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Keywords:

  • urgency;
  • bladder;
  • filling phase;
  • phasic activity;
  • nonmicturition contractions;
  • autonomous activity;
  • micromotions

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

Although caution should be used when applying animal data to human physiology, if care is taken to differentiate between general principles and complications of detail, particular to the species being examined, then experimentation on animal models can reveal basic phenomena in the bladder that offer clues to the origin of urgency. Recent data from the whole isolated bladder of guinea pigs showed unexpected complexities in autonomous activity during the filling phase of the micturition cycle: small, transient increases in intravesical pressure were associated with propagating waves of contractile activity and localized stretches of bladder wall. This complex, coordinated activity suggests that there are mechanisms within the bladder wall devoted specifically to generating phasic activity. Thus, there appear to be two systems controlling detrusor contractions: one associated with overall contractions similar to the micturition contraction and the other generating phasic activity. The mechanisms generating the phasic activity appear to be the point of complex integration of both excitatory and inhibitory inputs. There is evidence that local activity in the bladder wall generates afferent discharge, which probably contributes to bladder sensations. Animal data suggest a novel motor/sensory system incorporating contractile (motor) events, which cause stretches resulting in activation of afferent nerves (sensory). The motor element of this system appears to be controlled in a highly complex fashion such that the amplitude and frequency of the motor activity can be modulated by a variety of inputs. This raises the possibility that the sensitivity of the system informing the central nervous system, and thus awareness of the bladder's state during the micturition cycle, can be manipulated, possibly via novel drugs targeted at areas involved in overactive bladder, including urgency incontinence.


Abbreviations
CGRP

calcitonin gene-related peptide

α,βMATP

α,β methylene ATP

NO

nitric oxide.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

In this short review I take a sideways look at the current views of bladder function and the origins of bladder sensations. Failure to take into account basic observations made many years ago has constrained the thinking about the mechanisms that generate sensations in the bladder. When these observations are reconsidered and extended, a new perspective on the physiology of the bladder emerges, particularly for the filling phase of the micturition cycle. The systems being discovered open new avenues for investigating the origins and physiological control of sensation in the bladder. Importantly, increasing knowledge of the physiology of the bladder has the potential to lead to a more fundamental understanding of the origins of clinical disorders such as urgency and urgency incontinence.

HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

Control of the urinary bladder is of considerable clinical importance and has been the focus of a great deal of attention from both clinicians and basic scientists. Over the past century, experimental work on human bladder function has focused primarily on cystometric in vivo investigations and cellular, molecular and morphological studies of biopsy material. Because experiments in humans and human material raise legal, moral and ethical dilemmas, such studies are inherently limited. For example, it is not possible to study experimentally the cellular processes in the CNS that control micturition in humans. It also is becoming extremely difficult to acquire significant amounts of bladder tissue from healthy normal subjects for investigating cellular physiological events. Thus, basic science has resorted to using tissue from animal models to gain insights into the principles governing integrated control of the lower urinary tract and its cellular components.

It may not be unreasonable to suggest that the general principles regulating bladder function in mammals should be similar among different species. It also is not unreasonable to suspect that the detailed morphology, and the cellular and molecular mechanisms involved, may be different. Thus, caution should be exercised when applying animal data to human physiology. It is crucial to identify which are general principles and which are ‘complications’ of detail. This difficulty was recognized at the beginning of the last century in some of the earliest studies of bladder physiology. In an investigation into the actions of nerves on the bladder, Elliot wrote in 1905:

To determine the nervous control of the bladder with its simple structure and single function might seem no hard task. Yet some of the main facts are still disputed. The experiments of this paper reconcile most of these differing observations by showing that the innervation of the bladder varies from animal to animal, and that the error [conflicting data from different investigators] was the old one of arguing from the particular to the universal[1].

