SYMPATHETIC ACTIONS ON DETRUSOR MUSCLE AND GANGLIA

During physiologic bladder filling, little or no increase in intravesical pressure is observed, despite large increases in urine volume. This process, called accommodation, is caused primarily by passive elastic and viscoelastic properties of the smooth muscle and connective tissue of the bladder wall. During filling, muscle bundles in the bladder wall undergo reorganization, and the muscle cells are elongated up to four times their length. As bladder filling progresses and at a certain bladder wall tension, a desire to void is felt, although it has not been determined where this sensation is processed in the brain. Mechanoreceptors in the bladder wall are activated, and action potentials run with afferents following parasympathetic pelvic nerves to the spinal cord at the S2 to S4 and with afferents following sympathetic nerves to the thoracolumbar cord. As filling increases to a critical intravesical pressure, or with rapid bladder filling, detrusor muscle contractility is inhibited by activation of a spinal sympathetic reflex.

The sympathetic neural pathways are as follows: Sympathetic preganglionic fibers from thoracolumbar spinal segments form white rami communicantes to synapse in the paravertebral or prevertebral sympathetic pathways, the latter predominating. Postganglionic neurons reach inferior mesenteric ganglia by the lumbar splanchnic nerves and continue through the hypogastric plexus to the presacral fascia, across the upper posterior lateral pelvic wall, 1 to 2 cm behind and below the ureter. After these neurons join the pelvic nerves, the pelvic plexus is formed, running below and medial to the internal iliac vessels overlying the anterior lateral lower rectum near the anorectal junction. The plexus spreads in the lateral wall of the upper one third of the vagina beneath the uterine artery, medial to the ureter and 2 cm inferolateral to the cervix. Within the vesicovaginal space, the plexus supplies the upper vagina, bladder, proximal urethra, and lower ureter. Sympathetic preganglionic neurons generally use acetylcholine neurotransmitter acting on nicotinic receptors. The sympathetic postganglionic fibers are primarily noradrenergic, with norepinephrine being the chief neurotransmitter. Norepinephrine stimulation of β adrenergic receptors located in the bladder body causes relaxation of the smooth muscle, as the β receptors are stimulated by lower norepinephrine doses. Stimulation of α₁ receptors in bladder base and urethral smooth muscle by higher doses of norepinephrine causes muscle contraction. Norepinephrine also acts as a neurotransmitter at the parasympathetic ganglia, and α-adrenergic receptors, when stimulated, depress parasympathetic pelvic ganglion transmission by suppression of presynaptic cholinergic neurotransmitter release. Thus, sympathetic relaxation of detrusor body smooth muscle, contraction of bladder base and urethral smooth muscle, and depression of parasympathetic ganglionic transmission, all act to promote urine storage. Other sympathetic modulators of neurotransmission include purinergic, peptidergic, and nitrergic factors.

PARASYMPATHETIC ACTIONS: DETRUSOR

The parasympathetic preganglionic fibers arise from nerve roots S3 and S4 and, occasionally, S2, the cell bodies being in the sacral cord, the conus medullaris. These fibers emerge from the piriformis muscle overlying the sacral foramina and enter the presacral fascia near the ischial spine at the posterior layer of the hypogastric sheath, where they contribute to the already described pelvic plexus. The pelvic plexus has freely interconnected nerves in the pelvic fascia that supply the rectum, genitalia, and lower urinary tract. The parasympathetic fibers to the urinary tract terminate in pelvic ganglia located within the wall of the bladder, a location quite vulnerable to end-organ disease, such as overstretch, infection, or fibrosis. At the ganglia, excitatory transmission occurs from activation of nicotinic acetylcholine receptors, with some ganglionic cells having secondary muscarinic receptors. Multiple neuropeptide agents also function at ganglia. Transmission regulation is complex, and precise knowledge is not available at present.

At the detrusor muscle, postganglionic, parasympathetic detrusor nerve fibers diverge and store neurotransmitter agents in axonal varicosities called synaptic vesicles. The agent is diffused to neuromuscular bundles of 12 to 15 smooth muscle fibers enclosed in a collagen capsule that acts similarly to the tendon insertion of a muscle. Stimulating electrical pulses produce two episodes of depolarization, suggesting the release of two neurotransmitters. The chief neurotransmitter is cholinergic, with muscarinic receptors, and the second neurotransmitter is noncholinergic and nonadrenergic. This observation accounts for detrusor atropine resistance. The studies of Burnstock et al. in 1972 demonstrated that adenosine triphosphate (ATP) was the mediator of these noncholinergic, nonadrenergic contractions. Variability is present between species, and some studies suggest that the purine (ATP) pathway responses lead to more rapid bladder contractions, perhaps being useful in animals that use short, quick squirts of urine for property marking.

Muscarinic receptors have received much attention by pharmaceutical companies. The receptors are present in the CNS, eye lacrimal glands, salivary glands, heart, gallbladder, stomach, and colon. Five types (M_1–5) have been identified. In detrusor muscle, M₂ and M₃ predominate, with M₃ used more for detrusor contractions. Dry mouth, slowed gastrointestinal motility, blurred vision, increased heart rate, heat intolerance, sedation with reductions in memory and attention, delirium, drowsiness, fatigue, and other cognitive functions are side effects related to the various receptors. Anticholinergic medications using M₂ and M₃ receptors, without affecting the other muscarinic receptor pathways, should have more therapeutic effects against bladder overactivity with fewer side effects.

