title: Effects of the gonadotropin-releasing hormone antagonist ganirelix on normal micturition and prostaglandin E(2)-induced detrusor overactivity in conscious female rats.
abstract: BACKGROUND
  Gonadotropin-releasing hormone (GnRH) antagonists have been reported to have beneficial effects on lower urinary tract symptoms in patients with benign prostatic hyperplasia.
  
  
  OBJECTIVE
  Our aim was to investigate the effects of ganirelix, a GnRH receptor antagonist, on bladder function and detrusor overactivity (DO) in female rats.
  
  
  METHODS
  Female Sprague-Dawley rats received 2 wk of daily systemic (0.1 mg/kg) or acute intravesical administration (IVES; 0.14 mg/l or 1.4 mg/l) ganirelix or vehicle (controls).
  
  
  METHODS
  Assessments were obtained using cystometry in awake rats, organ bath studies, enzyme-linked immunosorbent assay, and western blot (WB).
  
  
  CONCLUSIONS
  Luteinising hormone levels were lower in rats treated systemically with ganirelix than in controls. No differences were observed in body or bladder weights. Micturition interval (MI), micturition volume (MV), residual volume, and bladder capacity (BC) were similar in both groups at baseline. No differences in urodynamic pressure parameters were observed between groups at baseline. Intravesical prostaglandin E(2) reduced MI, MV, and BC, and it increased basal pressure (BP), threshold pressure (TP), flow pressure (FP), and maximum pressure (MP) in all rats. MI, MV, and BC were reduced by 43%±4%, 50%±4%, and 43%±4% (controls) versus 22%±3%, 23%±3%, and 21%±3% (ganirelix-treated rats; p<0.001). TP and FP increased by 38%±8% and 30%±4% (controls) versus 16%±7% and 16%±5% (ganirelix; p<0.05). The maximal force of contractions for carbachol was larger in detrusor from ganirelix-treated rats (231% vs 177% of 60 mM K+-induced contractions). At 0.14 mg/l, but not 0.14 mg/l, IVES ganirelix increased MI, MV, and BC and decreased BP, TP, FP, and MP. In vitro, ganirelix had no effect on detrusor function. The gonadotropin-releasing hormone receptor was expressed (by WB) in the bladder mucosa.
  
  
  CONCLUSIONS
  Systemic treatment with ganirelix counteracted experimental DO in female rats. Because bladder preparations from these rats exhibited larger contractions to carbachol and because intravesical ganirelix affected both micturition intervals and urodynamic pressure profiles, a peripheral site of action of ganirelix in the urinary bladder cannot be excluded.
authors.affiliation: Urological Research Institute, San Raffaele University, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Russo
authors.forename: Fabio
authors.initials: F
authors.lastname: Castiglione
authors.forename: Andrea
authors.initials: A
authors.lastname: Salonia
authors.forename: Fabio
authors.initials: F
authors.lastname: Benigni
authors.forename: Patrizio
authors.initials: P
authors.lastname: Rigatti
authors.forename: Francesco
authors.initials: F
authors.lastname: Montorsi
authors.forename: Karl-Erik
authors.initials: KE
authors.lastname: Andersson
authors.forename: Petter
authors.initials: P
authors.lastname: Hedlund
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D015153:Blotting, Western; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003243:Consciousness; D015232:Dinoprostone; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007986:Luteinizing Hormone / Q000097:blood; D009119:Muscle Contraction / Q000187:drug effects; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D014554:Urination / Q000187:drug effects*; D014563:Urodynamics / Q000187:drug effects
chemical_list: D018679:Cholinergic Agonists; D006727:Hormone Antagonists; D007987:Gonadotropin-Releasing Hormone; D002217:Carbachol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C061018:ganirelix; D015232:Dinoprostone