The cellular basis of bladder instability

British Journal of Urology (1998), 81, 1–8

RE VI EW

The cellular basis of bladder instabilityC.H. FRY and C. WUInstitute of Urology & Nephrology, London, UK

Several areas will be addressed: much of the originalIntroductionwork was descriptive, documenting contractile proper-ties of detrusor and comparing properties betweenBladder instability is a symptomatic condition which can

have either a neurogenic or idiopathic origin. Idiopathic samples from normal and abnormal bladders. With theadvent of advanced techniques in electrophysiology,instability can be associated with several conditions, e.g.

outflow tract obstruction and the development, in several cellular biochemistry and molecular physiology, thecellular mechanisms responsible for contractile develop-of these cases, of bladder and detrusor cell hypertrophy.

The appearance of bladder instability is accompanied by ment can be described to explain such diCerences. Inaddition, the importance of tissue metabolism, and anchanges in the cell physiology of the detrusor and the

associated motor nerves. However, it remains unclear adequate blood supply, should be recognized as animportant modulator of detrusor function which maywhether such alterations are ubiquitous and are causal

in the appearance of abnormal bladder function or be the precursor of many of the observed cellularchanges.merely a secondary development.

The aim of this review is to describe changes to thecell physiology of detrusor smooth muscle in samples The generation of tension in detrusor smoothtaken from abnormal bladders. There are two advantages muscleto such an approach: first, a thorough investigation ofthe cellular basis of contractile activation will permit the A diagram of the steps involved in the generation of

active tension in detrusor smooth muscle is shown indevelopment of more specific therapeutic agents to regu-late detrusor function; second, if any functional alter- Fig. 1. Each has the possibility of being modulated and

could contribute to abnormal detrusor contractile func-ations can be documented and the cause identified, astrategy of prevention will be easier to formulate. tion. However, the pathophysiology of every step has

not been explored and only those which have beenAlthough the goal of such work is to understand thehuman condition, much experimental work has been investigated will be discussed.

1 A rise of the sarcoplasmic concentration of Ca2+ isperformed on animal models as they are easier to workwith and oCer a more homogeneous population. This the final step in generating tension. The sensitivity of

the myofibrils to Ca2+ is similar to that in other muscles,advantage has to be balanced by clear species diCerenceswhich may hinder extrapolation of these data. However, with a [Ca2+] of about 1 mmol/L required for half-

maximal activation. Ca2+ complexes with a solublework from animal models will be used here when it mayfacilitate understanding of bladder instability. Another protein, calmodulin, which through a cascade of reac-

tions activates, by phosphorylation, a portion of theproblem encountered with the literature, and thereforethe possibility of gaining a consensus opinion, is the myosin molecule and thus allows interaction of actin

and myosin, with the consumption of ATP.spectrum of bladder conditions described, both in humanand animal models; some are chosen on a primary basis 2 Sarcoplasmic Ca2+ originates from an intracellular

store, the sarcoplasmic reticulum (SR). Calcium is storedof proven urodynamic instability, others on the presenceof outflow tract obstruction with or without instability in the SR lumen via a powerful ATP-dependent Ca pump,

transporting Ca against a concentration gradient. Ca2+and/or hypertrophy. Therefore, there has been noattempt to deal solely with a particular symptomatic or is released from the store into the sarcoplasm via Ca2+

channels, regulated by intracellular messengers. Factorsmorphological condition but more to draw broad con-clusions from the variety of models chosen by various influencing the accumulation or release of Ca in the SR

will influence the development of tension. In these steps,authors.any interruption of the cellular metabolic processesgenerating ATP will thus compromise their eBciency.Accepted for publication 17 July 1997

1© 1998 British Journal of Urology

2 C.H. FRY and C. WU

Electriccurrent

Cell membrane

–60 mV

Myofibrils

12

7

Cell1

Cell2

6

L-typechannel

ACh ATP

Capump

Sarcoplasmicreticulum

ATP

l

Nerve

3

4

7

5 Ca2+

Ca2+

Ca2+

X+

Depoln

IP3

M3

P2X

Fig. 1. A schematic representation of the factors involved in contractile activation and relaxation of detrusor smooth muscle. The numbersrefer to the steps shown in the text.

Ca2+ release from the SR can generally be achieved in quantity of transmitter released, will determine the mag-nitude and likelihood of contractile activation.one of two ways.

3 There may be an increase in the concentration of a 6 Adjacent detrusor myocytes are poorly electricallycoupled [3] and any electrical activity would not spreaddiCusible second-messenger, linking the surface mem-

brane to intracellular Ca2+ release. In normal human easily between adjacent cells. Increasing the couplingeBciency would allow electrical activity to propagatedetrusor smooth muscle the predominant process is occu-

pation of the M3

muscarinic receptor by acetylcholine more easily in a detrusor syncitium.7 Relaxation results from a decline of the [Ca2+]

i(ACh) which initiates a chain of membrane-bound reac-tions leading to the production of inositol trisphosphate towards resting values. Little is known about this process

in detrusor, but it is presumed that the bulk is sequestered(IP3

) [2]. Modification of the sensitivity or gain of thissystem will aCect greatly the release of intracellular Ca2+. by the SR. However, some transmembrane Ca2+ flux

probably occurs during the resting phase by mechanisms4 A rise of the [Ca2+] in the vicinity of the SR stimulatesfurther Ca2+ release. This process of Ca2+-induced Ca2+- discussed below.release (CICR) is generally, but not always, triggered bya flux of Ca2+ across the surface membrane. In detrusor, Blood flow and detrusor metabolismthis is probably mediated by extracellular ATP whichbinds to a purinergic receptor and opens a non-specific Measurement of the blood flow and metabolic functions

of detrusor have been investigated in animal and humancation channel, X+ . The resultant depolarization canopen L-type Ca2+ channels and initiate Ca2+ influx. In bladders, including the influence that filling and outflow

tract obstruction may have. Blood flow is reduced duringdetrusor from several small animals, this process existsin parallel with the muscarinic pathway; its role in both bladder filling and spontaneous contractions, par-

ticularly in the obstructed bladder [4,5] where hypertro-human detrusor is discussed below.5 Variation in the electrical properties, number and phy would be expected to occur, and is accompanied by

a fall of tissue PO2

[5]. That this is suBcient to alterdistribution of excitatory nerves to the detrusor, or the

THE CELLULAR BASIS OF BL ADDER INSTABIL ITY 3

tissue metabolism was shown by the concomitant detrusor with short (∏100 ms) tetanic electrical pulses.This yields information about the modulation of pre-reduction of tissue aerobic metabolism [6] and acidosis

[7], explicable by the depletion of high-energy phos- synaptic function, including identification of particularneurotransmitters released or changes to the excitabilityphates and lactate accumulation. A characteristic of

detrusor smooth muscle is that intracellular acidosis and relative number of motor nerves;(ii) Direct muscle stimulation, with longer pulsesincreases its contractility [8], further enhancing ATP

utilization and sending the tissue into a vicious circle (>500 ms) in the presence of a neurotoxin, by theaddition of neurotransmitters or other agonists, or byof decline.

The eCects of hypoxia on contractile function are depolarization with a raised extracellular [K+]. Thisyields details about post-synaptic eBcacy of neuro-rapidly reversible [9], but because ischaemia produces

more long-lasting eCects, then additional actions are transmitters and detrusor contractility and excitability.Several altered contractile properties have beenpresumably exerted on smooth muscle during periods of

low blood flow [10]. It may thus be concluded that reported and some have been the subject of previousreviews [13,14]. However, these changes are not univer-maintained changes to the cellular functions of detrusor

develop after ischaemic conditions that may be experi- sally seen and their significance in the generation ofabnormal bladder behaviour such as instability is notenced by the bladder, and which should be amenable to

investigation by in vitro techniques. always clear.

Contractile responses of detrusor Reduced contractility and acetylcholine supersensitivity

A decrease in the absolute contractility of detrusor isVisco-elastic properties of detrusor

very diBcult to show as it would require not onlymeasurement of contractile strength in a preparation ofBefore considering the cellular properties of detrusor it

must be remembered that in vitro measurements record known dimensions, but also accurate knowledge of theproportion of muscle and the alignment of contractilechanges of tension within the muscle preparation, but

the urologist generally measures changes of luminal elements in the same specimen. The estimation of absol-ute muscle contractility will probably demand recordingspressure. The translation of muscle force to luminal

pressure will occur through the generation of wall from isolated, individual detrusor cells, a feat yet to beachieved. However, it has been observed that nerve-tension in the bladder, according to Laplace’s Law and,

moreover, the temporal and absolute quantitative mediated contractions are reduced compared with thoseelicited by direct muscle stimulation in samples fromrelationship will depend also upon the visco-elastic

properties of bladder tissue as a whole. Therefore, the obstructed and idiopathically unstable bladders. Often,but not always, this is associated with an increasedmagnitude of luminal pressure changes will be aCected

not only by muscle contractility but also by luminal sensitivity to ACh [13,15]. It has been proposed thatthese phenomena develop after denervation of thedimensions, the extent and nature of extramuscular

tissue, and fibre orientation. For example, the increased detrusor [13], caused for example by tissue hypoxiawhich accompanies the detrusor hypertrophy associateddeposition of collagen has been suggested to contribute

to the resting low compliance of some bladders [11] and with outflow tract obstruction. Whether these changesrepresent causal progenitors of instability is unknown.could amplify the magnitude of unstable active contrac-

tions. One study has attempted to compare the visco-elastic properties of human detrusor strips from normal

Spontaneous activityand low-compliance bladders, but no diCerences werefound [12]. However, this study lacked the resolving This is another variable phenomenon which has been

reported to have a higher incidence in preparations fromability required to determine accurately time-dependenttension changes of the order of seconds when detrusor unstable bladders [15]. It is relatively unaCected by

neurotoxins, e.g. tetrodotoxin, or atropine, suggestingrelaxes and contracts. Therefore, it remains unclearwhether changes to the visco-elastic characteristics of that it originates in the detrusor muscle itself. Figure 2

shows that this may occur also in the single cell. Inthe bladder wall will accentuate detrusor mechanicalactivity into measurable unstable contractions. freshly isolated detrusor myocytes, spontaneous oscil-

lations of the intracellular [Ca2+] can be elicited afterapplication of an agonist such as ACh or ATP, and with

Nerve-mediated and direct muscle contractionsa greater likelihood in cells from unstable bladders [16].The implication of this observation is that the regulationIn vitro, detrusor contractions can be elicited:

(i) Indirectly, by stimulating nerve terminals in the of intracellular [Ca2+] is deranged and after it has been


Fig. 2. Intracellular Ca2+ transients evokedin isolated human detrusor smooth musclescell from an unstable bladder. 10 mmol/L ofATP or carbachol were added during theperiod shown by the solid bar. Traces wereobtained from Fura-2 fluorescencemeasurements; 340/380 nm excitation,

2 min

100

10 µmol/L ATP

600

10 µmol/L carb [Ca2+]i nmol/L

37°C, 1.8 mmol/L Ca.

initially raised by the stimulus cannot be eBciently bladders, cholinergic supersensitivity and the greaterincidence of multiple intracellular Ca2+ transients inreturned and maintained at a resting level.isolated myocytes from these preparations after agonistapplication are all consistent with an increased contrac-

Atropine resistancetile sensitivity to stimulation.

Contractions resistant to atropine, but blocked by neuro-toxins, are common in detrusor from many small animals

Conclusionsbut largely absent in human tissue from normal bladders[17]. The atropine-resistant contraction is believed to be Changes to contractile function observed in muscle

samples from abnormally-functioning bladders couldneurally mediated by the release of ATP which thenbinds to a P

2Xreceptor. However, the appearance of result from relatively poor blood flow, especially when

the muscle mass enlarges to overcome an increasedatropine-resistant contractions in human tissue has beenreported in samples obtained from several bladder con- afterload. The appearance of an additional purinergic

system could exacerbate any eCects that ischaemia itselfditions [18,19]. Whether the purinergic-dependent con-traction is a pre- or post-synaptic development is has on myocyte function. A cellular scheme which may

explain abnormal contractile function will be explainedunresolved but it has been shown in human detrusormyocytes isolated from stable and unstable bladders that below, and throughout metabolic derangement will be

emphasized as a mediator of these processes. Whilstthe [Ca2+]i

increases with extracellular ATP [20].Furthermore, the magnitude of the rise, as well as its many events are speculative, they will indicate possible

experimental approaches. The variability of abnormalsensitivity to extracellular ATP, do not diCer in the twogroups. This suggests that post-synaptic sensitivity to muscle activity despite the occurrence of similar gross

changes, e.g. outflow tract obstruction, to the lowerATP is similar in myocytes from stable and unstablebladders, so that a pre-synaptic modification may have urinary tract may merely reflect the variability in meta-

bolic derangement imposed on the tissue.to be sought to explain the appearance of purinergic-dependent contractions in human detrusor.

Regulation of intracellular [Ca2+]The force-frequency relationship

Intracellular Ca2+ cyclingThe magnitude of the phasic contraction elicited bynerve-mediated electrical stimulation is dependent on The appearance of abnormal intracellular Ca2+ transi-

ents in detrusor myocytes implies dysfunction in thethe frequency of pulses in the tetanic train. Severalstudies [e.g. 15], but not all [21], using detrusor from regulation of the ion, in which the SR may be implicated.

A progressive reduction in the activity of the SR Ca-pumpunstable bladders have shown a greater eCectiveness oflow-frequency trains, suggesting an increase in the over- has been measured in detrusor obtained from obstructed

animal bladders as they pass from a compensated toall excitability of the preparation. Whether this is due toincreased excitability of the motor nerves, a larger decompensated contractile state [22]. This would hinder

the active sequestration of Ca2+ from the sarcoplasmincrease of neurotransmitter or an increase in the eCec-tiveness of the neurotransmitter to elicit a response in and tend to increase the basal [Ca2+] in this compart-

ment. Such an observation is consistent with the pres-the muscle remains to be established. The detection ofadditional neurotransmitters in muscle from unstable ence of tissue hypoxia which would reduce the


intracellular ATP content, thus leading to a reduction of elicited by repeated applications of cholinergic agonists[26]. It has been proposed that the L-type Ca2+ channelCa-pump turnover.

The release of SR Ca2+ may also be altered; the action plays a role in maintaining an adequate Ca2+ influxbetween contractions [27] and any factor which raisesof IP

3demands initial binding to an SR receptor, of

which there are several sub-types, although their Ca2+ influx by enhancing the average open-time of Ca2+channels would increase intracellular levels and contrib-diCerential properties in detrusor are unclear at present.

The Ca2+ release channel, the so-called ryanodine recep- ute to the unstable situation described above. To activatean ionic channel it is necessary to depolarize the celltor (RyR), also exists as several subtypes. In hypertro-

phied myometrium the receptor population changes from membrane over a range of potentials (activation curve),and to reactivate the channel the membrane must bean exclusive RyR

2type to a mixed RyR

2/RyR

3population

[23] and a similar observation may also be true in repolarized towards the resting potential (inactivationcurve). Any overlap of these two curves generates aunstable detrusor (Gillespie and Chambers, personal com-

munication). The significance of this shift is unknown range of potentials where the channel is partially openand a sustained current flows, a so-called ‘windowat present, but hypertrophy of the myometrium during

late pregnancy is associated with increased contractions current’. In myocytes from hypertrophied bladders therange of activation voltages is more positive, making itand improved coupling between adjacent cells.more diBcult to open the channel, but once open has alarger window current [28]. This, coupled with a slower

Ca2+ oscillations?turn-oC time (inactivation rate) of the current, wouldenhance Ca2+ influx. On the other hand, using cellsThe reduced ability to sequester Ca2+ , after initial release

by IP3

, would increase its tendency to remain in the from urodynamically-proven unstable bladders, the acti-vation curve was shifted to more negative potentials,sarcoplasm, which could then induce several secondary

events. These include a further release of Ca2+ from the thus making it easier to activate [28]. Therefore, thechannel appears to undergo fundamental modificationsSR via CICR and the possible opening of non-selective

membrane ion channels, as reported in other smooth which alter the ease by which Ca2+ can enter the cell.The L-type Ca2+ channel is composed of several sub-muscle types [24], which would depolarize the cell and

enhance Ca2+ influx through L-type Ca2+ channels. All units, each of which confer particular properties to thechannel [29]. An a

1subunit forms the actual channelthese secondary processes would be exacerbated by a

secondary direct depolarizing excitatory drive, such as a whilst a2

/d, b and c subunits modify its voltage- andtime-dependent properties. Interestingly, the abovepurinergic system. Therefore, alteration of the Ca2+-

uptake and -release system possesses considerable poten- changes in channel kinetics [28] can be accounted forby alteration of the eCectiveness or quantity of particulartial for positive feedback, after an initial stimulus, and

generates continuous cycles of Ca2+ release. subunits. In particular, the data would suggest that thecombination of a

2/d and b subunits is decreased inIntracellular Ca2+ oscillations as illustrated in Fig. 2

have been reported in many other cell types, including myocytes from hypertrophied bladders and perhapsincreased in cells from unstable bladders. This impliessmooth and cardiac muscle, neurons, oocytes, pituitary

gonadotrophs and pancreatic acinar cells. In many, a that modification of bladder function is mirrored inchanges to the molecular physiology of particular compo-common feature is the activation of both IP

3and CICR

mechanisms, as proposed above. Furthermore, it has nents of the detrusor myocyte, in this case the L-typeCa2+ channel. This oCers specific targets for markers ofbeen suggested that Ca2+ oscillations can mediate inter-

cellular communication independent of changes in mem- detrusor dysfunction and more importantly yields insightinto discrete cellular changes.brane potential, thus co-ordinating any activity of

cyclical Ca2+ release over several cells [25]. The signifi-cance of these oscillations in relation to spontaneous

Conclusionmechanical activity in detrusor from normal andunstable bladder represents an exciting future area of Derangement of the normal intracellular cycle of Ca2+

uptake and release can initiate a series of steps whichresearch.may induce cyclical variation of intracellular Ca2+ . Theparticular steps involved in this positive-feedback process

Ca2+ entry and the L-type Ca2+ channelcan be determined by investigating individual compo-nents of Ca2+ regulation and the electrophysiologicalAn important component of Ca2+ movement in the

contractile cycle is the intracellular process, although properties of detrusor, as well as using experience gainedfrom the study of other cells. The possible involvementthere must be some transmembrane flux as Ca-free

extracellular solutions eventually abolish contractions of the L-type Ca2+ current has been explored above, the


role of other electrophysiological properties will be con- depolarize the cell suBciently to open L-type Ca2+channels. Moreover, the shift of the Ca2+ channelsidered below.activation curve to more negative potentials in detrusorfrom unstable bladder [28] would suggest that Ca2+The electrophysiological properties of detrusorchannels can be opened more easily in this tissue. Thesmooth musclehypothesis that remains to be tested is that detrusorfrom patients with unstable bladders has a greater

The importance of electrophysiological phenomenatendency to generate action potentials than that fromstable bladders. If such a phenomenon is present, itThe role of electrical activity in initiating contraction in

normal human detrusor function remains equivocal. oCers an interesting opportunity to develop agentstargeted to unstable bladders.Detrusor muscle has a resting potential of about

−60 mV [27] and can generate an action potential Several other mechanisms have been proposed whichcould depolarize the detrusor myocyte suBciently toeither when electrically stimulated or occasionally

spontaneously [30]. The depolarizing phase of the open L-type Ca2+ channels. Stretch-activated channelshave been described in animal detrusor and could fulfilaction potential results from Ca2+ influx through L-type

channels. Various K+ channels are responsible for such a role [33]; these channels have be shown to beblocked by micromolar concentrations of gadoliniumrepolarization and maintenance of the resting potential

[30]. ions. Stretching of the surface membrane by immersingdetrusor in hypotonic solutions does indeed cause con-However, muscarinic agonists can generate a rise of

[Ca2+]i

independent of changes in membrane potential, traction, cell swelling and raises the [Ca2+]i, but these

eCects are unaCected by gadolinium ions (Proctor andsuggesting a dissociation between the phenomena [27].In detrusor from small animals, which possess both a Fry, unpublished data). This would suggest that stretch-

activated channels have little influence in modulatingcholinergic and purinergic excitatory drive, a muscleaction potential and excitatory junction potential detrusor activity.

An increase of [Ca2+]i

can itself trigger secondaryaccompany nerve stimulation and contractile activation[31]. L-type Ca2+ channel blockers and purinergic Ca2+ influx by activating additional channels. Such a

phenomenon has been reported in several other smoothreceptor antagonists abolish the electrical responses,but only partially attenuate the contraction, and it has muscles, where a spontaneous transient inward current,

probably carried by Cl−, is activated by elevated [Ca2+also been suggested that the cholinergic drive is notaccompanied by changes to the membrane potential ]

i[34]. The presence of such channels remains to be

demonstrated in detrusor smooth muscle.[31]. In normal human detrusor the virtual completedependence on a cholinergic mode of activation impliesthat the generation of tension is not accompanied by

Cell-to-cell couplingelectrical activity.

Adjacent detrusor myocytes are considered to be poorly,but significantly, electrically coupled, a view supported

Other factors aCecting transmembrane Ca2+ entryby the paucity of gap junctions in electron micrographs[3,35]. During obstruction, the picture becomes con-Despite the above observations, a role for electrophysio-

logical phenomena in contractile function of the human fused. An increase in areas of close cell apposition hasbeen reported [35] but the only direct estimate of cell-bladder cannot be eliminated, especially under pathologi-

cal situations. The role of the L-type Ca2+ channel in to-cell electric current spread in an animal model ofobstruction, albeit without associated instability, wouldre-filling the intracellular store, and modifying its kin-

etics, has been considered above. Elucidating those fac- suggest that intercellular coupling is worse [36]. Notonly does the direction of any change need to betors which depolarize the membrane is the key to

understanding the role of L-type Ca2+ channels in this evaluated in human detrusor, but the gap-junctionresistance needs to be measured. Equivalent estimates incontext and several are considered.

The appearance of purinergic-dependent contractions myocardium, which is well-coupled electrically, showthat conditions required for re-entrant arrhythmias arein detrusor from unstable bladders suggests that in such

tissue electrical activity could well accompany contrac- achieved critically when the gap-junction resistanceincreases above a particular value [37]. If electricaltile activation. Extracellular ATP can generate an

inward current [32] and in both animal and human phenomena do become important in detrusor fromabnormally functioning bladders, the ease which theydetrusor myocytes there is an increase of the [Ca2+]

i[20]. The [Ca2+] transient can be blocked by Ca2+ can propagate from cell-to-cell must be evaluated to

decide whether re-entrant type phenomena can exist.channel antagonists, suggesting that ATP is able to


pH on human and ferret detrusor muscle function. J PhysiolConclusions 1991; 432: 1–21

9 Thomas PJ, Fry CH. The eCects of cellular hypoxia onIt is possible to document several changes to the cellcontraction and extracellular ion accumulation in isolatedphysiology of the detrusor myocyte obtained from abnor-human detrusor smooth muscle. J Urol 1996; 155: 726–31mally-functioning bladders. The initiator of these pro-

10 van Arlesdan KN, Wein AJ, Levin RM. The contractile andcesses may well be tissue ischaemia and the abnormal

metabolic eCects of acute ischaemia on the rabbit urinarymetabolic demands it places on the tissue. Contractile bladder. J Urol 1983; 130: 180–2changes include several which are consistent with a 11 Ewalt DH, Howard PS, Blyth B et al. Is lamina propriapartial denervation of the detrusor, i.e. the appearance matrix responsible for normal bladder compliance? J Urolof an accessory purinergic excitatory system and defects 1992; 148, 544–9

12 German K, Bedwani J, Davies J, Brading AF, Stephenson T.of Ca2+ regulation in the myocyte. The last two phen-An assessment of the contribution of visco-elastic factorsomena may well combine to induce a positive-feedbackin the aetiology of poor compliance in the humanprocess whereby ineCective Ca2+ regulation triggersneuropathic bladder. Br J Urol 1994; 74: 744–8electrophysiological changes which then generate cycli-

13 Brading AF, Turner WH. The unstable bladder: towards acal alteration of intracellular Ca2+. Elucidation of thesecommon mechanism. Br J Urol 1994; 73: 3–8steps provides a strategy to develop agents which will

14 Chapple CR, Smith D. The pathophysiological changes inbreak this feedback. The additional hypothesis that

the bladder obstructed by benign prostatic hyperplasia. Brimproved intercellular electrical coupling in detrusor J Urol 1994; 73: 117–23from unstable bladders allows any electrical activity to 15 Kinder R, Mundy AR. Pathophysiology of idiopathicspread more readily would exacerbate the consequences detrusor instability and detrusor hyper-reflexia. An in vitroof the above cellular changes, but needs to be evaluated study of human detrusor muscle. Br J Urol 1987;

60: 509–15critically.16 Wu C, Sui G, Fry CH. Spontaneous action potential and

intracellular Ca2+ transients in human detrusor smoothAcknowledgements muscle cells isolated from stable and unstable bladders. Br

J Urol 1997; 80: 164The support of the Wellcome Trust, Action Research, St17 Sibley GNA. A comparison of spontaneous and nerve-Peter’s Research Trust and Pfizer plc is gratefully

mediated activity in bladder muscle from man, pig andacknowledged. We thank Jonathan Masters with whom

rabbit. J Physiol 1984; 354: 431–43we had useful discussions. 18 Palea S, Artibani W, Ostardo E, Trist DG, Pietra C. Evidence

for purinergic neurotransmission in human urinary bladderaCected by interstitial cystitis. J Urol 1993; 150: 2007–12

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The cellular basis of bladder instability