title: Effect of topically applied epithelial sodium channel inhibitors on tear production in normal mice and in mice with induced aqueous tear deficiency.
abstract: OBJECTIVE
  Dry eye syndromes affect a significant proportion of the population worldwide with reported prevalence ranging from 6% to more than 34%. Patients with dry eye can experience intense pain due to eye irritation, gritty/scratchy feeling in the eyes, blurry vision, and light sensitivity. Available treatments for dry eye syndromes remain mainly palliative. The purpose of the present study was to test the hypothesis that inhibiting sodium absorption via the epithelial sodium channel (ENaC) will increase ocular hydration in both normal as well as in animals with experimentally induced dry eye.
  
  
  METHODS
  ENaC inhibitors were dissolved in an aqueous buffer that mimics the composition of tears and were applied topically to the ocular surface of isoflurane-anesthetized mice. The effect of ENaC inhibitors was compared with that of the secretagogue uridine triphosphate (UTP; 1%), a purinergic receptor agonist which was shown to increase tear volume in animals. Tear production was measured for 10 s using phenol red-impregnated cotton threads. Fluorescein staining that assesses ocular surface damage was performed at baseline and then at days 1, 2, and 3 after the induction of dry eye in mice.
  
  
  RESULTS
  Our data show that the inhibition of ENaC led to a time- and concentration-dependent increase in tear volume in normal mice. The effect of ENaC inhibition after a single application outperformed UTP, as it was long-lasting with tear volume still above baseline values 8 h postdosing. ENaC inhibition, which led to increased tear production, improved fluorescein scores in our dry eye model, when compared with nontreated or animals treated with buffer or UTP.
  
  
  CONCLUSIONS
  We conclude that the inhibition of ENaC provides long-lasting increases in ocular surface hydration and that ENaC blockers could provide an effective new therapy for chronic dry eye.
authors.affiliation: Parion Sciences, Durham, North Carolina, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Thelin
authors.forename: M Ross
authors.initials: MR
authors.lastname: Johnson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hirsh
authors.forename: Claire L
authors.initials: CL
authors.lastname: Kublin
authors.forename: Driss
authors.initials: D
authors.lastname: Zoukhri
mesh_terms: D000287:Administration, Topical; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D004396:Coloring Agents; D004232:Diuretics / Q000494:pharmacology; D004285:Dogs; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000473:pathology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D019793:Fluorescein; D051379:Mice; D008807:Mice, Inbred BALB C; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013666:Tears / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D004396:Coloring Agents; D004232:Diuretics; D053503:Epithelial Sodium Channels; D058915:Purinergic P1 Receptor Antagonists; D026941:Sodium Channel Blockers; D000584:Amiloride; D019793:Fluorescein; D014544:Uridine Triphosphate