225 ADJUSTABLE PASSIVE STIFFNESS AND LENGTH ADAPTATION IN MOUSE DETRUSOR SMOOTH MUSCLE: A MECHANICAL MODEL FOR DISORDERS OF CONTRACTILITY AND OVERACTIVITY

Abstract

INTRODUCTION AND OBJECTIVES: Detrusor muscle is extremely compliant. Unlike skeletal muscle, which has a static lengthtension (L-T) curve, detrusor muscle has a L-T curve that shifts both actively and passively. We have termed these mechanical processes adjustable passive stiffness (APS) and length adaptation (LA). APS and LA likely underlie normal bladder function and account for its ability to undergo a sevenfold length change during filling and to contract efficiently throughout this range in volume and that the loss of APS and LA leads to disorders of contractility. These processes have been shown in rabbit detrusor muscle and are thought to exist across species. The purpose of this investigation is to demonstrate that the APS and LA exist in a mouse model which has a vast array of knockdowns and knockouts available. Understanding these processes will allow a more comprehensive understanding of disorders of contractility and overactive bladder, which may lead to identification of novel targets for the treatment of these disorders. METHODS: Mouse bladder strips were used. Two strips, one with and one without urothelium were created from each bladder. Both strips were hung vertically between clips attached to isometric force transducers. KCl or carbachol (CCh) was used to stimulate tissues. First, peak active tension (Lo) was found through a series of passive stretches with subsequent contractions. Next, three series of passive tension measurements were made at 50, 80, 90 and 95% of Lo to find APS. In a separate experiment, three consecutive contractions at Lo 1 mm (Lref) were completed to find adaptation. RESULTS: In bladder strips, passive tension at each length was increased if tissues were contracted at 50% Lo, but not increased if tissues were not contracted, revealing the existence of APS in the mouse bladder (p 0.05, N 5). Active tension in bladder strips at Lref in KCl with and without urothelium increased with successive contractions, confirming the presence of adaptation in the mouse bladder (p 0.05, N 4). This was also demonstrated in bladders contracted in CCh without urothelium (p 0.05, N 5). CONCLUSIONS: This is the first study to demonstrate that APS and adaptation occur in a mouse bladder model and seems to occur across species. Current studies show that these processes also occur in a whole bladder model. Further research into molecular pathways involved in these mechanical processes may identify novel therapies for treatment of disorders of bladder contractility and overactivity that are highly prevalent in our aging population.