In Vivo Entry of Glucose Analogs into
Lens and Cornea of the Rat
Joseph DiMarrio
Methods were developed for the in vivo estimation of rate constants for transport from blood to aqueous
and subsequently into lens and corneal water compartments. Glucose transport was characterized with
the nonmetabolized radiolabeled glucose analogs (l4C)-L-glucose (L-glu) and (3H)-3-O-methyl-D-gilucose
(mD-glu) that are considered to enter the ocular humors by passive and facilitated diffusion respectively.
The glucose analogs were introduced simultaneously as a bolus into a femoral vein in anesthetized
normal rats and the subsequent appearance in ocular humors, lens, and corneal tissue were determined
at various time periods after the initial introduction. Results indicate that mD-glu transport into lens
is faster than L-glu with mD-glu concentration in lens water approaching steady state aqueous humor
concentrations. Estimated steady state L-glu concentrations in lens remain well below aqueous concentrations, and entry into lens is seen to be slow with interior regions probably inaccessible to this
passive marker. This study gives in vivo support to the previous in vitro studies, which have suggested
a facilitated diffusion mechanism for glucose entry into lens. Corneal steady state concentrations of Lglu and mD-glu are higher than in either plasma or aqueous humor from which they are thought to
have originated via the endothelium. Transport of both L-glu and mD-glu into cornea is very fast, and
entry rate constants demonstrate no clear statistical difference, thereby suggesting the absence of a
stereospecific mechanism. The results indicate that glucose transport is not by simple or facilitated
diffusion or by stereospecific active transport. Although the mechanism for glucose entry into cornea
remains unclear, a pattern of bulk aqueous humor entry into cornea with subsequent water removal by
the endothelium and the equilibrium binding of selected glucose analogs is suggested and discussed.
Invest Ophthalmol Vis Sci 25:160-165, 1984
We have previously reported that D-glucose and the
nonmetabolizable test sugar 3-O-methyl-D-glucose
(mD-glu) cross both the blood-aqueous and bloodvitreous barriers by a mechanism consistent with carrier-mediated facilitated diffusion.1'2 By contrast, Lglu crosses these same barriers by passive diffusion.
As an extension of this work we explored the kinetics
of transport of radiolabeled L-glu and mD-glu from
blood to cornea and lens via aqueous humor using an
in vivo Sprague-Dawley rat model.
The lens utilizes D-glu as its primary source of metabolic energy. Most of the metabolism is anaerobic
since the O2 tension of the aqueous humor is low. Lens
glucose metabolism like the erythrocyte, is not limited
by transport and control over the rate of metabolism
occurs primarily via the enzymes hexokinase and
phosphofructokinase.3"5 Facilitated diffusion was suggested as the mechanism for glucose entry into lens
on the basis of numerous in vitro experiments with
mediation occurring primarily at the level of the fiber
cell membranes.6 The present study includes in vivo
data in the rat which supports the notion that glucose
entry into lens is consistent with a facilitated diffusion
mechanism.
Studies on the permeability characteristics of the
cornea have revealed that the endothelium is some
100 times more permeable than the epithelium.7"10 It
has been suggested that glucose and ami no acid supply
to the cornea occur primarily via the endothelium"
and that the endothelium is the principle barrier to
diffusion.912 Amino acid permeability was found to
be greater than anticipated, and carrier-mediated facilitated transport was suggested as the transport
mechanism.13
More recently14 the transport of amino acids has
been reported not to be active in that equal fluxes
across the endothelium were observed and that the
accumulation of labeled amino acids by the cornea
was due to an active accumulation by the stroma cells.
Glucose transport across the rabbit corneal endothelium has been examined by loading the corneal tissue
and then following the flux of glucose and methylglucose in the perfusate." It was suggested that the
From the Department of Physiology and Biophysics, New York
University Medical Center, 550 First Avenue, New York, New York.
Supported in part by NEI Grants EY-01340 and EY-04418.
Submitted for publication: March 28, 1983.
Reprint requests: Joseph DiMattio, Department of Physiology and
Biophysics, New York University Medical Center, 550 First Avenue,
New York, NY 10016.
160
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No. 2
161
ENTRY OF GLUCOSE ANALOGS INTO LENS AND CORNEA / DiMorrio
exchange was facilitated, since the flux out was faster
than expected; however, the mechanism by which glucose enters the cornea remains unclear. Data from the
present study suggests that both L-glu and mD-glu
enter the cornea rapidly, reaching concentrations
higher than in the aqueous from which they originate.
In addition, the mechanism by which glucose is transported into corneal tissue does not appear to discriminate between the D and L isomers, thus suggesting
an absence of molecular stereospecificity in glucose
transport.
Materials and Methods
Methods essentially follow and extend those outlined
previously.1'2 In short, the experimental procedure
consisted of the introduction of a double label bolus
of (14C)-L-glucose and (3H)-3-O-methyl-D-glucose at
time 0 into the circulation via a cannulated femoral
vein and determining the decay in concentration with
plasma samples taken periodically. At the prescribed
end of the experimental period, the animal was killed
and samples of aqueous and vitreous humor (10-20
n\) obtained. At this time the lens and cornea were
removed and weighed. Whole lens and cornea samples
(10-20 mg) were oven dried (125°F; 18 hr) and reweighed until no further weight change (0.1 mg) was
observed. The dried samples were dissolved in 0.5 ml
tissue solubilizer (0.5 N quaternary ammonium hydroxide in toluene-Beckman BTS 450) and isotopic
concentrations of the test glucose (CPM/mg dry wt)
determined via liquid scintilation spectrometry using
10-ml Dimiscint scintilation solution (National Diagnostics). Water content for each of the samples was
determined, and isotopic concentrations were then
converted to CPM/ml tissue water using the average
values listed in the Results section.
The blood data were analyzed to give a descriptive
plasma function for each labeled glucose over the period from t = 0 until the time the animal was killed.
This function along with aqueous, vitreous, lens and
corneal water concentrations of radiolabeled L-glu and
mD-glu at the end of the experiment (t = 8 min to 4
hr) was used to calculate transport rate constants. These
constants give a measure of how fast the concentrations
of the test glucose molecules are changed in idealized
aqueous and vitreous pools and subsequently in lens
and corneal water compartments.
_
KAI
Plasma
(P)
[ Aqueous |
dC P
7 T
/Aqueous \
Ti s sue
(T)
^ 1
dt
V (A) J
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(1)
. KT. l. C . - K T.o CTT
*
where A, B, C, bi and b2 are determined constants
and A was shown to be the plasma concentration at
t = oo, Cp(oo). A simplified system equation,
dC,
dt
(2)
is obtained from the plasma-aqueous transport scheme
illustrated in Figure 1. As was demonstrated previously1
the sugars used in this study, mD-glu and L-glu, are
transported into aqueous humor by facilitated and
passive diffusion mechanisms, respectively. This allows
a simplified approach in that at steady state the concentrations of both test sugars are very nearly the
plasma concentration. Thus, at steady state dCA/dt
= 0 and Equation 2 becomes:
CA(oo)
= 1.0
Cp(oo)
K
K A0
(3)
and
ii
=
KAQ
=
KA
The aqueous humor concentration versus time appearance function derived from Equations 1, 2, and
3 was also shown to be of the form:
AA3e- b l t
CA(t) = A A i + A A
(4)
where
(5)
AAi = A
KAB
AA2 =
Calculation of Rate Constants
C P = A + Be" blt + Ce
*iC""K*oCA
Fig. 1. Transport schemes: from plasma(P) to aqueous(A) and from
aqueous to lens (L) or corneal (C) tissue water compartments (T).
Subscripts for rate constants, K. (min" 1 ) refer to aqueous or tissue
compartments with i refering to entry and 0, exit notation. Concentration, C is in CPM/ml and t, time (min).
