12(R)-hydroxyeicosatetraenoic acid, an endogenous corneal arachidonate metabolite, lowers intraocular pressure in rabbits.
12(R)-hydroxyeicosatetraenoic acid (12(R)HETE) is an endogenous corneal epithelial arachidonic acid metabolite formed by the cytochrome P450 system and a potent inhibitor of Na(+)-K(+)-ATPase activity. We studied the effect of topically applied 12(R)HETE, either derived endogenously from corneal epithelium or synthetically prepared, on the IOP of the rabbit eye and compared it to its stereoisomer 12(S)HETE. Topical application of 1 microgram of biologically derived 12(R)HETE to both eyes of rabbits resulted in a marked reduction in IOP: a reduction of 4-7 mmHg occurred within 30-120 min. The IOP reduction effect of a single application of 12(R)HETE was long-lasting (9 days), whereas no effect on IOP was found for the vehicle control. Using synthetic compound, we demonstrated that the effect of 12(R)HETE on IOP is dose-dependent. Single topical application of 1, 10, and 50 micrograms of 12(R)HETE caused a reduction in IOP of 4, 6, and 12 mmHg, respectively. The stereoisomer, 12(S)HETE, did not have any effect on IOP at doses up to 5 micrograms. The IOP reduction effect of 12(R)HETE was not associated with hyperemia, appearance of flare, miotic response, or increased protein concentration of the aqueous humor. This study was the first to demonstrate that an endogenous inhibitor of Na(+)-K(+)-ATPase generated by the corneal epithelium potently and specifically lowers IOP in rabbits. Further studies are needed to elucidate the mechanism by which 12(R)HETE lowers IOP.
Masferrer
J L
JL
Department of Pharmacology, New York Medical College, Valhalla 10595.
Dunn
M W
MW
Schwartzman
M L
ML
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000287:Administration, Topical; D000704:Analysis of Variance; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D002417:Cattle; D003315:Cornea / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology*; D007429:Intraocular Pressure / Q000187:drug effects*; D007536:Isomerism; D011817:Rabbits; D013329:Structure-Activity Relationship
D005136:Eye Proteins; D006893:Hydroxyeicosatetraenoic Acids; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid