Review

Introduction

Sexual function and lower urinary tract function are most commonly considered in the context of the typical individual organ-specific diseases and complaints. Until recently, the clinical problems of erectile dysfunction (ED), lower urinary tract symptoms (LUTS) and problems with defecation were regarded as distinct. Several papers have recently pointed to the fact that it may be appropriate to regard these as clinically related issues. Epidemiological associations, potential pathophysiological links and common therapeutic strategies have been proposed and commonalities are being more widely acknowledged. We will argue here that complaints centred on individual pelvic structures and functions are often significantly linked with adjacent pelvic complaints. Although we will concentrate on commonalities that may link ED and LUTS, general issues of sexual function, including female sexual dysfunction, ejaculatory disorders, benign prostatic hyperplasia, bladder outlet obstruction, urgency incontinence, stress urinary incontinence, overactive bladder, pelvic pain disorders, disorders of faecal continence and colorectal motility, pelvic nerve and vascular status, relevant endocrine status and relevant central nervous system functioning such as depression should also be considered. All of these have manifestations in the functioning of pelvic structures and all should be considered mutual potentially comorbid or confounding conditions. The issue is the convergence of symptomatic conditions of the human pelvis and their pathophysiological basis.

The pelvic organs share many features: they are tubular structures, lined with endothelium and surrounded by smooth muscle, innervated by autonomic nerves and subject to both local and neural control (Figure 1). Striated muscle may also be involved in reflex activity. In the resting state, there is usually ongoing activity in the smooth muscle, and often any associated striated muscles are contracted. Local control of the smooth muscles may involve substances released from the endothelial linings in response to intralumenal flow or pressure changes. Released modulators may affect the smooth muscles either directly or indirectly through sensory axon collaterals and submucosal interstitial cells. Reflex activation in the normal person requires both changing sensory nerve input and descending central control of a spinal reflex centre. The efferent arm of the reflex is through autonomic nerves (parasympathetic or sympathetic), which may involve excitatory and/or inhibitory nerves, and a somatic output to associated striated muscle. This pattern occurs in the gut, the urinary tract and the organs of sexual function, and underlies need for control of storage and emptying of waste materials as well as sexual activity. In the gut an additional level of complexity exists in that the peristaltic reflex is organized within the enteric nervous system, but is a mechanism used in defecation, under the influence of a spinal reflex centre and descending control. All humans, from personal experience, understand that the reflexes programming the individual behavioural functions spread to involve multiple pelvic the systems, so that for instance sexual function suppresses micturition and defecation, and defecation modulates micturition.

Figure 1.

Diagrammatic representation of common arrangement of wall of pelvic organs.

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In this study, Several different overlapping lines of reasoning will draw together the important commonalities of pelvic structure and function. Epidemiological studies are an important source of understanding of disease as well as the basis for the business of disease management. The proliferation of these studies has provided new insight into overlapping pelvic system complaints, although these are essentially limited by the vision given through the instruments used to collect the information. The studies of the essential anatomic cellular types can be used to show some of the bases for functional similarities between the pelvic viscera. Further understanding of the complex patterns of local and higher innervation is gradually accumulating. Some issues of comparative autonomic function can now be demonstrated. And finally, once the general context of interdependence for pelvic visceral function is recognized, it becomes relevant to point to the inevitable overlap of the impact of systemic metabolic, endocrinological, vascular and other changes with regard to pelvic visceral function.

Epidemiology for LUTS and ED

The prevalence of both ED and LUTS increases with age,^{1, 2, 3, 4, 5, 6, 7, 8} which is a first simple signal that the link between LUTS and ED may be causal: if this is the case, there would be implications for the management of both conditions.

A community study has demonstrated that even accounting for factors such as age and other comorbidities, the likelihood of men being dissatisfied with sexual life increased by a factor of two in men with moderate LUTS and by four in those with severe symptoms.² A similar relationship was found in another study between many voiding and storage symptoms and the presence of reduced rigidity of erections. The strongest association was nocturnal incontinence, with an odds ratio of 5.63, although the reduction of rigidity of erection and ejaculatory ability and increased pain on ejaculation were strongly associated with storage symptoms.^{3, 4} When a quantitative measure of LUTS was employed, a linear relationship could be demonstrated between the prevalence of problematic reduced erections, reduced ejaculate and pain/discomfort on ejaculation, and an international prostate symptom score (IPSS) classified as mild, moderate and severe.⁵ This relationship has been confirmed in larger studies and there appears to be a clear association between the prevalence of ED and the IPSS, with a higher prevalence in older men.⁶

The association between ED and LUTS is as strong as that observed for the classical risk factors for ED such as hypertension and hyperlipidaemia.⁷ And it should be remembered that hypertension and hyperlipidaemia are now considered to be causally linked with ED. In the large Multinational Survey of the Aging Male (MSAM-7), sexual disorders and their bother were strongly related with the severity of LUTS, and the relationship was independent of comorbidities such as diabetes, hypertension, cardiac disease and hypercholesterolaemia.⁷ In fact these associations are more certain than the relationship between prostate size and LUTS.⁸ The weight of epidemiological evidence linking ED and LUTS is so strong, of the same magnitude as traditionally accepted links such as ED and vascular disease and LUTS and prostate size, that it has become important to establish a reasonable pathophysiological basis to explain it.

A comparative outline of what is known about the mechanisms operating in the various organs demonstrates that overlapping neural and reflex pathways exist, and that they may account both for the normal interactions seen and the comorbidity of various functional disorders.

Comparative function

Spontaneous activity and interstitial cells

Most of the smooth muscles in the pelvic organs show spontaneous contractile activity that persists in the absence of any neuronal input. Regular rhythmic activity is normally associated with action potentials in the smooth muscle cells. The smooth muscle cells in an organ almost always show a degree of electrical coupling through gap junctions, and thus action potentials can propagate between connected cells, resulting in synchronous activation. However, as will be seen, the degree of coupling varies between organs,⁹ and alterations in this may be important in the pathology of disease states. The upstroke of the action potential is carried by Ca²⁺ through L-type Ca channels, and this with additional Ca²⁺ released from internal stores, activates cross bridge cycling and contraction. Although this was originally called 'myogenic activity' and was assumed to be generated within the smooth muscle cells by some sort of endogenous pacemaker activity, it is now known that other cells are involved, namely interstitial cells.

Interstitial Cells of Cajal (ICC) have long been identified in the gut and have attracted much attention (reviewed^{10, 11}). Several classes with different roles have been identified, one of which has a primary pacemaker function, generating depolarizing currents that are injected through gap junctions into neighbouring smooth muscle cells, producing regular slow waves and corresponding contractions. Other types may help propagate the activity through the wall. The interstitial cells in the gut are the primary targets of the autonomic innervation.¹¹ Cells similar to ICC have been found in many other smooth muscles and are attracting considerable interest. ICC can be identified immunohistochemically, since they characteristically express the Kit receptor on their surface and contain vimentin filaments, antibodies to which can be used as markers. These markers identify cells with similar morphology in the ureters, bladder, urethra, prostate, vas deferens and erectile tissues.¹² We will refer to these as interstitial cells. Interstitial cells have now been shown to have important functional roles in all hollow pelvic viscera and in erectile tissue. Underlying changes in the interstitial cells have been suggested to be associated with overactivity in the tissues, as will be explored further below.

Erectile smooth muscle

Spontaneous activity in corporal smooth muscles

Spontaneous contractions contribute to the sustained smooth muscle tone in the flaccid penis.^{13, 14} Spontaneous contractions (Figure 2a) have been recorded from corpus cavernosum smooth muscle (CCSM) and corpus spongiosum smooth muscle from various mammals, including man.^{14, 15, 16} The mechanisms underlying these contractions are spontaneous action potentials and associated transient increases in [Ca²⁺]_i (Figures 2b and c) The contractions depend on extracellular Ca²⁺, and are blocked by L-type Ca²⁺ channel blockers, and by drugs, which hyperpolarize the cells, demonstrating the important role of L-type Ca²⁺ channels in the generation of spontaneous activity.

Figure 2.

Spontaneous activity in rabbit corpus cavernosum smooth muscle (CCSM). (a) CCSM preparation exhibiting bursting spontaneous contractions. (b) CCSM preparation exhibiting spontaneous increases in [Ca²⁺]_i. (c) CCSM preparation generating bursts of spontaneous depolarization. (d) In a CCSM preparation, which developed spontaneous contractions, transmural stimulation was applied during a contracting phase, and initiated phasic relaxations (first and second stimuli). In contrast, stimulation applied during a period of relaxation evoked a phasic contraction (third stimulus), or initiated spontaneous contractions (fourth stimulus). Modified from Figure 1 in Hashitani et al.²¹ CCSM, corpus cavernosum smooth muscle.

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Spontaneous contractions of CCSM are also inhibited by lowering the temperature, suggesting that some metabolic processes are involved in their generation.¹⁷ Spontaneous Ca²⁺ transients recorded from the guinea pig are readily blocked by cyclopiazonic acid (CPA), ryanodine or 2-APB, suggesting that Ca²⁺ release from intracellular Ca²⁺ stores via both InsP₃ and ryanodine receptors contributes to their generation.¹⁸ Spontaneous transient inward currents (STICs) can be recorded from rat and human CCSM. These appear to be mediated by Cl^– currents, and a role for a Ca²⁺-activated Cl^– current in generating spontaneous myogenic tone in CCSM has been proposed.¹⁹ In isolated rabbit CCSM, the generation of STICs relies on the opening of Ca²⁺-activated Cl^– channels by the release of Ca²⁺ from intracellular stores.²⁰ The resting membrane potential in CCSM, that is, about -45 mV, is close to the activation threshold for activation of L-type Ca²⁺ channels, and even a small depolarization may be sufficient to increase their opening and contract CCSM.

Spontaneous contractions of corporal smooth muscles (CSMs) are also known to be inhibited by indomethacin, and thus spontaneous formation of prostaglandins may be involved in their generation.¹⁷ In the rabbit CCSM, spontaneous action potentials and corresponding contractions were largely attenuated by cyclooxygenase-2 (COX-2) inhibitor, suggesting that spontaneous production of prostaglandins via COX-2 may contribute to the generation of spontaneous activity.²¹ Generally, COX-2 activity is thought to be induced upon inflammatory stimulation, while COX-1 is constitutively expressed. Indeed, mRNAs encoding COX-1 were expressed in both corpus cavernosum and corpus spongiosum. However, COX-2 but not COX-1 appears to work as a primary enzyme in synthesizing prostaglandins, to contribute to spontaneous contractions in the CCSM of the rabbit, and thus COX-2 may be constitutively expressed at least in this tissue.

In spontaneously active rabbit CCSM, transmural nerve stimulation, applied during a relaxing phase, either evoked transient contractions or initiated sustained contractions, which are very similar to spontaneous contractions. In contrast, during a contracting phase, nerve stimulation either initiated transient relaxations or terminated the spontaneous contractions (Figure 2d). These results indicate that whereas spontaneous activity is fundamental in determining the contractile state of CCSM, both excitatory and inhibitory neural input may be important physiologically for modulating spontaneous activity.

Interstitial cells in CSMs

Interstitial cells have been identified in the corporal tissue by their immunoreactivity for the Kit receptor.¹⁸ Immunohistochemical and biochemical findings show that COX-2 is highly expressed in interstitial cells in the corpus cavernosum and the corpus spongiosum. Haematoxylin and eosin staining revealed that cells with COX-2 immunoreactivity were spindle- or star-shaped, with some branches, and were connected with each other (Figure 3). Furthermore, COX-2 immunoreactive cells also express strong immunoreactivity to the Kit antibody or to vimentin, a marker for cells of mesenchymal origin (Figure 3). Therefore, unlike ICC in the gastrointestinal tract, which act as electrical pacemaker cells to drive the bulk of smooth muscle cells, interstitial cells in CCSM may modulate spontaneous activity originating in the smooth muscle cells, by releasing prostaglandins through activation of COX-2 (Figure 4).

Figure 3.

Immunohistochemistry of COX-2-and Kit-positive interstitial cells in the corpus cavernosum. (A) (a) COX-2 immunoreactive cells widely distributed throughout the corpus cavernosum. (b) COX-2 immunoreactivity in a population of cells which have spindle- or star-shaped cells with some branches. (B) (a) HE staining of smooth muscle cells and interstitial cells in corpus cavernosum. Smooth muscle cells had a large, clear nucleus (arrow heads), while interstitial cells were characterized by their smaller, darker nucleus (arrows). (b) Interstitial cells with typically spindle- or star-shaped cell bodies and some branches (arrows), which connect with neighbouring cells. (C) (a) The distribution of COX-2-positive cells. (b) The distribution of Kit-positive cells. Note almost completely overlap with COX-2-positive cells. Modified from Figure 7 in Hashitani et al.²¹ HE, haematoxylin.

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Figure 4.

Diagram to show the role of interstitial cells in regulating CCSM tone. Spontaneously produced prostaglandins (PGs) via COX-2 activity in interstitial cells (ICs) not only reinforce spontaneous excitation of CCSM but also facilitate nerve-mediated -adrenergic contractions. Conversely, spontaneously released NO from either endothelium (EC) or parasympathetic nerves suppresses excitation. Thus, the balance between spontaneously released PGs and NO is important in regulating CCSM tone to determine the contractile state of the penis. Modified from Figure 2 in Hashitani H. Interaction between interstitial cells and smooth muscles in the lower urinary tract and penis. J Physiol. 2006 Nov 1;576(Part 3):707–714. E-pub 2006 Aug 31. CCSM, corpus cavernosum smooth muscle; EC, endothelium; ICs, interstitial cells; NO, nitric oxide; PGs, prostaglandins.

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Interestingly, inhibition of COX-2 suppressed not only spontaneous contractions but also nerve-evoked -adrenergic contractions in the rabbit CCSM. It should be noted that COX-2 inhibitors reduced the amplitude of -adrenergic contractions, with a relatively small reduction in corresponding Ca transients. Conversely, the preapplication of PGF2 reinforced NAd-induced contractions, regardless of the presence of blockers of L-type Ca²⁺ channels. The contractions induced in CSMs by PGF2 are greatly suppressed by Rho kinase inhibitors, suggesting that PGF2 may reinforce the -adrenergic contractions through Ca²⁺-independent mechanisms, presumably by the activation of Rho kinase.

Possible role of interstitial cells in ED

Since the CCSM tone is determined by the balance between contracting and relaxing factors, the balance between spontaneously released nitric oxide (NO) and prostaglandins is important for the understanding the pathophysiology of ED (Figure 4). Blockade of guanylate cyclase in CCSM has been reported to increase both resting tension and NAd-induced contraction, and diminish ACh-induced relaxation, suggesting that the tonic production of cyclic GMP (cGMP) inhibits CCSM excitability.^{22, 23} Since the effects of guanylate cyclase inhibition were reversed by indomethacin, interaction and functional antagonism between cGMP and prostaglandins was also suggested. Furthermore, increased cyclooxygenase activity is reported to account for ischaemia-induced increased contractions of CSM in the rabbit.²³ It has been reported that diminished NO production in diabetic CCSM is associated with increased Rho kinase activity.²⁴ Conversely, increased Rho kinase activity may suppress the production of NO.²⁴ In rabbit CCSM, PGF2-induced contractions were largely suppressed by a Rho kinase inhibitor, suggesting that increased COX-2 activity in interstitial cells might stimulate Rho kinase activity and suppress NO production. There is a basis for suggesting, therefore, that local cyclooxygenase inhibition in conjunction with PDE5 inhibition may be synergistic in the treatment of ED.

Lower urinary tract

Spontaneous activity in the bladder

Pressure recordings in the normal human bladder during filling show low pressure and little evidence of spontaneous fluctuations in pressure. However, this does not mean that all bladder smooth muscle are relaxed, and in fact normal bladders are always found to take up a shape that gives the minimum surface area/volume ratio available to them. In small mammals where the bladder is in the abdominal cavity, this means that they normally are nearly spherical. The individual smooth muscle cells show spontaneous electrical and mechanical activity. The mechanical activity characteristically involves transient increases in contraction from a very low resting tone. So how does the bladder manage to remain at low pressure during filling? It has been found that the smooth muscle cells, although probably connected to their near neighbours within a smooth muscle bundle, are relatively poorly interconnected over larger distances,^{25, 26, 27} and thus during filling, the activity is not well synchronized through the entire bladder, and the result is that the cells can adjust their length continuously and allow the bladder to remain in a shape where synchronous activation initiated in the micturition reflex can rapidly raise intravesicular pressure. In fact, in small mammals, such as guinea pig, rats and mice, isolated normal bladders do show small continuous fluctuations in intravesicular pressure.

A common characteristic of bladder overactivity in the human is the appearance of 'unstable' contractions – that is spontaneous rises in intravesicular pressure that cannot be suppressed voluntarily, and may be provoked through rises in intra-abdominal pressure. It has been suggested that alterations in the coupling between the smooth muscle cells, as well as possible alterations in the micturition pathway underlie this change.^{28, 29, 30}

Investigations have been made into the mechanisms underlying the pacemaker activity in the bladder, and electrophysiological recordings have demonstrated that isolated detrusor smooth muscle cells of the bladder are capable of generating spontaneous action potentials which are almost identical to those recorded from intact preparations,^{31, 32} showing that interstitial cells in the bladder are not required for spontaneous activity, in contrast to gastrointestinal tissues in which electrical activity is clearly generated in the ICC. Interstitial cells are, however, found in the bladder, preferentially located on the boundary of muscle bundles from where spontaneous Ca²⁺ transients originate, which might suggest that they do play some role in spontaneous activity.³³ Spontaneous Ca²⁺ transients are seen in interstitial cells, but can be shown to occur independently of those of smooth muscles even when synchronous Ca²⁺ waves sweep across muscle bundles (Figure 5). Ca²⁺ transients recorded from interstitial cells persist in the presence of nifedipine, (Figure 5) as do carbachol-induced Ca²⁺ transients in isolated interstitial cells,³³ suggesting that voltage-dependent L-type Ca²⁺ channels are not involved in the generation of this activity. Therefore, although the location of boundary interstitial cells seems to be ideal to drive the bulk of smooth muscles, they clearly are not electrical pacemaker cells. However, experiments in which Glivec, a kit receptor antagonist, has been applied, show reduction in the activity of both isolated whole bladders^{34, 35, 36} and the contractile and electrical activity of strips of detrusor, suggesting that interstitial cells may be in some way involved in the integration of activity. Interstitial cells are also found in the submucosa, close to the urothelium and the suburothelial sensory nerves,^{37, 38, 39} where they may play a similar role in integrating activity.

Figure 5.

Spontaneous Ca²⁺ transients recorded from interstitial cells in the guinea pig detrusor smooth muscle layer. (A) (a) In a preparation loaded with fluo-4, an IC located near the muscle boundary had a higher fluorescence than that of smooth muscle. (b) A plane image with Nomarski optics visualizing the cell body of an IC. (c) Ca²⁺ transients recorded from IC (area 1) and from two smooth muscle areas (areas 2 and 3) located with a separation between each of some 50 m. Synchronous Ca²⁺ waves were detected at areas 2 and 3. However, the IC generated slow Ca²⁺ transients independent of those of smooth muscles. (B) (a) In another fluo-4-loaded preparation, which had been exposed to nifedipine (10 M) for some 30 min, IC continued to generate slow Ca²⁺ transients. (b) A series of frames with intervals of 2 s demonstrates a Ca²⁺ transient originating from an IC. Modified from Figure 3 in Hashitani et al.²⁷

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Spontaneous activity in the urethra

In contrast to the bladder, smooth muscle strips from the urethra show spontaneous tone, and underlying this the electrical activity in smooth muscle cells consists of regular slow wave activity.^{40, 41} As in the gut, this activity is not seen in isolated myocytes, but is generated in interstitial cells,⁴² and here they may have a genuine pacemaker role. The mechanical characteristics of the urethral smooth muscle strips, which display sustained tone, however, are clearly different from the isolated slow wave-associated contractions seen in the gut. The electrical coupling between urethral smooth muscle cells seems relatively poor, so lack of synchronicity between muscle bundles may contribute to this. Imaging experiments show that spontaneous Ca transients occur almost completely randomly in individual smooth muscle bundles, and even within a muscle bundle Ca transients often failed to form intercellular Ca waves (H Hashitani, unpublished results). Therefore, interstitial cells in the urethra may not form as extensive an electrical network as they do in the gut, and thus strong influence of adrenergic input may be required to maintain the sustained tone of the urethra.

Possible role of interstitial cells in LUTS

Bladder overactivity has been suggested to result from increased coupling between detrusor smooth muscle cells.²⁸ Recently, increased connexin43-mediated intercellular communications in a rat model of bladder overactivity has been reported.⁴³ Micromotion of the bladder wall, which may be attributed to spontaneous contractions of individual muscle bundles, has also been reported to be enhanced in a rat model of bladder overactivity.⁴⁴ Therefore, either quantitative or qualitative alteration in interbundle interstitial cells could account for the increased excitability in the overactive bladder. The finding in human bladder that Kit-positive cells are increased in number in samples of the bladder taken from the patients with overactive bladder may support this idea. Moreover, imatinib mesylate (Glivec), an inhibitor of Kit receptor tyrosine kinase, was more potent in inhibiting evoked and spontaneous contractions in overactive bladder than in normal bladder, and also improved parameters of cystometry.^{34, 35, 36}

ICC are thought to be involved in neuromuscular transmission, including inhibitory transmission mediated by NO;^{45, 46} therefore, they may also play an important role in the nerve-mediated modulation of detrusor smooth muscle excitability. Following stimulation with sodium nitroprusside, interstitial cells throughout the bladder demonstrated an intense induction of cGMP immunoreactivity, but detrusor muscle cells remained uniformly negative.⁴⁷ Therefore, interstitial cells in the bladder may be involved in the neuromuscular transmission, and again changes in interstitial cells may account for increased excitability of detrusor smooth muscle in overactive bladders.

In the suburothelium region, a network of vimentin-positive ICC-like 'myofibroblast' connecting thorough gap junction protein connexin43 (Cx43) has been identified.^{48, 49} However, these cells were found not to bind to Kit antibody, unlike interstitial cells in the detrusor layer of the guinea pig bladder.³³ In addition, these cells are contractile, unlike those in the detrusor smooth muscle layer, which do not contract either spontaneously or upon stimulation. Myofibroblast form very close association with suburothelial afferents and may also be the target of efferent nitrergic nerves.⁴⁷ Isolated cells are spontaneously active, and furthermore application of ATP initiates inward currents and corresponding transient increases of intracellular [Ca²⁺] through the activation of P2Y receptors.³⁷ These cells are ideally located to play a modulatory role in the process of bladder sensation and may play an intermediate and variable gain stage in the process of bladder fullness sensation. Therefore, pathological changes in suburothelial myofibroblast may also account for urgency in the overactive bladder.

Summary of functional properties

This description of the functional properties of the pelvic organs makes clear the overriding importance of the degree of spontaneous contractile activity in the various smooth muscles, and how this is modulated and controlled. Contraction is activated in the myocytes when intracellular calcium (Ca) concentration is elevated. This elevation is mainly triggered through action potentials or transient depolarizations in the myocytes, in which Ca is the main current carrier, and is thus responsible for both the depolarization and the contraction. The pattern of resting activity varies in the different tissues – in bladder, the contractions are phasic and poorly coordinated, and do not elevate intravesicular pressure, whereas in the erectile tissues and urethra, continuous tone is generated, which keeps the urethra closed and prevents engorgement of the erectile tissues, keeping them flaccid. The different patterns of activity may be the result of mechanisms purely intrinsic to the myocytes themselves, or to their interactions with interstitial cells. This resting activity can further be modulated through the intrinsic nerves and circulating hormones. In the bladder, synchronization of activity through parasympathetic nerves elevates intravesicular tone; in the urethra and erectile tissue, inhibitory innervation is dominant and allows relaxation of the urethral walls and engorgement of erectile tissues. Interstitial cells in all these organs can modulate spontaneous activity. Furthermore, interstitial cells are themselves innervated, and are thus under autonomic control, although their exact roles are not yet fully understood. Thus, there is, in pelvic structures, a shared importance of smooth muscle spontaneous contractile activity, its modulation by interstitial cells and control by diffuse neural and humoral factors.

