Skip to main content

Advertisement

SpringerLink
Log in

Lower urinary tract physiology and pharmacology

  • Published:
Current Urology Reports Aims and scope Submit manuscript

Abstract

This review focuses on what we consider to be the most important findings of the last year relating to the smooth muscle of the lower urogenital system and the different levels of regulation that control its contraction and relaxation. One level is through modulation of the smooth muscle itself or its environment. Recent findings examining myosin isoform composition and collagen content as well as mechanisms that appear to be involved in inducing hyperplasia/hypertrophy of smooth muscle are described. Another method of regulation is via calcium-dependent phosphorylation of the regulatory light chain of myosin, which increases its activity. Interesting results indicating an uncoupling of force from calcium in the bladder are discussed. A third level of regulation is pharmacologic. Thus, the most recent findings related to receptor subtypes, including muscarinic, endothelin, α-adrenergic and nicotinic receptors, are presented. In addition, the effects of diabetes, incontinence, and partial bladder outlet obstruction on these modes of contractile regulation are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Arens YH, Rosenfeld CR, Kamm KE: Maturational differences between vascular and bladder smooth muscle during ovine development. Am J Physiol 2000, 278:R1305-R1313.

    CAS  Google Scholar 

  2. Kuro-o M, Nagai R, Tsuchimochi H, et al.: Developmentally regulated expression of vascular smooth muscle myosin heavy chain isoforms. J Biol Chem 1989, 264:18272–18275.

    PubMed  CAS  Google Scholar 

  3. Kelley CA, Takahashi M, Yu JH, Adelstein RS: An insert of seven amino acids confers functional differences between smooth muscle myosins from the intestines and vasculature. J Biol Chem 1993, 268:12848–12854.

    PubMed  CAS  Google Scholar 

  4. DiSanto ME, Cox RH, Wang Z, Chacko S: NH2-terminalinserted myosin II heavy chain is expressed in smooth muscle of small muscular arteries. Am J Physiol 1997, 272:C1532-C1542.

    PubMed  CAS  Google Scholar 

  5. DiSanto ME, Wang Z, Menon C, et al.: Expression of myosin isoforms in smooth muscle cells in the corpus cavernosum penis. Am J Physiol 1998, 275:C976-C987.

    PubMed  CAS  Google Scholar 

  6. White SL, Zhou MY, Low RB, Periasamy M: Myosin heavy chain isoform expression in rat smooth muscle development. Am J Physiol 1998, 275:C581-C589.

    PubMed  CAS  Google Scholar 

  7. Watanabe N, Kurabayashi M, Shimomura Y, et al.: BTEB2, a Kruppel-like transcription factor, regulates expression of the SMemb/nonmuscle myosin heavy chain B (SMemb/ NMHC-B) gene. Circ Res 1999, 85:182–191. A transcription factor (BTEB2) that regulates the expression of a nonmuscle type of myosin expressed at high levels in embryonic smooth muscle has been identified. This is one of the first transcriptional factors identified for smooth muscle cell myosin and may provide a novel molecular target to control the differentiated state of the smooth muscle cell in the bladder.

    PubMed  CAS  Google Scholar 

  8. Chacko SK, DiSanto ME, Wein AJ: Changes in the composition of myosin isoforms in smooth muscle hypertrophy following urinary bladder outlet obstruction. Adv Org Biol 2000, 8:81–100.

    Article  CAS  Google Scholar 

  9. Shabsigh A, Hayek OR, Weiner D, et al.: Acute increase in blood flow to the rat bladder subsequent to partial bladder outlet obstruction. Neurourol Urodyn 2000, 19:195–206.

    Article  PubMed  CAS  Google Scholar 

  10. Gosling JA, Kung LS, Dixon JS, et al.: Correlation between the structure and function of the rabbit urinary bladder following partial outlet obstruction. J Urol 2000, 163:1349–1356.

