REGULATION OF DETRUSOR SMOOTH MUSCLE CONTRACTION

Summary

Principal Investigator: PAUL RATZ
Abstract: Overactive bladder is a debilitating disorder characterized by increased urinary frequency, urgency or incontinence. In the US, overactive bladder is a more common chronic condition than diabetes or peptic ulcer, yet, for most cases, the etiology of overactive bladder remains unknown. The aim of current pharmacologic treatment of overactive bladder has fallen short of its target to selectively reduce involuntary activity of detrusor smooth muscle (DSM) without affecting other organs, and to reduce detrusor contractions during bladder filling, and not during voiding. The discovery of novel pharmacological agents for the treatment of overactive bladder awaits the identification of regulatory mechanisms specific to DSM contraction. The long-term goal of my laboratory is to precisely identify the subcellular mechanisms that regulate DSM contractile protein activation, and to identify therapeutic agents to treat urinary conditions such as overactive bladder. Smooth muscle contractions occur when stimuli elevate [Ca2+]i. However, recent studies demonstrate that increased sensitivity of contractile proteins to Ca2+ represents an equally important regulatory mechanism. The recent discovery that overactivity of vascular smooth muscle Ca2+-sensitization is involved in the pathophysiology of hypertension has provided the impetus to study and understand the physiology of Ca2+-sensitization in all smooth muscle types. This discovery also raises the possibility that overactive Ca2+-sensitization contributes to overactive bladder. Aim 1 will test the hypothesis that Ca2+-sensitivity plays an essential role in regulation of OSM contractions. Whether RhoA kinase, phospholipase A2-generated arachidonic acid or extracellular signal-regulated kinase (ERK)-activated caldesmon phosphorylation, participate in Ca2+-sensitization-induced contractions will be tested, and the specific role M2 receptors play in this pathway will be determined. Aim 2 will test the hypothesis that detrusor-stretch and beta adrenergic receptor stimulation relax DSM by activating cAMP-dependent protein kinase, which reduces [Ca2+]i and Ca2+-sensitivity. The degree to which telokin phosphorylation, inactivation of RhoA, and reductions in ERK-induced caldesmon phosphorylation participate in reduced Ca2+-sensitivity will be elucidated. Collectively, these studies will provide new insights into the cellular mechanisms regulating DSM contractions.
Funding Period: 2002-04-01 - 2007-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal
    Clinton Collins
    Department of Surgery, Urology Division, Virginia Commonwealth University School of Medicine, VA 23298 0614, USA
    J Cell Mol Med 13:3236-50. 2009
  2. pmc Evidence that actomyosin cross bridges contribute to "passive" tension in detrusor smooth muscle
    Paul H Ratz
    Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 0614, USA
    Am J Physiol Renal Physiol 298:F1424-35. 2010
  3. ncbi ROK-induced cross-link formation stiffens passive muscle: reversible strain-induced stress softening in rabbit detrusor
    John E Speich
    Department of Mechanical Engineering, Virginia Commonwealth University, School of Medicine, 1101 E Marshall St, PO Box 980614, Richmond, Virginia 23298 0614, USA
    Am J Physiol Cell Physiol 289:C12-21. 2005
  4. ncbi A mechanical model for adjustable passive stiffness in rabbit detrusor
    John E Speich
    Department of Mechanical Engineering, Virginia Commonwealth University, 601 West Main St, P O Box 843015, Richmond, 23284 3015, USA
    J Appl Physiol (1985) 101:1189-98. 2006
  5. ncbi Adjustable passive length-tension curve in rabbit detrusor smooth muscle
    John E Speich
    Dept of Mechanical Engineering, Virginia Commonwealth University, Richmond, VA 23284 3015, USA
    J Appl Physiol (1985) 102:1746-55. 2007
  6. ncbi Sphingosine-1-phosphate and the immunosuppressant, FTY720-phosphate, regulate detrusor muscle tone
    Kenneth R Watterson
    Department of Biochemistry and Molecular Biology, VCU School of Medicine, 1101 E Marshall St, Richmond, VA 23298, USA
    FASEB J 21:2818-28. 2007
  7. pmc Stimulated calcium entry and constitutive RhoA kinase activity cause stretch-induced detrusor contraction
    Rainer N Poley
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, PO Box 980614, Richmond, VA 23298 0614, United States
    Eur J Pharmacol 599:137-45. 2008
  8. pmc Potentiation of carbachol-induced detrusor smooth muscle contractions by beta-adrenoceptor activation
    Adam P Klausner
    Department of Surgery Division of Urology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298 0614, United States
    Eur J Pharmacol 606:191-8. 2009

Scientific Experts

  • John E Speich
  • PAUL RATZ
  • Amy S Miner
  • Adam P Klausner
  • Clinton Collins
  • Rainer N Poley
  • Kenneth R Watterson
  • Harry P Koo
  • Keith F Rourke
  • Benjamin Herrick
  • Scott C Henderson
  • Christopher R Dosier
  • Robert Bittman
  • Dmitri Kapitonov
  • Shawn G Payne
  • Sarah Spiegel
  • Krystina M Berg
  • Sheldon Milstien

Detail Information

Publications8

  1. ncbi Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal
    Clinton Collins
    Department of Surgery, Urology Division, Virginia Commonwealth University School of Medicine, VA 23298 0614, USA
    J Cell Mol Med 13:3236-50. 2009
    ..Additional studies on prostaglandin-dependent SRC may generate opportunities for the application of novel treatments for disorders leading to overactive bladder...
  2. pmc Evidence that actomyosin cross bridges contribute to "passive" tension in detrusor smooth muscle
    Paul H Ratz
    Departments of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298 0614, USA
    Am J Physiol Renal Physiol 298:F1424-35. 2010
    ....
  3. ncbi ROK-induced cross-link formation stiffens passive muscle: reversible strain-induced stress softening in rabbit detrusor
    John E Speich
    Department of Mechanical Engineering, Virginia Commonwealth University, School of Medicine, 1101 E Marshall St, PO Box 980614, Richmond, Virginia 23298 0614, USA
    Am J Physiol Cell Physiol 289:C12-21. 2005
    ..Degradation of this signaling system could potentially contribute to urinary incontinence...
  4. ncbi A mechanical model for adjustable passive stiffness in rabbit detrusor
    John E Speich
    Department of Mechanical Engineering, Virginia Commonwealth University, 601 West Main St, P O Box 843015, Richmond, 23284 3015, USA
    J Appl Physiol (1985) 101:1189-98. 2006
    ..To explain these and previously identified characteristics, a mechanical model for adjustable passive stiffness is proposed based on the addition of a novel cross-linking element to a hybrid Kelvin/Voigt viscoelastic model...
  5. ncbi Adjustable passive length-tension curve in rabbit detrusor smooth muscle
    John E Speich
    Dept of Mechanical Engineering, Virginia Commonwealth University, Richmond, VA 23284 3015, USA
    J Appl Physiol (1985) 102:1746-55. 2007
    ....
  6. ncbi Sphingosine-1-phosphate and the immunosuppressant, FTY720-phosphate, regulate detrusor muscle tone
    Kenneth R Watterson
    Department of Biochemistry and Molecular Biology, VCU School of Medicine, 1101 E Marshall St, Richmond, VA 23298, USA
    FASEB J 21:2818-28. 2007
    ..Collectively, our results demonstrate that S1P may regulate detrusor smooth muscle tone and suggest that dysregulation of complex S1P signaling might contribute to OBS...
  7. pmc Stimulated calcium entry and constitutive RhoA kinase activity cause stretch-induced detrusor contraction
    Rainer N Poley
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, PO Box 980614, Richmond, VA 23298 0614, United States
    Eur J Pharmacol 599:137-45. 2008
    ..These data support the hypothesis that constitutive ROCK activity is required for a quick-stretch to activate Ca(2+) entry and cause a myogenic contraction of DSM...
  8. pmc Potentiation of carbachol-induced detrusor smooth muscle contractions by beta-adrenoceptor activation
    Adam P Klausner
    Department of Surgery Division of Urology, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298 0614, United States
    Eur J Pharmacol 606:191-8. 2009
    ..Moreover, beta-adrenoceptor stimulation changed the cellular mechanism by which carbachol produced contraction. The potential significance of multi-receptor and multi-cell crosstalk is discussed...