Sympathetic Pathways and Adrenergic Innervation of the Penis

BASIC SCIENCE RESEARCH Sympathetic pathways and adrenergic innervation of the penis

K-E Andersson1*, P Hedlund1 and P Alm2

1Department of Clinical Pharmacology, University of Lund, Lund University Hospital, Lund, Sweden; 2Department of Pathology, University of Lund, Lund University Hospital, Lund, Sweden;

The sympathetic nervous system is important for penile function: it mediates detumescence and may contribute to the maintenance of the penis in a non-erect state. The sympathetic preganglionic neurons are found in the intermediolateral gray matter of the spinal cord. Postganglionic neurons are located to the sympathetic chain ganglia, the inferior mesenteric, hypogastric and pelvic ganglia, and possibly to ganglia near the target organ. Sympathetic ®bres can be found in the pelvic, cavernous, and pudendal nerves. Stimulation of the sympathetic pathways to the penis may, however, also produce erection. It has been suggested that the suprasacral vasodilator pathway is a sympathetic cholinergic pathway, operating through cholinergic neurons in the pelvic plexus. In the penis, there is a rich sympathetic, adrenergic innervation of the corpus cavernosum (CC) and the vasculature, and in particular of the helicine arteries. Sympathetic, adrenergic nerves also contain neuropeptide Y. Parasympathetic cholinergic nerves, which mediate CC relaxation and erection, contain not only acetylcholine, but also vasoactive intestinal polypeptide, nitric oxide synthase, and probably other mediators and=or mediator-synthesizing enzymes. Activation of sympathetic adrenergic nerves causes release of noradrenaline, acting on a-adrenoceptors in the trabecular smooth muscle of the CC and in penile vessels. The role of interactions between different transmitters and mediators, released from nerves or generated locally, in the regulation of contraction and relaxation of CC and penile vessels, needs further study. International Journal of Impotence Research (2000) 12, Suppl 1, S5±S12

Keywords: noradrenaline; sympathetic nerves; penile erection; penile detumescence; alpha adrenoceptors

Introduction in the ¯accid state, in part, through release of noradrenaline (NA). NA stimulates a-adrenoceptors in the penile vasculature, contracting the helicine Penile erection is produced by an increased blood vessels, and in the CC, contracting the trabecular ¯ow to the corpora cavernosa (CC), made possible by smooth muscle.1 the opening of penile resistance vessels (helicine The different structures of the penis receive arteries), relaxation of the CC smooth muscle, and sympathetic, parasympathetic, somatic, and sensory occlusion of the venous out¯ow.1 The erectile innervation.1 The distribution of autonomic nerves response in several animal models has been shown within the CC has been studied by several investi- to depend upon nitric oxide (NO) relaxing both the gators,2 but the density of nerves and the quantita- vasculature and CC tissue. However, most of the tive relations between the number of nerve terminals time, both the vasculature and the CC are con- and the number of smooth muscle cells have not tracted, keeping the penis in a non-erected state. been established. The nerves contain different This is achieved in part, by tonic activity in the transmitters and the nerve populations have been sympathetic, adrenergic pathways to the penis. categorized as adrenergic, cholinergic, and non- Penile arteries, CC smooth muscle, and the principal adrenergic, non-cholinergic (NANC). The latter penile veins receive a rich adrenergic innervation, nerves may contain not only neuropeptides, but and it is generally accepted that the penis is kept also transmitters and transmitter=modulator gener- ating enzymes, such as nitric oxide synthase (NOS) and heme oxygenases (HO). NANC transmitters=modulators may be found in adrenergic and *Correspondence: Karl-Erik Andersson, MD, PhD, 3 Department of Clinical Pharmacology, Lund University cholinergic nerves, which should make it more Hospital, S-221 85 Lund, Sweden. meaningful to de®ne nerve populations based on Received 2 September 1999; accepted 15 November 1999 their transmitter content. Sympathetic pathways and adrenergic innervation of the penis K-E Andersson et al S6 Below, a short review is given of the sympathetic lateral gray matter of the lower thoracic (T10) and pathways to the penis, and of the penile adrenergic upper lumbar (L3) spinal cord segments (Figure 1). innervation and its relation to other nerve popula- The segmental levels show species variation.4,5 The tions believed to be involved in the control of penile origin in man is believed to be from T10 to T12.5,6 erectile function. The ventral roots of the corresponding spinal nerves leave the cord as preganglionic ®bres and then pass via the white rami communicantes to the sympa- Sympathetic pathways to the penis thetic chain ganglia. Synaptic connections are made with ganglion cells at various levels (Figure 1). The chain ganglion cells projecting to the penis The supraspinal adrenergic mechanisms involved in are located in the sacral and caudal lumbar gang- erection have not been established. In the spinal lia.2,5 Via the gray rami, the postganglionic axons cord, the sympathetic preganglionic nerve ®bres to reach the urogenital tract through the pelvic, the penis arise from neurons in the intermedio- cavernous, and pudendal nerves.2,5,7 Preganglionic ®bres may pass through the chain ganglia via the lumbar splanchnic nerves and reach the ganglia in the inferior mesenteric and superior hypogastric plexuses (presacral nerve), where synaptic contacts are made (Figure 1). Many of the noradrenergic cells in the inferior mesenteric and hypogastric ganglia (Figure 2a) are surrounded by ®ne terminals containing nitric oxide synthase (NOS; Figure 2b), but no ganglion cells containing NOS can be demon-

