Corneal toxicity of xylazine and clonidine, in combination with ketamine, in the rat.
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.
Tita
B
B
Department of Pharmacology of Natural Substances and General Physiology, University of Rome 'La Sapienza', Rome, Italy.
Leone
M G
MG
Casini
M L
ML
Corubolo
C
C
Bordi
F
F
Guidolin
D
D
Fumagalli
E
E
Romanelli
L
L
Mattioli
F
F
Fehér
J
J
Saso
L
L
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
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D019162:Anesthetics, Combined; D000778:Anesthetics, Dissociative; D014991:Xylazine; D015016:Yohimbine; D007649:Ketamine; D003000:Clonidine