title: Pharmacological preconditioning of ATP-sensitive potassium channel openers on acute urinary retention-induced bladder dysfunction in the rat.
abstract: What's known on the subject? and What does the study add? Acute urinary retention (AUR) and catheterization for AUR (AURC) or drainage of the urine is a well established cause of bladder dysfunction. Previously, we reported that the induction of AURC significantly reduced contractile responses to both carbachol and KCl compared with a control group, and that this reduction was prevented by nicorandil and cromakalim in a dose-dependent manner; however, although we reported a possible beneficial effect of nicorandil and cromakalim on bladder dysfunction caused by AURC, its molecular mechanism is still unknown. Our study establishes that nicorandil and cromakalim, but not glibenclamide, prevent AURC-induced bladder dysfunction via up-regulation of both K(IR)6.1 and K(IR)6.2 with a subsequent decrease in oxidative stress and decreased induction of apoptosis in the bladder.
  
  
  OBJECTIVE
  To investigate whether ATP-sensitive potassium (K(ATP)) channel openers prevent bladder injury after acute urinary retention (AUR) and subsequent catheterization for AUR (AURC) in the rat.
  
  
  METHODS
  Eight-week-old male Sprague-Dawley rats were divided into five groups: a sham-operated control group, an AUR group, and three AUR groups treated with: nicorandil (10 mg/kg); cromakalim (300 µg/kg); or glibenclamide (5 mg/kg). AUR was induced by intravesical infusion of 3.0 mL of saline via cystostomy with simultaneous clamping of the penile urethra and, after 30 min of AUR, the bladder was allowed to drain for 60 min. After the experimental period, bladder function was assessed using organ bath techniques (carbachol and KCl), and by measuring tissue levels of 8-isoprostane, a marker of oxidative stress. The participation levels of K(ATP) channel pores were investigated using ELISA and real-time PCR methods, respectively. The degree of apoptosis was estimated using the TUNEL method in the bladder smooth muscle and epithelium.
  
  
  RESULTS
  The AURC group showed significantly decreased contractile responses to carbachol and KCl, and significant increases in tissue 8-isoprostane levels and apoptosis index in the epithelium compared with the control group. Nicorandil and cromakalim, but not glibenclamide, significantly prevented these AURC-induced alterations. The expressions of K(IR)6.1 and K(IR)6.2 mRNAs were significantly up-regulated by the induction of AURC. Nicorandil and cromakalim, but not glibenclamide, significantly up-regulated expressions of K(IR)6.1 and K(IR)6.2 mRNAs in the bladder compared with the AUR group.
  
  
  CONCLUSIONS
  Our data indicate that nicorandil and cromakalim, but not glibenclamide, prevent AURC-induced bladder dysfunction via activation of K(ATP) channels, with a subsequent decrease in oxidative stress and decreased induction of apoptosis.
authors.affiliation: Division of Molecular Pharmacology, Department of Pathophysiological and Therapeutic Science, Tottori University School of Medicine, Yonago, Japan.
authors.forename: Fumiya
authors.initials: F
authors.lastname: Ohmasa
authors.forename: Motoaki
authors.initials: M
authors.lastname: Saito
authors.forename: Harunori
authors.initials: H
authors.lastname: Oiwa
authors.forename: Panagiota
authors.initials: P
authors.lastname: Tsounapi
authors.forename: Kohei
authors.initials: K
authors.lastname: Shomori
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kitatani
authors.forename: Fotios
authors.initials: F
authors.lastname: Dimitriadis
authors.forename: Yukako
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Keisuke
authors.initials: K
authors.lastname: Satoh
mesh_terms: D000818:Animals; D019806:Cromakalim / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D020108:Nicorandil / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016055:Urinary Retention / Q000150:complications / Q000503:physiopathology*
chemical_list: D054086:KATP Channels; D019806:Cromakalim; D020108:Nicorandil; D005905:Glyburide