the urethra (Fig. 4). This on/off switching circuit is activated by a critical threshold of afferent activity arising from tension receptors in the bladder and is relayed to the periaqueductal gray area in the pons [36]. These signals are transmitted and integrated in the pontine micturition center. The M region of the pons facilitates bladder activity, and the L region (located ventrolateral to the pontine micturition center) regulates the pelvic floor muscles. Spinal pathways in the posterior and lateral columns transmit signals from higher brain centers to the sacral micturition center. Excitatory and inhibitory input from regions of the brain rostral to the pons modulate the spinobulbospinal micturition reflex. Voiding is initiated by detrusor contraction with coincident relaxation of urethral striated muscle. Parasympathetic neural discharge and activation of cholinergic receptors in detrusor muscle stimulates bladder contraction. Sympathetic and
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Fig. 4. Schematic diagram of reflex pathways involved in micturition. (A) During bladder filling, distention of the bladder produces low-level vesical afferent firing, which stimulates sympathetic and pudendal outflow. Sympathetic firing promotes urethral closure, inhibits bladder smooth muscle, and modulates ganglionic transmission. Increased pudendal outflow augments external urethral sphincter activity (guarding reflex). (B) Activation of the spinobulbospinal reflex pathway results in elimination of urine. Intense bladder afferent firing at a threshold bladder pressure activates pathways that pass through the pontine micturition center to stimulate parasympathetic outflow to the bladder and urethral smooth muscle and to inhibit sympathetic and pudendal outflow to the urethra. Ascending afferent input from the spinal cord may pass through relay neurons in the periaqueductal gray (PAG) before reaching the pontine micturition center. (Adapted from Degroat WC, Downie JW, Levin RM, et al. Basic neurophysiology and neuropharmacology. In: Abrams P, Khoury S, Wein A, editors. Incontinence. United Kingdom: Health Publications Ltd; 1999. p. 106–54; with permission.)
pudendal activity is concurrently suppressed by higher centers and by ganglionic and intramural mechanisms. An open urethral conduit is attained by suppression of rhabdosphincter activity and cholinergic inhibition of a-adrenergic sympathetic input on urethral smooth muscle. The urethra remains rigid to withstand the force of the urinary stream by excitatory input from intrinsic cholinergic nerves. Urethral-to-bladder reflexes, which are activated by flow- or mechanical-induced stimulation of urethral afferent nerves, facilitate sustained bladder contractions and promote emptying efficiency. Termination of voiding is associated with
a reduction in parasympathetic excitatory influence on vesicourethral muscularis with simultaneous a-adrenergic mediated closure of the outlet. Activation of smooth muscle contraction Bladder smooth muscle cells are spindle shaped with a smooth contour in the relaxed state and a serrated appearance when contracted [1]. These cells are arranged in muscle bundles of various sizes. The sarcolemma appears as thick, dense bands interspersed with caveolae [46]. Plasmalemmal caveolae are flask-shaped invaginations of the
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plasma membrane that contain a variety of signal transduction molecules and calcium transport molecules [47]. These specialized plasmalemmal microdomains compartmentalize, modulate, and integrate signaling events at the cell surface and are thus thought to play a critical role in physiologic and pathologic signal transduction in many cell types [48]. Although relatively little is known about the role of caveolae in the bladder, these structures may facilitate the rapid regulation and integration of cellular responses to stimulation. Smooth muscle contraction is a calciumdependent process that can be induced by electromechanical coupling (triggered by action potentials and depolarization of the cell membrane) or by pharmacomechanical coupling (receptor-mediated activation of intracellular mechanisms). The increased intracellular calcium required for contraction of bladder smooth muscle occurs through activation of voltage- or receptor-operated calcium channels and through calcium release from intracellular stores. Recordings of electrical activity from isolated human bladder and urethral smooth muscle cells indicate a resting membrane potential of ÿ40 to ÿ60 mV [49]. Spontaneous action potentials can be shown in a small percentage of bladder cells. Once the smooth muscle cell is activated and intracellular calcium approaches threshold concentrations, contractile force is generated by properly oriented myofilaments anchored at regularly spaced sarcolemmal dense bands. These thin actin filaments form cross bridges with myosin filaments after phosphorylation of the regulatory myosin light chains by a calcium/calmodulin-dependent myosin light chain kinase. Crossbridges between phosphorylated myosin heads and actin cause the filaments to slide along each other, resulting in cell shortening and contraction. Activation of a ‘‘latch state’’ in the crossbridges allows maintenance of tonic force with low energy expenditure. A subsequent reduction in intracellular calcium inactivates myosin kinase, resulting in myosin dephosphorylation and smooth muscle cell relaxation. A unified voiding contraction requires transmission of contraction from an innervated cell to neighboring cells. Ultrastructure studies have shown that not every smooth muscle cell receives direct innervation because the ratio of nerve to muscle in the vesicourethral muscularis is reportedly less than one [1]. Thus, tension created by muscle cell shortening is transmitted to adjoining cells mechanically through intermediate cell junctions. An intercellular collagen fibrillar meshwork
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permits mechanical force transmission between muscle fascicles and bundles [31]. Recent studies suggest that electrical coupling between cells through gap junctions may also contribute to the transmission of the contractile response from cell to cell [50,51]. In addition to smooth muscle regulation by neurotransmitter receptor-mediated interactions, other peptidergic and humoral mechanisms in smooth muscle may be involved in modulation of lower urinary tract function. For example, endothelins and angiotensin II induce contractile responses, and parathyroid hormone-related protein produces relaxation of bladder smooth muscle [52–54]. The presence of these peptides and their receptors in the bladder and their stimulationinduced secretion by smooth muscle [55–58] suggest that smooth muscle tone may be modulated by autocrine/paracrine mechanisms. Estrogen and progesterone receptors are present in bladder and urethra. Although experimental studies investigating hormonal influences on the lower urinary tract are somewhat conflicting and difficult to interpret, it appears that alterations in the hormonal milieu dramatically affect autonomic receptor distribution and density, smooth muscle size and number, muscle metabolism and biochemistry, connective tissue density and distribution, and urothelial proliferation and permeability. Estrogen treatment has been shown to increase bladder and urethral mass, to decrease spontaneous contractions, and to enhance urethral sensitivity to a-adrenergic agonists in animals [59– 63]. In women, estrogen increases urethral closure pressure, improves pressure transmission to the proximal urethra, stimulates connective tissue metabolism [64], and increases the amplitude of vascular pulsations noted on urethral pressure profilometry [65]. Pregnancy and menstrual cycle appear to have a major impact on bladder function. For example, pregnancy increases the frequency of urination, decreases the effects of methoxamine and epinephrine in the bladder base, alters the relative contributions of cholinergic and purinergic components, and decreases muscarinic cholinergic receptor density in the rabbit [66,67]. In the rat after multiple gestations, bladder hypertrophy, bladder instability, increased voiding pressures and residual volume, and altered sensitivity to adrenergic and cholinergic stimulation have been demonstrated [68]. In women, a significantly greater prevalence of detrusor instability is found antenatal compared with postpartum, possibly mediated by
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progesterone [69]. Finally, in many women, urinary symptoms and the presence of detrusor instability may be influenced by their menstrual cycle [70,71]. Continence biomechanics The structure and composition of bladder and urethral tissues have a substantial impact on their physical and biomechanical properties. These properties allow bladder pressure to remain low and relatively constant until the bladder is full. According to Laplace’s law, the detrusor pressure is proportional to force and inversely related to bladder radius (assuming the bladder behaves as a thin-walled sphere). As a result of this physical property, force increases as the bladder stretches with filling; however, the bladder radius also increases, so that changes in bladder pressure are minimal. During bladder filling, a high degree of compliance, which is expressed as the ratio of a change in bladder volume to the change in intravesical pressure, is produced by a combination of the biomechanical properties of muscular and extracellular matrix elements of the bladder and inhibitory impulses from the sacral cord. The bladder and urethra behave as viscoelastic tissues; a passive physical mechanism that impedes deformation of a stressed tissue. Viscoelastic tissues exhibit features of stress relaxation, hysteresis, and creep. Stress relaxation allows a stretchinduced increase in tension to gradually decay when stretch slows or stops. Hysteresis describes the stress–strain relationship resulting from a loading/unloading process, and creep refers to the continued deformation resulting from a sudden constant stress. The viscoelastic properties of the bladder are determined by collagen and contractile elements of smooth muscle. Alterations in the viscoelasticity of bladder wall components can result in reduced bladder compliance. Maintenance of urinary continence is a complex physiologic process that can be attributed simplistically to a sustained urethral pressure that exceeds intravesical pressure regardless of posture and physical activity. The smooth muscle sphincter in women is less developed and has sparse noradrenergic innervation compared with men [72]. Thus, anatomic and neural evidence does not support the presence of a prominent smooth muscle sphincter in the vicinity of the bladder neck. In addition, studies have shown radiologic evidence of bladder neck incompetence in some women who are continent [73]. These factors suggest that
the bladder neck alone may not be the primary mechanism for continence provided that the distal urethral and pelvic floor mechanisms are intact. It therefore appears that the complex arrangement of the musculature of the bladder base, vesicourethral junction, and proximal urethra contribute to a functional smooth muscle sphincteric mechanism [46]. The specific contribution of the longitudinal and circular smooth muscle layers to urethral sphincter closure in females is uncertain. The maximum shortening velocity of the longitudinal smooth muscle has been shown, however, to be three times greater than that of the circular smooth muscle in the rabbit urethra, which is consistent with a phasic role of the longitudinal muscle in opening the urethra during voiding and a tonic role of the circular muscle in urethral closure during filling [74]. A recent alternate concept proposes that contraction of the longitudinal smooth muscle contributes to the sphincter closure mechanism rather than opening of the bladder neck because a contraction-induced increase in the diameter of the longitudinal muscles would promote closure of the urethra and would impede opening of the bladder neck [75]. This interesting proposal has not yet been experimentally validated. Continence mechanisms ensure that the urethra remains closed under both active and passive conditions. Active continence is an intermittent condition achieved by voluntary contraction of the periurethral and pelvic muscles, whereas passive continence is continuous, without voluntary assistance during bladder filling. Several neuromuscular and non-neuromuscular factors determine the physical properties that promote passive continence. Neuromuscular factors include the resting tone of somatically innervated pelvic floor musculature, somatically and likely autonomically innervated striated urethral sphincter, and sympathetically innervated urethral smooth muscle [76]. Recruitment of motor units in the pelvic floor and external sphincter occurs reflexly during vesical filling. Contraction of the pelvic floor and external sphincter affected by pudendal motor nerve discharge is associated with compression, elevation, and elongation of the urethra and with direct inhibition of the detrusor motor nucleus. Non-neuromuscular factors consist of the coaptation of the richly folded urothelium, collagen, and elastin in the urethra and periurethra and the submucosal vascular bed. The intrinsic characteristics of the urethra required for the urethral lumen to seal completely include inner urethral softness, inner compression,
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and outer tension [77]. Inner softness refers to the plasticity of the inner urethral wall, which allows it to mold into a collapsed state, regardless of the compression applied. Surface tension created by mucosal secretions ensures a watertight seal. Inner urethral compression is a passive response to tension produced outside the compressed region, which provides the capacity to mold and conform to shape. To promote continence, the region of inner compression must be subjected to urethral wall tension. This tension is determined by passive characteristics of collagen and elastin and by the passive and active tension of the urethral musculature. Proper anatomic support by extrinsic pelvic attachments is critical to effective urethral sphincter function. The anatomic configuration imparted by attachment of the endopelvic fascia and vaginal wall to the striated muscle of the levator ani and to the pelvic bones through the arcus tendineus fascia pelvis promotes urinary storage and permits transmission of pressure to the bladder neck and urethra [78]. During periods of increased intraabdominal pressure, such as during coughing, sneezing, and physical activity, the urethral pressure produced by passive transmission of intra-abdominal pressure is augmented by reflex contraction of the striated musculature. Thus effective urethral support requires the coordinated and integrated action of multiple structures subjected to neural control. Urethral tissues are strongly influenced by hormones. Lack of estrogen at menopause can cause thinning of urethral epithelium, reduced mucosal secretions, and atrophy of the vascular sponge [5]. Estrogens have been shown to improve submucosal blood flow and to enhance proliferation and maturation of atrophic urothelium. Thus, estrogens may play a role in alleviating incontinence. A physical measure of female urethral function is obtained by identifying the pressure along the urethra (Fig. 5). The shape of the resting urethral pressure profile reflects the contributions of the intrinsic anatomic components of the urethra, including the striated urethral and pelvic floor muscles, the urethral smooth muscle, the fibroelastic tissues of the urethra, and the submucosal vascular plexus. The normal urethral pressure profile in the female is nearly symmetric, with maximum urethral pressures averaging between 65 and 90 cm H2O. Maximum urethral pressures and functional urethral length have been shown to decrease with age in women [79,80]. Average functional urethral length is approximately 2.6 cm, although the anatomic length is approximately 4 to 5 cm.
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Fig. 5. Urethral closure pressure profile (UCPP) in an asymptomatic female. Urethral pressure begins to rise in the vicinity of the bladder neck (bn) and progressively increases through the midurethra (MU). Maximum urethral pressure is reached in the distal sphincter region. Urethral pressure decays progressively to atmospheric pressure at the external meatus. Top panel: intravesical pressure (B); middle panel: urethral pressure; bottom panel: rectal pressure (R).
Voiding biomechanics Micturition is normally a voluntary event, which is initiated at a convenient, socially appropriate time and location. For micturition to occur, the rise of intravesical pressure produced by bladder contraction must be coordinated with a reduction of urethral closure forces. Voluntary relaxation of the pelvic floor is a preliminary event to normal micturition that allows the bladder neck to descend and facilitates its opening. Further
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relaxation of the pelvic floor occurs as a reflex in association with the onset of contraction [81,82]. The interrelationships among the detrusor, bladder neck, and distal sphincter that occur during the initiation of voiding are complex and poorly appreciated. These physiologic events are further obscured by the supplemental responses that occur with urgency voiding. Volitional voiding is characterized by synchronous detrusor contraction and striated sphincter relaxation in both men and women [82]. During this period, the bladder neck remains closed, and fluid is not observed in the proximal urethra despite striated sphincter relaxation. Instead, pressure in the bladder neck region increases transiently in parallel with the isometric phase of the detrusor contraction. This transient contractile response of the bladder neck during initiation of micturition does not occur if the bladder neck is incompetent and not in an occlusive state during the filling phase. At a critical point during this transition phase, the bladder neck opens, flow begins through the already relaxed distal striated sphincter, and bladder neck pressure becomes isobaric with bladder pressure (Fig. 6) [83]. Although the precise mechanism responsible for bladder neck opening during initiation of voiding is not clear, a role can be postulated for sympathetic modulation and/or mechanical factors at the bladder neck. With urgency voiding, the voluntary hold on the striated sphincter is released, thus eliminating the reflex inhibition of the detrusor contraction. After this initial decrease in pressure in the midurethra, the onset of detrusor contraction occurs simultaneously with both reflex striated sphincter relaxation and transient bladder
neck contraction. Once urinary flow is established, a sustained detrusor contraction and open bladder neck and urethral regions result in uninterrupted voiding until the bladder is empty (Fig. 7). As urination progresses, the striated sphincter remains relaxed and becomes relatively refractory to afferent pudendal reflex arc stimulation [84]. Because of energy losses during micturition, urinary flow is approximately 30% to 50% less than the flow delivered by a rigid tube of comparable diameter and length subjected to an equivalent pressure [85]. These losses result from the distensible nature of the urethra (requiring energy to keep the urethra open) and the viscosity of the fluid (a property that extracts energy from the stream at local transition regions in the urethra). Compared with the considerable energy losses associated with tortuous male