Autonomic neuromuscular transmission

Although the 'classical' transmitters are the main ones released from the post-ganglionic autonomic nerves, that is, acetylcholine (ACh) from the parasympathetic and noradrenaline (NAd) from the sympathetic nerves, many other transmitters are also involved, and the effects of the transmitters can be excitatory, inhibitory or modulatory, depending on the receptors and second messenger pathways expressed by the muscles. Cholinergic and adrenergic nerves have both been shown to co-release ATP, and this is particularly important in those tissues that can respond rapidly to nerve stimulation, since the P2x purinoceptor is the only directly coupled, ion channel receptor on smooth muscles.⁵⁰ The other transmitters all work through G-protein-coupled receptors. Inhibitory nitrergic nerves innervate many of the smooth muscles, and these can probably be classified as parasympathetic. Smooth muscles, ganglia and interstitial cells can also be innervated by axon collaterals of afferent C fibres, releasing tachykinins, such as substance P and CGRP. Many of the autonomic nerves also release various modulatory peptides, which can have more sustained effects.

Neuromuscular transmission in CSM

CSM tone is controlled by the balance between contractile and relaxant factors to determine the functional state of the penis. Relaxation of CSM is principally mediated by NO, which is released from both parasympathetic nerves and endothelium, and results in penile erection.¹³ Neurally released NO is considered to play a central role in CSM relaxation, and may be particularly important in initiating erection.⁵¹ Endothelial NO is produced continuously in response to shear stress and seems to play a dominant role in maintaining erection.⁵¹ NO relaxes the CSM by activating soluble guanylate cyclase to increase cGMP content. Although NO/cGMP is capable of lowering [Ca²⁺]_i by stimulating Ca²⁺-ATPase or by inhibiting L-type Ca channels through the hyperpolarization of the membrane, reducing the sensitivity of contractile proteins to Ca²⁺ is now believed to a major mechanism to relax CSM.¹⁶

Unless CSM receives parasympathetic neural input, it remains contracted for the majority of time to maintain penile detumescence. Contraction of CSM is generally believed to depend on neurally released NAd, which acts tonically on -adrenoceptors on the CSM membrane.¹³ NAd-induced contractions of CSM are considered to result from both Ca release from intracellular stores through InsP₃ production and Ca influx through L-type Ca channels.¹³ Besides these Ca²⁺-dependent contractile mechanisms, increasing the sensitivity of contractile protein to Ca²⁺ is now considered to play an essential role in -adrenoceptor-mediated contractions of CSM.^{16, 52}

Neuromuscular transmission in bladder smooth muscle

The detrusor smooth muscle receives a dense excitatory parasympathetic innervation.^{53, 54, 55} Stimulation of the intrinsic nerves in a strip preparation or in isolated whole bladders initiates contraction. Frequency response curves using brief stimulus trains show frequency-dependent responses that usually peak at around 40 Hz. The response in all mammalian bladders studied, except normal humans, is mediated by a combination of acetylcholine and ATP. Muscarinic receptor blockade preferentially blocks the response at higher frequencies, and the degree of blockade is very species dependent, there being little atropine resistant response in normal human bladder, but about 60% or more remains in rat bladders.^{56, 57} The remaining nerve-mediated response is abolished by desensitization of the P2x purinoceptors with ,,methylene ATP.

In guinea pigs, electrical recordings show that the ATP released by a single stimulus results in generation of an excitatory junction potential (ejp), which triggers an action potentiation and a rise in intracellular [Ca²⁺].^{25, 58} In the presence of L-type Ca channel blockers, ejps can still be evoked, but there is little contractile response. The ejps are not blocked by atropine, but are blocked by desensitization of the P2x purinoceptors.⁵⁹ In strips of normal human bladder, a single stimulus elicits little contractile response, and no clear ejp. Human detrusor possesses P2x purinoceptors, which can be activated by bath applied ATP,⁶⁰ and the lack of a purinoceptors response in normal human detrusor suggests that the purinoceptors are not expressed on the post junctional membrane, but occur extra-junctionally. EctoATPases would ensure rapid breakdown of ATP and prevent activation of the extra-junctional receptors. In overactive bladders a purinoceptor responses is occasionally seen,⁶¹ suggesting that ATP can now reach the receptors.

In small mammals, the contractile response to longer trains of stimuli shows an initial peak, which is largely purinergic, and a slower sustained response, which appears to be important in ensuring bladder emptying during micturition, and which is mediated more through muscarinic receptor activation.⁶² It has been proposed that the rapid purinergic component that is absent in man, is used for producing small spurts of urine for scent marking.⁶³

There is no conclusive evidence for any direct neural inhibitory input to the smooth muscle, although this is often reported in textbooks. Sympathetic input to the bladder goes largely to the blood vessels, and also to the intramural ganglia, but there is little evidence for a direct effect on the detrusor. A proportion of the parasympathetic nerves are immunoreactive to nitric oxide synthase (NOS), and the function of these nerves in the detrusor is unknown. Unlike in the urethra or erectile tissues, where NO relaxes the smooth muscles, the detrusor does not respond to nitric oxide donors with relaxation, but often with contraction.⁶⁴ In response to NO donors, the smooth muscle does not react by generating cGMP, although the interstitial cells in the bladder do so.⁴⁷ It has been suggested that it is these cells that are targeted by the nitrergic nerves, although the functional significance is unknown.

The urethral smooth muscles have cholinergic and adrenergic excitatory innervation, and nitrergic inhibitory innervation, and also in many species a second non-nitrergic inhibitory innervation is also present, which can be activated at higher frequencies of stimulation and mediates a long lasting inhibition.^{65, 66} The electrical responses of the tissue to neural input are not fully understood. In the rabbit urethra, sodium nitroprusside, an NO donor, modestly reduced the frequency of spontaneous slow waves without changing the membrane potential.⁴¹ In the same tissue, neither exogenous NO nor transmural nerve stimulation had any effect on spontaneous electrical activity.⁶⁷ Therefore, it seems to be unlikely that NO relaxes the urethral smooth muscles by diminishing electrical activity through membrane hyperpolarization. Nevertheless, both SIN-1, an NO donor, and transmural nerve stimulation were able to suppress spontaneous Ca transients.⁶⁸ It should be noted that activation of the GMP/PKG pathway inhibited spontaneous electrical activity in isolated interstitial cells by reducing the spatial spread of Ca waves, rather than reducing wave frequency.⁶⁹ In the rabbit urethra, neurally released NAd increased the frequency of spontaneous Ca transients to cause a sustained rise in basal Ca level,⁶⁸ suggesting that -adrenergic stimulation may accelerate spontaneous electrical activity. Indeed, exogenously applied noradrenaline increased the frequency of spontaneous slow waves through stimulation of -adrenoceptors in the same tissue.⁴⁰

Possible role of nerves in bladder overactivity

Clear changes in the innervation of the bladder have been found in association with various types of overactivity. Histochemical studies reveal patchy denervation in human bladder biopsies associated with severe bladder overactivity of all aetiologies,²⁸ associated with functional reduction in the effectiveness of intrinsic nerve stimulation. Similar patchy denervation and reduced effectiveness has been seen in animal models of bladder overactivity.^{70, 71, 72} Hypertrophy of dorsal root ganglion cells carrying bladder afferents is also seen in animals after spinal injury.³⁰ The accumulation of evidence suggests the following possible scenario. Enhanced firing of sensory nerves during the micturition cycle, caused for example by local inflammation, partial outflow obstruction, detrusor sphincter dyssynergia or any other cause, will result in the hypertrophy of the dorsal root ganglia, but will also initially enhance efferent nerve activity and the contractile force generated by the detrusor. Smooth muscles are highly reactive to the degree of afferent nerve activity they receive, and changes in the level of activity may lead to compensatory changes in the sensitivity of the receptors, and also hypertrophy or atrophy of the smooth muscles. Initially, enhanced sensory nerve activity is likely to result in a reduction in electrical connectivity and the sensitivity of the receptors to the neurotransmitters, and this has been seen in guinea pig models⁷³ and also in hypertrophy. However, a consequence will be an increased metabolic demand from the smooth muscles, and if the blood flow to the bladder wall is compromised (as will occur if the intravesicular pressure exceeds the capillary pressure) local ischaemia may result. Many experiments have demonstrated that the smooth muscle itself is very resistant to ischaemic changes^{74, 75} but the intrinsic nerves are susceptible, and local ischaemia may then be responsible for neural damage, and result in the later development of an increase in the responsiveness of the smooth muscles to the transmitters. Patchy denervation and supersensitivity to agonists is frequently seen in overactive bladders.

Pathways with impact overlapping on pelvic viscera and sexual activity

Four common mechanisms, that may coexist, to link LUTS and sexual dysfunction have been suggested: changes in the NO pathway (affecting the prostate and penis), autonomic hyperactivity, pelvic atherosclerosis and sex hormone dependence.^{76, 77} In the explanations that follow here, some of these concepts may be found. However, instead of presuming links between discrete symptom complexes, the general proposal is that commonality is to be expected. This is because of shared anatomy, embryology, functionality, pathways, endocrinology, etc, in pelvic and sexual structures. In effect, there is expected to be convergence in patient complaints for pelvic organs, because there is convergence in the pharmacology and physiology.⁷⁸

The NO pathway

It has been suggested that risk factors for ED such as diabetes, smoking, dyslipidaemia and hypertension could reduce prostate and bladder NOS activity, and hence reduce local NO levels. Theoretically, this could result in increased smooth muscle cell proliferation, leading to enhanced bladder outlet obstruction, exacerbated by increased smooth muscle contractile force. Evidence for this hypothesis can be derived from studies in humans^{79, 80} and dogs⁸¹ demonstrating reduced nitrergic effect as a result of reduced NOS levels. If NO synthesis does significantly influence both LUTS and erectile function, it would be expected that inhibiting cGMP breakdown by PDE-5 inhibitors should have an impact on both conditions. At present, only results from small-scale, open-label data⁸² and announced but unpublished studies are available: randomized data will be needed before firm conclusions can be drawn. Speculative analysis has supported the potential for PDE-5 inhibitors in the treatment of LUTS.⁷⁸ In addition, data presented at the meeting of the Sexual Medicine Society of North America in November 2005 in New York suggested that men who took sildenafil experienced a significant improvement in erectile function, and a concomitant decrease in both the irritative and obstructive symptoms of benign prostatic hyperplasia (BPH). Similar unpublished findings have been released for tadalafil.

Autonomic hyperactivity

A more direct mechanism may be the induction of increased sympathetic tone, resulting in greater prostate cell proliferation. It is known that autonomic nervous system innervation is important for the control of prostate glandular growth and differentiation, as witnessed by the observations that sympathectomy results in a reduction of prostate volume,⁸³ while spontaneously hypertensive rats that have increased autonomic activity also develop BPH.⁸⁴ Given our understanding of the autonomic nervous system in modulating aspects of physiology in response to 'stress', it is plausible that hyperactivity could play a more direct role in altered voiding and erectile function. Direct evidence of a role of autonomic nervous system overactivity is derived from a recent study that identified that autonomic variables (urinary noradrenaline and adrenaline, plasma noradrenaline and change in plasma noradrenaline after a tilt test) were positively correlated with subjective measures of LUTS and BPH and objective markers, such as prostate volume and Q_max.⁷⁶ These data, derived from a sub-study of the MTOPS trial, raise the intriguing possibility that the known beneficial effect of -adrenergic blockers in men with LUTS may be caused, at least in part, by a central, rather than a peripheral effect; a hypothesis that has not been fully explored.

Pelvic atherosclerosis

Atherosclerosis, a common cause of ED, could result in decreased bladder perfusion, with an associated increase in smooth muscle cell proliferation and contractility, again leading to LUTS. There are some data to support the importance of hypoxia in LUTS,⁸⁵ although there is debate regarding potential mechanisms.⁸⁶ It is also reasonable to generalize the concept to incorporate other forms of vascular compromise that may contribute to hypoxia or other local perfusion-induced anatomical or functional problems. For instance, measures of perfusion have shown vascular changes in prostate and corpora cavernosa, suggesting disease common to both sites. These correlated with symptom scores related to BPH (the IPSS) and erections (the IIEF) significantly worse than in a control group. The findings were thought to be consistent with the hypothesis that impaired blood supply is important in the development of BPH and ED.⁸⁷ Blood supply to the bladder wall is also easily reduced, with relatively small increases in intravesicular pressure, and subsequent ischaemic damage to intrinsic neurons in the bladder wall has been suggested as one of the underlying causes of overactivity in the bladder.^{85, 88, 89} It is also probable that the vasculature may represent a common mechanism, whereby systemic disease such as diabetes mellitus, dyslipidaemia, the metabolic syndrome, chronic kidney disease, hypertension, etc, can have an indirect impact on the vascular supply to the lower urinary tract, penis and rectum.

Neural interactions

Interactions in the higher centres are beyond the scope of the present article. At the level of the spinal centres, many potential interactions have been revealed. Axonal tracing studies in small mammals have shown, for instance, that some of pelvic sensory axons apparently have peripheral branches in more than one pelvic organ bladder,⁹⁰ and electrophysiological experiments have shown that preganglionic efferent neurons have recurrent collaterals that can influence several local reflex centres.⁹¹ Dendrites of preganglionic neurons may overlap and be influenced by the same inputs.

Neural interactions in the periphery are more difficult to study, because the imprecise anatomical organization of the ganglia in the pelvis makes the identification, role and destination of individual neurons difficult to determine, but it is becoming obvious that the 'classical' picture that is described in most textbooks is a gross oversimplification. It is no longer possible to consider the parasympathetic and sympathetic systems as separate two neuron pathways, and it is clear that complex interactions occur between them. The next section will consider this in more detail.

Autonomic innervation of the pelvis

The preganglionic cells of the sympathetic nervous system lie in lateral columns of grey matter in the spinal cord, and emerge from the ventral routes T1 to L2 (Figure 6). The neurons may synapse in the paravertebral chain ganglia, or pass through the chains and synapse in the prevertebral ganglia. Neurons in the sympathetic pathways innervating the pelvic areas are thought to synapse mainly in the coeliac plexus (comprised of the coeliac, superior and inferior mesenteric ganglia) or in the pelvic plexus (containing the superior and inferior mesenteric ganglia). The preganglionic neurons of the parasympathetic system lie in the sacral cord, and their axons emerge from S2 to S4, run with the pelvic splanchnic nerves to the pelvic plexus and may synapse here or pass through to other ganglia in the walls of the organs.

Figure 6.

Diagrammatic representation of the autonomic innervation of the bladder and urethra.

Full figure and legend (96K)

The pelvic plexus, which is usually thought to contain the main array of ganglion cells in the pelvis, is a very diffuse structure in humans. Individual ganglia, varying markedly in the number of neurons they each contain, are also scattered around the organs and imbedded in their walls. It has not proved possible to categorize each ganglion as 'belonging' either to the parasympathetic or the sympathetic systems, and determining the inputs to and outputs from the various ganglia is almost impossible in the human, although in animals neuronal pathways have been traced, and viscerotopic organization of the neurons can be seen in several species.⁹² Various techniques are available to locate the ganglia in living tissues, and their properties can be studied. In animals, electrophysiology has been used to study ganglionic transmission,⁹³ but few if any such studies are available in human material. Immunohistochemistry is the most commonly used tool to investigate these ganglia, and has been used to analyse nerves and neurons for their content of enzymes involved in synthesis, packaging or breakdown of various transmitters, and of neuromodulatory peptides. The main transmitter used in the first synapse in each pathway seems almost invariably to be acetylcholine working through a nicotinic receptor, but a multitude of transmitters and modulators have been identified in neurons or nerve terminals in the ganglia and in the postsynaptic axons. Embryologically, it appears that peptidergic primary sensory fibres link early with autonomic preganglionic neurons and their selective targets.⁹⁴

Histochemical studies

It is informative to examine some of the published work in more detail. In a series of studies, Smet and co-workers have investigated the immunohistochemistry of the ganglia found in the human bladder wall, and the nerves innervating them.^{47, 95} The ganglia themselves were found in the lateral walls of the bladder and contained between 1 and 36 neurons. Most of the cell bodies were immunoreactive to various peptides (VIP, NPY, galanin) and thought to be postganglionic parasympathetic neurons, but the occasional neuron showed immunoreactivity to tyrosine hydroxylase, suggesting it to be a postganglionic sympathetic neuron. The majority of the neurons were also positive for NOS. None was positive for SubP, CGRP, encephalin or somatostatin. However, the varicose nerve terminals entering the ganglia and innervating the neurons could be divided into various subclasses (Figure 7).

Figure 7.

Diagram of nerve terminals innervating neurons in the human bladder wall.

Full figure and legend (52K)

The CGRP/SP containing terminals were thought to emerge from axon collaterals of afferent fibres, and those containing tyrosine hydroxide were postganglionic sympathetic neurons. In this study it was assumed that the other two more common classes include the presynaptic cholinergic neurons. However, the heterogeneity of inputs again supports the complexity of the autonomic innervation, and suggests that the parasympathetic transmission can be modulated at the level of the ganglia. The authors conclude that intrinsic neurons within the human urinary bladder could in principle form circuits with the potential to support integrative activity. Similar studies on human tissue of been carried out in collaboration between The Oxford Continence Group and Karl-Eric Andersson's group in Lund.⁹⁶ Nerves running in the suburothelium and detrusor of human bladders again showed colocalization of markers (Table 1). Similar heterogeneity of neurons in the human paraurethral ganglia was also found.⁹⁷

Table 1 - Colocalization of transmitters in nerves in samples of the bladder wall taken from urodynamically normal patients.

