Functional Neuroanatomy Of Penile Function

Parasympathetic and Nonadrenergic and Noncholinergic Outflow

Penile Erection

Parasympathetic preganglionic input to the human penis originates in the sacral (S2-S4) spinal cord (30). In most men, S3 is the main source of erectogenic fibers, with a smaller supply provided by either S2 or S4. These preganglionic neurons are situated in the intermediolateral cell column and send dendritic projections to laminae V, VII, IX, and X of the spinal cord. These distributions for axonal processes imply that sacral preganglionic neurons receive afferent information from both visceral and somatic structures.

Dendrites also project to areas containing descending axons from supraspinal centers that integrate and coordinate the autonomic nervous system, such as the hypothalamus, reticular formation, and midbrain (7). The preganglionic fibers from the sacral roots form the pelvic nerves (pelvic splanchnic nerves or nervi erigentes) and are joined by fibers from the inferior hypogastric nerves (sympathetic) to form the pelvic plexus (31). Alternatively known as the inferior hypogastric plexus, these nerves run in the pelvic fascia on the lateral side of the rectum, seminal vesicles, prostate, and posterior bladder. Additional sympathetic contribution arises from the sacral sympathetic chain ganglia via the gray rami.

Not all axons conveyed to hypogastric or pelvic nerves synapse in the pelvic plexus. Afferent and sympathetic postganglionic neurons pass through this plexus en route to the penis. The number of distinct pelvic nerves in men varies between three and six. The

Ischiocavernosus Erection
Fig. 4. Schematic representation of the venous drainage of the penis. (Adapted from ref. 282.)

Table 2 Penile Venous System

Penile outflow (venous)

Superficial drainage outflow (above Buck's fascia and below Colles's fascia)

Intermediate drainage outflow: deep dorsal vein and circumflex system (below Buck's fascia and above tunica)

Deep drainage outflow: deep penile or cavernous system

Dorsal skin and subcutaneous tissue by the superficial dorsal vein, emptying into a saphenous vein via the external pudendal vein or inferior epigastric vein.

Drains the glans and distal two-thirds corpora cavernosa corpora and spongiosum and corpus spongiosum. Small emissary veins penetrate tunica and combine into circumflex veins before draining into deep dorsal vein.

Empties into Santorini's plexus (periprostatic plexus).

Drains the proximal (cavernous veins, bulbar veins and crural veins).

Drains into the internal pudendal vein.

cavernous nerve (parasympathetic and sympathetic postganglionic fibers) leaves the pelvis between the transverse perineal muscles and the membranous urethra, passing between the arch of the pubic bone to supply each corpus cavernosum. The cavernous nerve divides into two branches. One is the lesser cavernous nerve, which supplies the erectile tissue of the corpus spongiosum and the penile urethra. The outer, greater cavernous nerve remains beneath the prostatic venous plexus and enters the corpora cavernosa around the cavernous vessels in the hilum of the penis. The cavernous nerve runs with branches of the prostatovesical artery and veins as part of the neurovascular bundle of the prostate. After passing the tip of the seminal vesicle and the nerves within the leaves of the lateral endopelvic fascia near its juncture with Denonvilliers' fascia, the cavernous nerve travels at the posterolateral border of the prostate and on the surface of the rectum. Passing posterolaterally to the prostate, the bundle emits fine branches to supply the prostatic capsule. At the prostatic apex, the nerve passes very near to the urethral lumen at the 3 and 9 o'clock positions and enters the penile crura more anteriorly, at 1 and 11 o'clock. The cavernous nerves represent the final pathway for vasodilator and vasoconstrictor neural input to the cavernous smooth muscles (30,32).

Parasympathetic input plays an important role in the case of the prostate, seminal vesicles, vasa deferentia, and bulbo-urethral glands. Parasympathetic efferents stimulate secretion in men from the bulbo-urethral and Littre's glands as well as from the seminal vesicles and prostate (33). Bulbo-urethral and Littre's glands produce mucus, which contributes to penile urethral lubrication. Prostatic and seminal vesicle secretions ensure the viability and motility of the sperm and account for much of the volume of the ejaculate (see Table 3).

