(The FASEB Journal. 2007;21:949.12)
© 2007 FASEB
Mechanistic Studies of Detrusor over Activity in Male Rats Following Partial Urethral Obstruction: Implications to Identification of Novel Therapeutics
Tamer Aboushwareb,
Yagna P.R. Jarajapu,
Steve Blaha,
Steve Hodges,
Chanda Turner,
Weixin Zhao,
Karl-Erik Andersson and
George J. Christ
Wake Forest University, Wake Forest Institute for Regenerative Medicine and Dept. of Physiology & Pharmacology, Medical Center Boulevard, Winston-Salem, NC, 27157
ABSTRACT
Millions of US patients suffer from urinary urgency and/or incontinence related to detrusor over activity (DO). The goal of this study was to improve mechanistic understanding of DO and leverage these insights to develop novel treatment options. DO was identified by in vivo cystometry in 28 male Sprague-Dawley rats 2 weeks after surgical placement of a ligature on the proximal urethra to produce partial urethral outflow obstruction (PUO). 7 sham-operated male rats served as age-matched controls. Despite similar degrees of obstruction/hypertrophy, strips from obstructed DO rats had higher contractile responses to carbachol (Car) (p<0.001) than obstructed non-DO and control rats. Car-induced steady-state increases in the intracellular cytosolic calcium levels were higher in DO strips (p<0.01) compared to control. Contractile responses to EFS were reduced in both DO and non-DO strips compared to control (p<0.05). Real-Time PCR techniques revealed that 4 of 7 molecular targets (i.e Alpha 1c, ROCK1, CPI-17, and RhoA) had higher transcript levels in hyperactive animals (p< 0.05; Exact Wilcoxon rank sum test). DO is associated with increased Car-induced detrusor contractility and parallel increases in the steady-state intracellular calcium levels and these changes correlated with increased transcript expression for several molecular targets known to be important to enhanced detrusor myocyte contractile.
