Investig Clin Urol.  2017 Dec;58(Suppl 2):S99-S106. 10.4111/icu.2017.58.S2.S99.

New therapeutic directions to treat underactive bladder

Affiliations
  • 1Department of Urology, Yale University School of Medicine, New Haven, CT, USA. toby.chai@yale.edu

Abstract

Underactive bladder (UAB) is a term used to describe a constellation of symptoms that is perceived by patients suggesting bladder hypocontractility. Urodynamic measurement that suggest decreased contractility of the bladder is termed detrusor underactivity (DUA). Regulatory approved specific management options with clinically proven ability to increase bladder contractility do not currently exist. While DUA specific treatments presumably will focus on methods to increase efficiency of bladder emptying capability relying on augmenting the motor pathway in the micturition reflex, other approaches include methods to augment the sensory (afferent) contribution to the micturition reflex which could result in increased detrusor contractility. Another method to induce more efficient bladder emptying could be to induce relaxation of the bladder outlet. Using cellular regenerative techniques, the detrusor smooth muscle can be targeted so the result is to increase detrusor smooth muscle function. In this review, we will cover areas of potential new therapies for DUA including: drug therapy, stem cells and regenerative therapies, neuromodulation, and urethral flow assist device. Paralleling development of new therapies, there also needs to be clinical studies performed that address how DUA relates to UAB.

Keyword

Detrusor underactivity; Future treatments; Underactive bladder

MeSH Terms

Drug Therapy
Humans
Methods
Muscle, Smooth
Reflex
Relaxation
Stem Cells
Urinary Bladder*
Urination
Urodynamics

Reference

1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003; 61:37–49.
2. Barendrecht MM, Oelke M, Laguna MP, Michel MC. Is the use of parasympathomimetics for treating an underactive urinary bladder evidence-based? BJU Int. 2007; 99:749–752.
3. Yamanishi T, Yasuda K, Kamai T, Tsujii T, Sakakibara R, Uchiyama T, et al. Combination of a cholinergic drug and an alpha-blocker is more effective than monotherapy for the treatment of voiding difficulty in patients with underactive detrusor. Int J Urol. 2004; 11:88–96.
4. Gilpin SA, Gilpin CJ, Dixon JS, Gosling JA, Kirby RS. The effect of age on the autonomic innervation of the urinary bladder. Br J Urol. 1986; 58:378–381.
5. Jiang YH, Kuo HC. Urothelial barrier deficits, suburothelial inflammation and altered sensory protein expression in detrusor underactivity. J Urol. 2017; 197:197–203.
6. Taylor JA 3rd, Kuchel GA. Detrusor underactivity: clinical features and pathogenesis of an underdiagnosed geriatric condition. J Am Geriatr Soc. 2006; 54:1920–1932.
7. Yoshida M, Miyamae K, Iwashita H, Otani M, Inadome A. Management of detrusor dysfunction in the elderly: changes in acetylcholine and adenosine triphosphate release during aging. Urology. 2004; 63:3 Suppl 1. 17–23.
8. Heppner TJ, Werner ME, Nausch B, Vial C, Evans RJ, Nelson MT. Nerve-evoked purinergic signalling suppresses action potentials, Ca2+ flashes and contractility evoked by muscarinic receptor activation in mouse urinary bladder smooth muscle. J Physiol. 2009; 587(Pt 21):5275–5288.
9. Bayliss M, Wu C, Newgreen D, Mundy AR, Fry CH. A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol. 1999; 162:1833–1839.
10. Petkov GV. Role of potassium ion channels in detrusor smooth muscle function and dysfunction. Nat Rev Urol. 2011; 9:30–40.
11. Petkov GV. Central role of the BK channel in urinary bladder smooth muscle physiology and pathophysiology. Am J Physiol Regul Integr Comp Physiol. 2014; 307:R571–R584.
12. Sekido N, Kida J, Wakamatsu D, Okada H, Matsuya H. Effects of α1 antagonist and cholinesterase inhibitor on cystometric parameters in lumbar canal stenosis rats with underactive bladder. Urology. 2014; 84:1248.e9–1248.e15.
13. Smith PP. Aging and the underactive detrusor: a failure of activity or activation? Neurourol Urodyn. 2010; 29:408–412.
14. Eastham JE, Gillespie JI. The concept of peripheral modulation of bladder sensation. Organogenesis. 2013; 9:224–233.
15. Fry CH, Sui GP, Kanai AJ, Wu C. The function of suburothelial myofibroblasts in the bladder. Neurourol Urodyn. 2007; 26:6 Suppl. 914–919.
16. Nomiya M, Yamaguchi O, Akaihata H, Hata J, Sawada N, Kojima Y, et al. Progressive vascular damage may lead to bladder underactivity in rats. J Urol. 2014; 191:1462–1469.
17. Tykocki NR, Bonev AD, Longden TA, Heppner TJ, Nelson MT. Inhibition of vascular smooth muscle inward-rectifier K(+) channels restores myogenic tone in mouse urinary bladder arterioles. Am J Physiol Renal Physiol. 2017; 312:F836–F847.
18. Birder LA. Urothelial signaling. Auton Neurosci. 2010; 153:33–40.
19. Chai TC, Russo A, Yu S, Lu M. Mucosal signaling in the bladder. Auton Neurosci. 2016; 200:49–56.
20. Sun Y, Keay S, De Deyne PG, Chai TC. Augmented stretch activated adenosine triphosphate release from bladder uroepithelial cells in patients with interstitial cystitis. J Urol. 2001; 166:1951–1956.
21. Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000; 407:1011–1015.
22. Cho KJ, Koh JS, Choi J, Kim JC. Changes in adenosine triphosphate and nitric oxide in the urothelium of patients with benign prostatic hyperplasia and detrusor underactivity. J Urol. 2017; 198:1392–1396.
23. Chancellor MB. The overactive bladder progression to underactive bladder hypothesis. Int Urol Nephrol. 2014; 46:Suppl 1. S23–S27.
24. Lu YT, Tingskov SJ, Djurhuus JC, Nørregaard R, Olsen LH. Can bladder fibrosis in congenital urinary tract obstruction be reversed? J Pediatr Urol. 2017; 09. 28. [Epub]. pii: S1477-5131(17)30385-6. DOI: 10.1016/j.jpurol.2017.08.013.
25. Austin PF, Casale AJ, Cain MP, Rink RC, Weintraub SJ. Lipopolysaccharide and inflammatory cytokines cause an inducible nitric oxide synthase-dependent bladder smooth muscle fibrotic response. J Urol. 2003; 170(2 Pt 1):645–648.
26. Schröder A, Newgreen D, Andersson KE. Detrusor responses to prostaglandin E2 and bladder outlet obstruction in wildtype and Ep1 receptor knockout mice. J Urol. 2004; 172:1166–1170.
27. Bergman A, Mushkat Y, Gordon D, David MP. Prostaglandin for enhancing bladder function after vaginal surgery. Does it work? J Reprod Med. 1992; 37:320–322.
28. Delaere KP, Thomas CM, Moonen WA, Debruyne FM. The value of intravesical prostaglandin E2 and F2 alpha in women with abnormalities of bladder emptying. Br J Urol. 1981; 53:306–309.
29. Desmond AD, Bultitude MI, Hills NH, Shuttleworth KE. Clinical experience with intravesical prostaglandin E2. A prospective study of 36 patients. Br J Urol. 1980; 52:357–366.
30. Hindley RG, Brierly RD, Thomas PJ. Prostaglandin E2 and bethanechol in combination for treating detrusor underactivity. BJU Int. 2004; 93:89–92.
31. Sekido N, Kida J, Mashimo H, Wakamatsu D, Okada H, Matsuya H. Promising effects of a novel EP2 and EP3 receptor dual agonist, ONO-8055, on neurogenic underactive bladder in a rat lumbar canal stenosis model. J Urol. 2016; 196:609–616.
32. Matsuya H, Sekido N, Kida J, Mashimo H, Wakamatsu D, Okada H. Effects of an EP2 and EP3 receptor dual agonist, ONO-8055, on a radical hysterectomy-induced underactive bladder model in monkeys. Low Urin Tract Symptoms. 2017; 04. 25. [Epub]. DOI: 10.1111/luts.12166.
33. Aikawa K, Sugino T, Matsumoto S, Chichester P, Whitbeck C, Levin RM. The effect of ovariectomy and estradiol on rabbit bladder smooth muscle contraction and morphology. J Urol. 2003; 170(2 Pt 1):634–637.
34. Eika B, Salling LN, Christensen LL, Andersen A, Laurberg S, Danielsen CC. Long-term observation of the detrusor smooth muscle in rats. Its relationship to ovariectomy and estrogen treatment. Urol Res. 1990; 18:439–442.
35. Persson K, Svane D, Glavind B, Uvelius B, Forman A, Andersson KE. Effects of ovariectomy on mechanical properties and collagen content in rabbit lower urinary tract smooth muscle. Scand J Urol Nephrol. 1996; 30:7–14.
36. Zhu Q, Ritchie J, Marouf N, Dion SB, Resnick NM, Elbadawi A, et al. Role of ovarian hormones in the pathogenesis of impaired detrusor contractility: evidence in ovariectomized rodents. J Urol. 2001; 166:1136–1141.
37. Hoffman GE, Merchenthaler I, Zup SL. Neuroprotection by ovarian hormones in animal models of neurological disease. Endocrine. 2006; 29:217–231.
38. Sharma AK, Fuller NJ, Sullivan RR, Fulton N, Hota PV, Harrington DA, et al. Defined populations of bone marrow derived mesenchymal stem and endothelial progenitor cells for bladder regeneration. J Urol. 2009; 182:4 Suppl. 1898–1905.
39. Chen S, Zhang HY, Zhang N, Li WH, Shan H, Liu K, et al. Treatment for chronic ischaemia-induced bladder detrusor dysfunction using bone marrow mesenchymal stem cells: an experimental study. Int J Mol Med. 2012; 29:416–422.
40. Dayanc M, Kibar Y, Ural AU, Onguru O, Yildiz O, Irkilata HC, et al. The histopathologic, pharmacologic and urodynamic results of mesenchymal stem cell's injection into the decompensated rabbit's bladder. Stem Cell Rev. 2012; 8:1245–1253.
41. Alimperti S, You H, George T, Agarwal SK, Andreadis ST. Cadherin-11 regulates both mesenchymal stem cell differentiation into smooth muscle cells and the development of contractile function in vivo. J Cell Sci. 2014; 127(Pt 12):2627–2638.
42. Yokoyama T, Huard J, Pruchnic R, Yoshimura N, Qu Z, Cao B, et al. Muscle-derived cell transplantation and differentiation into lower urinary tract smooth muscle. Urology. 2001; 57:826–831.
43. Lu SH, Wei CF, Yang AH, Chancellor MB, Wang LS, Chen KK. Isolation and characterization of human muscle-derived cells. Urology. 2009; 74:440–445.
44. Levanovich PE, Diokno A, Hasenau DL, Lajiness M, Pruchnic R, Chancellor MB. Intradetrusor injection of adult muscle-derived cells for the treatment of underactive bladder: pilot study. Int Urol Nephrol. 2015; 47:465–467.
45. Gonçalves MA, Holkers M, Cudré-Mauroux C, van Nierop GP, Knaän-Shanzer S, van der Velde I, et al. Transduction of myogenic cells by retargeted dual high-capacity hybrid viral vectors: robust dystrophin synthesis in duchenne muscular dystrophy muscle cells. Mol Ther. 2006; 13:976–986.
46. Tirney S, Mattes CE, Yoshimura N, Yokayama T, Ozawa H, Tzeng E, et al. Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid, adenovirus, and adenovirustransduced myoblast vectors. Mol Urol. 2001; 5:37–43.
47. Goins WF, Yoshimura N, Phelan MW, Yokoyama T, Fraser MO, Ozawa H, et al. Herpes simplex virus mediated nerve growth factor expression in bladder and afferent neurons: potential treatment for diabetic bladder dysfunction. J Urol. 2001; 165:1748–1754.
48. Kajbafzadeh AM, Sharifi-Rad L, Ladi-Seyedian SS, Mozafarpour S. Transcutaneous interferential electrical stimulation for the management of non-neuropathic underactive bladder in children: a randomised clinical trial. BJU Int. 2016; 117:793–800.
49. Chen SC, Lai CH, Fan WJ, Peng CW. Pudendal neuromodulation improves voiding efficiency in diabetic rats. Neurourol Urodyn. 2013; 32:293–300.
50. Gross C, Habli M, Lindsell C, South M. Sacral neuromodulation for nonobstructive urinary retention: a meta-analysis. Female Pelvic Med Reconstr Surg. 2010; 16:249–253.
51. Hennessey DB, Hoag N, Gani J. Sacral neuromodulation for detrusor hyperactivity with impaired contractility. Neurourol Urodyn. 2017; 36:2117–2122.
52. Goh M, Diokno AC. Sacral neuromodulation for nonobstructive urinary retention--is success predictable? J Urol. 2007; 178:197–199.
53. Chang A, Butler S, Sliwoski J, Valentino R, Canning D, Zderic S. Social stress in mice induces voiding dysfunction and bladder wall remodeling. Am J Physiol Renal Physiol. 2009; 297:F1101–F1108.
54. Desjardins C, Maruniak JA, Bronson FH. Social rank in house mice: differentiation revealed by ultraviolet visualization of urinary marking patterns. Science. 1973; 182:939–941.
55. Hou XH, Hyun M, Taranda J, Huang KW, Todd E, Feng D, et al. Central control circuit for context-dependent micturition. Cell. 2016; 167:73–86.e12.
56. Peng CW, Lin YT, Chen SC, Kuo TS. Pudendal neuromodulation with a closed-loop control strategy to improve bladder functions in the animal study. Conf Proc IEEE Eng Med Biol Soc. 2013; 2013:3626–3629.
57. Hokanson JA, Langdale CL, Sridhar A, Grill WM. Stimulation of the sensory pudendal nerve increases bladder capacity in the rat. Am J Physiol Renal Physiol. 2017; 11. 15. [Epub]. DOI: 10.1152/ajprenal.00373.2017.
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