title: Doxazosin relaxes ureteral smooth muscle and inhibits epinephrine-induced ureteral contractility in vitro.
abstract: OBJECTIVE
  Although recent evidence has supported increased ureteral stone passage with selective alpha(1)-adrenergic receptor antagonists, no mechanistic study evaluating ureteral relaxation by alpha(1) antagonism has been reported to date. We evaluated whether the alpha-blocker doxazosin reduces spontaneous, and inhibits alpha(1)-agonist-induced ureteral contractility. Additionally, alpha-receptor subtypes in normal and obstructed human ureter were analyzed.
  
  
  METHODS
  We exposed porcine ureters in organ tissue baths with 0.1, 1.0, or 10 microM doxazosin and recorded the tension for 90 minutes. After the initial treatment, a concentration-response curve of epinephrine or phenylephrine (1 nM to 10 microM) was generated. The experiment was repeated with the proximal, mid-, and distal ureter. The relative expression of the alpha 1A, 1B, and 1D receptor subtypes in normal and obstructed human ureters was analyzed using immunoblotting.
  
  
  RESULTS
  Doxazosin reduced the spontaneous ureteral contractility rates in a concentration-dependent fashion by 23% to 34%. A more pronounced relaxation effect by doxazosin was evident when epinephrine was introduced to the tissues. In 1 and 10-microM doxazosin-pretreated tissues, epinephrine caused 89% and 100% relaxation, respectively. Phenylephrine-induced contractions were antagonized by doxazosin but not reversed to any relaxant function. No differential expression of alpha(1)-receptor subtypes was identified in the obstructed versus normal ureters.
  
  
  CONCLUSIONS
  The results of our study have shown that alpha(1)-receptor blockade decreases ureteral contractility and inverses the effect of epinephrine, providing even greater relaxation. We hypothesize that alpha receptor blockade might relax the ureter and induce stone passage by way of epinephrine activation of beta receptors. Additional studies should be performed to validate this hypothesis and to compare various alpha(1)-receptor subtype antagonists.
authors.affiliation: Department of Surgery, Division of Urology, University of Wisconsin-Madison School of Medicine and Public Health, WI 53792, USA. nakada@surgery.wisc.edu
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Nakada
authors.forename: Tawnya L Cary
authors.initials: TL
authors.lastname: Coyle
authors.forename: Murali K
authors.initials: MK
authors.lastname: Ankem
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Moon
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Jerde
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin / Q000494:pharmacology*; D004837:Epinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000032:analysis; D034421:Sus scrofa; D014513:Ureter / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D017292:Doxazosin; D004837:Epinephrine