title: T- and L-type voltage-gated calcium channels: their role in diabetic bladder dysfunction.
abstract: OBJECTIVE
  We investigated the mechanisms of diabetic bladder dysfunction (BD) through analysis of the roles of L- and T-type voltage-gated calcium channels (VGCCs), with the ultimate goal of identifying potential drug targets for diabetic BD.
  
  
  METHODS
  Bladder function of db/db (type 2 diabetes) and wild type (Wt) mice was evaluated by behavioral tests and in vivo cystometry. Contractile responses of bladder strips to carbachol were measured with or without pre-treatment with nifedipine (a L-type VGCC blocker) or mibefradil (a T-type VGCC blocker). Furthermore, the effects of mibefradil and nifedipine on the proliferation of human bladder smooth muscle cells (BSMCs) were studied.
  
  
  RESULTS
  db/db mice had significantly increased voiding frequency, bladder weight, bladder compliance and capacity, and heightened contractile response to carbachol, compared to Wt mice. Nifedipine, but not mibefradil, dramatically suppressed bladder tissue contraction in Wt mice. Whereas nifedipine nearly completely inhibited bladder contraction in db/db mice, mibefradil "normalized" the heightened bladder contractility of db/db mice to the level of Wt mice. In culture, mibefradil, but not nifedipine, inhibited the proliferation of human BSMCs.
  
  
  CONCLUSIONS
  Our results indicate that while L-type VGCCs play a major role in the contraction of both diabetic and non-diabetic bladders, T-type VGCCs are involved in the contraction of diabetic bladders and mediate BSMC proliferation. This study provides support for further investigations on the effect of blockade of T-type VGCC or combined blockade of both types of VGCCs in the treatment of diabetic BD.
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Jiang
authors.forename: Ian
authors.initials: I
authors.lastname: Luttrell
authors.forename: Kanchan
authors.initials: K
authors.lastname: Chitaley
authors.forename: Claire C
authors.initials: CC
authors.lastname: Yang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001745:Urinary Bladder Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D012333:RNA, Messenger; D020748:Mibefradil; D009543:Nifedipine; D000109:Acetylcholine
keywords: bladder dysfunction; diabetes mellitus; smooth muscle; voltage-gated calcium channel