Role of Rac-GTPases for human detrusor contraction, growth of detrusor cells, and urodynamic regulation in vivo: mechanistic and functional investigations in preclinical models

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Overactive bladder syndrome (OAB) has a high prevalence in both sexes and all age groups, with negative impact on a person´s quality of life. From a pathophysiologic point of view, OAB is characterized by spontaneous contractions of bladder smooth muscle (detrusor), and concomitant bladder wall thickening. Current first line treatment options for irritative lower urinary tract symptoms (LUTS) caused by OAB include anticholinergics and beta3-agonists, to reduce detrusor contractions and symptoms. Even though these drugs have been shown to be effective and safe, a certain therapeutic ceiling has been reached, which is reflected by low adherence to these established medical therapies. Improved knowledge of detrusor contraction and hyperplasia provides the basis for understanding of current limits in therapy, and for development of future therapies.Rac GTPases are a group of small monomeric GTPases shown to participate in a broad spectrum of physiological processes. Among these functions, Rac isoforms have been proven to be involved in regulation of smooth muscle contraction and cell cycle in different organs. Latest findings from our group demonstrated a role of Rac, which promotes human prostate smooth muscle contraction and prostate smooth muscle cell growth. It appears reasonable to assume, that Rac has similar functions in bladder smooth muscle. Therefore, this project aims to find out effects of Rac inhibitors (NSC23766, EHT1864) on 1) contraction of human detrusor tissue, 2) growth of cultured bladder smooth muscle cells, and 3) micturition parameters in rats.