Over the next 60 years, this difficulty of ‘arguing from the particular to the universal’ had an important influence on the development of the understanding of the bladder and its functions. Among those interested in clinical urology, it was strongly argued that animal studies were of little relevance. Consequently, urologists focused on human studies, despite their limitations, apparently being minimally influenced by principles unravelled in other species. In 1960 in the Handbook of Physiology, Ruch wrote:

Although neurologists, urologists and physiologists have a community of interest in the bladder, they have little community of thought. The clinical disciplines have developed a fairly uniform view, apparently little influenced by physiological experiments on animals although there is a substantial similarity in methodology which should make translation from animals to man easy[2].

It is arguable whether this situation has changed throughout the years. In clinical research, the ‘fairly uniform view’ has been expanded and refined but remains relatively basic. At its very simplest, this view accepts that that are two phases of the micturition cycle, i.e. filling and voiding. The bladder is a quiescent, compliant reservoir during filling, and the onset of voiding is determined by the CNS. The initiation of micturition involves a complex reflex in which afferent input from stretch receptors in the bladder wall is integrated with other inputs in the pontine micturition centre and, when appropriate, this region of the CNS controls and coordinates sphincter relaxation, detrusor contraction and urine expulsion. The micturition contraction is triggered by postganglionic parasympathetic nerves with acetylcholine acting on muscarinic M3 receptors on the bladder smooth muscle to raise intracellular Ca2+[3]. The clinical perspective has developed to the point where the urinary system is conceived of as a ‘black box’ regulated according to the fairly uniform view of how the system functions.

In recent decades, one of the major forces driving lower urinary tract research has been the goal of discovering the origins of detrusor overactivity, urgency and urgency incontinence, and effective means to treat these conditions. The ‘black box’ technique has been widely adopted. In short, the approach has been to take a variety of basic drugs and their pharmaceutically designed derivatives, prescribe them to patients, and then attempt to determine their efficacy by assessing positive or negative outcomes. This method does not facilitate understanding of the fundamental mechanisms involved. One consequence has been that new insights into the physiological factors controlling the human bladder have been slow to emerge.

It is becoming clear that this simplistic approach will not suffice. Accumulating data suggest that the mechanisms involved in controlling bladder function are much more complex than supposed, and that these complexities must be discovered and taken into account. One example of this is the development of antimuscarinic drugs to treat overactivity and urgency incontinence. The clinical rationale for using these agents has been that they interfere with the detrusor contractions that are associated with the sensations of urgency [4]. For this reason, antimuscarinic drugs have been developed, intensively investigated clinically, and widely advocated for the treatment of the overactive bladder. Drugs such as tolterodine and oxybutynin, as well as the new agents darifenacin and solifenacin, reduce detrusor contractility and alleviate the symptom of urgency. At first glance, this is a positive outcome and a clinical advance. There can be no doubt that these drugs benefit patients suffering from detrusor overactivity, causing urgency and urgency incontinence. However, a scientific difficulty is posed, in that at clinically effective doses that reduce urgency, these agents do not significantly affect micturition contractions [4]. Such data imply that the neuromuscular junction is not the active site for these drugs at therapeutic doses [4,5]. This is not what was predicted from the ‘fairly uniform view’ and implies that there has to be something else in the ‘black box. Other examples of an oversimplified fairly uniform view include the lack of clear physiological roles for: (i) purinergic, adrenergic, nitrergic and peptidergic nerves (substance P, vasoactive intestinal peptide and calcitonin gene-related peptide, CGRP); (ii) the intramural and pelvic ganglia; (iii) the urothelium; and (iv) specialized cell types such as interstitial cells. For a full picture of the physiology of the bladder and its control mechanisms, all of these component systems should be considered. In this respect, animal-model experiments on the integrated control of lower urinary tract function can be extremely powerful. Further, such research is the only way to derive general principles that will affect the understanding of the human system. The following sections describe a single, highly specific view of how a comprehensive approach to bladder function may reveal complexities and interconnections between apparently unconnected observations and mechanisms. The data show that basic phenomena in the bladder remain unknown; revealing these mechanisms will advance our fundamental appreciation of these processes.

