IOP homeostatic feedback loop
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NITRIC OXIDE
INACTIVE eNOS
ACTIVE eNOS
ENDOTHELIN-1
Nitric Oxide Regulates Relaxation of Conventional Outflow Tissues
Nitric oxide produced in Schlemm’s canal diffuses into the TM and distal collector channels. There, nitric oxide activates guanylate cyclase, which increases production of cyclic guanosine monophosphate (cGMP), leading to protein kinase G (PKG) activation. Downstream suppression of Rho kinase and calcium signaling prevents actin-myosin interaction, allowing for cellular relaxation and improved aqueous outflow through the conventional pathway.7
Parallels in regulation: IOP and BP
Regulation of IOP and vascular blood flow both depend upon nitric oxide signaling.1,2,6,8
Nitric oxide regulates TM and vascular tone
When IOP is elevated, the TM stretches and the Schlemm’s canal (SC) narrows, thus increasing shear stress in the SC. This mirrors the increased shear stress in vascular endothelial cells when blood vessels narrow.
The endothelial cells respond to shear stress by activating endothelial nitric oxide synthase, leading to increased nitric oxide production. Nitric oxide then diffuses rapidly to relax cells, either in the TM or vascular smooth muscle, to increase fluid flow.
NITRIC OXIDE
INACTIVE eNOS
ACTIVE eNOS
ENDOTHELIN-1
“The physiology of IOP and systemic blood pressure regulation are closely related.” —DAN STAMER, phD
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References:
1. Aliancy J, Stamer WD, Wirostko B. A review of nitric oxide for the treatment of glaucomatous disease. Ophthalmol Ther. 2017;6(2):221-232. 2. Stamer WD, Lei Y, Boussommier-Calleja A, Overby DR, Ethier CR. eNOS, a pressure-dependent regulator of intraocular pressure. Invest Ophthalmol Vis Sci. 2011;52(13):9438-9444. 3. WuDunn D. Mechanobiology of trabecular meshwork cells. Exp Eye Res. 2009;88(4):718-723. 4. Waxman S, Wang C, Dang Y, et al. Structure-function changes of the porcine distal outflow tract in response to nitric oxide. Invest Ophthalmol Vis Sci. 2018;59(12):4886-4895. 5. Rasmussen CA, Kaufman PL. Trabecular meshwork and outflow. Glaucoma Now. 2013;(1):5-8. 6. Reina-Torres E, De Ieso ML, Pasquale LR, et al. The vital role for nitric oxide in intraocular pressure homeostasis. Prog Retin Eye Res. 2021;83:100922. 7. Cavet ME, DeCory HH. The role of nitric oxide in the intraocular pressure lowering efficacy of latanoprostene bunod: review of nonclinical studies. J Ocul Pharmacol Ther. 2018;34(1-2):52-60. 8. Ashpole NE, Overby DR, Ethier CR, Stamer WD. Shear stress-triggered nitric oxide release from Schlemm’s canal cells. Invest Ophthalmol Vis Sci. 2014;55(12):8067-8076.