Ocular hypotensive effects of the ATP sensitive potassium channel opener cromakalim in human and murine experimental model systems

Uttio Roy Chowdhury, Cindy K. Bahler, Bradley H. Holman, Peter I. Dosa, Michael P Fautsch

Research output: Contribution to journalArticle

7 Citations (Scopus)

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; pATP 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.

Original languageEnglish (US)
Article number141783
JournalPLoS One
Volume10
Issue number11
DOIs
StatePublished - Nov 4 2015

Fingerprint

Cromakalim
KATP Channels
antihypertensive effect
potassium channels
Intraocular Pressure
Theoretical Models
eyes
glaucoma
Glaucoma
mice
latanoprost
Trabecular Meshwork
Wild Animals
Aqueous Humor
Poisons
Blindness
therapeutics
blindness
Extracellular Matrix
Canals

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ocular hypotensive effects of the ATP sensitive potassium channel opener cromakalim in human and murine experimental model systems. / Chowdhury, Uttio Roy; Bahler, Cindy K.; Holman, Bradley H.; Dosa, Peter I.; Fautsch, Michael P.

In: PLoS One, Vol. 10, No. 11, 141783, 04.11.2015.

Research output: Contribution to journalArticle

Chowdhury, Uttio Roy ; Bahler, Cindy K. ; Holman, Bradley H. ; Dosa, Peter I. ; Fautsch, Michael P. / Ocular hypotensive effects of the ATP sensitive potassium channel opener cromakalim in human and murine experimental model systems. In: PLoS One. 2015 ; Vol. 10, No. 11.
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