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.
Highlights
Glaucoma is a complex, multifactorial ocular neuropathy and the leading cause of irreversible blindness, causing vision loss to millions of people worldwide.[1, 2] As the world population continues to age, the prevalence of glaucoma will increase and is estimated to reach over 110 million by 2040.[3]
To evaluate the hypotensive effects of the broad spectrum KATP channel opener cromakalim, anterior segments of human donor eyes were perfusion cultured and following attainment of stable baseline pressure, different concentrations of cromakalim were added to one eye while the contralateral eye received vehicle in the same proportion
Treatment with 2 μM cromakalim caused a reduction in pressure from 19.33 ± 2.78 mmHg at 0 hour to 13.22 ± 2.64 mmHg at 24 hours, while pressure in the vehicle treated eyes remained unchanged during the same time period (15.89 ± 5.33 mmHg at 0 hour to 15.56 ± 4.88 mmHg at 24 hours, p = 0.89.0; n = 9) (Fig 1B)
Summary
Multifactorial ocular neuropathy and the leading cause of irreversible blindness, causing vision loss to millions of people worldwide.[1, 2] As the world population continues to age, the prevalence of glaucoma will increase and is estimated to reach over 110 million by 2040.[3]. Despite recent advances in glaucoma research, the biology and pathophysiology behind the development of glaucoma remains poorly understood.[2, 5] Since glaucoma lacks good reference standards for diagnosis and can be asymptomatic until advanced stages, early detection of the disease can be challenging.[2, 5] Elevated intraocular pressure (IOP) is the most prevalent and only treatable risk factor for the disease.[5, 6] Various classes of drugs that are commonly used to reduce IOP include prostaglandin analogues (e.g. latanoprost), α2 adrenergic agonists (e.g. brimonidine), β blockers (e.g. timolol), carbonic anhydrase inhibitors (e.g. dorzolamide) and cholinergic agonists (e.g. pilocarpine).[5, 7] all these drugs have significant and sometimes irreversible side effects.[5, 8] For example, prostaglandin analogues cause hypertrichosis and permanent darkening of the iris and eyelashes; [9, 10] α2 adrenergic agonists can cause allergic conjunctivitis and hyperemia;[11] β blockers have detrimental cardiovascular as well as corneal effects;[12, 13] and cholinergic agonists can cause headaches due to ciliary spasm, blurring of vision and induce myopia.[2, 5, 14] As a result, continued research aimed at developing novel pharmacologic agents for the treatment of glaucoma is a priority. [15]
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