    Article  PubMed  CAS  Google Scholar 

  11. Khan MA, Thompson CS, Angelini GD, et al.: Prostaglandins and cyclic nucleotides in the urinary bladder of a rabbit model of partial bladder outlet obstruction. Prostaglandins Leukot Essent Fatty Acids 1999, 61:307–314.

    Article  PubMed  CAS  Google Scholar 

  12. Inui E, Ochiai A, Naya Y, et al.: Comparative morphometric study of bladder detrusor between patients with benign prostatic hyperplasia and controls. J Urol 1999, 161:827–830. Only in BPH cases with an estimated bladder weight of greater than 60 g did a significant correlation exist between the ratio of connective tissue-to-smooth muscle and bladder weight. Thus, the role that collagen plays in the altered contractility observed in response to BOO may be limited to fibrotic bladders that are severely decompensated.

    Article  PubMed  CAS  Google Scholar 

  13. Zderic SA, Gong C, DiSanto M, et al.: Calcium ion homeostasis in urinary bladder smooth muscle [review]. Adv Exp Med Biol 1999, 462:155–169.

    PubMed  CAS  Google Scholar 

  14. Kim JC, Yoon JY, Seo SI, et al.: Effects of partial bladder outlet obstruction and its relief on types I and III collagen and detrusor contractility in the rat. Neurourol Urodyn 2000, 19:29–42.

    Article  PubMed  CAS  Google Scholar 

  15. Haberstroh KM, Kaefer M, Retik AB, et al.: The effects of sustained hydrostatic pressure on select bladder smooth muscle cell functions. J Urol 1999, 162:2114–2118. Exposure of bladder smooth muscle cells to sustained hydrostatic pressures can result in increased cell proliferation. This may explain the altered urinary bladder development observed in infants who undergo high urinary diversion and may also be part of the mechanism that induces smooth muscle cell hyperplasia in response to partial bladder outlet obstruction.

    Article  PubMed  CAS  Google Scholar 

  16. Park JM, Yang T, Arend LJ, et al.: Obstruction stimulates COX-2 expression in bladder smooth muscle cells via increased mechanical stretch. Am J Physiol 1999, 276:F129-F136.

    PubMed  CAS  Google Scholar 

  17. Chai TC, Zhang CO, Shoenfelt JL, et al.: Bladder stretch alters urinary heparin-binding epidermal growth factor and antiproliferative factor in patients with interstitial cystitis. J Urol 2000, 163:1440–1444.

    Article  PubMed  CAS  Google Scholar 

  18. Park JM, Adam RM, Peters CA, et al.: AP-1 mediates stretchinduced expression of HB-EGF in bladder smooth muscle cells. Am J Physiol 1999, 277:C294-C301.

    PubMed  CAS  Google Scholar 

  19. Park JM, Bauer SB, Freeman MR, Peters CA: Oxybutynin chloride inhibits proliferation and suppresses gene expression in bladder smooth muscle cells. J Urol 1999, 162:1110–1114.

    Article  PubMed  CAS  Google Scholar 

  20. Waring JV, Wendt IR: Effects of streptozotocin-induced diabetes mellitus on intracellular calcium and contraction of longitudinal smooth muscle from rat urinary bladder. J Urol 2000, 163:323–330. Muscle strips from diabetic rat bladder produced higher force in response to stimuli than controls even though calcium levels were not elevated. These results indicate an uncoupling of force and calcium and suggest that calcium-independent mechanisms of force production may be involved in the pathogenesis of bladder dysfunction in diabetes.

    Article  PubMed  CAS  Google Scholar 

  21. Chang S, Hypolite J, Wein AJ, et al.: Expression of myosin light chain kinase and Rho-associated kinase in corpus cavernosum smooth muscle. Biophys J 2000, 78:A139.

    Article  Google Scholar 

  22. Waring JV, Wendt IR: Effects of anoxia on force, intracellular calcium and lactate production of urinary bladder smooth muscle from control and diabetic rats. J Urol 2000, 163:1357–1363.

    Article  PubMed  CAS  Google Scholar 

  23. Weidelt T, Isenberg G: Augmentation of SR Ca(2+) release by rapamycin and FK506 causes K(+)-channel activation and membrane hyperpolarization in bladder smooth muscle. Br J Pharmacol 2000, 129:1293–1300.

    Article  PubMed  CAS  Google Scholar 

  24. Lluel P, Palea S, Barras M, et al.: Functional and morphological modifications of the urinary bladder in aging female rats. Am J Physiol 2000, 278:R964-R972.

    CAS  Google Scholar 

  25. Clemow DB, Spitsbergen JM, McCarty R, et al.: Altered NGF regulation may link a genetic predisposition for hypertension with hyperactive voiding. J Urol 1999, 161:1372–1377.

    Article  PubMed  CAS  Google Scholar 

  26. Chancellor MB, Yokoyama T, Tirney S, et al.: Preliminary results of myoblast injection into the urethra and bladder wall: a possible method for the treatment of stress urinary incontinence and impaired detrusor contractility. Neurourol Urodyn 2000, 19:279–287. The concept of trying to alter the contractile function of the bladder by introducing exogenous smooth muscle cells is shown to be

    Article  PubMed  CAS  Google Scholar 

  27. Hypolite JA, DiSanto ME, Wein AJ, Chacko S: Myosin light chain phosphorylation at resting level and the composition of myosin isoforms in the bladder body and urethra [review]. Scand J Urol Nephrol Suppl 1999, 201(suppl):46–50.

    Article  PubMed  CAS  Google Scholar 

  28. Xu DG, DiSanto ME, Hypolite JA, et al.: Expression of smooth muscle myosin SM-B isoform in different layers of rabbit urethra correlates with shortening velocity. Biophys J 2000, 78:A117.

    Google Scholar 

  29. Gomes CM, DiSanto ME, Horan P, et al.: Improved contractility of obstructed bladders after Tadenan treatment is associated with reversal of altered myosin isoform expression. J Urol 2000, 163:2008–2013. Molecular alterations in the smooth muscle myosin isoform composition induced by BOO can be reversed by a plant extract known as Tadenan. This reversal correlates with a near complete recovery of physiological function.

    Article  PubMed  CAS  Google Scholar 

  30. Levin RM, Riffaud JP, Bellamy F, et al.: Effects of tadenan pretreatment on bladder physiology and biochemistry following partial outlet obstruction. J Urol 1996, 156:2084–2088.

    Article  PubMed  CAS  Google Scholar 

  31. Shenfeld OZ, McCammon KA, Blackmore PF, Ratz PH: Rapid effects of estrogen and progesterone on tone and spontaneous rhythmic contractions of the rabbit bladder. Urol Res 1999, 27:386–392.

    Article  PubMed  CAS  Google Scholar 

  32. Pinna C, Zanardo R, Cignarella A, et al.: Diabetes influences the effect of 17beta-estradiol on mechanical responses of rat urethra and detrusor strips. Life Sci 2000, 66:617–627. Diabetes appears to potentiate the effect of ovariectomy on decreasing contractile response in the urethra. Estrogen replacement at an early stage can restore function, at least partially, in both diabetic and control animals.

    Article  PubMed  CAS  Google Scholar 

  33. Yono M, Yoshida M, Takahashi W, et al.: Effects of ovarian hormones on beta-adrenergic receptor-mediated relaxation in the female rabbit bladder. Urol Res 2000, 28:38–45.

    Article  PubMed  CAS  Google Scholar 

  34. Sanchez-Ortiz RF, Wang Z, Menon C, et al.: Estrogen modulates the expression of smooth muscle myosin in rabbit urinary bladder. J Urol 1999, 161:41.

    Article  Google Scholar 

  35. Naseem KM, Mumtaz FH, Thompson CS, et al.: Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: modulation by hydrogen peroxide. Eur J Pharmacol 2000, 387:329–335.

    Article  PubMed  CAS  Google Scholar 

  36. Mumtaz FH, Sullivan ME, Thompson CS, et al.: Alterations in the nitric oxide synthase binding sites and non-adrenergic, non-cholinergic mediated smooth muscle relaxation in the diabetic rabbit bladder outlet: possible relevance to the pathogenesis of diabetic cystopathy. J Urol 1999, 162:558–566.

    Article  PubMed  CAS  Google Scholar 

  37. Lemack GE, Zimmern PE, Vazquez D, et al.: Altered response to partial bladder outlet obstruction in mice lacking inducible nitric oxide synthase. J Urol 2000, 163:1981–1987.

    Article  PubMed  CAS  Google Scholar 

  38. Krichevsky VP, Pagala MK, Vaydovsky I, et al.: Function of M3 muscarinic receptors in the rat urinary bladder following partial outlet obstruction. J Urol 1999, 161:1644–1650.

    Article  PubMed  CAS  Google Scholar 

  39. Stengel PW, Gomeza J, Wess J, Cohen ML: M(2) and M(4) receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro. J Pharmacol Exp Ther 2000, 292:877–885. Mice in which the M(2) receptor has been ablated show a role for the M(2) receptor in urinary bladder smooth muscle contraction, whereas mice in which the M(4) receptor has been ablated suggest that M(4) receptors do not participate in bladder smooth muscle contraction.

    PubMed  CAS  Google Scholar 

  40. Braverman AS, Ruggieri MR: Selective alkylation of rat urinary bladder muscarinic receptors with 4-DAMP mustard reveals a contractile function for the M2 muscarinic receptor. J Recept Signal Transduct Res 1999, 19:819–833.

    PubMed  CAS  Google Scholar 

  41. Braverman A, Legos J, Young W, et al.: M2 receptors in genitourinary smooth muscle pathology. Life Sci 1999, 64:429–436.

    Article  PubMed  CAS  Google Scholar 

  42. Tong YC, Chin WT, Cheng JT: Alterations in urinary bladder M2-muscarinic receptor protein and mRNA in 2-week streptozotocin-induced diabetic rats. Neurosci Lett 1999, 277:173–176.

    Article  PubMed  CAS  Google Scholar 

  43. D’Agostino G, Bolognesi ML, Lucchelli A, et al.: Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: involvement of the M4 receptor subtype. Br J Pharmacol 2000, 129:493–500.

    Article  PubMed  CAS  Google Scholar 

  44. Barras M, Coste A, Eon MT, Guillot E: Pharmacological characterization of muscarinic receptors implicated in rabbit detrusor muscle contraction and activation of inositol phospholipid hydrolysis in rabbit detrusor and parotid gland. Fundam Clin Pharmacol 1999, 13:562–570.

    Article  PubMed  CAS  Google Scholar 

  45. Okamoto-Koizumi T, Takeda M, Komeyama T, et al.: Pharmacological and molecular biological evidence for ETA endothelin receptor subtype mediating mechanical responses in the detrusor smooth muscle of the human urinary bladder. Clin Sci 1999, 96:397–402.

    Article  PubMed  CAS  Google Scholar 

  46. Saito M, Wada Y, Ikeda K, et al.: Gene expression, localization, and pharmacological characterization of endothelin receptors in diabetic rat bladder dome. Eur J Pharmacol 2000, 387:253–263. Endothelin receptors are increased at both the mRNA and functional level in the rabbit bladder dome in response to diabetes and administration of insulin appears to reverse this increase. Autoradiographic studies demonstrated that the endothelin receptors were located in all tissue components of the bladder, including muscular layers, but did not specifically localize them to the smooth muscle cells themselves. These results may partly explain the altered contractility associated with diabetes.

