Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

College of Pharmacy

Sub-Department

Pharmaceutical Science

First Advisor

Georgi V Petkov

Abstract

Overactive bladder (OAB), often characterized by increased detrusor smooth muscle (DSM) contractility, is a chronic and highly prevalent condition affecting ~17% of the US population. Alterations in the myogenic or neurogenic activity of DSM serve as a basis for involuntary detrusor contractions associated with OAB. Under physiological conditions, the opening of potassium (K+) channels causes membrane hyperpolarization and limits the entry of Ca2+ and thus decreases DSM contractility. Among the various K+ channels, Ca2+-activated K+ (KCa) channels are important in regulating DSM function. Based on their biophysical properties, KCa channels are divided into large-conductance (BK), intermediate conductance (IK), and small-conductance (SK) channels. In the current project, we examined systematically how selective pharmacological activation of KCa channels modulates DSM contractility in animal models and humans. NS1619, a selective BK channel activator, and SKA-31, a selective SK/IK channel activator, were utilized as pharmacological tools to investigate the effects of KCa channel activation on DSM contractility. We detected the expression of all known isoforms of SK and IK channels at mRNA and protein levels in DSM. Pharmacological activation of KCa channels substantially attenuated DSM spontaneous phasic contraction amplitude, muscle force integral, frequency, duration, and muscle tone. This effect was blocked by KCa channel selective inhibitors. KCa channel activation also inhibited DSM contractions induced by the cholinergic agonist, carbachol, the depolarizing agent, KCl, or electrical field stimulation (EFS)-induced contractions.

Previous studies by our laboratory showed that activation of cAMP signaling pathways reduces DSM contractility by increasing the BK channel activity. Here, we tested the hypothesis whether inhibition of phosphodiesterases (PDEs), which hydrolyze cAMP, can reduce guinea pig DSM contractility by increasing BK channel activity. Inhibition of PDEs by 3-isobutyl-1-methylxanthine (IBMX), a non-selective PDEs inhibitor, significantly reduced DSM myogenic and neurogenic contractions in a concentration-dependent manner. Blocking the BK channels diminished the inhibitory effects of IBMX on DSM contractility indicating a role for BK channels in PDE inhibition-mediated DSM relaxation.

We conclude that targeting the KCa channels directly with selective openers or indirectly with PDE inhibitors may offer a unique opportunity to reduce abnormally increased DSM contractility, regardless of the underlying cause.

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