Rho-kinase inhibition suppresses potassium chloride-induced bladder hyperactivity in a rat model
Mahadevan Rajasekaran1, Neal Mehta, Angelo Baquir
1Division of Urology, University of California, San Diego, Medical Center, San Diego, California 92103-8897, USA. mrajasek@ucsd.edu
Objectives:
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.
Insights
Potassium chloride causes bladder hyperactivity through the RhoA-Rho-kinase pathway. Inhibition of this pathway with Y-27632 effectively reduced bladder contractions, suggesting a new therapeutic target.
Area of Science:
- Urology
- Molecular Biology
- Pharmacology
Background:
- The precise molecular mechanisms underlying potassium-induced urinary bladder hyperactivity remain unclear.
- Investigating these mechanisms is crucial for understanding and treating bladder dysfunction.
Purpose of the Study:
- To test the hypothesis that potassium chloride (KCl)-induced bladder hyperactivity is mediated by a calcium-sensitizing RhoA-Rho-kinase pathway.
- To evaluate the efficacy of a Rho-kinase inhibitor in an in vivo model of bladder hyperactivity.
Main Methods:
- Adult male rats underwent continuous filling cystometrograms to assess baseline bladder activity.
- Bladder hyperactivity was induced using intravesical protamine sulfate followed by KCl.
- The Rho-kinase inhibitor Y-27632 was administered intra-arterially or intravesically to assess its effect on KCl-induced hyperactivity.
Main Results:
- Intravesical KCl significantly increased bladder contractions and decreased the interval between contractions.
- Administration of Y-27632 attenuated KCl-induced bladder hyperactivity.
- Y-27632 also decreased the pressure threshold for bladder contractions.
Conclusions:
- The RhoA-Rho-kinase pathway plays a significant role in mediating KCl-induced bladder smooth muscle contractions.
- Inhibition of Rho-kinase effectively suppresses bladder hyperactivity, highlighting its potential as a therapeutic target.
