Inhaled Nitric Oxide: an sGC-dependent IOP lowering agent
© Lieb et al. 2015
Published: 2 September 2015
The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine 3’5’-monophosphate (cGMP) pathway regulates intraocular pressure (IOP). Preclinical and clincial studies have demonstrated the ability of NO-donor compounds to lower IOP (e.g. VESNEO®). The use of inhaled NO gas (iNO), a specific pulmonary but not systemic vasodilator, is an approved therapy for pulmonary hypertension and is under development as a treatment for other cardiovascular diseases (e.g. for myocardial ischemia, the NOMI trial). We hypothesized that breathing NO lowers IOP in an sGC-dependent manner.
Anesthetized IOP model: 10- to 20-week-old male wild-type (WT) mice and mice deficient in the α1-subunit of sGC (sGCα1-/- mice; n=9, each) were anesthetized with isoflurane using a standard protocol resulting in a stable IOP baseline. Ten minutes after baseline measurement, IOP was measured again in mice breathing 1.8 % isoflurane and either control gas (N2 balanced in O2) or 40 ppm NO balanced in O2. Awake IOP model: WT mice were acclimated to awake IOP measurements (every other day for 2 weeks). 40 min after baseline measurements, IOP was measured in mice breathing either control gas or 40 ppm iNO (n=8, each) in an incubation chamber.
Inhalation of 40 ppm iNO decreased IOP in anesthetized and awake WT mice but not in sGCα1-/- mice. These findings confirm that NO is an IOP-lowering agent, and identify NO-gas as a possible therapeutic approach to acutely lower IOP. In addition, our results identify sGC as the downstream target of NO's ability to lower IOP. sGC stimulators, under development for treatment of cardiovascular diseases, such as the recently approved ADEMPAS®, may be considered as a novel treatment option for elevated IOP.
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