The cellular basis of bladder instability


Introduction

Bladder instability is a symptomatic condition which can have either a neurogenic or idiopathic origin. Idiopathic instability can be associated with several conditions, e.g. outflow tract obstruction and the development, in several of these cases, of bladder and detrusor cell hypertrophy. The appearance of bladder instability is accompanied by changes in the cell physiology of the detrusor and the associated motor nerves. However, it remains unclear whether such alterations are ubiquitous and are causal in the appearance of abnormal bladder function or merely a secondary development.
The aim of this review is to describe changes to the cell physiology of detrusor smooth muscle in samples taken from abnormal bladders. There are two advantages to such an approach: first, a thorough investigation of the cellular basis of contractile activation will permit the development of more specific therapeutic agents to regulate detrusor function; second, if any functional alterations can be documented and the cause identified, a strategy of prevention will be easier to formulate.
Although the goal of such work is to understand the human condition, much experimental work has been performed on animal models as they are easier to work with and offer a more homogeneous population. This advantage has to be balanced by clear species differences which may hinder extrapolation of these data. However, work from animal models will be used here when it may facilitate understanding of bladder instability. Another problem encountered with the literature, and therefore the possibility of gaining a consensus opinion, is the spectrum of bladder conditions described, both in human and animal models; some are chosen on a primary basis of proven urodynamic instability, others on the presence of outflow tract obstruction with or without instability and/or hypertrophy. Therefore, there has been no attempt to deal solely with a particular symptomatic or morphological condition but more to draw broad conclusions from the variety of models chosen by various authors.
Several areas will be addressed: much of the original work was descriptive, documenting contractile properties of detrusor and comparing properties between samples from normal and abnormal bladders. With the advent of advanced techniques in electrophysiology, cellular biochemistry and molecular physiology, the cellular mechanisms responsible for contractile development can be described to explain such differences. In addition, the importance of tissue metabolism, and an adequate blood supply, should be recognized as an important modulator of detrusor function which may be the precursor of many of the observed cellular changes.

The generation of tension in detrusor smooth muscle

Factors involved in contractile activation and relaxation of detrusor smooth muscle schematic
Fig. 1. A schematic representation of the factors involved in contractile activation and relaxation of detrusor smooth muscle. The numbers refer to the steps shown in the text.
A diagram of the steps involved in the generation of active tension in detrusor smooth muscle is shown in Fig. 1. Each has the possibility of being modulated and could contribute to abnormal detrusor contractile function [1]. However, the pathophysiology of every step has not been explored and only those which have been investigated will be discussed.
  1. A rise of the sarcoplasmic concentration of Ca2+ is the final step in generating tension. The sensitivity of the myofibrils to Ca2+ is similar to that in other muscles, with a [Ca2+] of about 1 µmol/L required for halfmaximal activation. Ca2+ complexes with a soluble protein, calmodulin, which through a cascade of reactions activates, by phosphorylation, a portion of the myosin molecule and thus allows interaction of actin and myosin, with the consumption of ATP.
  2. Sarcoplasmic Ca2+ originates from an intracellular store, the sarcoplasmic reticulum (SR). Calcium is stored in the SR lumen via a powerful ATP-dependent Ca pump, transporting Ca against a concentration gradient. Ca2+ is released from the store into the sarcoplasm via Ca2+ channels, regulated by intracellular messengers. Factors influencing the accumulation or release of Ca in the SR will influence the development of tension. In these steps, any interruption of the cellular metabolic processes generating ATP will thus compromise their efficiency. Ca2+ release from the SR can generally be achieved in one of two ways.
  3. There may be an increase in the concentration of a diffusible second-messenger, linking the surface membrane to intracellular Ca2+ release. In normal human detrusor smooth muscle the predominant process is occupation of the M muscarinic receptor by acetylcholine (ACh) which initiates a chain of membrane-bound reactions leading to the production of inositol trisphosphate (IP3) [2]. Modification of the sensitivity or gain of this system will affect greatly the release of intracellular Ca2+.
  4. A rise of the [Ca2+] in the vicinity of the SR stimulates further Ca2+ release. This process of Ca2+ – induced Ca2+ -release (CICR) is generally, but not always, triggered by a flux of Ca2+ across the surface membrane. In detrusor, this is probably mediated by extracellular ATP which binds to a purinergic receptor and opens a non-specific cation channel, X+ . The resultant depolarization can open L-type Ca2+ channels and initiate Ca2+ influx. In detrusor from several small animals, this process exists in parallel with the muscarinic pathway; its role in human detrusor is discussed below.
  5. Variation in the electrical properties, number and distribution of excitatory nerves to the detrusor, or the quantity of transmitter released, will determine the magnitude and likelihood of contractile activation.
  6. Adjacent detrusor myocytes are poorly electrically coupled [3] and any electrical activity would not spread easily between adjacent cells. Increasing the coupling efficiency would allow electrical activity to propagate more easily in a detrusor syncitium.
  7. Relaxation results from a decline of the [Ca2+]i towards resting values. Little is known about this process in detrusor, but it is presumed that the bulk is sequestered by the SR. However, some transmembrane Ca2+ flux probably occurs during the resting phase by mechanisms discussed below.

