Nitric oxide (NO) is an essential component in many cellular reactions. Understanding its action at the molecular level has been the subject of research for decades because of its importance to the vascular endothelium (Huveneers et al, 2015; McMaster et al, 2015). Implications for vascular viability have been in the sights of researchers in the realm of cardiovascular disease and renal integrity for decades.
NO is a volatile gas, which by its very nature makes its ephemeral status difficult to assess. The appropriate balance of NO at the cellular level is critical to many cellular reactions that govern capillary activity (Gradinarua et al, 2015). Vasodilation and vasoconstriction appear to be governed at least in part by NO. Regulation of vascular activity has obvious implication for systemic hypertension, which directly impacts longevity and mortality.
NO is also important for the regulation of matrix metalloproteinases (MMPs) that are crucial precursors to appropriate kidney and cardiac functioning (Vacek et al, 2015). Clearly, the systemic importance of NO is the role that it plays in regulating blood flow. What does this have to do with the eye?
NO and the Eye
Blood flow is increasingly seen as a factor in glaucoma. These effects have been shown as risk factors systemically (Flammer and Mozaffariaeh, 2007) as well as locally at the optic disc (Jia et al, 2014), for example. The effects of modifying NO reactions within the trabecular meshwork are now being identified as therapeutic targets not only for lowering intraocular pressure (potentially by enhancing trabecular aqueous outflow), but also to enhance blood flow locally, supporting trabecular functioning (Karmel, 2013). NO-donating compounds are in clinical trials for lowering intraocular pressure (IOP), which is the only FDA-approved means to manage glaucoma at the present time.
Latanoprostene bunod, 0.024% (Vyzulta, Bausch + Lomb) is a NO–donating prostaglandin F2-alpha analog that has been investigated clinically for lowering IOP in patients diagnosed with glaucoma or ocular hypertension; at press time, the FDA has the product’s PDUFA date as Aug. 24, 2017.
We have become familiar with the efficacy and impact of the prostaglandin analogs since the introduction of the first product two decades ago. The NO-donating compounds may represent a similar revolution for the management of glaucoma.
Concomitantly, there has been research surrounding the use of the rho-kinase (ROCK) inhibitors for treating glaucoma (Ciotu et al, 2015). The site of action for ROCK inhibition is likely the cell cytoskeleton of the juxtacanalicular region of the trabecular meshwork (TM) and surrounding region. This includes cells adjacent to the inner wall of Schlemm’s canal. Hypothetically, ROCK inhibitors shrink the cells, which creates space between the cells to facilitate aqueous outflow through the TM similar to the uveoscleral enhancement mechanism attributed to the prostaglandin analogs.
As previously stated, currently the only FDA-approved means to treat glaucoma is to lower IOP. With the new classes of topical medications on the horizon, we may be seeing a bright future for treating the second leading cause of blindness.
Manipulation of the vasculature at the molecular level has been elucidated in systemic vascular diseases. Now, knowing the role of vasculature within the trabecular meshwork and the emerging notion that this is the site of the disease we know as glaucoma, these new possibilities for maintaining vision and sight among our glaucoma patients offer a brighter prospect than ever.
The role of eyecare professionals in identifying the early changes in glaucomatous damage is now more critical than ever. With the geographic coverage of our profession and the enhanced diagnostic tools at our disposal, we are on the frontier of saying NO to glaucoma. CLS
For references, please visit www.clspectrum.com/references and click on document #257.