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Effects of Rho‐kinase inhibition on myosin light chain phosphorylation and obstruction‐induced detrusor overactivity
Author(s) -
Marx James O,
Basha Maureen E,
Mohanan Sunish,
Hypolite Joseph A,
Chang Shaohua,
Wein Alan J,
Zderic Stephen A,
Laping Nicholas J,
Chacko Samuel
Publication year - 2014
Publication title -
international journal of urology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.172
H-Index - 67
eISSN - 1442-2042
pISSN - 0919-8172
DOI - 10.1111/iju.12247
Subject(s) - myosin light chain kinase , phosphorylation , myosin , carbachol , medicine , overactive bladder , endocrinology , rho associated protein kinase , detrusor muscle , basal (medicine) , muscle contraction , urinary bladder , chemistry , biochemistry , pathology , stimulation , alternative medicine , insulin
Objectives To study the relationship between myosin light chain phosphorylation of the detrusor muscle and spontaneous smooth muscle contractions in a rabbit model of partial outlet obstruction. Methods N ew Z ealand white rabbit urinary bladders were partially obstructed for 2 weeks. Rabbits were euthanized, detrusor muscle strips were hung on a force transducer and spontaneous activity was measured at varying concentrations (0–0.03 μM/L) of the R ho‐kinase inhibitors GSK 576371 or 0.01 μM/L Y 27632. Basal myosin light chain phosphorylation was measured by 2‐ D gel electrophoresis in control and GSK 576371‐treated strips. Results Both drugs suppressed the force of spontaneous contractions, whereas GSK 576371 had a more profound effect on the frequency of the contractions. The IC 50 values for the inhibition of frequency and force of spontaneous contractions were 0.17 μM/L and 0.023 μM/L for GSK 576371, respectively. The compound significantly decreased the basal myosin light chain phosphorylation from 28.0 ± 3.9% to 13.5 ± 1.9% ( P < 0.05). At 0.01 μM/L, GSK 576371 inhibited spontaneous bladder overactivity by 50%, but inhibited carbachol‐elicited contractions force by just 25%. Conclusions These data suggest that Rho‐kinase regulation of myosin light chain phosphorylation contributes to the spontaneous detrusor activity induced by obstruction. This finding could have therapeutic implications by providing another therapeutic option for myogenic, overactive bladder.