Blood flow and detrusor metabolism

Measurement of the blood flow and metabolic functions of detrusor have been investigated in animal and human bladders, including the influence that filling and outflow tract obstruction may have. Blood flow is reduced during both bladder filling and spontaneous contractions, particularly in the obstructed bladder [3][4][5] where hypertrophy would be expected to occur, and is accompanied by a fall of tissue PO2 [5]. That this is sufficient to alter tissue metabolism was shown by the concomitant reduction of tissue aerobic metabolism [6] and acidosis [7], explicable by the depletion of high-energy phosphates and lactate accumulation. A characteristic of detrusor smooth muscle is that intracellular acidosis increases its contractility [8], further enhancing ATP utilization and sending the tissue into a vicious circle of decline.
The effects of hypoxia on contractile function are rapidly reversible [9], but because ischaemia produces more long-lasting effects, then additional actions are presumably exerted on smooth muscle during periods of low blood flow [10]. It may thus be concluded that maintained changes to the cellular functions of detrusor develop after ischaemic conditions that may be experienced by the bladder, and which should be amenable to investigation by in vitro techniques.

Contractile responses of detrusor

Visco-elastic properties of detrusor

Before considering the cellular properties of detrusor it must be remembered that in vitro measurements record changes of tension within the muscle preparation, but the urologist generally measures changes of luminal pressure. The translation of muscle force to luminal pressure will occur through the generation of wall tension in the bladder, according to Laplace’s Law and, moreover, the temporal and absolute quantitative relationship will depend also upon the visco-elastic properties of bladder tissue as a whole. Therefore, the magnitude of luminal pressure changes will be affected not only by muscle contractility but also by luminal dimensions, the extent and nature of extramuscular tissue, and fibre orientation. For example, the increased deposition of collagen has been suggested to contribute to the resting low compliance of some bladders [11] and could amplify the magnitude of unstable active contractions. One study has attempted to compare the viscoelastic properties of human detrusor strips from normal and low-compliance bladders, but no differences were found [12]. However, this study lacked the resolving ability required to determine accurately time-dependent tension changes of the order of seconds when detrusor relaxes and contracts. Therefore, it remains unclear whether changes to the visco-elastic characteristics of the bladder wall will accentuate detrusor mechanical activity into measurable unstable contractions.

Nerve-mediated and direct muscle contractions

In vitro, detrusor contractions can be elicited:
(i) Indirectly, by stimulating nerve terminals in the detrusor with short (≤100 µs) tetanic electrical pulses. This yields information about the modulation of presynaptic function, including identification of particular neurotransmitters released or changes to the excitability and relative number of motor nerves; (ii) Direct muscle stimulation, with longer pulses (>500 µs) in the presence of a neurotoxin, by the addition of neurotransmitters or other agonists, or by depolarization with a raised extracellular [K+]. This yields details about post-synaptic efficacy of neurotransmitters and detrusor contractility and excitability.
Several altered contractile properties have been reported and some have been the subject of previous reviews [13], [14]. However, these changes are not universally seen and their significance in the generation of abnormal bladder behaviour such as instability is not always clear.

Reduced contractility and acetylcholine supersensitivity

A decrease in the absolute contractility of detrusor is very difficult to show as it would require not only measurement of contractile strength in a preparation of known dimensions, but also accurate knowledge of the proportion of muscle and the alignment of contractile elements in the same specimen. The estimation of absolute muscle contractility will probably demand recordings from isolated, individual detrusor cells, a feat yet to be achieved. However, it has been observed that nerve-mediated contractions are reduced compared with those elicited by direct muscle stimulation in samples from obstructed and idiopathically unstable bladders. Often, but not always, this is associated with an increased sensitivity to ACh [13], [15]. It has been proposed that these phenomena develop after denervation of the detrusor [13], caused for example by tissue hypoxia which accompanies the detrusor hypertrophy associated with outflow tract obstruction. Whether these changes represent causal progenitors of instability is unknown.

Spontaneous activity

This is another variable phenomenon which has been reported to have a higher incidence in preparations from unstable bladders [15]. It is relatively unaffected by neurotoxins, e.g. tetrodotoxin, or atropine, suggesting that it originates in the detrusor muscle itself. Figure 2 shows that this may occur also in the single cell. In freshly isolated detrusor myocytes, spontaneous oscillations of the intracellular [Ca2+] can be elicited after application of an agonist such as ACh or ATP, and with a greater likelihood in cells from unstable bladders [16]. The implication of this observation is that the regulation of intracellular [Ca2+] is deranged and after it has been initially raised by the stimulus cannot be efficiently returned and maintained at a resting level.
Intracellular Calcium ion transients from an unstable bladder
Fig. 2. Intracellular Calcium ion transients evoked in isolated human detrusor smooth muscles cell from an unstable bladder. 10 µmol/L of ATP or carbachol were added during the period shown by the solid bar. Traces were obtained from Fura-2 fluorescence measurements; 340/380 nm excitation, 37°C, 1.8 µmol/L Ca.

Atropine resistance

Contractions resistant to atropine, but blocked by neurotoxins, are common in detrusor from many small animals but largely absent in human tissue from normal bladders [17]. The atropine-resistant contraction is believed to be neurally mediated by the release of ATP which then binds to a P2X receptor. However, the appearance of atropine-resistant contractions in human tissue has been reported in samples obtained from several bladder conditions [18], [19]. Whether the purinergic-dependent contraction is a pre- or post-synaptic development is unresolved but it has been shown in human detrusor myocytes isolated from stable and unstable bladders that the [Ca2+]i increases with extracellular ATP [20]. Furthermore, the magnitude of the rise, as well as its sensitivity to extracellular ATP, do not differ in the two groups. This suggests that post-synaptic sensitivity to ATP is similar in myocytes from stable and unstable bladders, so that a pre-synaptic modification may have to be sought to explain the appearance of purinergic-dependent contractions in human detrusor.

The force-frequency relationship

The magnitude of the phasic contraction elicited by nerve-mediated electrical stimulation is dependent on the frequency of pulses in the tetanic train. Several studies e.g. [15], but not all [21], using detrusor from unstable bladders have shown a greater effectiveness of low-frequency trains, suggesting an increase in the overall excitability of the preparation. Whether this is due to increased excitability of the motor nerves, a larger increase of neurotransmitter or an increase in the effectiveness of the neurotransmitter to elicit a response in the muscle remains to be established. The detection of additional neurotransmitters in muscle from unstable bladders, cholinergic supersensitivity and the greater incidence of multiple intracellular Ca2+ transients in isolated myocytes from these preparations after agonist application are all consistent with an increased contractile sensitivity to stimulation.

Conclusions

Changes to contractile function observed in muscle samples from abnormally-functioning bladders could result from relatively poor blood flow, especially when the muscle mass enlarges to overcome an increased afterload. The appearance of an additional purinergic system could exacerbate any effects that ischaemia itself has on myocyte function. A cellular scheme which may explain abnormal contractile function will be explained below, and throughout metabolic derangement will be emphasized as a mediator of these processes. Whilst many events are speculative, they will indicate possible experimental approaches. The variability of abnormal muscle activity despite the occurrence of similar gross changes, e.g. outflow tract obstruction, to the lower urinary tract may merely reflect the variability in metabolic derangement imposed on the tissue.

Regulation of intracellular [Ca2+]

Intracellular Ca2+ cycling

The appearance of abnormal intracellular Ca2+ transients in detrusor myocytes implies dysfunction in the regulation of the ion, in which the SR may be implicated. A progressive reduction in the activity of the SR Ca-pump has been measured in detrusor obtained from obstructed animal bladders as they pass from a compensated to decompensated contractile state [22]. This would hinder the active sequestration of Ca2+ from the sarcoplasm and tend to increase the basal [Ca2+] in this compartment. Such an observation is consistent with the presence of tissue hypoxia which would reduce the intracellular ATP content, thus leading to a reduction of Ca-pump turnover.
The release of SR Ca2+ may also be altered; the action of IP demands initial binding to an SR receptor, of which there are several sub-types, although their differential properties in detrusor are unclear at present. The Ca2+ release channel, the so-called ryanodine receptor (RyR), also exists as several subtypes. In hypertrophied myometrium the receptor population changes from an exclusive RyR type to a mixed RyR /RyR population [23] and a similar observation may also be true in unstable detrusor (Gillespie and Chambers, personal communication). The significance of this shift is unknown at present, but hypertrophy of the myometrium during late pregnancy is associated with increased contractions and improved coupling between adjacent cells.

