BRL37344, a β3-adrenergic Receptor Agonist, Decreases Nerve-evoked Contractions in Human Detrusor Smooth Muscle Isolated Strips: Role of BK Channels

• Published in: Urology (Ridgewood, N.J.) N.J.), 2013-09, Vol.82 (3), p.744.e1-744.e7
• Main Authors: Afeli, Serge A.Y, Rovner, Eric S, Petkov, Georgi V
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Adrenergic beta-3 Receptor Agonists - pharmacology; Aged; Atropine - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation; Ethanolamines - pharmacology; Female; Humans; In Vitro Techniques; Large-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Large-Conductance Calcium-Activated Potassium Channels - physiology; Male; Middle Aged; Muscarinic Antagonists - pharmacology; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth - drug effects; Muscle, Smooth - innervation; Peptides - pharmacology; Potassium Channel Blockers - pharmacology; Purinergic Agonists - pharmacology; Purinergic Antagonists - pharmacology; Suramin - pharmacology; Urinary Bladder - physiology; Urology
• ISSN: 0090-4295; 1527-9995
• DOI: 10.1016/j.urology.2013.05.027

Objective To investigate the mechanism by which BRL37344, a β3-adrenergic receptor (β3-ARs) agonist, facilitates the inhibition of nerve-evoked contractions in human detrusor smooth muscle (DSM) isolated strips and to identify the role of large-conductance Ca2+ -activated K+ (BK) channels in this process. Methods Human DSM specimens were obtained from open bladder surgeries on patients without preoperative history of overactive bladder symptoms. Isometric DSM tension recordings were conducted using force-displacement transducers and thermostatically controlled tissue baths. Nerve-evoked contractions were generated by electrical field stimulation (EFS). Results BRL37344, a β3-AR agonist, significantly decreased the amplitude, muscle force, and duration of the DSM contractions induced by 20 Hz EFS, in a concentration-dependent manner. This BRL37344-mediated inhibition of the amplitude and muscle force of the nerve-evoked DSM contraction was significantly reduced by iberiotoxin, a highly selective inhibitor of the BK channel, revealing a role for BK channels in the β3-AR-induced inhibition of human DSM nerve-evoked contractions. We further used atropine, α,β-methylene-ATP, and suramin to separate the cholinergic and purinergic components of human DSM nerve-evoked contractions. We found that the β3-AR agonist, BRL37344, inhibited both components of the EFS-induced (0.5-50 Hz) DSM contractions. Conclusion This study supports the concept that β3-AR agonists inhibit nerve-evoked contractions in human DSM. We have further revealed that BK channels play a critical role in BRL37344-mediated relaxation of nerve-evoked contractions in human DSM. The study suggests that in addition to β3-ARs, BK channels may also represent promising pharmacologic targets in the treatment of urinary bladder dysfunction.