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 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.