Ca2+ oscillations?

The reduced ability to sequester Ca2+ , after initial release by IP , would increase its tendency to remain in the sarcoplasm, which could then induce several secondary events. These include a further release of Ca2+ from the SR via CICR and the possible opening of non-selective membrane ion channels, as reported in other smooth muscle types [24], which would depolarize the cell and enhance Ca2+ influx through L-type Ca2+ channels. All these secondary processes would be exacerbated by a secondary direct depolarizing excitatory drive, such as a purinergic system. Therefore, alteration of the Ca2+ – uptake and -release system possesses considerable potential for positive feedback, after an initial stimulus, and generates continuous cycles of Ca2+ release.
Intracellular Ca2+ oscillations as illustrated in Fig. 2 have been reported in many other cell types, including smooth and cardiac muscle, neurons, oocytes, pituitary gonadotrophs and pancreatic acinar cells. In many, a common feature is the activation of both IP and CICR mechanisms, as proposed above. Furthermore, it has been suggested that Ca2+ oscillations can mediate intercellular communication independent of changes in membrane potential, thus co-ordinating any activity of cyclical Ca2+ release over several cells [25]. The significance of these oscillations in relation to spontaneous mechanical activity in detrusor from normal and unstable bladder represents an exciting future area of research.

Ca2+ entry and the L-type Ca2+ channel

An important component of Ca2+ movement in the contractile cycle is the intracellular process, although there must be some transmembrane flux as Ca-free extracellular solutions eventually abolish contractions elicited by repeated applications of cholinergic agonists [26]. It has been proposed that the L-type Ca2+ channel plays a role in maintaining an adequate Ca2+ influx between contractions [27] and any factor which raises Ca2+ influx by enhancing the average open-time of Ca2+ channels would increase intracellular levels and contribute to the unstable situation described above. To activate an ionic channel it is necessary to depolarize the cell membrane over a range of potentials (activation curve), and to reactivate the channel the membrane must be repolarized towards the resting potential (inactivation curve). Any overlap of these two curves generates a range of potentials where the channel is partially open and a sustained current flows, a so-called “window current”. In myocytes from hypertrophied bladders the range of activation voltages is more positive, making it more difficult to open the channel, but once open has a larger window current [28]. This, coupled with a slower turn-off time (inactivation rate) of the current, would enhance Ca2+ influx. On the other hand, using cells from urodynamically-proven unstable bladders, the activation curve was shifted to more negative potentials, thus making it easier to activate [28]. Therefore, the channel appears to undergo fundamental modifications which alter the ease by which Ca2+ can enter the cell.
The L-type Ca2+ channel is composed of several subunits, each of which confer particular properties to the channel [29]. An α1 subunit forms the actual channel whilst α2/δ, β and γ subunits modify its voltage – and time-dependent properties. Interestingly, the above changes in channel kinetics [28] can be accounted for by alteration of the effectiveness or quantity of particular subunits. In particular, the data would suggest that the combination of α2/δ and β subunits is decreased in myocytes from hypertrophied bladders and perhaps increased in cells from unstable bladders. This implies that modification of bladder function is mirrored in changes to the molecular physiology of particular components of the detrusor myocyte, in this case the L-type Ca2+ channel. This offers specific targets for markers of detrusor dysfunction and more importantly yields insight into discrete cellular changes.

Conclusion

Derangement of the normal intracellular cycle of Ca2+ uptake and release can initiate a series of steps which may induce cyclical variation of intracellular Ca2+ . The particular steps involved in this positive-feedback process can be determined by investigating individual components of Ca2+ regulation and the electrophysiological properties of detrusor, as well as using experience gained from the study of other cells. The possible involvement of the L-type Ca2+ current has been explored above, the role of other electrophysiological properties will be considered below.

The electrophysiological properties of detrusor smooth muscle

The importance of electrophysiological phenomena

The role of electrical activity in initiating contraction in normal human detrusor function remains equivocal. Detrusor muscle has a resting potential of about -60 mV [27] and can generate an action potential either when electrically stimulated or occasionally spontaneously [30]. The depolarizing phase of the action potential results from Ca2+ influx through L-type channels. Various K+ channels are responsible for repolarization and maintenance of the resting potential [30].
However, muscarinic agonists can generate a rise of [Ca2+]i independent of changes in membrane potential, suggesting a dissociation between the phenomena [27]. In detrusor from small animals, which possess both a cholinergic and purinergic excitatory drive, a muscle action potential and excitatory junction potential accompany nerve stimulation and contractile activation [31]. L-type Ca2+ channel blockers and purinergic receptor antagonists abolish the electrical responses, but only partially attenuate the contraction, and it has also been suggested that the cholinergic drive is not accompanied by changes to the membrane potential [31]. In normal human detrusor the virtual complete dependence on a cholinergic mode of activation implies that the generation of tension is not accompanied by electrical activity.