AA3 =
The plasma isotopic concentration data CP(t) versus
time, t for each test sugar wasfitgraphically to a double
exponential decay curve of the form:
K
AA4 =
b,-
KA
KA B
K A - -b,
KA C
KA-b2
KAC
+b,-K,
A
(6)
(7)
(8)
A trial and error solution to Equation 1 allows for
the estimation of transport constants KAi and KA0 from
162
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1984
Table 1. Water content lens and cornea
(Sprague-Dawley rat)
% H2O*
20
20
57.5
66.3
The remaining coefficients are:
AT2 =
SD
1+ 1+
Lens
Cornea
n
Vol. 25
KTi /
AA2
,
AA3
02.2
02.7
^A3
b2 - KT0
(14)
wt weight - dry weight
* % H,0 =
KTi /
wet weight
AA2
TO
the known plasma constants, the labeled glucose concentration in the aqueous at the end of the experimental
time period, t, and estimates of the steady state concentration ratios.
Since both lens and cornea are assumed to be bathed
by aqueous humor and the concentration of labeled
test glucose in the aqueous humor during the test period
can be represented by Equation 4, this equation is used
as the forcing function for transport into lens and cornea. Thus, the known constants of Equation 4 along
with experimentally determined cornea and lens concentrations of labeled glucose at the end of the experimental time period, t, and estimated steady state
concentration ratios were used to calculate tissue (lens
and cornea) rate constants, KTi and KT0, entrance and
exit constants, respectively. The transport of sugar into
lens and cornea is taken to be simple first order as
illustrated also in Figure 1. The system equation is
—— — K T i C A
dt
KT0CP,
(9)
where T refers to either lens or corneal tissue. As a
first approximation, the concentration of test sugars
are assumed to be uniform throughout either lens or
corneal water compartments, with no distinction being
made between intracellular or extracellular water. The
equation that describes label concentration in lens and
cornea derived from Equations 4 and 9 is:
C T (t) = A T 1 + A T 2 e- KTOt
AT4e -blt
A T 5 e - b2t
(10)
and,
KT1
= 7T~ (AAi) =
KT0
CT(OO)
CA(oo)
CT(oo),A
n
.
. (AA.)
CA(oo)
(Cp(oo)) = C T (oo)
(11)
noting that the steady state solution to Equation 9
gives:
KTi
C-Koo)
(12)
KTO
C A (OO)
and that
CA(oo) = CP(oo)
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(13)
KTi/
—
KTi/
^
AA3
A
(16)
A4
Thus, rate entry and exit transport constants KT;
and KT0 are calculated from determined label concentrations in tissue samples at time, t, and the previously calculated aqueous concentration function of
Equation 4. It was also necessary to determine the
tissue to aqueous steady state ratio, Cr(oo)/CA(oo) for
each test sugar for both lens and cornea, so that K Ti /
KJO could be replaced in Equations 13-16 and individual rate constants KTi and K T0 calculated.
Results
Table 1 lists the determined water contents of normal
rat lens and cornea. These values were used to calculate
average concentrations of labeled glucose (CPM/ml
H2O) from dried tissue samples.
Tables 2 and 3 report the concentration ratios of
(3H)-3-0-methyl-D-glucose and (14C)-L-glucose determined experimentally at various times after a bolus
double label injection into the femoral vein of an anesthetized rat. Thus, each group lists the experimental
end time (taken to be when the heart is observed to
cease beating after the lethal dose of Nembutal is administered); the number of experiments, n; the vitreous
to plasma ratio, CV/CP; the aqueous to plasma ratio,
CA/CP; the concentration ratios of lens tissue water to
plasma, CL/C P , and lens tissue water to aqueous, CJ
CA; and corneal tissue water to plasma, CC/CP; and
tissue water to aqueous, CC/CA concentration ratios.
Graphic inspection of this raw data reveals asymptotic
trends from which steady state concentration ratios
were estimated and reported at each column bottom.
The estimated steady state ratios are used in the subsequent rate constant calculation and can be taken as
reflective evidence as to the possible transport mechanism. Thus, the mD-glu steady state concentrations
in both ocular humors are about equal to the steady
state plasma concentration, which is compatible with
a facilitated diffusion mechanism previously reported.'
Passive L-glu entry into both ocular humors appears
ENTRY OF GLUCOSE ANALOGS INTO LENS AND CORNEA / DiMorrio
No. 2
163
Table 2. