- Email: [email protected]
Pharmacotherapy in detrusor underactivity: A new challenge for urologists and pharmacologists (from lab to clinic)
Pharmacological Reports 68 (2016) 703–706
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Review article
Pharmacotherapy in detrusor underactivity: A new challenge for urologists and pharmacologists (from lab to clinic) Kajetan Juszczak a,*, Tomasz Drewa b,c a
Department of Urology, Memorial Rydygier Hospital, Krako´w, Poland Department of Urology, Nicolaus Copernicus University, Bydgoszcz, Poland c Department of General and Oncological Urology, Nicolaus Copernicus Hospital, Torun´, Poland b
A R T I C L E I N F O
Article history: Received 21 January 2016 Received in revised form 1 March 2016 Accepted 9 March 2016 Available online 19 March 2016 Keywords: Underactive bladder Treatment Detrusor underactivity Rat
A B S T R A C T
Higher incidence of functional urinary bladder dysfunction (detrusor overactivity – DO and detrusor underactivity – DU) occurs in elderly people. Effective therapy is widely used in patients with DO, in contrast DU seems to be a serious burden for the older population due to the lack of successful treatment. The aim of the study was to review the potential pharmacological targets in DU treatment in the animal model. This review is based on systemic literature research. The Medline/Pubmed, Scopus, Embase, and Web of Science databases were searched in order to identify original and review articles, as well as editorials relating to underactive bladder, detrusor underactivity. The following Medical Subject Headings (MeSH) terms were used to ensure the sensitivity of the searches: urinary bladder, animal models, humans and therapy. 19 papers met the criteria and were included for this review. 19 papers met the criteria and were included for this review. The pathophysiology of DU and its animal models were described. Moreover, the potential pharmacological targets in DU therapy were discussed, such as bombesin receptors, prostaglandin-, ATP-, NO-, CGRP-, SP-, Dopamine-, NGF-, M2-, and agrin-dependent pathways. In conclusion, due to the lack of effective treatment strategies in DU, further research is necessary. Close cooperation between urologists and pharmacologists should be maintained for optimal research on DU pharmacotherapy. ß 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of the detrusor underactivity (DU) . . . . . . . . . . Animal models of DU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential pharmacological targets in DU therapy. . . . . . . . . . . . . Bombesin receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prostaglandin-dependent pathway . . . . . . . . . . . . . . . . . . ATP- and NO-dependent pathways . . . . . . . . . . . . . . . . . . CGRP- and/or SP- and/or dopamine-dependent pathway . NGF-dependent pathway . . . . . . . . . . . . . . . . . . . . . . . . . . Muscarinic M2 receptor and Agrin-dependent pathway. . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
* Corresponding author. E-mail address: [email protected] (K. Juszczak).
Higher incidence of functional urinary bladder dysfunction (detrusor overactivity – DO and detrusor underactivity – DU) occurs in elderly people. Effective therapy is widely used in
http://dx.doi.org/10.1016/j.pharep.2016.03.007 1734-1140/ß 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
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K. Juszczak, T. Drewa / Pharmacological Reports 68 (2016) 703–706
patients with DO [1,2]. In contrast, DU seems to be a serious burden for the older population due to the lack of successful treatment. DU affects more and more patients due to the ageing population and number of comorbidities affecting urinary bladder function. Underactive bladder (UAB) is strictly linked with DU. Epidemiological data show that DU is not an uncommon disease. Urodynamic study in patients with non-neurogenic LUTS confirmed DU in about 9–48% men and 12–45% women [3]. Although these data do not contain in themselves information about whether DU is clinically significant, or is only urodynamic findings. International Continence Society (ICS) defines DU as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span [4]. Chapple et al. [5] proposed the definition of UAB as a symptom complex suggestive of DU and is usually characterized by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and a slow stream. On the other hand post-void residual should be considered in all cases suspected for DU. Repetitive post-void residual is a characteristic feature of DU. Etiopathogenesis of overactive bladder/detrusor overactivity (OAB/DO) is well described. Available therapeutic methods allow to achieve a good response of the patient and alleviate LUTS associated with OAB. In contrast to OAB/ DO, little is still known about UAB/DU. Moreover it is postulated that long-lasting OAB due to DO may result in DU in the future (Fig. 1). In the course of OAB/DO the urinary bladder wall thickens. The alteration in the urinary bladder wall structure (muscles, connective tissue) may affect proper detrusor contractility. The aim of the study was to review the potential pharmacological targets in underactive bladder treatment in the animal model. This review is based on systemic literature research. The following databases such a Medline/Pubmed, Scopus, Embase, and Web of Science were searched in order to identify original papers, review articles, as well as editorials relating to detrusor underactivity. Additionally, we used the following Medical Subject Headings (MeSH) terms to ensure the sensitivity of the searches: urinary bladder, animal models, humans and therapy. 19 papers (2 review and 17 original) met the criteria and were included for this review. A small number of publications on DU seems to be due to the fact that DU is not fully known disease. Probably the complex ethiopathogenesis of DU make difficult to find satisfactory results worth publishing. Many studies in animal models published recently may allow research on a large scale in humans. Pathophysiology of the detrusor underactivity (DU) The three main theories underlying DU were defined: (1) neurogenic, (2) myogenic and (3) integrative. The neurogenic
theory suggests that DU results from the damage of either peripheral innervations of lower urinary tract (afferent and/or efferent nerves) or of spinal and/or supraspinal micturition control systems. The myogenic theory describes the direct defect of urinary bladder muscles leading to diminished cells excitability and loss of intrinsic contractility of the muscle cells of the urinary bladder driving spontaneous detrusor contraction. The third promising integrative theory combine factors (muscles, connective tissue, urothelium, afferent and efferent innervations) which are responsible for the physiological generation of localized spontaneous muscle activity (micromotions – localized contractions and stretches). Lack of proper interaction of these factors can lead to DU. The most common causes of DU include diabetes mellitus, bladder outlet obstruction and ageing. In addition, other risk factors of DU have been described, such as: (1) neurogenic disorders (e.g. multiple sclerosis, Parkinson disease, cerebrovascular events), (2) spinal cord, cauda equina and pelvic plexus injury (e.g. pelvic surgery, pelvic fractures, herniated disc, pudendal nerves lesions, radical prostatectomy), (3) infective disorders affecting the nervous system (e.g. AIDS, syphilis, herpes zoster and herpes simplex infection, Guillain–Barre syndrome), (4) drugs (neuroleptics, Ca2+-channel antagonists, etc.). With ageing the neurotransmitter release from the urothelium and coupling of the interstitial cells in suburothelial space with afferent nerves endings are significantly changed [6–9]. Additionally it is worth nothing that long lasting DO may lead to DU. In patients with OAB the urinary bladder wall thickens and also the urine concentration of nerve growth factor (NGF) increases. These facts indicate that during OAB the bladder components (connective tissue, muscle) may be affected, which leads to impaired detrusor activity [10]. Animal models of DU Many similarities in the physiology of urinary bladder and its neural control in rodents as in humans were observed. Therefore, animal models of DU are appropriate experimental tools for research of underlying pathomechanisms of DU development. Several animal models of DU were developed as follows: (1) diabetes bladder dysfunction model (DBD), (2) neurogenic model, (3) ageing models, (4) ischaemia model, (5) obstructive model, (6) urinary bladder overdistension model, and (7) oxidative stress model. DBD, neurogenic and ageing models are widely used. Most of the aforementioned models depend on myogenic and neurogenic mechanisms of DU development. DBD is induced by the intraperitoneal administration of streptozotocin in dose of 65 mg/ kg [11]. The neurogenic model of DU is due to bilateral pelvic nerves damage. Ageing animals (over 12–24 months) present urinary bladder dysfunction similar to DU due to ischaemia, neuronal damage and sacropenia with accumulation of connective tissue [12]. Potential pharmacological targets in DU therapy
Fig. 1. Potential clinical relationship between detrusor underactivity and overactivity.
A wide range of neurotransmitters control urine storage and voiding such as acetylcholine (ACh), norepinephrine (NE), dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate (ATP), nitric oxide (NO) and neuropeptides. ACh via detrusor muscarinic receptors remains the primary neurotransmitter affecting bladder emptying. The storage phase is mediated by NE released from sympathetic nerve endings. Moreover during voiding NO is released from parasympathetic nerve terminals within urethra providing relaxation of urethral smooth muscles [13]. The armamentarium of DU management is sparse. Still indwelling or intermittent catheterization remain recommended and a conventional option. Standard pharmacotherapy includes
K. Juszczak, T. Drewa / Pharmacological Reports 68 (2016) 703–706
the use of: (1) a-adrenoreceptors antagonists, (2) muscarinic receptor agonists (e.g. bethanechol, carbachol), and (3) inhibitors of acetylocholinesterase (e.g. distigmine). The beneficial response of patient with DU to available treatment options is limited due to its efficacy and tolerability, in addition to side-effects. Additionally, with ageing decrement of acetylocholinesterase-positive nerves and musarinic receptors type M3 causing reduced parasympathetic innervations of urinary bladder is observed [14]. Therefore, further research is underway to find a novel and optimal therapeutic target with less unfavourable effects. Currently, researchers are studying the potential pathways modulating urinary bladder function via bombesin receptors, prostaglandins, ATP, NO, calcitonin gene-related peptide (CGRP), substance P (SP), dopamine (D), nerve growth factor (NGF), muscarinic receptor M2 and agrin proteins. Bombesin receptors Rodents present positive expression of bombesin receptors (BR) and bombesin-related peptides within urinary tracts. Kullmann et al. [15] study showed that BR activation facilitates neurogenic bladder contractions. Neuromedin B (NMB – BR1 agonist) and Gastrin-releasing peptide (GRP – BR2 agonist) induced increased micturition frequency and amplitude of detrusor contractions in streptozotocin-treated rats. Interestingly, NMB triggered voiding of underfilled bladders. Bombesin receptors stimulation leads to increased sensitivity of smooth muscle cells to neuronally-induced response via cholinergic pathway. It is worth noting that the most common side effects of BR agonists were increased blood pressure and heart rate in the case of highest doses. Prostaglandin-dependent pathway In patients with diabetes mellitus urinary bladder dysfunction is quite common. The feature includes a decreased sensation of urinary bladder fullness, improper detrusor contractility and increased residual urine volume. Nirmal et al. [16] study revealed that prostaglandin EP3 receptors are potential targets in the management of diabetes-induced underactive bladder. Previous studies described that prostaglandins play a role in micturition. Prostaglandin E (PGE2) is produced in urothelium and smooth muscles, as well as modulates capsaicin-sensitive afferent nerves and efferent one. Moreover, PGE2 via prostaglandin EP receptors (type 1–type 4) induces urinary bladder overactivity in rats and humans [17]. In vitro experiments using isolated urothelium strips from diabetic bladder showed an increased level of prostaglandins (E2 and F2a) as compared to normal strips. ATP and bradykinin stimulates the release of prostaglandins from urothelial cells. It is believed that increased diabetic bladder sensitivity to the contractile factor is mediated via prostaglandins-dependent pathways [18].
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inhibitory neurotransmitter affecting the afferent and efferent branch of the nervous system. Ozawa et al. [21] described that NO instilled into urinary bladder leads suppression of detrusor contraction, and that the NO synthase (NOS) blockers provoked the opposite effect. Moreover, NO suppress dopamine and norepinephrine reuptake from motor neurons. Munoza et al. [22] defined a parameter (potential biomarker) such a ATP/NO ratio which reflects the urinary bladder sensory transmission and its dysfunction (OAB or UAB). High or low values of ATP/NO ratio were observed in DO and DU respectively. ATP and NO release have a respectively positive and negative correlation with detrusor contraction frequency. The role of ATP and NO was confirmed in diabetic DU model. In the case of diabetes mellitus the DU was characterized by increased NO release with simultaneous release of ATP at physiological ranges. It is also postulated that DU is caused by two parallel mechanisms such as: (1) diminished activity of purinergic receptors P2X3 and (2) up-regulation of neuronal NO synthase (nNOS) providing greater synthesis of NO. NO may also directly damage detrusor via increased oxidative stress and proteasoms activations within urinary bladder wall. Previous studies of Poladia and Bauer [23] described that different isozymes of NO synthase (NOS) such as inducible (iNOS), neuronal (nNOS) and endothelial (eNOS) are up-regulated in urothelium, lamina propria and smooth muscle cells. CGRP- and/or SP- and/or dopamine-dependent pathway Animal studies showed that with ageing, the level of calcitonin gene-related peptide (CGRP) and SP in lumbosacral dorsal root ganglion neurons decreases. Also, the reduction of nerves containing CGRP and SP within detrusor were observed [24]. In general patients with Parkinson’s disease (PD) present DO; however, some of them may develop DU. In monkeys with PD dopamine D1 receptor agonists administration increase the urinary bladder volume and intravesical threshold pressure inducing micturition [25]. Thus, dopamine-dependent pathway may be present in pathomechanism of DU development. Further research is needed to explain this hypothesis. NGF-dependent pathway Urothelium and detrusor muscle release NGF. NGF is believed to modulate urothelium function due to different stimuli especially in diabetic cystopathy. In rats with streptozotocin-induced diabetes, the decreased NGF level was observed within the urinary bladder, bladder afferent innervations and in dorsal root ganglia (L6 and S1) [26,27]. Moreover, Sasaki et al. [28] described that NGF-gene therapy reverses detrusor underactivity in rats. These facts show a potential role of NGF in pathogenesis of DU. Muscarinic M2 receptor and Agrin-dependent pathway
ATP- and NO-dependent pathways Neurotransmitters such as ATP and NO affect urinary bladder activity. ATP and NO are released from the urothelium in the bladder. Previous studies showed that ATP via purinergic receptors P2X3 of afferent nerve endings and urothelial cells activate afferent pathways innervating lower urinary tract [19]. ATP and NO have two different effects on the urinary bladder. One of the most common stimulus for ATP and NO release is bladder wall stretch. Pandita et al. [20] results revealed that intravesically ATP administration induces urinary bladder overactivity, which depends on concentration. ATP leads to decrement of bladder capacity and voided volumes with increment of intravesical pressures (basal and during micturition). NO is believed as an
The rat model of DU induced by lumbar canal stenosis presented down-regulation of agrin proteins and up-regulation of muscarinic M2 receptors within the urinary bladder [29]. Agrin is a molecule produced by motor neurons that induces the aggregation of nicotinic ACh receptors. Thus, agrin proteins- and M2 receptor-dependent pathways should be considered as a potential molecular targets for DU therapy. Conclusion DU is a widespread disease. However, due to mulitfactorial etiopathogenesis DU remains a poorly understood urinary bladder dysfunction. The armamentarium of DU management is sparse.