Figure 2 A. Guinea pig, inferior mesenteric ganglion (IMG). Most neuronal cell bodies are adrenergic and express tyrosine hydroxylase- (TH-) immunoreactivity. Fluorescein isothiocyanate Figure 1 A. Sympathetic pathways to the penis. B. Neurotrans- (FITC) immuno¯uorescence. B. Rat, IMG. Varicose NOS-immuno- mission in penile sympathetic pathways. IMP inferior mesen- reactive (IR) nerve terminal surrounding NOS-negative neuronal teric plexus, HP hypogastric plexus, PP pelvic plexus. cell bodies. FITC immuno¯uorescence.

International Journal of Impotence Research Sympathetic pathways and adrenergic innervation of the penis K-E Andersson et al S7

Figure 4 A. Rat, MPG. Most neuronal cell bodies are cholinergic and express choline acetyltransferase (ChAT) immunoreactivity. TR immuno¯uorescence. B. Same section as in 4 A. Numerous NOS-(IR) cell bodies, which to a great extent correspond to the ChAT-IR cell bodies in 4 A. Figure 3 A. Rat, major pelvic ganglion (MPG). Numerous neuronal cell bodies showing cytoplasmic NOS-immunoreactivity. FITC immuno¯uorescence. B. Same section as in 3A, with (Figures 3a and 3b), but not in cells containing NPY adrenergic neuronal cell bodies displaying TH-immunoreactivity, which lack NOS-immunoreactivity (arrow heads). Texas Red (TR) (Figure 6b). immuno¯uorescence. Sympathetic postganglionic axons originating in the pelvic plexus, as well as in paravertebral and prevertebral ganglia, travel to the penis as the strated. In humans, the superior hypogastric plexus cavernous nerve, which is identi®able in close lies on the great vessels at the level of the third proximity to the prostate, and possibly as other, lumbar to the ®rst sacral vertebrae.8 Stimulation of smaller nerves, which follow the blood vessels this plexus in humans can cause either erection or (Figure 1). penile shrinkage.9 Stimulation of the lumbar sympathetic chain, From the superior hypogastric plexus, the left and hypogastric nerves, or sympathetic ®bres in the right hypogastric nerves extend caudally toward the pudendal nerves, produced detumescence of an pelvic plexus (Figure 1). The hypogastric nerves erection elicited by electrical stimulation of the contain postganglionic ®bres from prevertebral sacral spinal roots in cats.10 In rabbits, electrical ganglion cells, as well as preganglionic axons that stimulation of the lowest parts of the sympathetic pass through the prevertebral ganglia to make trunks caused shrinkage of the penis, even when the synaptic connections in the pelvic plexus. This connections of the nerve trunks to the central plexus is an important integrator site for the penile nervous system were cut.11 In the dog, erection autonomic innervation (Figure 3). In rodents, the caused by stimulation of the cavernous nerves was major pelvic ganglion (MPG) thus contains not only blocked by simultaneous stimulation of the hypo- NA (Figure 3a), but also acetylcholine (ACh; Figure gastric nerves; additional hypogastric nerve stimula- 4a), NOS (Figures 3b, 4b, 5a), vasoactive intestinal tion caused a rapid detumescence once erection had peptide (VIP; Figure 5b and neuropeptide Y (NPY; been established by cavernous nerve stimulation.12 Figure 6a). NA (as indicated by the presence of Stimulation of the sympathetic trunk at the level of tyrosine hydroxylase, TH) is located in ganglion L4±S1, applied directly after discontinuation of cells different from those containing ACh and NOS cavernous nerve stimulation, accelerated this detu-

International Journal of Impotence Research Sympathetic pathways and adrenergic innervation of the penis K-E Andersson et al S8

Figure 6 A. Rat, MPG. Neuronal cell bodies expressing cytoplasmic granular NPY-immunoreactivity around unlabelled nuclei. FITC immuno¯uorescence. B. Same section as in 6 A. Adrenergic (TH-IR) cell bodies, which correspond to the NPY-IR cell bodies in 6 A. TR immuno¯uorescence.

tion at L2-L3 produced only an increase in intracorporeal pressure.14 In contrast, several investigators have shown that stimulation of the sympathetic out¯ow produced tumescence responses, and that the peripheral pathways for these tumescence responses were contained in the hypogastric nerve.15±17 In a dog from which the entire sacral cord and the greater part of Figure 5 A. Rat, MPG. Numerous NOS-IR neuronal cell bodies. the lumbar cord had been removed, marked erec- TR immuno¯uorescence. B. Same section as in 5 A. VIP-IR tions developed whenever it was placed with a bitch neuronal cell bodies, which correspond to the NOS-immunor- in heat; local re¯ex penile responses (somatic, eactive celll bodies in 5a. C. Same section as in 5 A and 5 B. 16 NADPH-diaphorase positive neural Cell bodies corresponding to spinal) could no longer be elicited. The same NOS-IR and VIP-IR cell bodies in Figures 5 A and 5 B. observation was made in male cats, where all spinal segments below L4 had been removed. Erections developed when exposed to an estrous female,17 mescence process.13 In dogs, where erection had while re¯ex erections in response to penile manip- been established by pelvic nerve stimulation, sym- ulation did not occur. Inferior mesenteric ganglion- pathetic chain stimulation of the L4±L5 segments ectomy or bilateral removal of the abdominal produced a biphasic response consisting of an initial sympathetic chains abolished these erections, but increase followed by a decrease in intracorporeal not removal of sacral sympathetic chain ganglia. It pressure was observed. Sympathetic chain stimula- was concluded, based on these studies, that the

International Journal of Impotence Research Sympathetic pathways and adrenergic innervation of the penis K-E Andersson et al S9 The lumbar sympathetic pathways mediating erection have also been demonstrated in humans.1 Thus, cerebrally elicited erections were found more frequently in patients with lower motor neuron lesions below T12 than in those with lesions above this segment. No such `psychogenic' erections occurred in patients with lesions above T9.20,21 Based on these observations, the efferent out¯ow involved in psychogenic erection was suggested to leave the spinal cord at the levels T11 and T12.21 Re¯exogenic erections remained intact if the sacral cord or conus medullaris was undamaged. Electrical stimulation of the intact hypogastric plexus by a surgically implanted device consistently caused erectile responses.22 Thus, it appears that pathways between the brain and lumbar sympathetic out¯ow could preserve certain types of erectile function.

Adrenergic innervation of the penis

The total innervation of penile structures, as revealed by the non-speci®c nerve-marker protein gene product 9.5 (PGP 9.5), is dense (Figure 7a). A large fraction of the nerves supplying trabecular smooth muscle are adrenergic as indicated by positive immunoreactivity of tyrosine hydroxylase (Figure 7b). Particularly around the helicine arteries, a rich adrenergic innervation can be found (Figure 8a). Jen et al reported that NOS and TH were co- Figure 7 Mouse, corpus cavernosum (CC). Protein gene product localized in nerves supplying the postnatal human 9.5- (PGP 9.5-) IR nerves encircling helicine arteries (A), and 23 adrenergic (TH-IR) nerves supplying trabecular smooth muscle penis. Tamura et al reported that NOS could also (B). TR immuno¯uorescence. be found in nerves containing TH in the adult human penis, suggesting that NO may be generated by adrenergic nerves.24 Whether or not this really is the case has not been de®nitely established. erections were mediated via a sympathetic pathway, Hedlund et al, using immunohistochemistry simul- and that the suprasacral `erector' out¯ow was taneously for two nerve markers and confocal laser composed of ®bers which originate chie¯y from scanning microscopy, showed that in the rat penis, the 2nd to 4th lumbar segments of the spinal cord, NOS- and TH-, VAChT- and TH-, or VIP- and TH- passing through the lumbar portion of the sympa- immunoreactivities were found in separate nerve thetic chains and reaching the pelvis via inferior ®bres and terminals.25 Similar results were found mesenteric ganglia and hypogastric nerves.17 in the human CC. Further supporting the view that SjoÈstrand and Klinge showed that electrical TH and NOS are not colocalized, chemical sym- stimulation of the hypogastric plexus, where the pathectomy by 6-OH dopamine (6-OHDA) was central connections were cut, consistently caused found to abolish TH-IR nerve structures in the rat erection.11 Hypogastric nerve stimulation in the cat and mouse CC (Figure 8b). However, the amount also evoked an erectile response which was partially and distribution of nerves containing immunoreac- sensitive to atropine.18 In rats with the spinal cord tivities for NOS (Figure 8c), VAChT (Figure 8d), removed below L5, electrical stimulation of the and VIP were unaffected. The distribution of medial preoptic area in the hypothalamus evoked nNOS=VAChT=VIP-IR and TH-IR nerves were, how- penile erection in 85% of the animals, despite a ever, found close together in similar patterns, which complete loss of peripheral erectile re¯exes.19 These should make possible cholinergic modulation of the observations further support the view that erection release of NA from adrenergic nerves. In summary, may result from a sequence of processes in the available evidence favors the view that NOS and TH sympathetic nervous system. It has been suggested are localized to separate nerve populations. that this suprasacral vasodilator pathway is a In contrast to NOS and TH, in several peripheral sympathetic cholinergic pathway, operating through vessels, NA and NPY are co-localized and may act in cholinergic neurons in the pelvic plexus.2 synergy.3 This is also the case in the penis (Figure

International Journal of Impotence Research Sympathetic pathways and adrenergic innervation of the penis K-E Andersson et al S10

Figure 8 A. Mouse, CC. Helicine arteries supplied with adrenergic (TH-IR) nerves. TR immuno¯uorescence. B. Mouse, CC. Following chemical sympathectomy by 6-OH dopamine no adrenergic (TH-IR) nerve structures remain. TR immuno¯uorescence. C and D. Same section, mouse, CC. Chemical sympathectomy by 6-OH dopamine does not affect number and distribution of NOS-IR (C) and cholinergic (vesicular acetylcholine transporter- (VAChT-) IR nerves (D). Note the similar distribution of NOS- and VAChT-IR nerves. TR immuno¯uorescence.

9a), where chemical sympathectomy using 6-OHDA and that NPY may represent this neurotransmitter.29 abolishes NPY immunoreactivity (Figure 9b). Mod- NPY was thus suggested to take part in detumes- erately high concentrations of NPY were found in cence. Experimental evidence for this suggestion is, the human corpus cavernosum and it was suggested however, lacking. that NPY could be intimately involved in the control of erection.26 NPY has been demonstrated in penile vasculature and erectile tissue in several species Noradrenaline and a-adrenoceptors including humans, monkey, rabbit, guinea-pig, and rat.1 Wespes et al found a concentration of NPY containing nerve ®bres in the inner part of the NA, released from adrenergic nerves, stimulates adventitia close to the media of the arterial and postjunctional a-adrenoceptors and contracts heli- venous vessels, and among the trabecular smooth cine vessels and trabecular smooth muscle.1 Also muscle cells of human penis.27 They speculated that b-adrenoceptors are stimulated, but since in the NPY could act as a neurotransmitter or neuromodu- human CC the density of a-adrenoceptors is almost lator, especially during detumescence. Crowe et al ten times higher than that of b-adrenoceptors,30 the found that the media of the deep dorsal vein of the end result of NA stimulation will be contraction. human penis contained numerous NPY-immuno- Androgens and other factors, e.g. endothelins, may reactive nerves.28 If NPY has an enhancing effect regulate the a-adrenoceptor responsiveness of CC on the vasoconstriction caused by NA, this may smooth muscle. Thus, compared to normal rats, contribute to the venous occlusion necessary for castrated animals showed an enhanced reactivity to 31 obtaining an erection. In rats, chemical sympathect- a1-adrenoceptor stimulation, and the presence of omy, but not a-adrenoceptor blockade, increased the endothelin increased the contractile effect of NA in emptying rate of the erect penis. Giuliano et al isolated CC preparations.32 postulated that a NANC transmitter co-localized Both a1-anda2-adrenoceptors have been demon- with NA exerted a contractile effect on penile veins, strated in human CC,1,33,34 but available information