urethral anatomy, losses in the female urethra are reportedly lower because of its relatively minor curvature and smooth funnelshaped internal meatus [86]. During the terminal phase of micturition, striated sphincter pressures gradually increase, urinary flow rate diminishes, detrusor contraction pressure decreases, and urethral pressures gradually return to resting closure pressures. Contraction of the striated external sphincter and pelvic floor musculature elevates the bladder base, whereas bladder smooth muscle simultaneously relaxes, thus restoring the prevoid relationship of the bladder and urethra. The lower urinary tract is a hydrodynamic system requiring mechanical equilibrium of its components. Interactions between the bladder and urethra must obey hydrodynamic laws governing
Fig. 6. Schematic representation of the relationship among bladder, bladder neck, and distal urethral pressures during voiding. Bladder contraction (Pves) occurs simultaneously with a reduction in external sphincter pressure (PEUS) and an attenuation of the electromyogram (EMGEUS). Pressure in the vicinity of the bladder neck (PBN) increases in parallel with rising bladder contraction. During flow (Q), the electromyogram remains silent.
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Fig. 7. Voiding cystourethrogram of an asymptomatic 35-year-old women showing a smooth contoured bladder that is well suspended in the pelvis. The bladder neck is open and the urethra fully distended.
fluid systems. As a result, measurement of fluidmechanical properties inevitably reflects the function of the system [87]. During the initiation of flow, the outlet is hydraulically distended by fluid entering the urethra. The pressure required to open the urethra (i.e., the opening pressure) depends on the degree of muscle relaxation and the tension remaining in the urethral wall in the fully relaxed state. In normal women, the opening pressure is low compared with that of men, apparently because of the absence of mechanical forces contributed by the prostate. As a result, voiding pressure is lower in women than in men. With additional increases in bladder pressure, the urethra is opened further until it is fully distended. The flow rate is then related to the narrowest portion of the urethra. In women, this ‘‘flow controlling zone’’ is located in the distal urethra [83]. With this zone fully distended, flow becomes stable and steady as long as bladder pressure exceeds opening pressure [88]. Once bladder pressure falls below the critical opening pressure, the urethra closes and flow stops. During the mechanical process of voiding, bladder pressure plateaus or may diminish with steady flow as a result of the conversion of pressure-work into kinetic energy and the physical limitations of muscle. When the contractile machinery is activated, smooth muscle consumes energy to either generate force or shorten its length. Thus, the strength of contracting muscle is determined
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by its force–velocity relationship. When transformed to clinically relevant parameters, this function describes the inverse relationship between pressure generated and the resulting flow rate. Pressure in the bladder is determined by the outflow conditions and the mechanical power of the detrusor. Thus, for a constant power, a narrow outlet will result in high pressure at low flow, whereas low resistance causes higher flow rate at low pressure. Moreover, for a given outlet condition, increased bladder power increases pressure and flow rate [89]. A measurement of bladder contractility using an isometric test can be used to characterize the ability of the bladder to develop power [90]. Isometric pressures in women are significantly lower than in normal men [91,92]. A teleologic explanation for this difference could be the need for an increased bladder muscle mass in men required to overcome the increased resistance of the male urethra in contrast to lower resistance offered by the female urethral anatomy. Normal function of the lower urinary tract depends on complex interactions among many factors, including neural innervation, properties of smooth muscle, proportion of connective tissue, urothelial integrity, and effective supportive structures. A complete understanding of the structural and functional characteristics of the bladder and urethra is essential for the ability to recognize and effectively treat lower urinary tract dysfunctions. Although our knowledge of lower urinary tract function has greatly increased over the last decade, continued research promises to offer new insights into the complex bladder–urethral interactions and to provide a basis for developing better management strategies for a variety of voiding dysfunctions in women.
Acknowledgements This work was supported by the Medical Research Service, Department of Veterans Affairs, Washington, DC.
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