Blebbistain, a myosin II inhibitor, as a novel strategy to regulate detrusor contractility in a rat model of partial bladder outlet obstruction.

Abstract

Partial bladder outlet obstruction (PBOO), a common urologic pathology mostly caused by benign prostatic hyperplasia, can coexist in 40-45% of patients with overactive bladder (OAB) and is associated with detrusor overactivity (DO). PBOO that induces DO results in alteration in bladder myosin II type and isoform composition. Blebbistatin (BLEB) is a myosin II inhibitor we recently demonstrated potently relaxed normal detrusor smooth muscle (SM) and reports suggest varied BLEB efficacy for different SM myosin (SMM) isoforms and/or SMM vs nonmuscle myosin (NMM). We hypothesize BLEB inhibition of myosin II as a novel contraction protein targeted strategy to regulate DO. Using a surgically-induced male rat PBOO model, organ bath contractility, competitive and Real-Time-RT-PCR were performed. It was found that obstructed-bladder weight significantly increased 2.74-fold while in vitro contractility of detrusor to various stimuli was impaired ∼50% along with decreased shortening velocity. Obstruction also altered detrusor spontaneous activities with significantly increased amplitude but depressed frequency. PBOO switched bladder from a phasic-type to a more tonic-type SM. Expression of 5' myosin heavy chain (MHC) alternatively spliced isoform SM-A (associated with tonic-type SM) increased 3-fold while 3' MHC SM1 and essential light chain isoform MLC(17b) also exhibited increased relative expression. Total SMMHC expression was decreased by 25% while the expression of NMM IIB (SMemb) was greatly increased by 4.5-fold. BLEB was found to completely relax detrusor strips from both sham-operated and PBOO rats pre-contracted with KCl, carbachol or electrical field stimulation although sensitivity was slightly decreased (20%) only at lower doses for PBOO. Thus we provide the first thorough characterization of the response of rat bladder myosin to PBOO and demonstrate complete BLEB-induced PBOO bladder SM relaxation. Furthermore, the present study provides valuable evidence that BLEB may be a novel type of potential therapeutic agent for regulation of myogenic and nerve-evoked DO in OAB.

• Authors: Xinhua Zhang, Allen Seftel, Michael E DiSanto
• Journal: PloS one (PLoS One) Vol. 6 Issue 10 Pg. e25958 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22016792 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• Protein Isoforms
• blebbistatin
• Carbachol
• Myosin Type II

Topics

• Animals
• Carbachol (pharmacology)
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• In Vitro Techniques
• Male
• Muscle Contraction (drug effects)
• Muscle Relaxation (drug effects)
• Muscle, Smooth (drug effects, metabolism, physiopathology)
• Myosin Type II (antagonists & inhibitors, genetics, metabolism)
• Protein Isoforms (metabolism)
• Rats
• Urinary Bladder (drug effects, metabolism, physiopathology)
• Urinary Bladder Neck Obstruction (genetics, metabolism, physiopathology)