Spontaneous Detrusor Contractions Research Articles

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

IntroductionLower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or β3-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues.MethodsFemale and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 µM) and EHT1864 (100 µM) on detrusor contractions were studied in an organ bath.ResultsElectric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC50 values, but unchanged Emax values. EHT1864 reduced carbachol-induced contractions, resulting in reduced Emax values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864.ConclusionsNSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A2-induced detrusor contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is noncholinergic. In vivo, both compounds may improve OAB-related LUTS.

ATP transients accompany spontaneous contractions in isolated guinea-pig detrusor smooth muscle.

What is the central question of this study? Overactive bladder is associated with enhanced spontaneous contractions, but their origins are unclear. The aim of this study was to characterize the accompanying ATP transients. What is the main finding and its importance? Spontaneous detrusor contractions were accompanied by transient increases of ATP, and their appearance was delayed by previous activation of efferent nerves to the detrusor. This indicates that spontaneous ATP release from nerve terminals supports spontaneous contractions. ATP is a functional excitatory neurotransmitter in human bladder only in pathologies such as overactive bladder. A potential drug target is revealed to manage this condition. Spontaneous contractions are characteristic of the bladder wall, but their origins remain unclear. Activity is reduced if the mucosa is removed but does not disappear, suggesting that a fraction arises from the detrusor. We tested the hypothesis that spontaneous detrusor contractions arise from spontaneous ATP release. Guinea-pig detrusor strips, without mucosa, were superfused with Tyrode solution at 36°C. Preparations were subjected to electrical field stimulation (EFS; 3s trains at 90s intervals) to produce nerve-mediated contractions, abolished by 1µm TTX. Amperometric ATP electrodes on the preparation surface recorded any ATP released. Spontaneous contractions and ATP transients were recorded between EFS trains. Nerve-mediated contractions were attenuated by atropine and α,β-methylene ATP; in combination, they nearly abolished contractions, as did nifedipine. Contractions were accompanied by ATP transients that were unaffected by atropine but inhibited by TTX and greatly attenuated by nifedipine. Spontaneous contractions were accompanied by ATP transients, with a close correlation between the magnitudes of both transients. ATP and contractile transients persisted with TTX, atropine and nifedipine. Immediately after a nerve-mediated contraction and ATP transient, there was a longer interval than normal before spontaneous activity resumed. Spontaneous contractions and ATP transients are proposed to arise from ATP leakage from nerve terminals innervating the detrusor. Extracellular ATP has a greater functional significance in humans who suffer from detrusor overactivity (spontaneous bladder contractions associated with incontinence) owing to its reduced hydrolysis at the nerve-muscle interface. This study shows the origin of spontaneous activity that might be exploited to develop a therapeutic management of this condition.

Sophisticated models and methods for studying neurogenic bladder dysfunction

To describe how the use of new and established animal models and methods can generate vital and far reaching experimental data in the study of mechanism underlying neurogenic bladder overactivity. Bladder and colonic irradiated mice and those with upper and lower motor neuron lesions were used to study neurogenic bladder overactivity. Methods included cystometry, tension measurements, afferent nerve recordings and optical mapping of action potentials and intracellular Ca(2+) transients. Recordings were made in a number of innovative preparations including in-line cultured cells, bladder-urethra sheets and cross-sections, spinal cord slices and the cerebral cortex. The animal models and methods used allow for the study of peripheral and central mechanisms of neurogenic overactivity. While colonic irradiation results in solely neurogenic dysfunction, spinal cord lesions also induce non-neural changes resulting in increased spontaneous detrusor contractions that can directly stimulate afferent nerves. Imaging of cultured bladder interstitial cells reveals spontaneous firing that could contribute to detrusor overactivity, while optical imaging of the spinal cord and brain could identify changes in central pathways that underlie lower urinary tract dysfunction. The animal models and methods described allow for the study of neurogenic overactivity at the peripheral, spinal and cortical levels. This may lead to greater understanding of sensory and motor mechanisms involved in incontinence, the contributions of interstitial cells and spontaneous detrusor contractions, and the involvement of the cortex.

790 LIPOSOMES ASSISTED BLADDER UPTAKE OF NGF ANTISENSE OLIGONUCLEOTIDES AMELIORATE SYMPTOMS OF DETRUSOR OVERACTIVITY IN RAT MODEL

sensor & custom analog-to-digital data acquisition circuitry were assembled & packaged for acute implantation. Wires conducted power & a timing signal to the prototype. A single line returned digital data to a custom external receiver for analog waveform reconstruction & collection on a PC. System frequency response was characterized in vitro by sinusoidal pressure changes swept in frequency (10mHzCHz). Devices were implanted into the bladder wall submucosa of feline (n 1) & canine (n 1) models. External reference sensors (via a catheter) & implanted devices recorded simultaneous intravesical pressures in vivo during cystometry, manual manipulation, and spontaneous & evoked detrusor contractions. Data were detrended, smoothed, and simultaneous reference & device recordings were correlated (riÝ0.8 indicated significance). RESULTS: The device exhibited a flat frequency response iU 30Hz. Device output correlated significantly with bladder lumen pressure during spontaneous detrusor contractions (duration 115s; r 0.992) & manual manipulation (duration 13.5s; r 0.997) in the feline model. Significant correlation between device & lumen pressure was also found during evoked canine detrusor contractions (n 3; r 0.893 iA 0.28). CONCLUSIONS: We have demonstrated feasibility of sensing bladder pressure from a submucosal location. This data suggests that a wireless submucosal pressure sensor can provide feedback for conditional electrical stimulation.

