In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin

Xinhua Zhang, Dwaraka Srinivasa R Kuppam, Arnold Melman, Michael E. Disanto

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

OBJECTIVE To investigate the in vitro and in vivo effects of blebbistatin (a small cell-permeable molecule with high affinity and selectivity toward the myosin II contractile molecule) on bladder smooth muscle (SM) contractility, as antimuscarinic therapy is only 65-75% effective in treating overactive bladder (OAB) and is associated with considerable side-effects, with a <25% continuation rate at 1 year. MATERIALS AND METHODS Bladder and aortic strips from adult male rats, and human bladder strips obtained from open prostatectomy, were used for organ-bath studies of blebbistatin. Awake cystometry was also used in rats in both the presence and absence of intravesically delivered blebbistatin. RESULTS Blebbistatin dose-dependently and completely relaxed both KCl- and carbachol-induced rat detrusor and endothelin-1-induced human bladder contraction. Pre-incubation with 10 Âμm blebbistatin attenuated carbachol responsiveness by ≈65% while blocking electrical field stimulation-induced bladder contraction reaching 50% inhibition at 32 Hz. The basal tone and amplitude of spontaneous contraction were also significantly diminished. Urodynamic variables were obviously altered by intravesical infusion with blebbistatin. CONCLUSION Our novel data show that blebbistatin strongly relaxes both rat and human bladder contraction induced by various physiological stimuli. Coupled with our in vivo data showing that nanomole doses of blebbistatin significantly alter urodynamic variables to produce a less active bladder, our results suggest the possibility of intravesically administered blebbistatin binding at myosin II being developed as a therapeutic treatment for OAB via a novel targeting of the SM contractile apparatus.

Original languageEnglish (US)
Pages (from-to)310-317
Number of pages8
JournalBJU International
Volume107
Issue number2
DOIs
StatePublished - Jan 2011

Fingerprint

Smooth Muscle Myosins
Myosin Type II
Urinary Bladder
Overactive Urinary Bladder
Urodynamics
Carbachol
Smooth Muscle
In Vitro Techniques
blebbistatin
Muscarinic Antagonists
Endothelin-1
Prostatectomy
Baths
Electric Stimulation
Therapeutics

Keywords

  • blebbistatin
  • cross-bridge cycling
  • detrusor overactivity
  • myosin
  • smooth muscle contraction

ASJC Scopus subject areas

  • Urology

Cite this

In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin. / Zhang, Xinhua; Kuppam, Dwaraka Srinivasa R; Melman, Arnold; Disanto, Michael E.

In: BJU International, Vol. 107, No. 2, 01.2011, p. 310-317.

Research output: Contribution to journalArticle

Zhang, Xinhua ; Kuppam, Dwaraka Srinivasa R ; Melman, Arnold ; Disanto, Michael E. / In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin. In: BJU International. 2011 ; Vol. 107, No. 2. pp. 310-317.
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abstract = "OBJECTIVE To investigate the in vitro and in vivo effects of blebbistatin (a small cell-permeable molecule with high affinity and selectivity toward the myosin II contractile molecule) on bladder smooth muscle (SM) contractility, as antimuscarinic therapy is only 65-75{\%} effective in treating overactive bladder (OAB) and is associated with considerable side-effects, with a <25{\%} continuation rate at 1 year. MATERIALS AND METHODS Bladder and aortic strips from adult male rats, and human bladder strips obtained from open prostatectomy, were used for organ-bath studies of blebbistatin. Awake cystometry was also used in rats in both the presence and absence of intravesically delivered blebbistatin. RESULTS Blebbistatin dose-dependently and completely relaxed both KCl- and carbachol-induced rat detrusor and endothelin-1-induced human bladder contraction. Pre-incubation with 10 {\^A}μm blebbistatin attenuated carbachol responsiveness by ≈65{\%} while blocking electrical field stimulation-induced bladder contraction reaching 50{\%} inhibition at 32 Hz. The basal tone and amplitude of spontaneous contraction were also significantly diminished. Urodynamic variables were obviously altered by intravesical infusion with blebbistatin. CONCLUSION Our novel data show that blebbistatin strongly relaxes both rat and human bladder contraction induced by various physiological stimuli. Coupled with our in vivo data showing that nanomole doses of blebbistatin significantly alter urodynamic variables to produce a less active bladder, our results suggest the possibility of intravesically administered blebbistatin binding at myosin II being developed as a therapeutic treatment for OAB via a novel targeting of the SM contractile apparatus.",
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