Table 3

Neuroeffector of Ejaculation

Table 3

Neuroeffector of Ejaculation

Mechanism

Autonomic pathway

Function

Afferent

Touch, vibration, friction

Pudendal center (S2-S4)

Sensory

Efferent

Secretion Emission

Ejaculation

Parasympathetic center

Sympathetic center (T11-L2)

Pudendal somatic center

(S2-S4)

Secretion from prostate, seminal vesicles, ampullary glands, bulbo-urethral gland (Cowper's gland), Litter's glands.

Contraction of:

1. Internal accessory organs: seminal vesicle, prostate smooth muscle, bulbourethral gland.

2. Closure of internal urethral sphincter.

3. Contraction of ducts: ductuli efferentes, ductus epididymidis, vasa deferentia, ejaculatory ducts, smooth muscle of testicular capsule.

Projectile ejaculation involves:

1. Relaxation of external sphincter.

2. Rhythmic contractions of

ischiocavernosus and bulbocavernosus. 3. Contraction of pelvic musculature.

ischiocavernosus and bulbocavernosus. 3. Contraction of pelvic musculature.

Sympathetic Outflow

Penile Flaccidity, Seminal Emission, and Ejaculation

The sympathetic preganglionic fibers to the penis arise from cells in the intermedio-lateral gray cell column and dorsal commissure (intercalated nucleus) of the upper lumbar and lower thoracic segments ofthe spinal cord (T10-L2). Dendrites from thoracolumbar preganglionic neurons project mediolaterally toward the central canal. One interpretation of the distribution of these dendritic projections is that they enable preganglionic neurons to receive input from descending supraspinal centers. The preganglionic fibers leave the cord in the ventral roots of the corresponding spinal nerve, passing via the white rami communicantes to the paravertebral sympathetic chain. At this point, there are two different pathways for axons to reach the penis.

1. Some preganglionic fibers descend to ganglia at a lower lumbar or sacral level and synapse. The fibers then leave the chain at the sacral level and travel through pelvic nerves to the pelvic plexus and cavernous nerve. Alternatively, they travel via the pudendal nerves.

2. Other fibers pass through the corresponding chain ganglia without making synaptic contact and travel in lumbar splanchnic nerves to synapse in the ganglia of the superior hypogastric plexus, or the presacral nerve. This nerve subsequently divides into left and right hypogastric nerves, descending to the inferior hypogastric, or pelvic, plexus. The hypogastric nerves contain postganglionic sympathetic fibers as well as preganglionic nerves, which descend in the pelvis to synapse in the pelvic plexus.

Ejaculation

The process of ejaculation involves two steps: emission and ejaculation proper. Emission consists of the deposition of secretions from the peri-urethral glands, seminal vesicles, and prostate as well as sperm from the vas deferens into the posterior urethra. This results from the rhythmic contraction of smooth muscle in the walls of these organs. The accumulation of this fluid precedes ejaculation proper by 1 to 2 s and provides the sensation of ejaculatory inevitability. Emission is under sympathetic control from the presacral and hypogastric nerves that originate in the T10-L2 spinal cord levels (33). Ejaculation proper (projectile ejaculation) involves sympathetic controlled closure of the bladder neck, the opening of the external urethral sphincter, and contraction of the bulbo-ure-thral muscles for propulsion of the ejaculate. These are striated muscles innervated by somatic fibers carried in the pudendal nerve. Orgasm can occur despite damage to the sympathetic ganglia; however, it is rarely possible after injury to the pudendal nerve.

Somatosensory Innervation

Pudendal and Dorsal Nerve of Penis

Penile sensation is unique compared to other cutaneous regions. Approximately 80 to 90% of afferent terminals in the glans are free nerve endings, with mostly C or A-8 fibers (34). These sensory fibers belong to spinal segments S2-S4 and travel via the dorsal nerve of the penis, which joins the pudendal nerve (35). The afferent input conveyed from the penile skin, prepuce, and glans through the dorsal nerve is the mechanism responsible for the initiation and maintenance of reflexogenic erections.

The motor neuronal cells ofthe pudendal nerve form a ventrolateral group in the anterior grey column of S2-S4. The axons of these neurons supply the striated muscles of the penis and perineum. The pudendal nerve leaves the pelvis through the lower part of the greater sciatic foramen and enters the gluteal region close to the ischial spine on the medial side of the internal pudendal artery. It then travels through the lesser sciatic foramen into the pudendal canal with the internal pudendal artery. After giving off the inferior rectal nerve, it divides into the perineal nerve and dorsal nerve ofthe penis. The perineal branch innervates the ischiocavernosus and bulbocavernosus muscles as well as the skin of the genitalia, the urogenital diaphragm, and a branch to the spongiosum. The dorsal nerve of the penis runs along the ramus of the ischium, inferior to the pubis with the pudendal artery on the surface of the urogenital diaphragm. It then runs with the dorsal artery, terminating at the glans (36).

Rhythmic movements of the penis are the result of contraction of ischiocavernosus muscles, which compress the crura (37). These periods are brief and are readily observed as rhythmic movements ofthe penis. It has been suggested that intermittent suprasystolic contraction occurs during pelvic thrusting, when tactile stimulation and friction of the penis triggers the spinal "bulbocavernosus reflex" (38).

PENILE ERECTION AND FLACCIDITY: PHYSIOLOGICAL MECHANISMS

Penile erection is a neurovascular event controlled by corporal smooth muscle tone. In the flaccid state, the corporal smooth muscle of cavernous arteries, helicine arteries, and trabeculae are tonically contracted. This limits the blood flow to the penis at 5 mL/min, which is sufficient for nutritional purposes (39). There are four physiological components necessary to achieve a penile erection:

Neuro Anatomy Erection
Fig. 5. Schematic representation of neural innervation of the pelvic structures and penile erection.

1. Intact neuronal innervation.

2. Intact arterial supply.

3. Appropriately responsive smooth muscle.

4. Intact veno-occlusive mechanism.

Tactile or psychic stimuli caused by erotic activity initially are processed in the limbic system. The median pre-optic nucleus and the paraventricular nucleus transmit messages coordinated in the midbrain that generate a neuronal signal, which is carried through spinothalamic tracts. The sympathetic signals exit the spinal cord through nerve routes at T11 through L2 to travel via hypogastric nerves. Parasympathetic signals exit at S2 through S4 and travel through the pelvic plexus and cavernous nerve to the penis (see Fig. 5). The neural signals cause release of neurotransmitter, which promotes smooth muscle relaxation. The signal that arrives in the penile tissue spreads rapidly through corporal tissue by gap junctions, leading to entire corporal smooth muscle relaxation and expansion of the corporal sinusoids. Corporal smooth muscle relaxation is presumably achieved by a decrease in adrenergic tone, with a simultaneous increase in the release of cholinergic and nonadrenergic, noncholinergic neurotransmitters.

The dilation of cavernosal and helicine arteries is estimated to bring a 5- to 10-fold increase in penile blood flow. This increased inflow of blood temporarily exceeds the capacity of the veins to drain the blood. The sinusoids expand, and the volume of blood in the corpora increases. Compliance of the sinusoid initially prevents the rapid increase of intracavernosal pressure. When the sinusoidal system is adequately stretched, the intercavernous pressure begins to rise. Venules draining the sinusoidal spaces coalesce into a peripheral plexus below the outer fibro-elastic tunica of the corporal bodies. Egress from the subtunical venular plexus occurs via emissary veins exiting obliquely through the bilayer tunica albuginea into the deep dorsal vein in the distal two-thirds and via the short cavernous and crural veins in the proximal one-third of the corporal bodies. As the lacunae fill with blood, expanding sinusoids compress the subtunical venules against the inner layer of tunica albuginea and dampen the drainage of the emissary veins by differential stretching ofthe two primary layers ofthe tunica. The increased resistance to venous outflow results in increased turgidity of the corpora (see Fig. 6; Table 4).

The unique geometry of the corpora allows for the formation of erection. The following are some of the factors that promote penile rigidity:

1. The intrasinusoidal pressure within the corpora cavernosa distends the tunica albuginea to its maximal capacity.

2. Midline septal fibers are stretched tightly between the dorsal and ventral corpora, thus creating a functional "I-beam" arrangement that accounts for the anteroposterior rigidity of the penis seen with erection.

