Maintenance of normal lower urinary tract function is a complex process that requires coordination between the central nervous system and the autonomic and somatic components of the peripheral nervous system. This article provides an overview of the basic principles that are recognized to regulate normal urine storage and micturition, including bladder biomechanics, relevant neuroanatomy, neural control of lower urinary tract function, and the pharmacologic processes that translate the neural signals into functional results. Finally, the emerging role of the urothelium as a sensory structure is discussed.
Normal lower urinary tract function requires the storage of urine at low intravesical pressure, without leakage. Intermittently, this storage function is interrupted by the voluntary and complete expulsion of urine. These processes (storage and voiding) are unique in that they involve the coordination of the peripheral autonomic, peripheral somatic, and central nervous systems (CNS). This article provides an overview of the basic principles that are recognized to regulate these functions, although many of these processes remain poorly understood. Furthermore, much of this knowledge has been obtained from in vivo animal models, and the relevance of these findings to human physiology is not always clear.
Bladder anatomy and biomechanics
The bladder base refers to the trigone and bladder neck, whereas the body consists of the supratrigonal portion. The bladder wall consists (from the outside, away from the bladder lumen) of the serosa, smooth muscle and extracellular matrix (ECM) (in approximately 50-50 distribution), the lamina propria, and the urothelium. Like other smooth muscles, the detrusor muscle is oriented in a seemingly random fashion, is not attached to tendon or bone, is able to maintain steady tension over a wide range of muscle lengths, and has a slower contraction velocity than the skeletal muscle. The detrusor muscle uses the ECM as a scaffold to generate tension, which produces a bladder contraction.
Bladder accommodation refers to the changes that occur during bladder filling to permit low-pressure urine storage across a wide range of bladder volumes. This process is measured by calculating the bladder compliance (change in bladder volume/change in intravesical pressure), which is expressed in mL/cm H 2 O. Normal compliance is maintained throughout filling by reorientation of the detrusor smooth muscle fibers and connective tissue so that they are parallel to the lumen, thinning of the lamina propria, and flattening of the urothelium. Bladder accommodation is a complex and poorly understood process that can be altered because of neurologic damage or changes in the ECM content. For instance, an increase in type III collagen has been found in bladders with decreased compliance.
General neuroanatomy
The CNS consists of the brain and spinal cord, and the peripheral nervous system (PNS) consists of the sensory (afferent) and motor (efferent) neurons that communicate with the CNS. The PNS is divided into the somatic and the autonomic nervous systems. The somatic nervous system is responsible for regulating structures that are under conscious control (such as the striated external urethral sphincter and the levator muscles in the pelvic floor). The autonomic nervous system controls visceral and endocrine functions, including bladder contraction and relaxation. The autonomic nervous system is subdivided into the parasympathetic and sympathetic nervous systems. Sympathetic and parasympathetic are anatomic terms that indicate the location from where the nerve fibers emanate. Parasympathetic fibers emerge from the cranial and sacral segments of the spinal cord, whereas sympathetic fibers emerge from the thoracic and lumbar segments of the spinal cord.
General neuroanatomy
The CNS consists of the brain and spinal cord, and the peripheral nervous system (PNS) consists of the sensory (afferent) and motor (efferent) neurons that communicate with the CNS. The PNS is divided into the somatic and the autonomic nervous systems. The somatic nervous system is responsible for regulating structures that are under conscious control (such as the striated external urethral sphincter and the levator muscles in the pelvic floor). The autonomic nervous system controls visceral and endocrine functions, including bladder contraction and relaxation. The autonomic nervous system is subdivided into the parasympathetic and sympathetic nervous systems. Sympathetic and parasympathetic are anatomic terms that indicate the location from where the nerve fibers emanate. Parasympathetic fibers emerge from the cranial and sacral segments of the spinal cord, whereas sympathetic fibers emerge from the thoracic and lumbar segments of the spinal cord.
Cross-sectional anatomy of the spinal cord
Peripheral sensory information is carried via afferent nerves fibers, which enter the dorsal (posterior) aspect of the spinal cord and then travel upward to the central processing centers in the CNS ( Fig. 1 ). Afferent cell bodies are located in the dorsal root ganglia. The white matter of the spinal cord contains bundles of myelin-coated neurons, whereas the gray matter contains the cell bodies of interneurons and efferent motor neurons. Within the gray matter, nerve cell bodies are generally organized into functional clusters called nuclei (such as Onuf nucleus). Axons within the white matter are functionally grouped into tracts. Efferent motor axons exit from the ventral root of the spinal cord.
Relevant neuroanatomy: PNS and spinal cord
Preganglionic parasympathetic efferent nerves exit from the sacral segment of the spinal cord at S2 through S4. The axons travel a long distance within the pelvic nerve to the ganglia (pelvic plexus) that are located immediately adjacent to the end organ (bladder) ( Fig. 2 ). These fibers modulate bladder contractions. The primary neurotransmitter for both pre- and postganglionic parasympathetic fibers is acetylcholine (ACh).
Preganglionic sympathetic efferent nerves exit from the thoracolumbar segment of the spinal cord at T10 through L2. The ganglia for these nerves have variable locations: some are next to the vertebrae (paraganglia), some are between the vertebrae and the target organ (preganglia), and some are located with the end organ (peripheral ganglia). Sympathetic efferent nerves to the lower urinary tract are located within the hypogastric nerve. The sympathetic efferent nerves modulate contractions of the urethral smooth muscle and bladder outlet and inhibit parasympathetic activity that promotes bladder contraction. The primary neurotransmitter for postganglionic sympathetic fibers is norepinephrine, but the primary neurotransmitter for preganglionic sympathetic fibers is ACh.
Preganglionic somatic efferent nerves exit from the sacral segment of the spinal cord at S2 through S4. Nerve bodies for these nerves are located in the Onuf nucleus, along the lateral border of the ventral gray matter in the sacral region of the spinal cord. The nerve fibers travel within the pudendal nerve to the external urethral sphincter, where they modulate striated (voluntary) sphincter contraction.
In humans and animals, afferent nerves have been identified in the detrusor muscle and the suburothelium. The suburothelial afferent nerve fibers form a plexus that lies immediately beneath the urothelial lining, with some nerve terminals extending into the urothelium itself. This plexus is more prominent in the trigone and bladder neck and relatively sparse in the bladder dome. Afferent nerve fibers from the lower urinary tract travel within the pelvic, hypogastric, and pudendal nerves. Therefore, these peripheral nerves carry bidirectional (afferent and efferent) information between the end organs and the spinal cord. The sensory fibers enter the spinal cord via the dorsal root, and the nerve cells bodies are located within the dorsal root ganglia. Afferent nerves release numerous neurotransmitters (eg, substance P, neurokinins, calcitonin gene–related polypeptide, vasoactive intestinal polypeptide). Most sensory innervation of the bladder and urethra originates in the thoracolumbar region of the spinal cord and travels within the pelvic nerve. Within the pelvic nerve, 2 types of bladder afferent nerves have been identified, myelinated Aδ fibers and unmyelinated C fibers. The Aδ fibers respond to normal bladder distention and are thought to be the primary functional afferent nerves during normal micturition. Conversely, the C fibers respond to chemical irritation (nociception) or to cold, and most of these fibers are inactive during normal micturition. However, during certain pathologic states (eg, inflammation, suprasacral spinal cord injury), these “silent” C fibers appear to activate, become mechanosensitive, and modulate pathologic voiding reflexes.
Relevant neuroanatomy: brainstem and above
Conclusive experimental evidence using brain-lesioning techniques, electric stimulation, and axonal tracing studies indicate that an area of the pons (the pontine micturition center [PMC] or Barrington nucleus) mediates the normal micturition reflex by coordinating the activity of the detrusor and urethral sphincter muscles. Therefore, spinal cord lesions below this level often result in discoordination between the detrusor and urethral sphincter (detrusor-sphincter dyssynergia). The PMC receives input from multiple higher brain centers, including the basal ganglia, periaqueductal gray, thalamus, and hypothalamus. Brain imaging studies in healthy volunteers suggest a model of supraspinal bladder control, in which afferent signals from the lower urinary tract are received in the periaqueductal gray and relayed via the thalamus to the insula (which makes the sensations accessible to conscious awareness). According to this model, the cortex (via the anterior cingulate gyrus) monitors and controls micturition reflexes and also makes voluntary voiding decisions (via the prefrontal cortex).