Reflex interaction from the urinary bladder and the rectum on anal motility in the cat

The intrinsic recto-anal inhibitory reflex (RAIR) and the extrinsic vesico-anal excitatory reflex were studied in anaesthetized cats in order to explore the nervous components of anal pressure regulation. The magnitude of the RAIR was documented at varying levels of anal pressure. Minimal anal pressure during RAIR was positively correlated to anal pressure immediately prior to rectal distension. It was possible to elicit the vesico-anal excitatory reflex concomitantly with an ongoing RAIR. It was also possible to elicit a RAIR during the vesico-anal excitatory reflex. The magnitude of the pressor reflex response was not changed by concomitant activation of the inhibitory reflex and vice versa. This suggests an independent action on the internal anal sphincter (IAS) of the two reflexes. Spontaneous detrusor contractions were abolished by rectal distension. However, an escape phenomenon from this inhibition was observed, suggesting a spinal, associative, connection. The results support the concept of a direct action of both extrinsic and intrinsic nervous mechanisms on the smooth muscle of the IAS.

Effects of Magnesium Ions on Detrusor Contraction in Rat

Contraction of smooth muscle including detrusor is initiated by an increase in the concentration of intracellular free calcium ions. Magnesium affects the translocation of calcium ions through the smooth muscle cell membrane. The effect of magnesium ions on detrusor contraction was investigated in vitro using the rat detrusor muscle. Detrusor contractility caused by intramural nerve stimulation increased in a magnesium-free solution but decreased in a high-magnesium solution (MgCl2 5 mM). Cumulative addition of MgCl2 suppressed the detrusor response induced by field stimulation dose-dependently, and 30 mM MgCl2 completely eliminated it. Mg ion also suppressed atropine-resistant detrusor contraction in a dose-dependent manner. After blocking nerve-mediated detrusor contractility with tetrodotoxin, Mg ions inhibited spontaneous detrusor contractions and reduced tonus of the muscle strips. Mg ions suppressed the detrusor contraction induced by carbachol and potassium. The effect of Mg ions on detrusor contraction was enhanced by verapamil but inhibited by Bay-K8644. These results suggest that Mg ions suppress detrusor muscle contractility through an inhibitory mechanism acting on calcium channels in the smooth muscle cell membrane.

Anal and rectal motility responses to distension of the urinary bladder in the cat

The neural pathways and possible transmission mechanisms of the integrated autonomic nervous control of the urinary bladder and anorectum, were investigated in chloralose anaesthetized cats. Bladder distension and spontaneous detrusor contractions increased internal anal sphincter-tone, a response which was blocked by an α-adrenoceptor antagonist. Moreover, a nicotinic transmission step was present. Both the afferent and efferent limbs of the reflex were conveyed in the postganglionic hypogastric nerves and the preganglionic lumbar splanchnic nerves. Intact connection with the central nervous system was therefore essential. Contrasting to the specific reflex response in the internal anal sphincter, bladder distension also elicited a nociceptive vaso-pressor response. Rectal motility appeared to be unaffected by bladder distension.

Hydrodynamic model of the urinary bladder derived from stepwise cystometry in the rat.

The urinary bladder of the rat was examined by nearly ideal, unit step volume infusions. Spontaneous detrusor contractions occurred in vivo but ceased soon after death. A hydrodynamic model of the post mortem bladder wall was evaluated. Elastic properties were described by introducing two types of compliances; a dynamic compliance for fast response characteristics and a static compliance for the relaxed bladder wall. These compliances were easy to measure and found to vary with the degree of bladder expansion. The influence of viscosity was well described by a model with two relaxation time constants and was the optimal model in almost 50 per cent of the measurements. The long time constant was found to increase with bladder expansion.

Experience with self intermittent catheterisation for women with neurological dysfunctions of the bladder.

Self intermittent catheterisation (SIC) was taught to 24 women with neurological diseases involving the bladder. The major causes of neuropathic bladders were traumatic lesions of the spinal cord (17 cases, 70 per cent), diabetes and multiple sclerosis. Patients were aged 16--65 years (mean 36 years). Initial acceptance of the procedure proved to be a temporary problem in some fastidious women, but the majority eagerly accepted the opportunity to be free of permanent drainage equipment. A bladder relaxant drug was used in order to suppress spontaneous detrusor contractions in patients with intact lower motor neurones. A training period of 1 day to 2 weeks, depending on manual dexterity, was sufficient to ensure competence in the technique. All patients were able to perform the procedure with few incidents of infection while in the Hospital, but in four patients it proved to be impractical and was discontinued after 1 to 2 weeks. After discharge home three patients have gone back to permanent Foley drainage. Women who have good home settings or who are able to ambulate to some degree, do well on SIC, but the advantages of prevention of infection and freedom from drainage bags do not, as yet, outweigh the social problems for many women confined to wheelchairs such as architectural barriers, time schedules and suitable clothing. Selected patients must be both well motivated and independent in transfers so that while an excellent solution for some, SIC is far from being the solution for all women with neurological dysfunction of the bladder.