Transcript PriyaARVO2005_26April(III)-1 - Wildsoet Lab

Abstract # 1990
Acetazolamide Prevents Choroidal Thickening in Response to Plus Lens-induced Defocus in
Chicks Reared in Constant Light.
P.Mathur, S.R.Bhat & C.F.Wildsoet
School of Optometry, University of California Berkeley, Berkeley, CA, USA
Purpose
Introduction
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)
Methods
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.
Results
5
14
12
0
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.
10
8
-5
DMSO_nolens
DMSO_pluslens
AZM70_nolens
AZM70_pluslens
AZM100_nolens
AZM100_pluslens
6
-10
4
2
-15
0
Daynight
Figure 1. Schematic diagram summarizing the likely signaling
pathway linking the retina with choroid and sclera, and the
effects of plus lenses.
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).
Daynight
Constant light
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).
*,^
0.4
#,&
0.3
&
0.2
0
&
^
0.1
*
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)]
DMSO_nolens
DMSO_pluslens
AZM70_nolens
AZM70_pluslens
AZM100_nolens
AZM100_pluslens
0.6
0.5
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 lensinduced 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)].
-0.1
Daynight
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.
Constant light
References
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 #1241
Lauber JK (1987) Light-induced avian glaucoma as an animal model for human primary glaucoma. J Ocul Pharmacol. 1987 Spring;3(1):77-100.
.
Discussion & Conclusions
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.
Grant Support: NEI RO1 EY12932