Rho-kinase inhibition suppresses potassium chloride-induced bladder hyperactivity in a rat model.
OBJECTIVE
The molecular mechanisms by which potassium induces urinary bladder hyperactivity are not clear. In the present study, we tested our hypothesis that potassium chloride (KCl)-induced bladder hyperactivity might be mediated through a calcium-sensitizing RhoA-Rho-kinase pathway in an in vivo animal model using urodynamic parameters.


METHODS
Two groups of adult male rats (n = 8) were anesthetized, their bladder exteriorized, and a saline-filled Intracath fixed into the bladder dome. This Intracath was connected to a pressure transducer and an infusion pump. Continuous filling cystometrograms were performed by infusing warm saline (0.04 mL/min) to obtain baseline data on each rat. The number of contractions per unit time (intercontractile intervals in seconds), pressure threshold, and peak pressure during micturition were recorded. To create bladder hyperactivity, protamine sulfate (30 mg/mL) followed by KCl (500 mM) was infused intravesically, and a continuous filling cystometrogram was again recorded. Y-27632, a specific RhoA-Rho-kinase inhibitor, was administered either intra-arterially (group 1) or intravesically (group 2) to each rat, and an additional continuous filling cystometrogram was recorded with KCl (500 mM) to observe the effects of Rho-kinase inhibition on bladder contractility.


RESULTS
Intravesical KCl infusion after protamine exposure resulted in significantly greater contractions and decreased the intercontractile interval (P <0.05). Y-27632 administration attenuated the effect of KCl on the contractions and intercontractile interval and decreased the mean pressure threshold.


CONCLUSIONS
Suppression of KCl-induced bladder contractility by the Rho-kinase inhibitor Y-27632 confirmed the involvement of this novel calcium-sensitizing RhoA-Rho-kinase pathway in mediating these smooth muscle contractions.
Rajasekaran
Mahadevan
M
Division of Urology, University of California, San Diego, Medical Center, San Diego, California 92103-8897, USA. mrajasek@ucsd.edu
Mehta
Neal
N
Baquir
Angelo
A
Kuntz
Steven
S
D000818:Animals; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D009119:Muscle Contraction; D011189:Potassium Chloride / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000503:physiopathology*; D014563:Urodynamics; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D011189:Potassium Chloride; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases