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Brittany Carr, Neil Nathanson, William Stell; Atropine Prevents Myopia via a Nitric Oxide-Mediated Relay. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3677.
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Myopia is an incurable refractive disorder that affects a large minority of the world’s population. Atropine, a broad-spectrum muscarinic receptor (mAChR) antagonist, is known to prevent myopia progression, but unpleasant side-effects limit its wider use and its mechanism is unknown. Although there is evidence for coupling of muscarinic receptor activation with production of nitric oxide (NO) by NO-synthase (NOS) in the retina (Cimini et al. JCN ‘08), this muscarinic-NO synthesis mechanism has not been applied so far to myopia pathology. Here we tested the hypothesis that NO is the primary mediator of myopia-inhibition by atropine, using a nonselective NOS-inhibitor (L-NIO) to block NO-mediated signaling.
The right eyes (T) of White Leghorn cockerels (P7-P8) were goggled with diffusers to induce FDM (day 0); the left eyes served as ungoggled controls (C). 20 µL of PBS, atropine (A; 45.3 nmol), L-NIO (300 nmol), or both (A+L-NIO) [all n=23-24] was injected intravitreally on treatment days 1, 3, 5. On day 6, refractive error, axial length, equatorial length, and eye weight were measured. Control eyes were not affected by treatments to the goggled eyes so the interocular difference (T-C; one-way ANOVA, Tukey post-hoc) was taken as the measure of treatment effect.
In PBS control, goggles induced myopic refractive error (-14 ± 3D) and excessive axial length (0.5 ± 0.3mm) [T-C]. Atropine significantly reduced [T-C] for refractive error (-9 ± 3D; p<0.001) and axial length (0.3 ± 0.2mm; p=0.027). A+L-NIO (T) eyes were not significantly larger or more myopic than PBS or L-NIO eyes.
These results show that atropine inhibits FDM in chicks via a NO-mediated relay. M2/M4 mAChRs, the most likely mediators of atropine’s effects, are Gi-coupled; they constitutively inhibit cAMP synthesis, thus atropine acts as an inverse agonist at these receptors (Tietje et al. JBC ‘90; Migeon et al. JBC ‘94). We suggest that atropine stimulates cAMP synthesis in NO-ergic neurons, accounting for the blockade of atropine’s anti-myopia effect by L-NIO. Given that NO prevents FDM in chick, and that prevention of FDM by dopamine requires activation of NOS via D2/D4-like receptors, it is reasonable that atropine provides another input to a common myopia-preventing network. Pathways such as these (i.e. downstream effectors of atropine-activated receptors) may be preferable to atropine as targets for anti-myopia drug therapy.
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