The ability of nitric oxide to lower intraocular pressure is dependent on guanylyl cyclase

PURPOSE. While nitric oxide (NO) donors are emerging as treatments for glaucoma, the mechanism by which NO lowers intraocular pressure (IOP) is unclear. NO activates the enzyme guanylyl cyclase (GC) to produce cyclic guanosine monophosphate. We studied the ocular effects of inhaled and topically applied NO gas in mice and lambs, respectively. METHODS. IOP and aqueous humor (AqH) outflow were measured in WT and GC-1α subunit null (GC-1^-/-) mice. Mice breathed 40 parts per million (ppm) NO in O₂ or control gas (N₂/O₂). We also studied the effect of ocular NO gas exposure (80, 250, 500, and 1000 ppm) on IOP in anesthetized lambs. NO metabolites were measured in AqH and plasma. RESULTS. In awake WT mice, breathing NO for 40 minutes lowered IOP from 14.4 ± 1.9 mm Hg to 10.9 ± 1.0 mm Hg (n = 11, P < 0.001). Comparable results were obtained in anesthetized WT mice (n = 10, P < 0.001). In awake or anesthetized GC-1^-/- mice, IOP did not change under similar experimental conditions (P ≥ 0.08, n = 20). Breathing NO increased in vivo outflow facility in WT but not GC-1^-/- mice (+13.7 ± 14.6% vs. -12.1 ± 9.4%, n = 4 each, P < 0.05). In lambs, ocular exposure to NO lowered IOP in a dosedependent manner (-0.43 mm Hg/ppm NO; n = 5 with 40 total measurements; P = 0.04) without producing corneal pathology or altering pulmonary and systemic hemodynamics. After ocular NO exposure, NO metabolites were increased in AqH (n = 8, P < 0.001) but not in plasma. CONCLUSIONS. Breathing NO reduced IOP and increased outflow facility in a GC-dependent manner in mice. Exposure of ovine eyes to NO lowers IOP.