title: Ocular Hypotensive Effects of the ATP-Sensitive Potassium Channel Opener Cromakalim in Human and Murine Experimental Model Systems.
abstract: Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for glaucoma, a leading cause of irreversible blindness worldwide. Unfortunately, all current therapeutics used to treat elevated IOP and glaucoma have significant and sometimes irreversible side effects necessitating the development of novel compounds. We evaluated the IOP lowering ability of the broad spectrum KATP channel opener cromakalim. Cultured human anterior segments when treated with 2 μM cromakalim showed a decrease in pressure (19.33 ± 2.78 mmHg at 0 hours to 13.22 ± 2.64 mmHg at 24 hours; p<0.001) when compared to vehicle treated controls (15.89 ± 5.33 mmHg at 0 h to 15.56 ± 4.88 mmHg at 24 hours; p = 0.89). In wild-type C57BL/6 mice, cromakalim reduced IOP by 18.75 ± 2.22% compared to vehicle treated contralateral eyes (17.01 ± 0.32 mmHg at 0 hours to 13.82 ± 0.37 mmHg at 24 hours; n = 10, p = 0.002). Cromakalim demonstrated an additive effect when used in conjunction with latanoprost free acid, a common ocular hypotensive drug prescribed to patients with elevated IOP. To examine KATP channel subunit specificity, Kir6.2(-/-) mice were treated with cromakalim, but unlike wild-type animals, no change in IOP was noted. Histologic analysis of treated and control eyes in cultured human anterior segments and in mice showed similar cell numbers and extracellular matrix integrity within the trabecular meshwork, with no disruptions in the inner and outer walls of Schlemm's canal. Together, these studies suggest that cromakalim is a potent ocular hypotensive agent that lowers IOP via activation of Kir6.2 containing KATP channels, its effect is additive when used in combination with the commonly used glaucoma drug latanoprost, and is not toxic to cells and tissues of the aqueous humor outflow pathway, making it a candidate for future therapeutic development.
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Uttio
authors.initials: U
authors.lastname: Roy Chowdhury
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Bahler
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Bradley H
authors.initials: BH
authors.lastname: Holman
authors.affiliation: Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Dosa
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, MN, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fautsch
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D019806:Cromakalim / Q000494:pharmacology* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005123:Eye / Q000166:cytology / Q000473:pathology; D005260:Female; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D054086:KATP Channels / Q000819:agonists* / Q000378:metabolism; D000077338:Latanoprost; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008954:Models, Biological; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology / Q000627:therapeutic use; D014019:Tissue Donors
chemical_list: D054086:KATP Channels; D011461:Prostaglandins F, Synthetic; D019806:Cromakalim; D000077338:Latanoprost