3. The relative indispensability of the paired lateral columns adds lateral stability to the penis during erection.

Vascular pulsation of the fully erect penis becomes visible when a steady state has been achieved. Pressure in the lacunar space during an erection results from the equilibrium between the perfusion pressure in the cavernosal artery and the resistance to blood outflow through the compressed subtunical vessels. Therefore, the penis acts as a reservoir that accumulates blood under pressure. During maximal rigidity, both inflow ofblood to and outflow of blood from the corpora cavernosa are practically zero.

Although the glans penis does not have the same hemodynamic structure as the corpora cavernosa, it does experience substantial change in blood flow during erection and detumescence. The glans penis does not possess a tunica albuginea, and the veins draining the glans (the retrocoronal plexus) prevent a pressure rise like that occurring in the shaft of the penis during erection. Blood flow through the glans and corpus spongiosum is increased compared to that in the flaccid penis. The glans maintains a steady and high arterial inflow and venous outflow; therefore, it acts as a large arteriovenous fistula. This enables the glans penis to share in erection but not in rigidity. The deep dorsal vein becomes partially compressed between three expanded corpora and Buck's fascia; this contributes to pressure rise in the deep dorsal vein.

Detumescence can be triggered either by the cessation of sexual stimuli or by the sympathetic burst of orgasm and ejaculation. Detumescence is simply a reversal ofthe events occurring during erection—that is, contraction of the corporal smooth muscle cells and helicine arteries, decrease in arterial blood flow, and resumption of normal venous outflow. Adrenergic nerve activation and release of NE from sympathetic nerve terminals is the primary mediator of this event (40). Norepinephrine has generally been accepted as the principal neurotransmitter in the control of penile flaccidity. However, it has recently been demonstrated that endothelin (ET) may have an important role in the regulation of corporal smooth muscle tone in vivo. Therefore, similarly to erection, the advent of detumescence also may require the concerted efforts of several endogenous substances.

Penile Turgidity

Fig. 6. Mechanism ofnormal penile erection. Erection is a neurovascular phenomenon initiated by the psychosomatic environment. To obtain penile erection, four physiological events are needed: intact neuronal innervation, intact arterial supply, appropriately responsive corporal smooth muscle, and intact veno-occlusive mechanics. Erection involves increased arterial flow, increased venous resistance, and relaxation of sinusoidal spaces Functional or organic pathologic features at different stages or an individual component will lead to erectile dysfunction.

Fig. 6. Mechanism ofnormal penile erection. Erection is a neurovascular phenomenon initiated by the psychosomatic environment. To obtain penile erection, four physiological events are needed: intact neuronal innervation, intact arterial supply, appropriately responsive corporal smooth muscle, and intact veno-occlusive mechanics. Erection involves increased arterial flow, increased venous resistance, and relaxation of sinusoidal spaces Functional or organic pathologic features at different stages or an individual component will lead to erectile dysfunction.

Table 4 Mechanism of Erection

1. Active dilatation of arterioles and arteries increases blood flow (inflow).

2. Expansion of sinusoids causes trapping of blood (capacitor).

3. Subtunical venular plexuses are compressed between the tunica albuginea and peripheral sinusoids, reducing venous drainage (outflow).

4. The tunica albuginea is stretched to its capacity and the emissary veins are compressed to maximum, further reducing venous outflow (veno-occlusive mechanism).

5. Intracavernous pressure is increased to mean blood pressure to achieve full erection state.

6. Contraction of ischiocavernous muscle further increases the intracavernosal pressure during contraction to several hundred millimeters of mercury for short duration but mainly causes rhythmic movement of the pendulous body of erect penis (throbbing).

PENILE ERECTION AND FLACCIDITY: MOLECULAR MECHANISM OF CORPORAL SMOOTH MUSCLE RELAXATION AND CONTRACTION

Ultrastructural examination of a smooth muscle cell reveals thin, intermediate, and thick filaments. Thin filaments are composed of actin; intermediate filaments are composed of desmin or vimentin; and thick filaments are formed of myosin. Each type of filament has a specific function, but the interaction between actin and myosin and their role in smooth muscle contraction and force generation are critically important. The acto-myosin cycle begins with phosphorylation of myosin by adenosine triphosphate (ATP), leading to attachments or "cross-bridges" between the regulatory myosin light chain (MLC20) globular heads and actin. These cross-bridges confer contractile tone on the smooth muscle (41). Sustained maintenance of this tone requires a small amount of energy generated from ATP hydrolysis but primarily depends on a high concentration of cytoplasmic free Ca2+.