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Still, indwelling or intermittent catheterization remain recommended and a conventional option. The beneficial response of patients with DU to available treatment options is limited due to its efficacy and tolerability, in addition to side-effects. Therefore, the lack of effective treatment strategies in DU creates the need for further research in this field. Close cooperation between urologists and pharmacologists should be maintained for optimal research on DU therapy. Conflict of interests None declared. References [1] Kosilov K, Loparev S, Iwanowskaya M, Kosilova L. Effectiveness of combined high-dosed trospium and solifenacin depending on severity of OAB symptoms in elderly men and women under cyclic therapy. Cent Eur J Urol 2014;67(1): 43–8. [2] Malki M, Mangera A, Reid S, Inman R, Chapple C. What is the feasibility of switching to 200IU OnabotulinumtoxinA in patients with detrusor overactivity who have previously received 300IU? Cent Eur J Urol 2014;67(1):35–40. [3] Osman NI, Chapple CR, Abrams P, Dmochowski R, Haab F, Nitti V, et al. Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology, and diagnosis. Eur Urol 2014;65(2):389–98. [4] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167–78. [5] Chapple CR, Osman NI, Birder L, van Koeveringe GA, Oelke M, Nitti VW, et al. The underactive bladder: a new clinical concept? Eur Urol 2015;68(3):351–3. [6] Brierly RD, Hindley RG, McLarty E, Harding DM, Thomas PJ. A prospective controlled quantitative study of ultrastructural changes in the underactive detrusor. J Urol 2003;169(4):1374–8. [7] Drake MJ, Harvey IJ, Gillespie JI, Van Duyl WA. Localized contractions in the normal human bladder and in urinary urgency. BJU Int 2005;95(7):1002–5. [8] Tyagi P, Smith PP, Kuchel GA, de Groat WC, Birder LA, Chermansky CJ, et al. Pathophysiology and animal modeling of underactive bladder. Int Urol Nephrol 2014;46(1):S11–21. [9] Azadzoi KM, Radisavljevic ZM, Siroky MB. Effects of ischemia on tachykinincontaining nerves and neurokinin receptors in the rabbit bladder. Urology 2008;71(5):979–83. [10] Kim JC, Park EY, Seo SI, Park YH, Hwang TK. Nerve growth factor and prostaglandine in the urine of female patients with overactive bladder. J Urol 2006;175:1773–6. [11] Torimoto K, Fraser MO, Hirao Y, De Groat WC, Chancellor MB, Yoshimura N. Urethral dysfunction in diabetic rats. J Urol 2004;171:1959–64. [12] Chai TC, Andersson KE, Tuttle JB, Steers WD. Altered neural control of micturition in the aged F344 rat. Urol Res 2000;28:348–54.
[13] de Groat WC. Integrative control of the lower urinary tract: preclinical perspective. Br J Pharmacol 2006;147(2):S25–40. [14] Mansfield KJ, Liu L, Mitchelson FJ, Moore KH, Millard RJ, Burcher E. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Br J Pharmacol 2005;144(8):1089–99. [15] Kullmann FA, Wells GI, McKenna D, Thor KB. Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo. Life Sci 2014;100(1):35–44. [16] Nirmal J, Tyagi P, Chuang YC, Lee WC, Yoshimura N, Huang CC, et al. Functional and molecular characterization of hyposensitive underactive bladder tissue and urine in streptozotocin-induced diabetic rat. PLOS ONE 2014;9(7): e102644. [17] Lee T, Andersson KE, Streng T, Hedlund P. Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious rats – effects of bladder outlet obstruction and intravesical PGE2. Neurourol Urodyn 2008;27:88–95. [18] Pinna C, Zanardo R, Puglisi L. Prostaglandin release impairment in the bladder epithelium of streptozotocin-induced diabetic rats. Eur J Pharmacol 2000;388: 267–73. [19] Birder LA. Urinary bladder urothelium: molecular sensors of chemical/thermal/mechanical stimuli. Vasc Pharmacol 2006;45:221–6. [20] Pandita RK, Andersson KE. Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol 2002;168:1230–4. [21] Ozawa H, Chancellor MB, Jung SY, Yokoyama T, Fraser MO, Yu Y, et al. Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis. J Urol 1999;162:2211–6. [22] Munoza A, Smith CP, Boone TB, Somogyi GT. Overactive and underactive bladder dysfunction is reflected by alterations in urothelial ATP and NO release. Neurochem Int 2011;58(3):295–300. [23] Poladia DP, Bauer JA. Early cell-specific changes in nitric oxide synthase, reactive nitrogen species formation, and ubiquitinylation during diabetes related bladder remodeling. Diabetes Metab Res Rev 2003;19:313–9. [24] Mohammed HA, Santer RM. Distribution and changes with age of calcitonin gene-related peptide and substance P-immunoreactive nerves of the rat urinary bladder and lumbosacral sensory neurons. Eur J Morphol 2002;40: 293–301. [25] Yoshimura N, Mizuta E, Kuno S, Sasa M, Yoshida O. The dopamine D1 receptor agonist SKF38393 suppresses detrusor hyperreflexia in the monkey with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuropharmacology 1993;32(4):315–21. [26] Sasaki K, Chancellor MB, Phelan MW, Yokoyama T, Fraser MO, Seki S, et al. Diabetic cystopathy correlate with long-term decrease in nerve growth factor (NGF) levels in the bladder and lumbosacral dorsal root ganglia. J Urol 2002;168(3):1259–64. [27] Li Y, Shi B, Wang D, Wang P, Laudon V, Zhang J, et al. Nerve growth factor and substance P: expression in a rat model of diabetic bladder. Int Urol Nephrol 2011;43:109–16. [28] Sasaki K, Chancellor MB, Goins WF, Phelan MW, Glorioso JC, de Groat WC, et al. Gene therapy using replication-defective herpes simplex virus vectors expressing nerve growth factor in a rat model of diabetic cystopathy. Diabetes 2004;53(10):2723–30. [29] Wang HJ, Tyagi P, Chuang YC, Yoshimura N, Huang CC, Chancellor MB. Pharmacologic and molecular characterization of underactive bladder induced by lumbar canal stenosis. Urology 2015;85(6):1284–90.
Contents lists available at ScienceDirect
Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep
Review article
Pharmacotherapy in detrusor underactivity: A new challenge for urologists and pharmacologists (from lab to clinic) Kajetan Juszczak a,*, Tomasz Drewa b,c a
Department of Urology, Memorial Rydygier Hospital, Krako´w, Poland Department of Urology, Nicolaus Copernicus University, Bydgoszcz, Poland c Department of General and Oncological Urology, Nicolaus Copernicus Hospital, Torun´, Poland b
A R T I C L E I N F O
Article history: Received 21 January 2016 Received in revised form 1 March 2016 Accepted 9 March 2016 Available online 19 March 2016 Keywords: Underactive bladder Treatment Detrusor underactivity Rat
A B S T R A C T
Higher incidence of functional urinary bladder dysfunction (detrusor overactivity – DO and detrusor underactivity – DU) occurs in elderly people. Effective therapy is widely used in patients with DO, in contrast DU seems to be a serious burden for the older population due to the lack of successful treatment. The aim of the study was to review the potential pharmacological targets in DU treatment in the animal model. This review is based on systemic literature research. The Medline/Pubmed, Scopus, Embase, and Web of Science databases were searched in order to identify original and review articles, as well as editorials relating to underactive bladder, detrusor underactivity. The following Medical Subject Headings (MeSH) terms were used to ensure the sensitivity of the searches: urinary bladder, animal models, humans and therapy. 19 papers met the criteria and were included for this review. 19 papers met the criteria and were included for this review. The pathophysiology of DU and its animal models were described. Moreover, the potential pharmacological targets in DU therapy were discussed, such as bombesin receptors, prostaglandin-, ATP-, NO-, CGRP-, SP-, Dopamine-, NGF-, M2-, and agrin-dependent pathways. In conclusion, due to the lack of effective treatment strategies in DU, further research is necessary. Close cooperation between urologists and pharmacologists should be maintained for optimal research on DU pharmacotherapy. ß 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology of the detrusor underactivity (DU) . . . . . . . . . . Animal models of DU. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential pharmacological targets in DU therapy. . . . . . . . . . . . . Bombesin receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prostaglandin-dependent pathway . . . . . . . . . . . . . . . . . . ATP- and NO-dependent pathways . . . . . . . . . . . . . . . . . . CGRP- and/or SP- and/or dopamine-dependent pathway . NGF-dependent pathway . . . . . . . . . . . . . . . . . . . . . . . . . . Muscarinic M2 receptor and Agrin-dependent pathway. . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction
* Corresponding author. E-mail address: [email protected] (K. Juszczak).
Higher incidence of functional urinary bladder dysfunction (detrusor overactivity – DO and detrusor underactivity – DU) occurs in elderly people. Effective therapy is widely used in
http://dx.doi.org/10.1016/j.pharep.2016.03.007 1734-1140/ß 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
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patients with DO [1,2]. In contrast, DU seems to be a serious burden for the older population due to the lack of successful treatment. DU affects more and more patients due to the ageing population and number of comorbidities affecting urinary bladder function. Underactive bladder (UAB) is strictly linked with DU. Epidemiological data show that DU is not an uncommon disease. Urodynamic study in patients with non-neurogenic LUTS confirmed DU in about 9–48% men and 12–45% women [3]. Although these data do not contain in themselves information about whether DU is clinically significant, or is only urodynamic findings. International Continence Society (ICS) defines DU as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span [4]. Chapple et al. [5] proposed the definition of UAB as a symptom complex suggestive of DU and is usually characterized by prolonged urination time with or without a sensation of incomplete bladder emptying, usually with hesitancy, reduced sensation on filling, and a slow stream. On the other hand post-void residual should be considered in all cases suspected for DU. Repetitive post-void residual is a characteristic feature of DU. Etiopathogenesis of overactive bladder/detrusor overactivity (OAB/DO) is well described. Available therapeutic methods allow to achieve a good response of the patient and alleviate LUTS associated with OAB. In contrast to OAB/ DO, little is still known about UAB/DU. Moreover it is postulated that long-lasting OAB due to DO may result in DU in the future (Fig. 1). In the course of OAB/DO the urinary bladder wall thickens. The alteration in the urinary bladder wall structure (muscles, connective tissue) may affect proper detrusor contractility. The aim of the study was to review the potential pharmacological targets in underactive bladder treatment in the animal model. This review is based on systemic literature research. The following databases such a Medline/Pubmed, Scopus, Embase, and Web of Science were searched in order to identify original papers, review articles, as well as editorials relating to detrusor underactivity. Additionally, we used the following Medical Subject Headings (MeSH) terms to ensure the sensitivity of the searches: urinary bladder, animal models, humans and therapy. 19 papers (2 review and 17 original) met the criteria and were included for this review. A small number of publications on DU seems to be due to the fact that DU is not fully known disease. Probably the complex ethiopathogenesis of DU make difficult to find satisfactory results worth publishing. Many studies in animal models published recently may allow research on a large scale in humans. Pathophysiology of the detrusor underactivity (DU) The three main theories underlying DU were defined: (1) neurogenic, (2) myogenic and (3) integrative. The neurogenic
theory suggests that DU results from the damage of either peripheral innervations of lower urinary tract (afferent and/or efferent nerves) or of spinal and/or supraspinal micturition control systems. The myogenic theory describes the direct defect of urinary bladder muscles leading to diminished cells excitability and loss of intrinsic contractility of the muscle cells of the urinary bladder driving spontaneous detrusor contraction. The third promising integrative theory combine factors (muscles, connective tissue, urothelium, afferent and efferent innervations) which are responsible for the physiological generation of localized spontaneous muscle activity (micromotions – localized contractions and stretches). Lack of proper interaction of these factors can lead to DU. The most common causes of DU include diabetes mellitus, bladder outlet obstruction and ageing. In addition, other risk factors of DU have been described, such as: (1) neurogenic disorders (e.g. multiple sclerosis, Parkinson disease, cerebrovascular events), (2) spinal cord, cauda equina and pelvic plexus injury (e.g. pelvic surgery, pelvic fractures, herniated disc, pudendal nerves lesions, radical prostatectomy), (3) infective disorders affecting the nervous system (e.g. AIDS, syphilis, herpes zoster and herpes simplex infection, Guillain–Barre syndrome), (4) drugs (neuroleptics, Ca2+-channel antagonists, etc.). With ageing the neurotransmitter release from the urothelium and coupling of the interstitial cells in suburothelial space with afferent nerves endings are significantly changed [6–9]. Additionally it is worth nothing that long lasting DO may lead to DU. In patients with OAB the urinary bladder wall thickens and also the urine concentration of nerve growth factor (NGF) increases. These facts indicate that during OAB the bladder components (connective tissue, muscle) may be affected, which leads to impaired detrusor activity [10]. Animal models of DU Many similarities in the physiology of urinary bladder and its neural control in rodents as in humans were observed. Therefore, animal models of DU are appropriate experimental tools for research of underlying pathomechanisms of DU development. Several animal models of DU were developed as follows: (1) diabetes bladder dysfunction model (DBD), (2) neurogenic model, (3) ageing models, (4) ischaemia model, (5) obstructive model, (6) urinary bladder overdistension model, and (7) oxidative stress model. DBD, neurogenic and ageing models are widely used. Most of the aforementioned models depend on myogenic and neurogenic mechanisms of DU development. DBD is induced by the intraperitoneal administration of streptozotocin in dose of 65 mg/ kg [11]. The neurogenic model of DU is due to bilateral pelvic nerves damage. Ageing animals (over 12–24 months) present urinary bladder dysfunction similar to DU due to ischaemia, neuronal damage and sacropenia with accumulation of connective tissue [12]. Potential pharmacological targets in DU therapy
Fig. 1. Potential clinical relationship between detrusor underactivity and overactivity.
A wide range of neurotransmitters control urine storage and voiding such as acetylcholine (ACh), norepinephrine (NE), dopamine, serotonin, excitatory and inhibitory amino acids, adenosine triphosphate (ATP), nitric oxide (NO) and neuropeptides. ACh via detrusor muscarinic receptors remains the primary neurotransmitter affecting bladder emptying. The storage phase is mediated by NE released from sympathetic nerve endings. Moreover during voiding NO is released from parasympathetic nerve terminals within urethra providing relaxation of urethral smooth muscles [13]. The armamentarium of DU management is sparse. Still indwelling or intermittent catheterization remain recommended and a conventional option. Standard pharmacotherapy includes
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the use of: (1) a-adrenoreceptors antagonists, (2) muscarinic receptor agonists (e.g. bethanechol, carbachol), and (3) inhibitors of acetylocholinesterase (e.g. distigmine). The beneficial response of patient with DU to available treatment options is limited due to its efficacy and tolerability, in addition to side-effects. Additionally, with ageing decrement of acetylocholinesterase-positive nerves and musarinic receptors type M3 causing reduced parasympathetic innervations of urinary bladder is observed [14]. Therefore, further research is underway to find a novel and optimal therapeutic target with less unfavourable effects. Currently, researchers are studying the potential pathways modulating urinary bladder function via bombesin receptors, prostaglandins, ATP, NO, calcitonin gene-related peptide (CGRP), substance P (SP), dopamine (D), nerve growth factor (NGF), muscarinic receptor M2 and agrin proteins. Bombesin receptors Rodents present positive expression of bombesin receptors (BR) and bombesin-related peptides within urinary tracts. Kullmann et al. [15] study showed that BR activation facilitates neurogenic bladder contractions. Neuromedin B (NMB – BR1 agonist) and Gastrin-releasing peptide (GRP – BR2 agonist) induced increased micturition frequency and amplitude of detrusor contractions in streptozotocin-treated rats. Interestingly, NMB triggered voiding of underfilled bladders. Bombesin receptors stimulation leads to increased sensitivity of smooth muscle cells to neuronally-induced response via cholinergic pathway. It is worth noting that the most common side effects of BR agonists were increased blood pressure and heart rate in the case of highest doses. Prostaglandin-dependent pathway In patients with diabetes mellitus urinary bladder dysfunction is quite common. The feature includes a decreased sensation of urinary bladder fullness, improper detrusor contractility and increased residual urine volume. Nirmal et al. [16] study revealed that prostaglandin EP3 receptors are potential targets in the management of diabetes-induced underactive bladder. Previous studies described that prostaglandins play a role in micturition. Prostaglandin E (PGE2) is produced in urothelium and smooth muscles, as well as modulates capsaicin-sensitive afferent nerves and efferent one. Moreover, PGE2 via prostaglandin EP receptors (type 1–type 4) induces urinary bladder overactivity in rats and humans [17]. In vitro experiments using isolated urothelium strips from diabetic bladder showed an increased level of prostaglandins (E2 and F2a) as compared to normal strips. ATP and bradykinin stimulates the release of prostaglandins from urothelial cells. It is believed that increased diabetic bladder sensitivity to the contractile factor is mediated via prostaglandins-dependent pathways [18].
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inhibitory neurotransmitter affecting the afferent and efferent branch of the nervous system. Ozawa et al. [21] described that NO instilled into urinary bladder leads suppression of detrusor contraction, and that the NO synthase (NOS) blockers provoked the opposite effect. Moreover, NO suppress dopamine and norepinephrine reuptake from motor neurons. Munoza et al. [22] defined a parameter (potential biomarker) such a ATP/NO ratio which reflects the urinary bladder sensory transmission and its dysfunction (OAB or UAB). High or low values of ATP/NO ratio were observed in DO and DU respectively. ATP and NO release have a respectively positive and negative correlation with detrusor contraction frequency. The role of ATP and NO was confirmed in diabetic DU model. In the case of diabetes mellitus the DU was characterized by increased NO release with simultaneous release of ATP at physiological ranges. It is also postulated that DU is caused by two parallel mechanisms such as: (1) diminished activity of purinergic receptors P2X3 and (2) up-regulation of neuronal NO synthase (nNOS) providing greater synthesis of NO. NO may also directly damage detrusor via increased oxidative stress and proteasoms activations within urinary bladder wall. Previous studies of Poladia and Bauer [23] described that different isozymes of NO synthase (NOS) such as inducible (iNOS), neuronal (nNOS) and endothelial (eNOS) are up-regulated in urothelium, lamina propria and smooth muscle cells. CGRP- and/or SP- and/or dopamine-dependent pathway Animal studies showed that with ageing, the level of calcitonin gene-related peptide (CGRP) and SP in lumbosacral dorsal root ganglion neurons decreases. Also, the reduction of nerves containing CGRP and SP within detrusor were observed [24]. In general patients with Parkinson’s disease (PD) present DO; however, some of them may develop DU. In monkeys with PD dopamine D1 receptor agonists administration increase the urinary bladder volume and intravesical threshold pressure inducing micturition [25]. Thus, dopamine-dependent pathway may be present in pathomechanism of DU development. Further research is needed to explain this hypothesis. NGF-dependent pathway Urothelium and detrusor muscle release NGF. NGF is believed to modulate urothelium function due to different stimuli especially in diabetic cystopathy. In rats with streptozotocin-induced diabetes, the decreased NGF level was observed within the urinary bladder, bladder afferent innervations and in dorsal root ganglia (L6 and S1) [26,27]. Moreover, Sasaki et al. [28] described that NGF-gene therapy reverses detrusor underactivity in rats. These facts show a potential role of NGF in pathogenesis of DU. Muscarinic M2 receptor and Agrin-dependent pathway
ATP- and NO-dependent pathways Neurotransmitters such as ATP and NO affect urinary bladder activity. ATP and NO are released from the urothelium in the bladder. Previous studies showed that ATP via purinergic receptors P2X3 of afferent nerve endings and urothelial cells activate afferent pathways innervating lower urinary tract [19]. ATP and NO have two different effects on the urinary bladder. One of the most common stimulus for ATP and NO release is bladder wall stretch. Pandita et al. [20] results revealed that intravesically ATP administration induces urinary bladder overactivity, which depends on concentration. ATP leads to decrement of bladder capacity and voided volumes with increment of intravesical pressures (basal and during micturition). NO is believed as an
The rat model of DU induced by lumbar canal stenosis presented down-regulation of agrin proteins and up-regulation of muscarinic M2 receptors within the urinary bladder [29]. Agrin is a molecule produced by motor neurons that induces the aggregation of nicotinic ACh receptors. Thus, agrin proteins- and M2 receptor-dependent pathways should be considered as a potential molecular targets for DU therapy. Conclusion DU is a widespread disease. However, due to mulitfactorial etiopathogenesis DU remains a poorly understood urinary bladder dysfunction. The armamentarium of DU management is sparse.
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Still, indwelling or intermittent catheterization remain recommended and a conventional option. The beneficial response of patients with DU to available treatment options is limited due to its efficacy and tolerability, in addition to side-effects. Therefore, the lack of effective treatment strategies in DU creates the need for further research in this field. Close cooperation between urologists and pharmacologists should be maintained for optimal research on DU therapy. Conflict of interests None declared. References [1] Kosilov K, Loparev S, Iwanowskaya M, Kosilova L. Effectiveness of combined high-dosed trospium and solifenacin depending on severity of OAB symptoms in elderly men and women under cyclic therapy. Cent Eur J Urol 2014;67(1): 43–8. [2] Malki M, Mangera A, Reid S, Inman R, Chapple C. What is the feasibility of switching to 200IU OnabotulinumtoxinA in patients with detrusor overactivity who have previously received 300IU? Cent Eur J Urol 2014;67(1):35–40. [3] Osman NI, Chapple CR, Abrams P, Dmochowski R, Haab F, Nitti V, et al. Detrusor underactivity and the underactive bladder: a new clinical entity? A review of current terminology, definitions, epidemiology, aetiology, and diagnosis. Eur Urol 2014;65(2):389–98. [4] Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167–78. [5] Chapple CR, Osman NI, Birder L, van Koeveringe GA, Oelke M, Nitti VW, et al. The underactive bladder: a new clinical concept? Eur Urol 2015;68(3):351–3. [6] Brierly RD, Hindley RG, McLarty E, Harding DM, Thomas PJ. A prospective controlled quantitative study of ultrastructural changes in the underactive detrusor. J Urol 2003;169(4):1374–8. [7] Drake MJ, Harvey IJ, Gillespie JI, Van Duyl WA. Localized contractions in the normal human bladder and in urinary urgency. BJU Int 2005;95(7):1002–5. [8] Tyagi P, Smith PP, Kuchel GA, de Groat WC, Birder LA, Chermansky CJ, et al. Pathophysiology and animal modeling of underactive bladder. Int Urol Nephrol 2014;46(1):S11–21. [9] Azadzoi KM, Radisavljevic ZM, Siroky MB. Effects of ischemia on tachykinincontaining nerves and neurokinin receptors in the rabbit bladder. Urology 2008;71(5):979–83. [10] Kim JC, Park EY, Seo SI, Park YH, Hwang TK. Nerve growth factor and prostaglandine in the urine of female patients with overactive bladder. J Urol 2006;175:1773–6. [11] Torimoto K, Fraser MO, Hirao Y, De Groat WC, Chancellor MB, Yoshimura N. Urethral dysfunction in diabetic rats. J Urol 2004;171:1959–64. [12] Chai TC, Andersson KE, Tuttle JB, Steers WD. Altered neural control of micturition in the aged F344 rat. Urol Res 2000;28:348–54.
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