Psychological Medicine, 1979, 9, 249-263 Printed in Great Britain

Physiological and pharmacological basis for the chemotherapy of enuresis1 J. D. STEPHENSON2 From the Department of Pharmacology, Institute of Psychiatry, London Enuresis is a disorder of micturition occurring in the absence of an organic urinary tract lesion. To understand its possible causation, the mechanisms controlling micturition are described together with the possible sites of action of various anti-enuretic agents, particularly imipramine. It is concluded that further research into the central control of micturition is required before the precise actions of centrally-acting anti-enuretic agents can be elucidated. Knowledge of these may give insight into the nature of the defect causing enuresis.

SYNOPSIS

INTRODUCTION Nocturnal enuresis may be defined as the voiding of urine during sleep in a person above the age at which continence is usually acquired (4-6 years) and with an anatomically and physiologically normal urinary tract. At least two studies (Starfield, 1967; Troup & Hodgson, 1971) have shown that enuretic children void more frequently and with smaller volumes than nonenuretic controls, although there is considerable overlap between the two populations. The symptom spontaneously remits in the majority of children (Miller et al. 1960; Forsythe & Redmond, 1974), which is further evidence of an anatomically normal urinary tract. It is therefore necessary to consider normal bladder physiology not only to understand the mechanism of action of anti-enuretic drugs but also to search for mechanisms which might cause enuresis. PHYSIOLOGY OF MICTURITION So little is understood about the function of smooth muscle and of the central nervous system that a presentation on bladder physiology can be little more than a series of working hypotheses linking known facts and inevitably has a large content of personal concepts (Yeates, 1974).

The bladder has two recognized functions. The first is to store urine and the second is to expel the urine at a socially convenient time and place. These two processes are controlled by several spinal and brain stem reflexes subject to modulation from higher suprapontine centres, but our understanding of them has been severely retarded by two misconceptions. First, the denial of a role, via the hypogastric nerves, of the sympathetic nervous system in micturition and, secondly, the belief that the bladder is in a state of imminent contraction, voiding being prevented by a constant inhibitory influence of corticospinal tracts on the sacral micturition centre. Micturition was thought to be initiated by voluntary withholding of this cortical inhibitory influence on the sacral micturition centre and terminated by allowing normal cortical inhibition to resume. This mechanism, proposed by Denny-Brown & Robertson (1933), was a means by which voluntary control could be exercised over the smooth involuntary muscle of the detrusor. Later, Muellner (1958) postulated an alternative and more accurate explanation but the earlier concept still persists in terms such as the 'uninhibited neurogenic bladder'.

Sympathetic innervation of the bladder: internal sphincter 1 This article formed the basis of a lecture given at the In- In 1907, Elliott proposed that the bladder was stitute of Psychiatry, London, October 1977. innervated by both divisions of the autonomic • Address for correspondence: Dr J. D. Stephenson, nervous system. The dual innervation supplied Department of Pharmacology, Institute of Psychiatry, De both the detrusor muscle and the internal Crespigny Park, Denmark Hill, London SE5 8AF. 249

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sphincter; an antagonistic action mediated by the two innervations controlled the simultaneous opening of the bladder neck and contraction of the detrusor during micturition (parasympathetic nerves) and the opposite events during bladder filling (sympathetic nerves). The controversy relating to the importance of the sympathetic innervation is inseparable from that relating to the internal sphincter. In a classic paper, Learmonth (1931) described how, if an instrument was introduced at operation through the internal sphincter and the hypogastric nerves stimulated, the instrument was grasped so tightly that considerable force was necessary to move it. Some forty years later Hutch (1972) wrote 'many authorities have concluded that there is no internal sphincter, yet any surgeon who has inserted his finger into it during surgery on the bladder knows that there must be a sphincter located at the bladder neck'. The apparent similarity of these two statements conceals two very different concepts of the internal sphincter. Thus, Learmonth believed in a true innervated sphincter, whereas Hutch envisaged a mechanical sphincter. This divergence in view has its origins in the role of the sympathetic nervous system in micturition for, despite experimental studies by physiologists around the turn of the century (e.g. Elliott, 1907) and later by clinicians such as Learmonth (1931), subsequent investigators could not consistently demonstrate effects on voiding of stimulation or division of the sympathetic nerves or by sympathomimetic drugs and it was accepted teaching that only the parasympathetic innervation was of importance, e.g. 'the sympathetic nervous system plays no part in the process of micturition' (Lapides et al. 1958). Although this statement derived predominantly from a clinical interest in the maintenance of voiding and continence, rather than in mechanisms which might enhance functional bladder volume, it nevertheless meant that the dual functions of voiding and continence had to be subserved by a single nervous input (the pelvic nerves). This nurtured the concept of the mechanical opening of the bladder neck (Hutch, 1972) and, since the mechanism by which the bladder neck opens is still unresolved, it will be considered in some detail. The literature contains a number of accounts of circular smooth muscle which partially or

completely surround the bladder neck and proximal urethra. Some workers have considered this to be evidence for a sphincteric mechanism (either neuronal or mechanical) but others have argued the converse for, if it is believed that the detrusor muscle is directly continuous with and structurally identical to that forming the bladder neck and proximal urethra (Woodburne, 1960; Tanagho & Smith, 1966), then it follows that the smooth muscle of the bladder neck and proximal urethra would contract in synchrony with that of the bladder opposing the voiding of urine. The detrusor loop was seen as one solution to the above difficulty (Fig. 1). During bladder filling, tension in the right and left lateral posterior outer longitudinal muscles increases, pulling the detrusor loop and transverse precervical arc into the apex of the trigone. This action complements that of the base plate which remains flat so that the rings of circular smooth muscle constantly force the apex of the trigone into the detrusor loop (Fig. 2). At voiding, contraction of the anterior and medial posterior outer longitudinal muscles disengages the apex of the trigone from the detrusor loop, causing the vesico-urethral orifice to open and the bladder neck to assume a funnel shape (Fig. 3). The evidence for muscular continuity between the urethra and detrusor which necessitated the above complex, albeit elegant, 'engineering' was based on studies of human post mortem material examined by either gross dissection or standard histological procedures and has not been supported by more recent embryological, histological and histochemical studies on human foetal and animal material (McNeal, 1972; Droes, 1974; Gosling & Dixon, 1975). Thus, in human foetuses, Droes (1974) described three distinct smooth muscle systems, the detrusor and urethral muscles developing separately at a crown rump length of between 6 and 10 cm and the trigonal system, later to form the bladder neck, developing at a crown rump length of between 10 and 20 cm. This embryological differentiation of the bladder neck region from the bladder body is supported by many histochemical studies showing a difference in distribution of nerve endings to the two regions. The bladder neck region, that is the area which lies circumferentially distal to the level at which the ureters enter the detrusor muscle, received a rich adrenergic innervation whereas the rest of the

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Chemotherapy of enuresis Medial posterior outer longitudinal muscle

Lateral posterior outer longitudinal muscle

Transverse precervical

Waldeyer's sheath

Anterior outer longitudinal muscle FIG. 1. The detrusor loop in the bladder neck region. The right and left lateral posterior outer longitudinal muscles, which lie under each Waldeyer's sheath, pass around the bladder neck to form the anterior and lateral walls of the urethra just below the base plate (see Fig. 2) and constitute the detrusor loop. The loop is so positioned that the apex of the trigone fits into its concave surface. Thus, as the bladder fills, the loop is pulled tighter against the trigone, keeping the bladder neck closed. (Redrawn from Hutch, 1972.)

Lateral posterior outer longitudinal muscle

Detrusor loop

Apex

FIG. 2. The base plate in the bladder neck region. The base plate remains flat during bladder filling and the rings of circular smooth muscle constantly force the apex of the trigone into the concavity of the detrusor loop thus keeping the bladder neck closed. (Redrawn from Hutch, 1972.)

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(a) Filling

(b) Voiding

Lateral posterior outer longitudinal muscle

k • Waldeyer's sheath

Medial posterior outer longitudinal muscle

Anterior inner longitudinal muscle Trigone

Anterior outer longitudinal muscle Transverse precervical arc

Detrusor loop

FIG. 3. The bladder neck region (a) during continence and (A) during voiding. During voiding, contraction of the medial posterior outer longitudinal muscle disengages the apex of the trigone from the concavity of the detrusor loop. At the same time the precervical arc is pulled upward and forward by the anterior outer longitudinal muscle and backwards by the detrusor loop. These actions produce funnelling of the bladder neck region (trigonal canal) and result in its opening. (Redrawn from Hutch, 1972.)

bladder, that is the detrusor, had only a scant innervation (Raezer et al. 1973; Gosling & Dixon, 1975). Histochemically the trigonal area of the posterior base could not be distinguished from the detrusor muscle of the anterior base. A recent study on human tissue contrasts with the above description obtained from cats and dogs since a rich innervation was only observed in the male proximal urethra; the adrenergic innervation was sparse in the male and female bladder neck and in the female proximal urethra (Gosling et al. 1977). The true mechanism of bladder neck opening is still unresolved and it seems likely that neuronal and mechanical factors interact. McNeal (1972) rejects the mechanistic theory of Hutch and argues cogently that the base plate (crucial to Hutch's concept) is simply an anatomical buttress blocking transmission of tension within the vesical wall to the true internal sphincter. In a study of the base plate region of 382 children whose ages ranged from 4 days to 14 years, Hutch & Shopfner (1968) observed that all 93 children below the age of 3 years had rounded or infantile base plates; no attempt was made to distinguish between enuretic and non-enuretic children in this group. In the older children, development of the base plate was imperfectly correlated with the ability to remain dry at night for 81 % of 100 non-enuretic boys, and 83 % of 100 non-enuretic girls had flattened or adult base plates compared with only 54 % of the enuretic

boys and 46 % of the enuretic girls in the remaining 89 children. There have been many studies of the responsiveness of the intact bladder and of bladder strips to a- and /?-adrenoceptor stimulation and the consensus of these is that a-adrenoceptors predominate in the neck region where their activation causes constriction and the /?-adrenoceptors, which mediate relaxation, predominate in the detrusor muscle (Edvardsen & Setekleiv, 1968; Nergadh & Boreus, 1972; Raezer et al. 1973; Awad et al. 1974). This distribution suggests that the sympathetic innervation acts to promote continence in the manner described by Elliott (1907) 'the hypogastrics facilitate retention of urine by constricting the urethra and inhibiting the tone of the detrusor urinae'. The vascular component of the urethral response is small (Raz et al. 1972; De Groat & Saum, 1972; Tulloch, 1974). De Groat & Saum (1972) demonstrated that the hypogastric nerves might also directly depress activity of postganglionic parasym pathetic fibres to the bladder by an inhibitory action at the pelvic ganglia (Fig. 4). The hypogastric nerves, which could be activated by stimulation of vesical afferents (the vesico-sympathetic inhibitory reflex), therefore have the potential to oppose rises in intravesical pressure by increasing inhibitory input to the parasympathetic vesical ganglia and detrusor muscle, thus allowing the bladder to accommodate larger volumes, and simultaneously increasing tone in the bladder outlet region.

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I're _^ Adrenergic V inhibitory neurone (J-Adrenoceptor blocking agents

Noradrenaline isoprenaline Post

Noradrenaline Dopamine a - Adrenoceptor blocking agents

Pelvic ganglion Bladder

FIG. 4. Diagrammatic representation of receptors mediating adrenergic inhibition in the urinary bladder of the cat. The dashed line from the adrenergic inhibitory neurone indicates that the postganglionic axon to the bladder and the pelvic ganglia do not necessarily originate from the same adrenergic inhibitory neuron. (Redrawn from de Groat & Saum, 1972.)

However, the sequel of surgical interference indicates only a minor role for this reflex. It may be that, for example, after presacral neurectomy there is a tendency to void smaller urine volumes and a reduced ability to suppress the desire to micturate but that these are not commented on, the prime clinical interest being in the preservation of continence and the ability to void. Nevertheless, drugs affecting the sympathetic nervous system have been successfully introduced into urological practice. For example, a-adrenoceptor blocking agents (phentolamine and phenoxybenzamine), prescribed for benign prostatic obstruction and certain types of urinary retention (Krane & Olsson, 1973a, b; Caine et al. 1976; Caine, 1977), reduce outflow resistance (Whitfield et al. 1976), whereas /?-adrenoceptor stimulants have been used to control incontinence (Stanton, 1978); a-methyl dopa may reduce the otherwise large residual volumes of multiple sclerosis victims (Raz et al. 1977). The complexity of the autonomic innervation to the bladder (Fig. 5) may be part of the reason for the apparently greater effects of sympatho-

mimetic stimulating and blocking agents on micturition than of surgical interruption. Thus, the hypogastric nerves contain both pre- and postganglionic fibres (some of which may not be noradrenergic, Taira (1972)), and adrenergic ganglion cells have been described within the bladder musculature (Elbadawi & Schenck, 1968, 1971). As might be expected from this, and as shown by Norle"n et al. (1976), hypogastric nerve transection does not deplete the bladder of noradrenaline. Thus, after bilateral nerve transection, noradrenaline may still be released by local reflexes and have an effect, whereas the pharmacological agents interfere with the action of noradrenaline at the neuromuscular junction. Further research is needed to determine the relevance of the hypogastric nerves to micturition for, although their transection in anaesthetized cats produces a marked and immediate reduction in the micturition threshold volume (Edvardsen, 1968), this effect is not obtained after recovery from anaesthesia (Craggs & Stephenson, 1979). An important question to be answered is whether the hypogastric innervation PSM 9

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Lumbar

Bladder wall

Sacral

FIG. 5. Diagrammatic representation of postganglionic synapses within the bladder. These synapses enable the sympathetic pathway to modulate transmission in the parasympathetic pathway and vice versa. Thus, postganglionic neurons, either sympathetic or parasympathetic, may be influenced by both preganglionic and postganglionic synapses. , Preganglionic neurones; , postganglionic neurones. (Redrawn from Elbadawi & Schenck, 1971.)

is active only when suppressing the desire to void until socially convenient or whether it is tonically active throughout the continence phase. Reflexes involved in the storage of urine and onset of micturition

Appreciation of bladder filling which results in the urge to void is conveyed to the sacral micturition centre and central nervous system by the activity of detrusor afferents ascending in the pelvic and hypogastric nerves. These afferents are tension receptors and therefore respond to both active bladder contraction and passive bladder distension (Iggo, 1955; Winter, 1971). In the empty bladder there is little or no afferent activity but, as the bladder fills and contractions occur, the afferent activity increases and is essential for normal micturition. There are several reflexes involved in the storage of urine (Table 1). After, or during, voiding these reflexes are re-established by the perineobulbar detrusor inhibitory reflex which is activated by voluntary contractions of the perineal and pelvic muscles. The first two

reflexes, which are activated by stretch of the detrusor muscle form the vesicosympathetic inhibitory reflex (de Groat & Lalley, 1972). The importance of this to continence is unclear and has already been discussed. The third reflex, the perineodetrusor inhibitory reflex is activated by tension within the perineum and pelvic floor muscles (Denny-Brown & Robertson, 1933). It exerts a powerful inhibitory effect on the sacral micturition centre reducing parasympathetic activity and hence detrusor tone. The last of the storage reflexes, a guarding reflex, is activated by increased tension within the bladder base as filling continues or by escape of urine into the proximal urethra (Garry et al. 1959); the effect of the reflex is to increase tone of the external striated sphincter. During micturition this reflex is obviously inhibited by other reflexes. To summarize, during bladder filling, activity travelling within pelvic, hypogastric and pudendal afferents increases. These afferent impulses activate the above reflexes which relax the detrusor and increase tone in both the internal and external sphincters. As filling continues, an increasing number of

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Table 1. The reflexes concerned with the storage of urine. The first reflex, the perineobulbar detrusor inhibitory reflex, is largely responsible for the suppression and voluntary cessation of voiding and reestablishes the storage reflexes Route Location

Name

Activating stimulus

Afferent

Perineobulbar detrusor inhibitory reflex

Contraction of perineal and pelvic muscles

Pudendal nerves and sacrobulbar tracts

Ventral reticulospinal tracts

Sympathetic detrusor inhibitory reflex Sympathetic sphincter constrictor reflex Perineodetrusor inhibitory reflex Urethrosphincteric guarding reflex

Increasing detrusor mural tension Increasing detrusor mural tension Tension of perineal and pelvic floor muscles Tension of trigone or entry of urine into proximal urethra

Pelvic nerves

Hypogastric nerves Thoracolumbar cord

Pelvic nerves

Hypogastric nerves Thoracolumbar cord

Pudendal nerves

Pelvic nerves

Pudendal nerves

Pudendal nerves

[

Efferent

Medulla to sacral micturition centre

Sacral micturition reflex centre Pudendal nucleus in sacral cord

Adapted from Mahony et al. 1977.

Table 2. The reflexes concerned with the initiation of voiding. Voiding may also be initiated by urine flowing across the urethral mucosa {the urethrodetrusor facilitative reflex); this reflex is normally concerned with the continuation of voiding once initiated Route Name Perineobulbar detrusor facilitative reflex

Detrusodetrusor facilitative reflex

Activating stimulus

Efferent

Location

Lateral reticulospinal tracts and pelvic nerves

Medulla to sacral micturition reflex centre

Lateral reticulospinal tracts and pelvic nerves

Rostral pons to sacral micturition reflex centre

Afferent

Relaxation of perineal Pudendal nerves sacrobulbar tract and pelvic muscles associated with increase in intra-abdominal pressure Increasing detrusor Pelvic nerves and mural tension dorsal funiculus

Adapted from Mahony et al. 1977.

sensory afferents are activated (Table 2), raising the excitability of the pontine and sacral micturition centres by way of the detrusodetrusor facilitative reflex (Barrington, 1931; Mahony et al. 1977). When this facilitation exceeds a critical threshold, voluntary inhibition (for example by the perineobulbar detrusor inhibitory reflex) is required to prevent a motor discharge to the detrusor and the bladder is said to be unstable (Mahony et al. 1977). When the sacral micturition reflex centre is below this critical level, the bladder is said to be stable and a coordinated detrusor contraction does not occur without additional facilitation, for example by voluntarily relaxing the perineum and contract-

ing the lower abdominal muscles, thus activating the perineobulbar detrusor facilitative reflex. This mechanism, postulated by Muellner (1958) to explain the onset of normal micturition, is not of relevance to a discussion on nocturnal enuresis in which voiding occurs involuntarily during sleep. Similarly, the reflexes concerned with the maintenance of voiding are not considered for the same reason. Thus, voiding during sleep must arise from an excessive excitatory input to the sacral micturition centre or from an inadequate inhibitory input, and the effects of anti-enuretic agents must be to alter this balance so that the motor discharge to the detrusor from the sacral micturition reflex centre is prevented. 17-2

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PHARMACOLOGY OF ANTI-ENURETIC AGENTS Drugs are given to enuretic children either to reduce the volume of urine produced during a given period or to make the bladder hold more urine before voiding is initiated. For example, anti-diuretic hormone decreases urine production and a synthetic analogue is claimed to be of use in children previously unresponsive to the tricyclics or to the 'bell and pad' (Dimson, 1977); pituitary snuff is ineffective (Jones & Tibbetts, 1959). Most anti-enuretic drugs are given with the intention of increasing functional bladder capacity. These include the tricyclic antidepresants, the most effective and intensively studied of the drugs used. Imipramine has many pharmacological actions and it may act either centrally or peripherally to produce its effect in enuresis. The peripheral actions of imipramine and of other anti-enuretics are considered first. Peripheral actions The only relevant peripheral action would be a reduction in afferent impulses to the sacral micturition reflex centre. At a constant bladder volume this could be achieved either by a direct

local anaesthetic action so reducing afferent impulses from the bladder, or by a reduction in intramural tension within the bladder wall, for example, by a smooth muscle depressant (or anti-spasmodic action), by a cholinolytic action inhibiting detrusor contractions or by potentiation or mimicry of the effects of the hypogastric innervation. Imipramine may act by any of the above mechanisms. Its effects on these mechanisms have been studied in experiments on conscious and anaesthetized cats and the results of these investigations will be discussed pad passu with the actions of other anti-enuretic agents. Imipramine (20 mg/kg s.c.) significantly increased (P < 001) functional bladder volume of conscious cats by approximately 50 % from 34 ± 6 to 54 ± 6 ml (mean ± S.E.M. ; N = 5) (Fig. 6); voiding was induced by a constant infusion of sterile saline (0-7 ml/min) into the bladder via a chronically implanted catheter, the free end of which terminated in a Luer connector anchored to the skull. This effect on bladder volume, obtained with doses of imipramine (0-5-2 mg/kg s.c.) which on a body weight basis were approximately equivalent to 12-5-50 mg for a 7 year old child, persisted for up to 15 h and was

Imiprcimine

(2 mg/kg s.c.) 60-1

50-

E •5

3 0

10 -

I 100

1; 200 Time (min)

I 300

400

FIG. 6. The effect of imipramine (2 mg/kg s.c.) on the voiding pattern of a conscious cat; voiding was induced by continuous infusion of sterile saline into the bladder via a chronically implanted bladder catheter. Imipramine increased functional bladder capacity from approximately 25 ml to a mean of 44 ml (4 voidings).

Chemotherapy of enuresis

considered analogous to its clinical effect (Shaffer et al. 1979). Imipramine increased functional bladder volume of a group of children by a mean of 34 % (Hagglund & Parkkulainen, 1964). Cliolinolytic activity In a review by Blackwell & Currah (1973), a peripheral cholinolytic action was thought to be the most likely explanation for its observed clinical effect. This was despite findings that selective cholinolytics, such as propantheline, were ineffective in treating enuresis (Wallace & Forsyth, 1969). Since the response of the cat bladder to pelvic nerve stimulation is scarcely affected by atropine (Langley & Anderson, 1895) and imipramine possesses only weak cholinolytic activity, this was unlikely to explain the increased bladder capacity seen after imipramine in conscious cats; peripheral cholinolytic activities of atropine and scopolamine assessed on different systems were approximately 160 and 2500 times greater respectively than that of imipramine (Sigg, 1959; Rehavi et al. 1977). As expected, imipramine did not significantly affect rises in intravesical pressure to sacral ventral root stimulation (Shaffer et al. 1979); in spinal

100

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cats, imipramine (0-5 mg/kg i.v.) slightly increased intravesical pressure and potentiated responses to pelvic nerve stimulation (Sigg & Sigg, 1964). In man (Fig. 7), spontaneous bladder contractions were unaffected by imipramine (75 mg I.M.) but completely abolished by propantheline (60 mg i.v.; Diokno et al. 1972). These results, which also preclude significant muscle depressant activity, were confirmed in experiments performed on anaesthetized baboons (Brindley & Craggs, unpublished results) since their bladder, like that of man, is sensitive to atropine (Brindley & Craggs, 1975). With larger doses, for example when used as an anti-depressant, cholinolytic side-effects (e.g. mydriasis, urinary retention, dry mouth) may be present, particularly after amitriptyline. Anti-spasmodic activity Imipramine in clinically effective doses was, as described above, devoid of bladder smooth muscle depressant activity. Selective anti-spasmodics, such as flavoxate (Gururaj et al. 1975) and oxybutynin (Buttarazzi, 1977; Thompson & Lauvetz, 1976), have been advocated as antienuretics, particularly when tricyclic therapy has failed. Unfortunately, the number of trials is

:oo Bhiddcr volume (ml.)

FIG. 7. Comparison of the actions of imipramine (50 mg I.M.) and propantheline (60 mg i.v.) on intravesical bladder pressure of a patient with uncontrolled detrusor contractions. , Control; , imipramine; , propantheline. (Redrawn from Diokno et al. 1972.)

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limited and it is not possible to evaluate their usefulness. However, if proven to be effective, they are unlikely to possess the disturbing cardiotoxic side-effects of the tricyclics. Potentiation or mimicry of the effects of hypogastric stimulation The effect of imipramine on the sympathetic input to the bladder is likely to be complex because imipramine can both prevent the action of the sympathetic transmitter, noradrenaline, at a-adrenoceptors (by a-adrenoceptor blockade; Callingham, 1966) and enhance the action of noradrenaline at a- and /?-adrenoceptors (by inhibition of noradrenaline reuptake; Hertting et al. 1961). Moreover, significance of results obtained in acute animal experiments is difficult to evaluate because of poor understanding of the

role of the hypogastrics in micturition. In anaesthetized cats, hypogastric nerve stimulation usually produces an initial short-lasting increase in intravesical pressure followed by a longer lasting decrease in pressure. This initial effect was at different times in the same experiment both reduced and potentiated by imipramine (Shaffer et al. 1979); in spinal cats only potentiation was described (Sigg & Sigg, 1964). The consequence of this effect, possibly on a-adrenoceptors (Sigg & Sigg, 1964; but see de Sy et al. 1974), is difficult to interpret since it is not certain whether the rise in pressure is due to detrusor contraction, which would oppose continence, or and more likely, to contraction of the bladder neck region, which would maintain continence. Clinically, an a-adrenoceptor blocking agent was not found to be an effective anti-

fa) Control 40-

Bladder

Meatus

20-

I 2 Length (cm)

(b) Imipramine (50 mg)

80-, 60-

4020-

1 Length (cm) FIG. 8. Urethral pressure profiles from a 9 year old enuretic girl (a) before and (6) after successful treatment with imipramine (50 mg). After imipramine, peak urethral pressure increased from 46 to 85 cm water and enuresis stopped. The child remained dry after drug administration discontinued. (Redrawn from Khanna, 1976.)

Chemotherapy of enuresis

enuretic agent (Shaffer etal. 1978). The relaxation phase of the response to hypogastric nerve stimulation was consistently potentiated by imipramine (Shaffer et al. 1979). This phase is mediated by detrusor /?-adrenoceptors (de Groat & Saum, 1972; de Sy et al. 1974) and its potentiation would shift the intravesical pressure/ volume curve to the right, thus reducing the intravesical pressure at a given bladder volume and so promoting continence. In conscious cats the increase in functional bladder volume seen after imipramine was largely unaffected by hypogastric nerve transection (Craggs & Stephenson, 1979). There is some clinical evidence that imipramine affects tonus in the region of the bladder neck and proximal urethra. Thus, Khanna (1976) obtained a urethral pressure profile in a 9 year old enuretic girl before and after imipramine (50 mg) and found successful treatment to be associated with an increase in the peak pressure of from 46 to 84 cm H2O (Fig. 8). There was no relapse on withdrawing therapy but, unfortunately, Khanna does not describe the urethral pressure profile taken at this time. In the absence of simultaneous recordings of intravesical pressure, this finding is not easy to interpret but was taken as evidence that imipramine increased tone in the bladder neck/proximal urethra. Similar conclusions, but from voiding cystourethrograms, were drawn from the observation that imipramine decreased bladder neck urethral diameter during voiding in 15 of 29 successfully treated children compared with 9 of 27 unsuccessfully treated children in a doubleblind placebo controlled trial (Mahony et al. 1973). Clearly a reduction in bladder neck urethral diameter (increased internal sphincter tone) was not a consistent feature of successful imipramine therapy. Ephedrine, a sympathomimetic amine which activates a- and y?-adrenoceptors both directly and indirectly by releasing noradrenaline, significantly reduced the number of wet nights in a population of enuretics, but it was less effective than imipramine (General Practitioner Research Group, 1970). Its mode of action is presumably to mimic the effects of hypogastric nerve stimulation and after large doses even urinary retention can occur (Boston, 1928; Glidden & Di Bonna, 1977). Lake (1975) quotes an instance of alprenolol

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(a /?-adrenoceptor blocking agent) being given to a 24 year old female with a long history of enuresis. The drug was prescribed for the symptomatic control of thyrotoxicosis, but surprisingly the enuresis was also controlled as long as therapy was maintained. The effect of alprenolol was attributed to a reduced depth of sleep. Local anaesthetic action The possibility that imipramine might reduce sensory afferent activity by a direct local anaesthetic action was excluded in experiments on anaesthetized cats. Thus, imipramine lacked effect on the phasic and tonic increases in sacral dorsal root activity recorded during bladder filling and from the full bladder respectively (Shaffer et al. 1979). The experiments in conscious cats described earlier also excluded a local anaesthetic action of urinary imipramine on the bladder mucosa as causal (von Harrer, 1961), since frequent voiding resulting from the infusion of saline into the bladder prevented the accumulation of imipramine (and its metabolites) within the bladder lumen. It is unlikely on the basis of the above findings that the one peripheral action of imipramine to be identified (potentiation of the relaxation phase to hypogastric nerve stimulation) would be sufficient to account for the marked increase in functional bladder volume, particularly since the effect was observed after hypogastric nerve transection. The possibility remains, however, that imipramine might be acting on noradrenaline released by local bladder reflexes, an action which still persists after nerve transection. Central actions The increase in functional bladder volume produced by imipramine in conscious cats was observed irrespective of whether the cat was awake or asleep and therefore could not be attributed to an action of imipramine on vigilance or on sleep states. There was no association between the anti-enuretic activity of imipramine and its effect on the sleep states of enuretic children (Kales et al. 1977). Evidence for such an action was thought unconvincing by Blackwell & Currah (1973), the more so since imipramine reduced rapid eye-movement sleep (Oswald, 1968), a sleep state in which enuresis is not

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prevalent (Ritvo et al. 1969; Kales et al. 1977). Nor could the effect of imipramine be attributed to an anti-diuresis (von Harrer, 1961) since, in cat experiments, bladder filling was determined primarily by the saline infusion rather than the rate of urine production. Within the central nervous system there are many sites at which imipramine may exert important inhibitory influences on the bladder (Ruch, 1960). While the relevant site has yet to be identified, preliminary experiments indicate that a central action of imipramine profoundly affects reflex contractions of the bladder evoked by stimulation of pelvic nerve afferents in cerveau isole cats. The possible usefulness of other centrally acting drugs in enuresis (e.g. dexamphetamine) has been excellently reviewed by Blackwell & Currah (1973). In cats, lesions of the medial amygdala disrupt passive avoidance behaviour and also decrease the micturition threshold (Edvardsen & Ursin, 1968; Edvardsen, 1972). The functional relationship between passive avoidance and inhibition of micturition is obvious in the conditioning therapy of enuresis (bell and pad). Too much emphasis should not be placed on this relation, as there is no agreement among psychiatrists of consistent or typical emotional changes in enuretic children apart from those which might be considered secondary to their condition. Thus, Douglas (1973), Rutter et al. (1973) and Shaffer (1973) have shown that environmental, developmental and psychiatric factions contribute, while major psychopathology is rarely involved. Nevertheless, involvement of the amygdala in emotional behaviour does have some bearing on MacKeith's (1972) concept of a sensitive learning period during the 2nd to 4th years of life during which time acquisition of nocturnal bladder control was frequent, thereafter becoming more difficult. MacKeith suggested that anxiety generated (for example, by birth of a sibling, illness, separation from mother, etc.) in the third year was often the major factor causing children's failure to acquire nocturnal bladder control before they enter the period of more difficult learning. Werry et al. (1977) recently showed that a group of enuretic children only differed from control children on a battery of behavioural tests in that they were significantly more anxious. However, in this last study imipramine significantly decreased the

frequency of wetting but without affecting the anxiety ratings. Interestingly, the anxiolytics, diazepam and chlordiazepoxide, have been reported to be effective anti-enuretic agents (Guttin, 1964; LeCompte & Orval, 1965; Kline, 1968; Salmon, 1973) and to potentiate the action of imipramine (Noack, 1964). The lack of effect in other studies of oxazepam (Salmon, 1973) and chlordiazepoxide (Werry et al. 1977) may have been due to inadequate dosage, although some reports suggest that the anxiolytics may provoke enuresis in some patients (Roy et al. 1963). The immediate effect of intravenous injection of diazepam (10 mg) in adults is a reduction in bladder capacity (Doyle & Briscoe, 1976). Clearly, further controlled studies are required before the usefulness of benzodiazepines in enuresis can be accurately assessed. CONSIDERATIONS FOR FUTURE RESEARCH Imipramine increases functional bladder capacity of children (Hagglund & Parkkulainen, 1964) and significantly retards the occurrence of nocturnal enuretic episodes, perhaps enabling the child to slumber until the lighter and later stages of sleep when awareness of sensory stimuli from the bladder would be more likely (Kales et al. 1977). The purported effectiveness of anti-spasmodics in nocturnal enuresis supports this explanation. These drugs relax the bladder by a peripheral action, presumably enabling it to accommodate the urine secreted during the night. If imipramine is effective in daytime enuresis, it would be of interest to know whether this simply reflects the reduced number of voidings in a given time (secondary to increased bladder capacity) or whether the ratio of 'wettings' to correct voidings is affected. Descriptions by older children and adults with diurnal enuresis suggests that during the day the desire to void is not felt until the onset of the evacuating bladder contraction (Yeates, 1973). Does imipramine affect this 'urgency'? The suggestion is that imipramine might further reduce sensory awareness since it was 'quite effective in relieving functional perineal discomfort, prostatic aching and urethralgia' (Diokno et al. 1972), but further information could be obtained either from enuretics or from adult psychiatric patients receiving tricyclic anti-

Chemotherapy of enuresis depressant therapy. However, this apparent diminished awareness of bladder filling may only be an epiphenomenon and alone cannot explain the increased frequency of daytime voiding in enuretics. The mechanism for this must reside within the spinal and brain stem reflex centres and the higher centres which influence these reflexes. To date, experiments to study these central mechanisms have invariably been performed in anaesthetized animals, often using electrical stimulation techniques simultaneously activating mechanisms which normally would operate sequentially. It is therefore essential that experiments which attempt to unravel the complexities of the control of bladder function be performed in conscious animals, in which cortical control is also present and with appropriate pharmacological and physiological techniques. Such investigations could endorse the use of imipramine as an investigative tool into the mechanisms underlying enuresis, as first suggested by Rutter (1973). The benzodiazepines, the clinical and pharmacological profiles of which are markedly different from those of imipramine, will be useful in this context since, and if proven to be effective anti-enuretics, their mode of action is likely to be different from that of the tricyclics. The author thanks Drs M. D. Craggs and D. V. Thomas for assistance with the cat experiments, Professor D. Shaffer for stimulating the author's interest in bladder control and enuresis and Professor E. Marley for reading the manuscript. The Bethlem Royal and Maudsley Hospitals Research Fund provided financial support. I should like to acknowledge indebtedness to authors and publishers for kind permission to reproduce Figs. 1-5, 7 and 8. REFERENCES Awad, S. A., Bruce, A. W., Carro-Ciampi, G., Downie, J. W., Lin, M. & Marks, G. S. (1974). Distribution of stand /?-adrenoceptors in human urinary bladder. British Journal of Pharmacology 50, 525-529. Barrington, F. J. F. (1931). The component reflexes of micturition in the cat. Brain 54, 177-189. Blackwell, B. & Currah, J. (1973). The psychopharmacology of nocturnal enuresis. In Bladder Control and Enuresis (ed. I. Kolvin, R. MacKeith and S. R. Meadow), pp. 231-257. SIMP Clinics in Developmental Medicine 48/49. Heinemann: London. Boston, L. N. (1928). Dysuria following ephedrine therapy. Medical Times 56, 94. Brindley, G. S. & Craggs, M. D. (1975). The effect of atropine on the urinary bladder of the baboon and of man. Journal of Physiology {London) 256, 55P.

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