title: Voltage-gated Na+ channel blockers reduce functional bladder capacity in the conscious spontaneously hypertensive rat.
abstract: OBJECTIVE
  To evaluate the consequence of pharmacologic inhibition of voltage-gated Na(+) channels (Nav) in the conscious rat, based on Nav having been implicated as modulators of rodent urodynamics using knockout as well as antisense oligodeoxynucleotide approaches.
  
  
  METHODS
  The urodynamic response to standard Nav blockers, lamotrigine, amitriptyline, mexiletine, and carbamazepine were evaluated using conscious, continuous-filling cystometry in spontaneously hypertensive rats (SHRs). As a selectivity evaluation, the activity of the Nav blockers at muscarinic receptors was assessed via effect on carbachol-evoked bladder contractions.
  
  
  RESULTS
  Lamotrigine, amitriptyline, mexiletine, and carbamazepine decreased peak micturition pressure, micturition interval, and void volume. These effects were markedly similar to observations with muscarinic antagonists. Therefore, we evaluated the selectivity of these agents against bladder muscarinic receptors. Lamotrigine, mexiletine, and carbamazepine had no effect on muscarinic bladder contractions, whereas amitriptyline displayed a robust antagonism of carbachol-induced contractility.
  
  
  CONCLUSIONS
  Three Nav blockers--lamotrigine, mexiletine, and carbamazepine--demonstrated a reduction in micturition pressure and functional bladder capacity, similar to previous observations with muscarinic antagonists. These 3 Nav blockers are free of muscarinic antagonism, consistent with their cystometric effects being mediated via their Nav blocking activities. The negative findings reported here with Nav blockers suggest that Nav channel blockade is unlikely to reflect an improved treatment strategy for bladder disorders over currently prescribed muscarinic antagonists.
authors.affiliation: Metabolic Pathways and Cardiovascular Unit, GlaxoSmithKline, Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Clouse
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Jugus
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Eisennagel
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Laping
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Westfall
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Thorneloe
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D002220:Carbamazepine / Q000494:pharmacology; D005260:Female; D000077213:Lamotrigine; D008801:Mexiletine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011976:Receptors, Muscarinic / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*; D014563:Urodynamics / Q000187:drug effects
chemical_list: D011976:Receptors, Muscarinic; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014227:Triazines; D000639:Amitriptyline; D008801:Mexiletine; D002220:Carbamazepine; D000077213:Lamotrigine