Cholinergic receptors are more present in the body than in the base of the bladder, whereas adrenergic and neuropeptide receptors are more prevalent in the base. Neuropeptide modulators include vasoactive intestinal polypeptide and substance P. Histaminic and purinergic receptors may also be present in detrusor smooth muscle.

SMOOTH MUSCLE OF TRIGONE AND URETHRA

The trigone is a separate anatomic and embryologic region where smooth muscle fibers have an almost exclusively adrenergic innervation with chiefly α₁ receptors. Cholinergic development in the bladder is present at birth, whereas adrenergic development occurs later. Prostaglandins act as intracellular messengers to relax trigonal muscles.

The proximal urethral smooth muscle is rich in α-adrenergic receptors responsive to norepinephrine neurotransmitter. Acetylcholine, substance P, vasoactive intestinal polypeptide, and histamine are all additional potential transmitters in the urethra. Nitric oxide (NO) is prominent in the parasympathetic postganglionic innervation of the urethra, and exogenous NO or parasympathetic nerve stimulation relaxes urethral smooth muscle. Parasympathetic stimulation has been thought by Khanna (1981) to cause contraction of urethral smooth muscle, using acetylcholine neurotransmission and muscarinic receptors. However, McGuire (1978) thought this increase in urethral “resistance” was due to simple transmission of intravesical pressure. He demonstrated, by diverting the urinary stream, that pelvic nerve stimulation caused urethral smooth muscle relaxation. The relaxation effect was blocked by propranolol, indicating a β-adrenergic response.

SKELETAL MUSCLE OF LOWER URINARY TRACT: SOMATIC INNERVATION

In the lower urinary tract, the somatic system involves skeletal muscle in the lower urinary tract outlet. The neuronal cell bodies for the urethral sphincter and for the distal periurethral striated muscles and pelvic floor muscles are located in Onuf’s somatic nucleus in the lateral aspect of the anterior horn of the gray matter of the sacral spinal cord from S2 to S4. This nucleus gives rise to the pudendal nerve, which is classically thought to provide the efferent innervation of the striated sphincter. Thor (2004) has shown that serotonin and norepinephrine enhance the effects of glutamate, the primary excitatory neurotransmitter for pudendal motor neurons. The pudendal nerve, using acetylcholine, activates nicotinic cholinergic receptors to contract the rhabdosphincter.

The exact neuropathways supplying the urethral sphincter skeletal muscle are controversial. The proximal intramural component of the striated urogenital sphincter muscle (urethral sphincter, rhabdosphincter) is variably innervated by somatic efferent branches of the pelvic nerves, a component of the pelvic plexus. Elbadawi (1983) believed this intramural component to have somatic and autonomic (both cholinergic and adrenergic) innervation. However, the more distal periurethral striated muscles (compressor urethra and urethrovaginal sphincter) are innervated by the pudendal nerve, as is the skeletal muscle of the external anal sphincter and perineal muscles.

Typically, somatic motor activity regulates skeletal muscle contraction by spinal reflexes, with the afferent arm of the reflex originating in muscle spindles, synapses taking place in the spinal cord, and the efferent arm originating in anterior horn cells with the axon going to the muscle. Unlike typical somatic reflex pathways that are regulated by sensory nerves from muscle spindles, the afferent regulation of the urethral sphincter somatic reflex is different because urethral skeletal muscle has no spindles.

Embryologic speculation is that pelvic caudal muscles (tail waggers), which compose the levator group in humans, are supplied from the pelvic plexus on the pelvic surface side, whereas the sphincter cloacal derivatives are supplied from the perineal aspect by the pudendal nerve.

The pudendal nerve passes between the coccygeus and piriformis muscles, leaves the pelvis through the greater sciatic foramen, crosses the ischial spine, and reenters the pelvis through the lesser sciatic foramen. Here the nerve accompanies the pudendal vessels along the lateral wall of the ischiorectal fossa in a tunnel formed by a splitting of the obturator fascia, called Alcock’s canal. At the perineal membrane, the nerve divides into the inferior rectal nerve, supplying the external anal sphincter, the perineal nerve, and the dorsal nerve to the clitoris (see Fig. 2-8). The perineal nerve splits into a superficial branch to the labia and a deep branch to the periurethral striated muscles. The branching of the pudendal nerve shows considerable variation.

The urethral sphincter muscle is an integral part of the urethral wall and is made up of all slow-twitch (type 1) fibers. The periurethral muscles (compressor urethra and urethrovaginal sphincter) are composed of mostly slow-twitch fibers with a variable concentration of fast-twitch (type 2) fibers. These fibers combine to provide constant tonus, with emergency reflex activity mainly in the distal half of the urethra.

The response of segmental spinal reflex leading to pudendal nerve function involves several spinal cord segments. Afferent fibers involved in the reflex have both segmental and supraspinal routing. This dual routing explains the bimodal response of pudendal motor neurons when pudendal sensory nerves are stimulated, and it differs from stimulation of pelvic detrusor afferents.

The neurotransmitter at the periurethral skeletal neuromuscular junction is acetylcholine and the receptors are nicotinic type. The intimate adherence of the neuromuscular junction to the striated muscle fibers conveys a resistance to blockade by neuromuscular blocking agents.

CORTICAL AND SUBCORTICAL PATHWAYS

The brainstem’s importance in the lower urinary tract function has been known since 1921, when Barrington ablated this area in cats and produced permanent urinary retention. He demonstrated that the middle pons was the level in the brain at which the motor tone of the bladder arises. This region in the pons has been called the pontine micturition center

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