Muenster Stefan, Lieb Wolfgang S, Fabry Gregor, Allen Kaitlin N, Kamat Shivani S, Guy Ann H, Dordea Ana C, Teixeira Leandro, Tainsh Robert E, Yu Binglan, Zhu Wei, Ashpole Nicole E, Malhotra Rajeev, Brouckaert Peter, Bloch Donald B, Scherrer-Crosbie Marielle, Stamer W Daniel, Kuehn Markus H, Pasquale Louis R, Buys Emmanuel S
Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts, United States.
Department of Anesthesiology and Critical Care Medicine, University Hospital Bonn, Bonn, Germany.
Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4826-4835. doi: 10.1167/iovs.17-22168.
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.
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.
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 dose-dependent 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.
Breathing NO reduced IOP and increased outflow facility in a GC-dependent manner in mice. Exposure of ovine eyes to NO lowers IOP.
虽然一氧化氮（NO）供体正逐渐成为青光眼的治疗方法，但NO降低眼压（IOP）的机制尚不清楚。NO激活鸟苷酸环化酶（GC）以产生环磷酸鸟苷。我们分别研究了吸入和局部应用NO气体对小鼠和羔羊的眼部影响。
在野生型（WT）和GC-1α亚基缺失（GC-1-/-）小鼠中测量眼压和房水（AqH）流出率。小鼠吸入含40 ppm NO的氧气或对照气体（N2/O2）。我们还研究了眼部暴露于NO气体（80、250、500和1000 ppm）对麻醉羔羊眼压的影响。测量房水和血浆中的NO代谢产物。
在清醒的WT小鼠中，呼吸NO 40分钟可使眼压从14.4±1.9 mmHg降至10.9±1.0 mmHg（n = 11，P < 0.001）。在麻醉的WT小鼠中也获得了类似的结果（n = 10，P < 0.001）。在清醒或麻醉的GC-1-/-小鼠中，在类似实验条件下眼压没有变化（P≥0.08，n = 20）。呼吸NO可增加WT小鼠而非GC-1-/-小鼠的体内流出率（+13.7±14.6%对-12.1±9.4%，每组n = 4，P < 0.05）。在羔羊中，眼部暴露于NO以剂量依赖性方式降低眼压（-0.43 mmHg/ppm NO；n = 5，共40次测量；P = 0.04），且未产生角膜病变或改变肺和全身血流动力学。眼部暴露于NO后，房水中的NO代谢产物增加（n = 8，P < 0.001），但血浆中未增加。
在小鼠中，呼吸NO以GC依赖的方式降低眼压并增加流出率。羊眼暴露于NO可降低眼压。