Full table

Sensory axons

The demonstration of CGRP and SP containing terminals innervating ganglia leads us to consider in more detail the sensory arms of the reflex behaviour controlling the pelvic organs. Information from the organs must enter the spinal cord to trigger the central reflex systems, but as suggested above, some networks may exist completely in the periphery. These sensory neurons in many cases send collaterals to innervate ganglia or other more local effector systems through the release of tachykinins or other modulatory substances. It is becoming apparent that local factors control the sensitivity of these pathways, and two other important players that are involved are the endothelial linings of the pelvic organs and the interstitial cells.

Sensory nerves frequently run close to the endothelial lining of the organs, and in the same location are found interstitial cells – specialized cells that have thin processes interconnecting with each other through gap junctions, and forming close contacts with the nerve terminals. These cells are not fibroblasts, neurons or smooth muscle and are also found associated with the smooth muscle bundles.¹²

The endothelial linings of the organs may be very specialized, and have a secretory function – not only secreting substances into their lumens but also secreting factors that can modulate the sensitivity of adjacent sensory axons. An early example from the gut was the finding that 5-hydroxytryptamine (5HT) secreted from mast cells in the endothelium in response to toxins in the food triggered a peristaltic reflex by enhancing the sensitivity of the pressure sensitive axons involved.⁹⁸ Similarly, in the bladder, stretch or the contents of the bladder can cause secretion of several substances (notably NO and ATP) that can modulate the sensitivity of the sensory axons.⁹⁹ The interstitial cells have been shown to possess receptors for many different substances, and so anything secreted from the endothelium may affect sensory nerve terminals directly, or indirectly through the interstitial cells. The sensory nerves themselves have axon collaterals, which run in the suburothelium. Their activation may liberate tachykinins locally, which can potentially interact with the interstitial cells, the endothelium and probably the smooth muscle, modulating activity (Figure 1).

Furthermore, these sensory neurons may play a role in bidirectional cross-sensitization of the colon and LUTS. This has been demonstrated to be possible in a rat model of colorectal and bladder irritation. Cross-sensitization may account for several aspect of convergence in symptoms from pelvic viscera.

Conclusions

The diseases and symptoms affecting pelvic organs are coming under increasing scrutiny as the independence of any one condition appears progressively more linked to conditions in adjacent structures. Recent thinking has begun to assemble pelvic problems in clusters, based initially on epidemiological evidence. The notable lead in this is the association between LUTS and ED, and it is one that has attracted new epidemiological studies, new research thinking, efforts at identifying common therapies and a growing list of possible explanations. The consequences of recognizing the links between distinct organ systems are great for patients, in terms of disease understanding and the development of therapeutic strategies. At present this linkage is most clearly seen through examining the convergence of LUTS and ED, and the epidemiological evidence has been reviewed here and the theoretical and scientific explanations are being assembled in the literature. It seems likely that it may be important to take the convergence, overlap, clustering or linkage arguments further in light of the evidence that is accumulating particularly that based on smooth muscle function.

Smooth muscle cells have intrinsic rhythmicity that can be modulated locally and through parasympathetic neural input. Smooth muscle cells are also present and contributing to the function of all the structures in the pelvis. Parasympathetic transmission can be modulated at the level of the ganglia and there is a significant heterogeneity of inputs that creates great complexity of the autonomic innervation within the pelvis. The ganglia themselves have representations of autonomic and sensory innervation from multiple local structures – a fundamental factor facilitating cross talk between otherwise distinct organ systems. Intrinsic neurons within the human urinary bladder and lower gastrointestinal tract, for example, form circuits that influence integrative activity within the pelvis. The endothelial linings of the organs have secretory functions that can modulate the sensitivity of adjacent sensory axons. The interstitial cells also have receptors for many different substances, and so anything secreted from the endothelium may also affect sensory nerve traffic indirectly through the interstitial cells. The sensory nerves themselves have axon collaterals, which run in the suburothelium that can be influenced by local tachykinins, and interact with the interstitial cells, the endothelium and probably the smooth muscle itself.

There are a number of simple commonalities that are undoubtedly important in studying what may be called disease overlap. Multiple organ systems will be affected by systemic diseases such as those that impact the vasculature (hypertension, metabolic syndrome etc), metabolic targets directly (oxygenation etc), or those that affect endocrinological targets (sex hormone status, circulating noradrenaline etc). Regional organ systems will be affected by regional diseases (spinal cord and higher neural lesions etc). Pelvic organ systems are however uniquely vulnerable to collateral changes in their physiology through more locally interconnected autonomic pathways.

Information from the organs must enter the spinal cord to trigger the central reflex systems, but as suggested above, some networks may exist completely in the periphery. These sensory neurons in many cases send collaterals to innervate ganglia or other more local effector systems, through the release of tachykinins or other modulatory substances. It is becoming apparent that local factors control the sensitivity of these pathways, and two other important players that are involved are the endothelial linings of the pelvic organs and the interstitial cells.

There is therefore good evidence that certain complaints relating to pelvic structures are associated, and there is emerging evidence that the overlap may be much more extensive than just an association between LUT and ED in ageing men. In this paper, we propose that it is the impact of autonomic control within the pelvis that uniquely predisposes pelvic and sexual organs to crosstalk. With the consequence that diseases and conditions of the pelvis are subject to, convergence on a functional level such that it should be expected that disturbance of the function of one system will inevitably impact adjacent systems. Thus, studies that limit their view, say, to bladder function, in response to disease or treatment, will inherently be overlooking potentially important changes in adjacent systems. Human pelvic and sexual function is therefore essentially integrated, to a unique extent, and considering single dimensions, risks oversimplifying or fundamentally misunderstanding these conditions and their treatments.

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