Obstruction-induced changes in urinary bladder smooth muscle contractility: a role for Rho kinase.
Detrusor smooth muscle (DSM) undergoes hypertrophy after partial bladder outlet obstruction (PBOO) in male rabbits, as it does in men with PBOO induced by benign prostatic hyperplasia. Despite detrusor hypertrophy, some bladders are severely dysfunctional (decompensated). In this study, the rabbit model for PBOO was used to determine the biochemical regulation of the contractile apparatus and force maintenance by the detrusor from decompensated bladders (DB). Bladders from sham-operated rabbits served as a control. On stimulation with 125 mM KCl, the DSM from sham-operated (SB) rabbits showed phasic contractions, whereas the detrusor from DB was tonic, exhibiting slow development of force, a longer duration of force maintenance, and slow relaxation. The Rho kinase (ROK) inhibitor Y-27632 enhanced the relaxation of precontracted DSM strips from DB. The enhancement of relaxation of the KCl-induced contraction of DB by Y-27632 was associated with dephosphorylation of myosin light chain (MLC20). The DSM extract from DB showed low phosphatase activity compared with that from SB. The DB also showed more Ca2+-independent MLC20 phosphorylation, which was partially inhibited by Y-27632. RT-PCR and Western blotting revealed similar expression levels of MLC kinase and ROK-alpha in SB and DB, but ROK-beta was overexpressed in DB. These results suggest that the ROK-mediated pathway is partly responsible for the high degree of force maintenance and slow relaxation in the detrusor from DB.
Bing
Wu
W
Department of Pathobiology, University of Pennsylvania, Philadelphia 19104, USA.
Chang
Shaohua
S
Hypolite
Joseph A
JA
DiSanto
Michael E
ME
Zderic
Stephen A
SA
Rolf
Lester
L
Wein
Alan J
AJ
Chacko
Samuel
S
D000577:Amides / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006984:Hypertrophy; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000473:pathology / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D001748:Urinary Bladder Neck Obstruction / Q000473:pathology / Q000503:physiopathology*; D054460:rho-Associated Kinases
D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D018994:Myosin Light Chains; D011725:Pyridines; D012333:RNA, Messenger; C108830:Y 27632; D011189:Potassium Chloride; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase