title: Corneal toxicity of xylazine and clonidine, in combination with ketamine, in the rat.
abstract: OBJECTIVE
  To compare the corneal toxicity of xylazine (XYL)/ketamine (KET) with that of clonidine (CLO)/KET in the rat, in the presence or not of the alpha(2)-adrenergic antagonist yohimbine (YOH).
  
  
  METHODS
  XYL (10 mg/kg) and CLO (0.15 mg/kg) were administered subcutaneously in the rat in combination with KET (50 mg/kg), in the presence or not of YOH (2 mg/kg).
  
  
  RESULTS
  The corneas immediately lost transparency and luster, but recovered within 120 min. By both light and electron microscopy, a marked stromal edema and alterations of all layers were observed. In addition, XYL/KET altered the permeability of the cornea as indicated by the augmented levels of (14)C-indomethacin, topically administered 30 min after the anesthetic combination.
  
  
  CONCLUSIONS
  The mechanism of the corneal toxicity of XYL and CLO in the rat is unclear but we speculate that: (a) proptosis and inhibition of normal blinking did not play a major role because topical application of hyaluronic acid did not protect against it; corneal decompensation, edema and opacification could be due to (b) osmotic or (c) mechanical endothelial stress: the first resulting from the sudden increase of the glucose concentration in the aqueous humor due to the well-known inhibition of insulin release by alpha(2)-adrenergic agonists, and the second from the acute elevation of intraocular pressure caused by these alpha(2)-adrenergic mydriatics in the rat; (d) addition, XYL and CLO could act by directly interacting with local alpha(2)- or, possibly, alpha(1)-adrenergic receptors, whose function is still not clear but probably essential for corneal homeostasis.
authors.affiliation: Department of Pharmacology of Natural Substances and General Physiology, University of Rome 'La Sapienza', Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Tita
authors.forename: M G
authors.initials: MG
authors.lastname: Leone
authors.forename: M L
authors.initials: ML
authors.lastname: Casini
authors.forename: C
authors.initials: C
authors.lastname: Corubolo
authors.forename: F
authors.initials: F
authors.lastname: Bordi
authors.forename: D
authors.initials: D
authors.lastname: Guidolin
authors.forename: E
authors.initials: E
authors.lastname: Fumagalli
authors.forename: L
authors.initials: L
authors.lastname: Romanelli
authors.forename: F
authors.initials: F
authors.lastname: Mattioli
authors.forename: J
authors.initials: J
authors.lastname: Fehér
authors.forename: L
authors.initials: L
authors.lastname: Saso
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000633:toxicity; D000317:Adrenergic alpha-Antagonists / Q000633:toxicity; D019162:Anesthetics, Combined / Q000633:toxicity*; D000778:Anesthetics, Dissociative / Q000633:toxicity; D000818:Animals; D003000:Clonidine / Q000633:toxicity*; D003315:Cornea / Q000187:drug effects* / Q000648:ultrastructure; D015715:Corneal Edema / Q000139:chemically induced* / Q000473:pathology; D003318:Corneal Opacity / Q000139:chemically induced / Q000473:pathology; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D014991:Xylazine / Q000633:toxicity*; D015016:Yohimbine / Q000633:toxicity
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D019162:Anesthetics, Combined; D000778:Anesthetics, Dissociative; D014991:Xylazine; D015016:Yohimbine; D007649:Ketamine; D003000:Clonidine