THE PHYSIOLOGY OF THE FILLING PHASE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

In normal subjects, bladder sensations increase as the bladder fills. In patients with overactive bladder and urgency, these sensations can be excessive and lead to urgency incontinence. The activity of the bladder during the filling phase is central to the origins of sensation. Therefore, it seems obvious that the physiology of the filling phase should be examined to understand the causes of urgency and urgency incontinence.

It is widely thought that the human bladder is not active during the filling phase [6]. Furthermore, it has become generally accepted that any detrusor activity during filling is pathological [6]; however, this is not actually true. There is a body of evidence indicating that the bladders of healthy young subjects are capable of generating phasic increases in pressure during the filling phase (see [7–9] for an overview). The original observations of Mosso and Pellacani [10] on nonrhythmic contractions in the human bladder before voiding were made more than 120 years ago; however, they seem to have been forgotten. In animals, the situation is clearer. It has been known for over a century that the bladder is active during filling: again, the original observations of this phenomenon in cats were made in 1892 by Sherrington [11]. Indeed, Sherrington also showed that this phasic activity originated in the absence of any CNS input and occurred when the bladder was removed and maintained in vitro. A plausible conclusion is that this is autonomous activity, which should be an inherent property of the bladder wall. However, since 1892 there have been few detailed studies of nonmicturition or autonomous activity; the absence of basic information about these processes represents a fundamental gap in the understanding of the physiology of the lower urinary tract [7,8].

The forgotten aspects of spontaneous activity in the whole bladder prompted a re-evaluation of its manifestations, the mechanisms involved, and the possible physiological roles it may play. In a series of recent papers, the nature of autonomous activity was described using the isolated whole bladder of the guinea pig [9,12]. These experiments revealed unexpected complexities in the nature of the spontaneous activity: small transient increases in intravesical pressure were associated with propagating waves of contractile activity and localized stretches of the wall. This complex coordinated activity suggested the presence of mechanisms within the wall devoted specifically to generating phasic activity. Subsequent experiments showed that the ‘autonomous activity’ was augmented by muscarinic agonists and nicotinic ligands [9,12]. This ‘augmented activity’ consists of phasic increases in intravesical pressure of 10–20 cmH2O [12]; each transient increase is associated with waves of contractile activity and discrete stretches of the bladder wall. These observations led to the conclusion that there are two systems within the bladder generating contractions: one associated with the overall contractions of the detrusor similar to the micturition contraction and the other generating complex phasic activity [12] (Fig. 1) [13–15].

image

Figure 1. Complex contractile activity generated in an isolated whole bladder preparation (guinea pig). (a) shows records of intravesical pressure during repeated brief exposures to varying concentrations of carbachol. (b) and (c) illustrate on expanded time bases the records at 0.3 and 10 µmol/L, respectively. At the lower dose, the phasic activity predominated, whereas at the higher dose the phasic activity is superimposed on a slower contracture. Reprinted with permission from Gillespie et al.[12]. (d) illustrates an overview of the mechanisms involved in these complex responses: (1) represents the ‘classic’ view of detrusor activation involving parasympathetic cholinergic neurones; (2) illustrates distinct mechanisms generating phasic activity. Excitatory and inhibitory inputs from the CNS and the urothelium may affect the frequency and amplitude of the activity [13], and intracellular mechanisms involving cAMP and cGMP also have a role [14,15].

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Support for the presence of two systems controlling bladder contractions emerged from studies conducted to determine the actions of an analogue of ATP, i.e. α,β methylene ATP (α,βMATP) and substance P on the isolated whole bladder [13]. The data showed that α,βMATP and substance P at low doses (<300 nmol/L) had little direct effect on the resting whole bladder in terms of producing overall contractions. In contrast, the same or lower doses dramatically increased the frequency of the phasic contractions (Fig. 2). These observations, in addition to showing that there may be two distinct systems involved in effecting detrusor contractions, also suggest important regulatory roles for ATP and substance P in the bladder wall [13]. The sources of these agents are not known, but nerve fibres containing ATP and substance P are found throughout the bladder wall. In addition, ATP (and nitric oxide, NO) are released from the urothelium [16–18]. These different physiological inputs appear to act on the phasic mechanism.

image

Figure 2. The actions of the analogue of ATP (α,βMATP) and substance P on phasic activity in the isolated guinea pig bladder induced by the muscarinic agonist arecaidine. (A)(a) both α,βMATP and substance P cause a dramatic increase in the frequency of the phasic activity (see instantaneous frequency analysis, b). Further, on removing each agonist, there was a marked inhibition of the activity, with a reduction in both amplitude and frequency of the transients. Examples are shown of the responses to (B) αβMATP and (C) substance P on expanded time scales. Reprinted with permission from Gillespie [13].

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An enigma of bladder physiology has been the role of adrenergic, peptidergic and nitrergic nerves. In some species, adrenergic nerves reduce bladder tone and the micturition contraction, whereas in others there is no effect. Furthermore, although the bladder has many nerves containing CGRP, no specific function has been ascribed to them. Examination of the effects of noradrenaline and CGRP on the phasic activity in the isolated bladder showed that these agents inhibit phasic activity (Fig. 3; [14], Gillespie, unpublished observations). Taken together, these observations suggest that the mechanisms generating phasic activity involve complex integration of both excitatory and inhibitory inputs.

image

Figure 3. The effects of noradrenaline and CGRP on the phasic activity generated by the muscarinic agonist arecaidine in the isolated guinea pig bladder. (A) and (B) show that noradrenaline and CGRP profoundly reduce and slow phasic activity. This is also seen in the analysis of the effects of noradrenaline and CGRP on the instantaneous frequency of the transients. Note that on removing each agent, there is a transient increase in the frequency of the phasic contractions. Reprinted with permission from Gillespie [14], and unpublished data.

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LOCAL REFLEXES IN THE BLADDER WALL

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

Autonomous activity in the isolated bladder increases as the bladder is filled [9]. Figure 4 shows that phasic activity, augmented in the presence of a muscarinic agonist, also increases as the bladder volume rises. This observation is deceptively simple. It raises basic questions about the nature of the mechanism that senses bladder volume and how the output from these elements becomes integrated to influence phasic activity. These questions remain unanswered, but they suggest the possibility of ‘local reflex’ mechanisms operating in the bladder wall that may be involved in some way in modulating detrusor activity.

image

Figure 4. The effects of increasing intravesical volume on muscarinic-induced phasic activity in the isolated whole guinea pig bladder. (a) upper panel, shows an original record from an experiment where the intravesical volume was increased from an initial value of 700 µL in increments of 200 µL to a final volume of 1700 µL. The lower panel shows an analysis of this record in which the instantaneous frequency (reciprocal of inter-spike interval) is plotted against time. (b) shows sections of the record on an expanded scale (Gillespie, unpublished observations).

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The components of such a reflex are unknown. One possibility involves sensory nerves. Sensory nerve endings lie in the suburothelial spaces [19], and in many tissues these axons produce collaterals that remain in the tissue. Such a microanatomical arrangement was first described by Bayliss [20] in 1901 to account for local vasodilator reflexes in the skin. Activation of the afferent fibres results in antidromic activation of the collaterals, which then have their effect on the tissue. This local axonal reflex has been suspected in many other tissues, including the bladder (see Maggi and Meli for a review [21,22]). In an attempt to discover evidence of any involvement of afferent nerves in the volume-induced responses, bladders were treated with capsaicin to effectively eliminate Aδ- and C-fibre responses. One of the actions of capsaicin is to initially stimulate nerves, causing them to release the contents of their terminals [21,22]. Applying capsaicin to whole isolated bladders caused transient complex changes in the frequency of the phasic activity: an initial increase, a decrease and a secondary increase (Fig. 5). This may be the consequence of a capsaicin-induced release of substance P and CGRP, with consequent excitatory and inhibitory effects (see above) [13,21,22]. A tentative conclusion is that sensory nerve activity may affect phasic activity, which may implicate local antidromic reflexes involving axon collaterals.

image

Figure 5. The effects of capsaicin on muscarinic-induced phasic activity. The upper panel shows data from one experiment where a bladder was exposed to capsaicin (30 µmol/L). On applying capsaicin there was a complex series of changes involving an initial increase, a decrease, and a secondary increase. The lower panel shows the data analysed in terms of changes in instantaneous frequency (Gillespie, unpublished data).

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The volume-induced changes were not affected by capsaicin treatment, nor were they affected by tetrodotoxin (Gillespie, unpublished observations), suggesting that although these axonal reflexes may modulate phasic activity, nerves using Na+ channels or Aδ- or C-afferent nerves are not involved with the primary mechanism generating volume-induced activity. Thus, other components should be considered. It was suggested recently that interstitial cells in the suburothelial space may serve some form of sensory function [23–25]. It is not known how these cells contribute to sensation and how this mechanism may operate physiologically, but they could play a role in volume responses.

The above section shows that there are basic phenomena relating to the integrated physiology of the bladder that have yet to be described. The physiological role of these complex systems is not known, but it is worth speculating whether they can be integrated into a coherent picture of complex bladder functions that are not associated with micturition.

MICROMOTIONS AND SENSATIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

A potentially important clue to the role of this complex activity can be traced to the observations of Coolsaet and others [26,27] of small localized contractions, which they described as ‘micromotions’, in the bladder wall of the pig. However, the mechanisms generating these events were not investigated, nor was their physiological role considered in any detail. It was speculated from these observations that each micromotion, as it was localized, could lead to a ‘microstretch.’ These localized stretches could, in turn, excite afferent nerves and contribute to bladder sensations [26]. The phasic activity of the guinea pig bladder (described earlier) confirms and extends this idea. In the guinea pig the contractions can be large, allowing stretches of the wall to be clearly demonstrated. Thus, an important concept is that localized activity generating local stretches may activate afferent discharge.

Published evidence suggests that this is a credible idea. The original work by Iggo [28] to investigate afferent nerve discharge from the cat bladder showed that there was a population of adapting stretch receptors in the bladder wall. These receptors fell silent in the presence of a constant or slowly changing stimulus, but were clearly active during rapid filling or during the rising phase of spontaneous phasic contractions that occur in the cat bladder (Fig. 6) [11]. These observations were confirmed by showing that there is a definite correlation between bursts of afferent discharge in the pelvic nerve of the cat and phasic pressure changes [8]. Thus, there is evidence to suggest that local activity in the bladder wall can generate afferent discharge. The afferent discharge more than likely contributes to bladder sensations.

image

Figure 6. Afferent recordings from the pelvic nerve of the cat. (a) afferent discharge from a single unit during the infusion of 50 mL of saline into the bladder (infusion started at the arrow). The upper record shows bladder pressure, while the lower record indicates nerve activity. The receptor discharge reaches a maximum and then falls silent as the filling reaches completion. (b) afferent discharge in a single afferent unit during a spontaneous nonmicturition contraction. The upper record shows bladder volume, the middle record shows bladder pressure, and the lower record indicates nerve activity. Time markers 1 second apart. Reprinted with permission from Iggo [28].

