title: Rho-kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats.
abstract: OBJECTIVE
  Spontaneously hypertensive rats (SHR) exhibit overactive bladder (OAB) symptoms and have an up-regulated calcium sensitizing RhoA/Rho-kinase pathway in their vascular smooth muscle tissues. This study examined the role of RhoA/Rho-kinase pathway in bladder hyperactivity by evaluating the effect of a specific Rho-kinase inhibitor (Y-27632) on SHR bladder function.
  
  
  METHODS
  Adult male SHR (n = 9) and their normotensive controls (Wistar-Kyoto; WKY) (n = 8) were anesthetized and the carotid artery cannulated for blood pressure monitoring. A catheter was fixed into the bladder dome and connected to a pressure transducer and an infusion pump. After equilibration, systemic and bladder pressure were recorded. Continuous filling cystometrograms (CMGs) were performed and threshold pressure (TP), peak pressure (PP), and number of voids and non-voiding contractions (NVCs) per unit time recorded. Each SHR then received Y-27632, 10 mumol intra-arterially. After 10 min, CMG was repeated and the same measurements recorded. Bladder tissues were evaluated immunohistochemically (IHC) for RhoA protein expression.
  
  
  RESULTS
  SHR exhibited significantly higher number of voids and NVCs than normotensive WKY rats (P < 0.05). In SHR, Y-27362 administration significantly decreased the number of voids (29%, from 0.83 +/- 0.3 to 0.63 +/- 0.17 voids/min) and NVCs (61%, from 1.8 +/- 0.54 to 0.64 +/- 0.167 NVC/min). IHC showed significantly higher RhoA protein expression in SHR bladder tissues.
  
  
  CONCLUSIONS
  Overexpression of RhoA may play a role in hypertension-related OAB. Inhibition of Rho-kinase activity with Y-27632 produced a significant suppression of bladder overactivity. Identification of Rho-kinase isoforms that are bladder-tissue specific and their selective inhibitors may help to disassociate the unwanted hypotensive effects of this approach.
authors.affiliation: Division of Urology, University of California San Diego Medical Center, San Diego, California 92103-8897, USA. mseva@ucsd.edu
authors.forename: Mahadevan
authors.initials: M
authors.lastname: Rajasekaran
authors.forename: Nathan
authors.initials: N
authors.lastname: Wilkes
authors.forename: Steven
authors.initials: S
authors.lastname: Kuntz
authors.forename: Michael
authors.initials: M
authors.lastname: E Albo
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000150:complications*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology; D014549:Urinary Incontinence / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D014563:Urodynamics / Q000187:drug effects; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein