References

Introduction

Figure 3. 10-day old chicks reared in CL (n=17) had significantly lower IOP (average of both eyes) than those reared in DN (n=13) before commencing drug or lens treatments (p=0.0092).

Figure 4. Fall in IOP in response to AZM (70 or 100 mg) seen in DN birds but not in CL birds. Differences between CL and DN groups statistically significant (p=0.0079). CL [(DMSO, n=6), (AZM70, n=5), (AZM100, n=5)], DN [(DMSO, n=4) ,(AZM70, n=3), (AZM100, n=3)]

Discussion & Conclusions

Emmetropization, the process by which young eyes adjust their growth to eliminate neonatal refractive errors, can be demonstrated experimentally using defocusing lenses.In response to defocus, the chick eye shows compensatory changes in both choroidal thickness & scleral growth (axial length). (Fig.1)

P.Mathur, S.R.Bhat & C.F.Wildsoet School of Optometry, University of California Berkeley, Berkeley, CA, USA

Abstract # 1990

Methods

Wolfensberger TJ (1999). The role of carbonic anhydrase inhibitors in the management of macular edema. Doc Ophthalmol. 1999;97(3-4):387-97. CF Wildsoet, P Mathur, GK Wong (2004) Acetazolamide, a carbonic anhydrase inhibitor, interferes with compensation to lens-induced defocus in chicks. ARVO abstracts #1241Lauber JK (1987) Light-induced avian glaucoma as an animal model for human primary glaucoma. J Ocul Pharmacol. 1987 Spring;3(1):77-100..

Acetazolamide Prevents Choroidal Thickening in Response to Plus Lens-induced Defocus in Chicks Reared in Constant Light.

Figure 5. Both CL and DN chicks receiving DMSO (*,#) show significant choroid thickening (p<0.0001) in response to plus lenses. AZM significantly (p<0.0001) reduced lens-induced choroid thickening under both CL and DN conditions (&,^). CL (DMSO, n=6 , (AZM70, n=6), (AZM100, n=6)] DN [(DMSO, n=5), (AZM70, n=3), (AZM100, n=4)].

Figure 2. Schematic cell showing the location of different isoenzymes of carbonic anhydrase (CA), which catalyzes the formation of HCO 3 - from CO2 & H2O. CAII is located intracellularly while CAIV is membrane-bound.  

Results

Grant Support: NEI RO1 EY12932

Under DN, ACZ lowers IOP and decreases choroidal thickening in response to plus lens wear. In contrast under CL, ACZ does not lower IOP but still inhibits the choroidal thickening response to plus lens wear. The latter result implies that the effect of AZM on the choroidal thickening response is not mediated by a lowering of IOP (CA-II). While CA-IV in the RPE represents an alternative site of site of action that could underlie this effect of AZM, our previous study with benzolamide, a selective CA-IV inhibitor, showed that inhibition of CA-IV alone has no effect on the choroidal response to plus lenses or on IOP (Wildsoet et al. 2004).

The finding in present study that at 10 days of age, chicks reared in CL had significantly lower IOP than chicks reared under DN cycle, confirmed the findings of Lauber et al (1987). These workers found that at 8 to 10 weeks of age, IOP was slightly lower in CL chicks compared to DN chicks even though aqueous outflow was markedly reduced. This inhibitory effect of CL on aqueous outflow might explain why AZM did not lower IOP under the CL conditions.

Because AZM inhibits the choroidal thickening response to plus lenses under both DN and CL conditions and it also can be expected to decrease aqueous production under both conditions, we speculate that these effects of AZM are causally linked. Our model has aqueous humor flowing into the choroid in significant quantity via the uveoscleral outflow pathway, so contributing to the thickening response of the choroid.

Acetazolamide (ACZ), a nonselective inhibitor of carbonic anhydrase (CA), which is found in many ocular tissues, is known to reduce intraocular pressure (IOP), via CA II on the ciliary epithelium; it also decreases subretinal pH and volume via inhibition of CA IV on the basolateral membrane of the retinal pigment epithelium (RPE) (Fig.2).

One-day old chicks were assigned to either a 12hr light/12 hr dark cycle (DN) or CL. After 10 days, they were fitted with a +15D lens over one eye; the contralateral eye served as a control. Chicks received either 70 or 100 mg/day ACZ or vehicle (dimethyl sulfoxide) (DMSO) in 2 divided oral doses daily for 5 days. Treatment effects were measured at baseline and after 5 days of treatment using high frequency A-scan ultrasonography. IOP was measured using a Tonopen at baseline and on day 5, 3 hrs after the last ACZ/DMSO dose. Data were analyzed by ANOVA followed by Tukey-Kramer post-hoc test and are shown graphically as Mean ± SEM.

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To investigate the effect of acetazolamide on choroidal thickening in response to plus lenses in chicks reared under constant light conditions. We have shown that ACZ interferes with the compensatory responses to imposed defocus in chicks raised under diurnal light/dark conditions (Wildsoet, Mathur & Wong 2004). To further investigate the mechanism of action of ACZ’s effect on eye growth we employed a constant light (CL) model of eye growth.

Purpose

Figure 1. Schematic diagram summarizing the likely signaling pathway linking the retina with choroid and sclera, and the effects of plus lenses.