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It can be concluded that what may be present is a ‘motor/sensory’ system incorporating contractile (motor) events, which cause stretches resulting in activation of afferent nerves (sensory) (Fig. 7). The data summarized here suggest that the motor element of this system may be controlled in a highly complex fashion such that the amplitude and frequency of the motor activity can be modulated by a variety of inputs. The key input may be that derived from the volume of fluid in the bladder. By this mechanism, bursts of afferent discharge proportional to bladder volume may be relayed to the CNS. Other inputs to this motor/sensory system, involving certain neurotransmitters (substance P, CGRP, noradrenaline, NO), may indicate the involvement of intramural nerves, whereas others involving ATP and NO may suggest components derived from the urothelium. The overall emerging concept is of a modulated sensory system.

image

Figure 7. Schematic diagram of the mechanisms that might contribute to the generation of sensation in the bladder. (A) represents the ‘classic’ view of sensory nerve ending, deformed by bladder distension, sending signals to the CNS. (B) points to an extension to this concept whereby substances released by the urothelium (NO and ATP) act directly on the afferent nerve ending to modulate discharge. (C) represents the complex scheme outlined in this article: it proposes the existence of specific mechanisms within the bladder wall capable of generating phasic activity. This phasic activity (comprising local contractions and stretches) activates afferent discharge. The amplitude and frequency of the phasic activity is influenced by the bladder volume, possibly via local reflexes and also by excitatory and inhibitory inputs from the CNS. In this way, this complex system functions as a motor/sensory system.

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It is important to realise that the integrated actions of such a system have not yet been confirmed unequivocally. However, if such a system does exist, then it has the potential to relay information to the CNS about bladder volume; inputs from the bladder wall and the CNS could potentially modulate related sensations. By involving such a complex series of interrelated mechanisms, it would be possible to increase and decrease the sensitivity of the system informing the CNS and therefore consciousness about the state of the bladder throughout the micturition cycle.

RELEVANCE TO HUMANS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES

The data presented above indicate that complex mechanisms serving basic physiological processes are present. However, it is clear that little is known about the detailed integrated physiology of the bladder wall and the structures involved. In the case of autonomous activity, data are highly suggestive that this system plays a role in generating and modulating sensations originating in the bladder wall. The system is complex, perhaps because it is involved in both these functions. It has only been possible to gain a perspective on this sensory system from a detailed analysis of the whole isolated organ. Such complex events could not have been predicted from data on small isolated pieces of muscle or single cells, or from molecular data. Moreover, these experiments are typically not feasible using the human bladder. This, once again, shows the importance of animal models for revealing basic principles of bladder function and control.

The possibility of a potential novel motor/sensory mechanism in animal bladders elicits the query: ‘does this motor/sensory system operate in humans?’ This question cannot be answered at present. However, if nonmicturition phasic activity and its modulation are general principles, then they will become apparent in future studies on the human bladder. There is circumstantial evidence for such activity from ambulatory monitoring studies in normal human subjects [29,30] and in women with chronic pelvic pain [31]. Although it is unlikely that exactly the same phenomena are present in the human bladder, it is probable that there is some form of motor/sensory system. The challenge for the coming years will be to identify such a system in humans and to elucidate its underlying mechanisms. One research focus will be to determine if this system is involved in the aetiology of detrusor overactivity and associated symptoms such as sensory urgency. Due to its number of inputs and varied pharmacology, this motor/sensory system may be a productive hunting ground for the design of new drugs aimed at specific targets affecting overactivity and urgency incontinence. Such research may provide insight into the actual therapeutic mode of actions of currently used drugs such as the antimuscarinics. However, a word of caution should be reiterated: any new insight into how an animal system may function only relates, in the first instance, to that species. It is hoped that further experimentation will yield new general principles. The important advances will come from recognition of what is particular and what is universal.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. HISTORICAL OVERVIEW OF THE VALUE OF ANIMAL STUDIES
  5. THE PHYSIOLOGY OF THE FILLING PHASE
  6. LOCAL REFLEXES IN THE BLADDER WALL
  7. MICROMOTIONS AND SENSATIONS
  8. RELEVANCE TO HUMANS
  9. REFERENCES