ATP-sensitive potassium (KATP) channel openers diazoxide and nicorandil lower intraocular pressure by activating the Erk1/2 signaling pathway

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD). In the current study, we evaluated the role of Erk1/2 signaling pathway in KATP channel opener mediated reduction of intraocular pressure (IOP). Western blot analysis of DZ and NCD treated primary normal trabecular meshwork (NTM) cells, human TM (isolated from perfusion cultures of human anterior segments) and mouse eyes showed increased phosphorylation of Erk1/2 when compared to vehicle treated controls. DZ and NCD mediated pressure reduction (p<0.02) in human anterior segments (n = 7 for DZ, n = 4 for NCD) was abrogated by U0126 (DZ + U0126: -9.7 ± 11.5%, p = 0.11; NCD + U0126: -0.1 ± 11.5%, p = 1.0). In contrast, U0126 had no effect on latanoprostfree acid-induced pressure reduction (-52.5 ± 6.8%, n = 4, p = 0.001). In mice, DZ and NCD reduced IOP (DZ, 14.9 ± 3.8%, NCD, 16.9 ± 2.5%, n = 10, p<0.001), but the pressure reduction was inhibited by U0126 (DZ + U0126, 0.7 ± 3.0%; NCD + U0126, 0.9 ± 2.2%, n = 10, p>0.1). Histologic evaluation of transmission electron micrographs from DZ + U0126 and NCD + U0126 treated eyes revealed no observable morphological changes in the ultrastructure of the conventional outflow pathway. Taken together, the results indicate that the Erk1/2 pathway is necessary for IOP reduction by KATP channel openers DZ and NCD.

Original languageEnglish (US)
Article numbere0179345
JournalPLoS One
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

diazoxide
Nicorandil
Diazoxide
KATP Channels
potassium channels
Intraocular Pressure
Potassium
Adenosine Triphosphate
eyes
Anterior Eye Segment
Trabecular Meshwork
Optic Nerve Diseases
antihypertensive effect
glaucoma
Phosphorylation
optics
disease course
Glaucoma
Disease Progression
Optics

ASJC Scopus subject areas

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

Cite this

ATP-sensitive potassium (KATP) channel openers diazoxide and nicorandil lower intraocular pressure by activating the Erk1/2 signaling pathway. / Chowdhury, Uttio Roy; Bahler, Cindy K.; Holman, Bradley H.; Fautsch, Michael P.

In: PLoS One, Vol. 12, No. 6, e0179345, 01.06.2017.

Research output: Contribution to journalArticle

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abstract = "Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD). In the current study, we evaluated the role of Erk1/2 signaling pathway in KATP channel opener mediated reduction of intraocular pressure (IOP). Western blot analysis of DZ and NCD treated primary normal trabecular meshwork (NTM) cells, human TM (isolated from perfusion cultures of human anterior segments) and mouse eyes showed increased phosphorylation of Erk1/2 when compared to vehicle treated controls. DZ and NCD mediated pressure reduction (p<0.02) in human anterior segments (n = 7 for DZ, n = 4 for NCD) was abrogated by U0126 (DZ + U0126: -9.7 ± 11.5{\%}, p = 0.11; NCD + U0126: -0.1 ± 11.5{\%}, p = 1.0). In contrast, U0126 had no effect on latanoprostfree acid-induced pressure reduction (-52.5 ± 6.8{\%}, n = 4, p = 0.001). In mice, DZ and NCD reduced IOP (DZ, 14.9 ± 3.8{\%}, NCD, 16.9 ± 2.5{\%}, n = 10, p<0.001), but the pressure reduction was inhibited by U0126 (DZ + U0126, 0.7 ± 3.0{\%}; NCD + U0126, 0.9 ± 2.2{\%}, n = 10, p>0.1). Histologic evaluation of transmission electron micrographs from DZ + U0126 and NCD + U0126 treated eyes revealed no observable morphological changes in the ultrastructure of the conventional outflow pathway. Taken together, the results indicate that the Erk1/2 pathway is necessary for IOP reduction by KATP channel openers DZ and NCD.",
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