    Article  PubMed  CAS  Google Scholar 

  47. Mumtaz FH, Dashwood MR, Thompson CS, et al.: Increased expression of endothelin B receptors in the diabetic rabbit urinary bladder: functional relevance. BJU Int 1999, 83:113–122.

    Article  PubMed  CAS  Google Scholar 

  48. Khan MA, Dashwood MR, Thompson CS, et al.: Up-regulation of endothelin (ET[A] and ET[B]) receptors and down-regulation of nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet obstruction. Urol Res 1999, 27:445–453.

    Article  PubMed  CAS  Google Scholar 

  49. Khan MA, Dashwood MR, Thompson CS, et al.: Up-regulation of endothelin-B (ETB) receptors and ETB receptor-mediated rabbit detrusor contraction in partial bladder outlet obstruction. BJU Int 1999, 84:714–719.

    Article  PubMed  CAS  Google Scholar 

  50. Khan MA, Dashwood MR, Thompson CS, et al.: Time-dependent up-regulation of endothelin-A receptors and down-regulation of endothelin-B receptors and nitric oxide synthase binding sites in the renal medulla of a rabbit model of partial bladder outlet obstruction: potential clinical relevance. BJU Int 1999, 84:1073–1080.

    Article  PubMed  CAS  Google Scholar 

  51. Khan MA, Dashwood MR, Thompson CS, et al.: Down-regulation of endothelin-B receptor sites in cavernosal tissue of a rabbit model of partial bladder outlet obstruction: potential clinical relevance. World J Urol 1999, 17:290–295.

    Article  PubMed  CAS  Google Scholar 

  52. Daniels DV, Gever JR, Jasper JR, et al.: Human cloned alpha1Aadrenoceptor isoforms display alpha1L-adrenoceptor pharmacology in functional studies. Eur J Pharmacol 1999, 370:337–343.

    Article  PubMed  CAS  Google Scholar 

  53. Nishimatsu H, Moriyama N, Hamada K, et al.: Contractile responses to alpha1-adrenoceptor agonists in isolated human male and female urethra. BJU Int 1999, 84:515–520.

    Article  PubMed  CAS  Google Scholar 

  54. de Groat WC, Yoshiyama M, Ramage AG, et al.: Modulation of voiding and storage reflexes by activation of alpha1-adrenoceptors [review]. Eur Urol 1999, 36(suppl):68–73.

    Article  PubMed  Google Scholar 

  55. Alberts P, Bergstrom PA, Fredrickson MG: Characterisation of the functional alpha-adrenoceptor subtype in the isolated female pig urethra. Eur J Pharmacol 1999, 371:31–38.

    Article  PubMed  CAS  Google Scholar 

  56. De Biasi M, Nigro F, Xu W: Nicotinic acetylcholine receptors in the autonomic control of bladder function. Eur J Pharmacol 2000, 393:137–140.

    Article  PubMed  Google Scholar 

  57. Davis B, Goepel M, Bein S, et al.: Lack of neuropeptide Y receptor detection in human bladder and prostate. BJU Int 2000, 85:918–924.

    Article  PubMed  CAS  Google Scholar 

  58. Gilbert AM, Antane MM, Argentieri TM, et al.: Design and SAR of novel potassium channel openers targeted for urge urinary incontinence. 2. Selective and potent benzylamino cyclobutenediones. J Med Chem 2000, 43:1203–1214.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Urology, 3010 Ravdin Courtyard, University of Pennsylvania, 3400 Spruce Street, 19104, Philadelphia, PA, USA

    Michael E. DiSanto PhD, Alan J. Wein MD & Samuel Chacko DVM, PhD

Authors
  1. Michael E. DiSanto PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan J. Wein MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel Chacko DVM, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

DiSanto, M.E., Wein, A.J. & Chacko, S. Lower urinary tract physiology and pharmacology. Curr Urol Rep 1, 227–234 (2000). https://doi.org/10.1007/s11934-000-0023-3

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11934-000-0023-3

Keywords

Search

Navigation