Other factors affecting transmembrane Ca2+ entry

Despite the above observations, a role for electrophysiological phenomena in contractile function of the human bladder cannot be eliminated, especially under pathological situations. The role of the L-type Ca2+ channel in re-filling the intracellular store, and modifying its kinetics, has been considered above. Elucidating those factors which depolarize the membrane is the key to understanding the role of L-type Ca2+ channels in this context and several are considered.
The appearance of purinergic-dependent contractions in detrusor from unstable bladders suggests that in such tissue electrical activity could well accompany contractile activation. Extracellular ATP can generate an inward current [32] and in both animal and human detrusor myocytes there is an increase of the [Ca2+]i, [20]. The [Ca2+] transient can be blocked by Ca2+ channel antagonists, suggesting that ATP is able to depolarize the cell sufficiently to open L-type Ca2+ channels. Moreover, the shift of the Ca2+ channel activation curve to more negative potentials in detrusor from unstable bladder [28] would suggest that Ca2+ channels can be opened more easily in this tissue. The hypothesis that remains to be tested is that detrusor from patients with unstable bladders has a greater tendency to generate action potentials than that from stable bladders. If such a phenomenon is present, it offers an interesting opportunity to develop agents targeted to unstable bladders.
Several other mechanisms have been proposed which could depolarize the detrusor myocyte sufficiently to open L-type Ca2+ channels. Stretch-activated channels have been described in animal detrusor and could fulfil such a role [33]; these channels have be shown to be blocked by micromolar concentrations of gadolinium ions. Stretching of the surface membrane by immersing detrusor in hypotonic solutions does indeed cause contraction, cell swelling and raises the [Ca2+]i, but these effects are unaffected by gadolinium ions (Proctor and Fry, unpublished data). This would suggest that stretch-activated channels have little influence in modulating detrusor activity.
An increase of [Ca2+]i can itself trigger secondary Ca2+ influx by activating additional channels. Such a phenomenon has been reported in several other smooth muscles, where a spontaneous transient inward current, probably carried by Cl-, is activated by elevated [Ca2+]i [34]. The presence of such channels remains to be demonstrated in detrusor smooth muscle.

Cell-to-cell coupling

Adjacent detrusor myocytes are considered to be poorly, but significantly, electrically coupled, a view supported by the paucity of gap junctions in electron micrographs [3][35]. During obstruction, the picture becomes confused. An increase in areas of close cell apposition has been reported [35] but the only direct estimate of cell-to-cell electric current spread in an animal model of obstruction, albeit without associated instability, would suggest that intercellular coupling is worse [36]. Not only does the direction of any change need to be evaluated in human detrusor, but the gap-junction resistance needs to be measured. Equivalent estimates in myocardium, which is well-coupled electrically, show that conditions required for re-entrant arrhythmias are achieved critically when the gap-junction resistance increases above a particular value [37]. If electrical phenomena do become important in detrusor from abnormally functioning bladders, the ease which they can propagate from cell-to-cell must be evaluated to decide whether re-entrant type phenomena can exist.

Conclusions

It is possible to document several changes to the cell physiology of the detrusor myocyte obtained from abnormally-functioning bladders. The initiator of these processes may well be tissue ischaemia and the abnormal metabolic demands it places on the tissue. Contractile changes include several which are consistent with a partial denervation of the detrusor, i.e. the appearance of an accessory purinergic excitatory system and defects of Ca2+ regulation in the myocyte. The last two phenomena may well combine to induce a positive-feedback process whereby ineffective Ca2+ regulation triggers electrophysiological changes which then generate cyclical alteration of intracellular Ca2+ . Elucidation of these steps provides a strategy to develop agents which will break this feedback. The additional hypothesis that improved intercellular electrical coupling in detrusor from unstable bladders allows any electrical activity to spread more readily would exacerbate the consequences of the above cellular changes, but needs to be evaluated critically.

Acknowledgements

The support of the Wellcome Trust, Action Research, St Peter’s Research Trust and Pfizer plc is gratefully acknowledged. We thank Jonathan Masters with whom we had useful discussions.

Authors

  • C.H. Fry, DSc, Professor of Cellular Physiology. C. Wu, PhD, Lecturer.
  • Correspondence: Professor C.H. Fry, Institute of Urology & Nephrology, 67 Riding House Street, London W1P 7PN, UK.

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