Neural control of the lower urinary tract
During the storage phase of micturition, bladder filling activates myelinated Aδ afferent nerve fibers in the bladder wall. This afferent input results in stimulation of sympathetic efferent activity (via the hypogastric nerve), leading to contraction of smooth muscles in the bladder base and proximal urethra (via activation of α-adrenergic receptors) and relaxation of the detrusor (via activation of β-adrenergic receptors in the bladder body). Somatic efferent activity (via the pudendal nerve) also increases, resulting in increased tone of the striated external urethral sphincter. These responses occur by spinal reflex pathways organized in the lumbosacral region of the spinal cord and represent guarding reflexes, which promote continence. The parasympathetic system is largely inactive during urine storage, which may partly be because of the sympathetic inhibition of parasympathetic transmission at the ganglia level.
The voiding phase of micturition is initiated voluntarily by signals from the cerebral cortex. The initial event is relaxation of the striated external urethral sphincter, caused by inhibition of somatic efferent activity. There is inhibition of sympathetic efferent activity, with concomitant activation of parasympathetic outflow to the bladder and urethra. Bladder contraction is mediated via muscarinic receptors in the bladder body, and urethral smooth muscle relaxation is mediated through the release of nitric oxide (NO). Maintenance of the voiding reflex is a complicated phenomenon that is mediated via communication between the spinal cord and the pons (spinobulbospinal reflex), with the involvement of midbrain structures such as the periaqueductal gray.
Pharmacology of the lower urinary tract
Cholinergic Mechanisms
In certain neurons of the CNS and PNS, the neurotransmitter ACh is synthesized from the essential nutrient choline by the enzyme choline acetyltransferase. In response to various stimuli, ACh is released into the synaptic cleft, where it either binds to cholinergic receptors or is broken down by acetylcholinesterase. ACh is released from postganglionic parasympathetic neurons, preganglionic autonomic neurons (sympathetic and parasympathetic), and somatic neurons. Two main types of cholinergic receptors exist: nicotinic and muscarinic. Nicotinic receptors (which are responsive to ACh and nicotine) are ligand-gated ion channels and are found on the skeletal muscle motor end plates, on the autonomic ganglia, and in the CNS. The nicotinic receptors seem to have a limited role in the control of micturition. Muscarinic receptors (which are responsive to ACh and muscarine) are G protein–coupled receptors that activate ion channels via second-messenger cascades. These receptors are found on all autonomic effector cells (eg, bladder, sweat glands, bowel) and in the CNS. Five subtypes of muscarinic receptors (M 1 through M 5 ) have been identified, and the M 2 and M 3 subtypes predominate in the bladder. Although M 2 receptors are the most plentiful in the detrusor (70% M 2 vs 30% M 3 receptors), in vitro studies indicate that the M 3 receptors are responsible for detrusor muscle contraction. The functions of the detrusor M 2 receptors are less clear. Muscarinic receptors are also found on presynaptic nerve terminals in the bladder and elsewhere, where they may play a regulatory role via feedback inhibition.
Excitation-contraction Coupling
Excitation-contraction coupling refers to the process whereby binding of a ligand to a receptor causes force generation (muscle contraction) ( Fig. 3 ). In the detrusor smooth muscle, the ligand is ACh and the receptor is the M 3 receptor. At rest, there is a very low concentration of free calcium ions (Ca 2+ ) in the smooth muscle cell. Binding of ACh to the M 3 receptor triggers a G protein–mediated process, which causes Ca 2+ release from the sarcoplasmic reticulum as well as Ca 2+ influx from transmembrane ion channels. The free Ca 2+ binds to calmodulin, and the Ca 2+ -calmodulin complex then activates the enzyme myosin light chain kinase, which phosphorylates the light chain of the contractile protein, myosin. This phosphorylation causes the myosin light chain to change shape and interact with actin, causing force generation. Alongside this process, alternate methods are at work to facilitate subsequent muscle relaxation. The Ca 2+ -calmodulin complex activates transmembrane Ca 2+ pumps to remove free Ca 2+ from the cell, the ligand-receptor complex is degraded, and excess extracellular ACh is degraded by acetylcholinesterase. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free ACh from the synapse is essential for proper muscle function.
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Review of Neurologic Diseases for the Urologist
Spinal Cord/Brain Injury and the Neurogenic Bladder
The Neurogenic Bladder and Incontinent Urinary Diversion
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Urologic Complications of the Neurogenic Bladder
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