Modulation of corporal smooth muscle tone is a complex process requiring coordination between a myriad ofextracellular signals and intracellular events. Neurotransmitters that participate in erection and detumescence largely modulate smooth muscle tone through their effects on ion channels, activation of downstream second messengers, and gap junctions (4,42-52). The maintenance of adequate calcium homeostasis is extremely important in the regulation of smooth muscle tone. This is achieved by one of three different mechanisms: influx of extracellular Ca2+ via voltage-gated channels; activation of membrane-bound receptors, allowing influx of Ca2+ through receptor-operated channels; and activation of specific signaling pathways stimulated by the release of Ca2+ from the sarcoplasmic reticulum. Initiation, sustained contraction, and modulation of corporal smooth muscle depends on the continuous transmembrane influx of calcium, whereas relaxation (penile erection) is achieved by processes that lower cytosolic calcium.

SMOOTH MUSCLE CONTRACTION AND RELAXATION IS REGULATED BY Ca2+-INDUCED MYOSIN PHOSPHORYLATION AND DEPHOSPHORYLATION

The primary stimulus for corporal smooth muscle contraction (penile flaccidity) again depends on the concentration of intracellular calcium. When the intracellular concentration of calcium increases to 10.5 mol/L, Ca2+ forms an active complex with the calcium-

binding protein calmodulin. The Ca2+-calmodulin complex then activates a Ca2+-cal-modulin-dependent myosin light chain kinase (MLCK). The activated MLCK phospho-rylates the regulatory MLC20, leading to smooth muscle contraction (53). A decrease in intracellular calcium to basal levels (<10.5 mol/L) inactivates MLCK and allows for dephosphorylation ofthe MLC20 by a Ca2+-independent MLC phosphatase, lowering the actin-activated ATPase activity of myosin (54). This allows for the myosin to detach from actin and leads to corporal smooth muscle relaxation (penile erection). It has been demonstrated that activation of both ET-1 and a1-adrenoreceptors leads to a transient 3-to 10-fold increase in intracellular calcium levels in corporal smooth muscle cells (44, 55,56). Additional mechanisms by which cytoplasmic Ca2+ are reduced include cyclic adenosine monophosphate (cAMP) acting through protein kinase A (PKA) and cGMP acting via PKG or directly via activation of potassium channels that lead to cell membrane hyperpolarization. Hyperpolarization prevents the opening of voltage-dependent calcium channels.

Calcium Sensitization and the RhoA/Rho Kinase Pathway

In addition to calcium-dependent mechanisms of activation, recent studies have demonstrated the presence of a calcium-independent pathway that further regulates corporal smooth muscle contraction. Originally described in other smooth muscle types, this process, termed calcium sensitization, is regulated by the small, monomeric G protein RhoA and its immediate downstream target Rho-kinase (ROK). Following its activation, ROK inhibits MLC phosphatase (or smooth muscle myosin phosphatase) through phospho-rylation of its regulatory subunit (smooth muscle myosin phosphatase-lM), leading to sensitization of myofilaments to Ca2+ (57). Both RhoA and ROK have been demonstrated in the corpora of several animal species as well as human corporal tissue (58,59). Furthermore, intracavernosal injection as well as topical application of the ROK inhibitor Y-27632 resulted in an increased erectile response, as demonstrated in an in vivo rat model (58,60). This pathway apparently acts via a NO-independent pathway, because co-administration of NO synthase (NOS) inhibitors to animals injected with Y-27632 did not alter the erectile response. Chitaley et al. (61) also demonstrated that transfection of rats with a dominant-negative RhoA enhanced erectile function in rats.

Finally, ROK likely potentiates corporal smooth muscle tone via a common pathway involving ET-1 and noradrenaline-induced vasoconstriction (62). Therefore, agents targeting the RhoA/ROK pathway are potential targets for the treatment of erectile dysfunction.

Second Messenger Signaling (see Fig. 7; Table 5)

For corporal smooth muscle relaxation to occur, elevations in both intracellular cAMP and cGMP are important (4,63-67). PKG and PKA activate downstream targets that reduce intracellular calcium levels (Fig. 8). Binding of first messengers to specific receptors on the smooth muscle cell membrane results in the formation of ligand-receptor complexes that interact with downstream G proteins that then stimulate adenylate cyclase. Adenylate cyclase increases intracellular levels of cAMP, which, in turn, activates PKA. Once activated, PKA phosphorylates downstream target proteins, altering their activity. Binding of neuro-effectors, such as prostaglandin E1 (PGE1), to their respective receptors leads to activation of the cAMP-adenylate cyclase pathway, as demonstrated by the 3- to 10-fold increase in cAMP levels observed in human corporal smooth muscle cells after activation by PGE1 (63). Subsequently, cAMP is cleaved back to AMP by the action of

Papav Rine Sur Les Canaux Calciques

Fig. 7. Major intracellular mechanisms regulating corporal smooth-muscle tone. Pro-contractile ligands (i.e., endothelin-1 and norepinephrine) bind to their respective receptors, leading to activation of second messengers. This leads to the mobilization of calcium via voltage-gated calcium channels and its release from the sarcoplasmic reticulum, resulting in cell membrane depolarization and phosphorylation of MLC20. Corporal smooth muscle relaxation occurs when pro-erectile ligands (i.e., PGEj) bind to their receptors, or in the case of nitric oxide, diffusion across the cell membrane leads to activation ofdownstream messengers (PKA, PKG). These molecules lead to corporal smooth muscle cell hyperpolarization and hence relaxation. The effects of second messengers on K channels, Ca2+ channels, and gapjunctions are thought to be dependent on the phosphorylation of specific amino acid residues within the regulatory elements of these channels. This simplified model illustrates the complex interactions involved in the regulation of corporal smooth muscle tone.

Fig. 7. Major intracellular mechanisms regulating corporal smooth-muscle tone. Pro-contractile ligands (i.e., endothelin-1 and norepinephrine) bind to their respective receptors, leading to activation of second messengers. This leads to the mobilization of calcium via voltage-gated calcium channels and its release from the sarcoplasmic reticulum, resulting in cell membrane depolarization and phosphorylation of MLC20. Corporal smooth muscle relaxation occurs when pro-erectile ligands (i.e., PGEj) bind to their receptors, or in the case of nitric oxide, diffusion across the cell membrane leads to activation ofdownstream messengers (PKA, PKG). These molecules lead to corporal smooth muscle cell hyperpolarization and hence relaxation. The effects of second messengers on K channels, Ca2+ channels, and gapjunctions are thought to be dependent on the phosphorylation of specific amino acid residues within the regulatory elements of these channels. This simplified model illustrates the complex interactions involved in the regulation of corporal smooth muscle tone.

cAMP-binding phosphodiesterases (PDEs). Smooth muscle relaxants such as papaverine exert their effects through inhibition of PDE, thus inducing the accumulation of either cAMP or cGMP, depending on its selectivity (68).

NO acts via guanylate cyclase, which catalyzes the conversion of guanosine triphos-phate to cGMP. In turn, cGMP activates PKG, which then phosphorylates downstream targets (e.g., target proteins and ion channels), leading to cell membrane hyperpolarization and corporal smooth muscle relaxation via the opening of potassium channels and thus diminishing intracellular calcium levels by preventing influx and promoting calcium sequestration within the sarcoplasmic reticulum.

Binding of inhibitory ligands (first messengers) to their respective receptors leads to corporal smooth muscle contraction. This occurs via activation of phospholipase C, which generates inositol (1,4,5)-triphosphate (IP3) and diacylglycerol. Diacylglycerol

Table 5

Primary Effectors of Corporal Smooth Muscle Tone

Table 5

Primary Effectors of Corporal Smooth Muscle Tone

Neurotransmitter

Source

Receptor

Second Messenger

CSM Ca2+

CSM response

Norepinephrine

Adrenergic

a-Adrenergic

IP3/DAG/

Increase

Contraction

(NE)

(NE)

(a1 and a2)

Ca2+/PKC

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Responses

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