International Journal of Impotence Research Sympathetic pathways and adrenergic innervation of the penis K-E Andersson et al S11 onstrated the presence of a1A-, a1B-, a1D-adrenoceptors, and they suggested that the NA-induced contraction in erectile tissue is mediated by two or possibly three receptor subtypes. There is increasing evidence that an additional a1- adrenoceptor subtype with low af®nity for prazosin (a1L), which has not been cloned and which is not yet fully characterized, may occur in, for example, vascular smooth muscle.39 The possibility that the a1L-adrenoceptor subtype may be of importance in penile erectile tissues has apparently not been explored. Whether or not antagonists, selectively acting at any of the a1-adrenoceptor subtypes, would offer any advantages over presently used non-subtype selective drugs (phentolamine, moxisylyte) in the treatment of erectile dysfunction, remains to be established. Also the a2-adrenoceptor subtypes in human CC have been studied. Thus, Traish et al demonstrated expression of mRNA for a2A-, a2B-, and 34 a2C-adrenoceptors in whole human CC tissue. Radioligand binding studies with a highly selective ligand for a2-adrenoceptors revealed speci®c a2- adrenoceptor binding sites, and functional experiments showed that the selective a2-adrenoceptor agonist UK 14,304, induced concentration-dependent contractions of isolated strips of CC smooth muscle. Similar results were obtained in isolated rabbit CC.40 These results suggest the occurrence of postjunctional a2-adrenoceptors in human as well as rabbit CC, and that these receptors may be of functional importance. However, whether or not a2-adrenoceptors play an Figure 9 A. Mouse, CC, with NPY-IR terminals around a helicine important role in the contractile regulation of tone in artery and supplying trabecular smooth muscle. B. Mouse, CC, CC smooth muscle in patients is still unclear. following chemical sympathectomy with 6-OH dopamine all NPY-IR nerves have disappeared. Bars 100mm. Prejunctional a2-adrenoceptors have been shown to modulate stimulus-evoked release of NA from noradrenergic nerves in the human CC.41 Further, stimulation of prejunctional a2-adrenoceptors in supports the view of a functional predominance of horse penile resistance arteries was shown also to 42 a1-adrenoceptors. This may be the case also in the inhibit NANC-transmitter release. This might be penile vasculature, although a contribution of a2- one of the mechanisms by which NA maintains adrenoceptors to the contraction induced by NA and detumescence. electrical stimulation of nerves cannot be excluded (see below). In horse penile resistance arteries, NA Conclusions activated predominantly a1-adrenoceptors, whereas postjunctional a2-adrenoceptors seemed to play a minor role.35 The sympathetic pathways and the adrenergic The subtypes of a1-adrenoceptor with high innervation of the penis have important roles in 36 af®nity for prazosin, currently designated as a1A, the regulation of contractile activity in CC smooth a1B and a1D (the cloned counterparts are termed a1a, muscle and penile vasculature. However, many a1b,anda1d) have been demonstrated in human CC. details in the functional organization of the path- Price et al reported that in human CC, mRNAs for ways, and in the interrelations, both morphological a1a, a1b, and a1d (current terminology) could be and functional, between NA-containing nerves and identi®ed, the a1a- and a1d-adrenoceptors predomi- other nerve populations, remain to be elucidated. nating.37 This was con®rmed by Traish et al.38 It is known that the levels of mRNA expression do not always parallel the expression of a functional Acknowledgements receptor protein. Traish et al characterized the functional a1-adrenoceptor proteins in human cor- This work was supported by grants from the pus cavernosum tissue, using receptor binding and Swedish Medical Research Council (grants no 6837 isometric tension experiments.33 Their results dem- and 11205), the Royal Physiographic Society, and

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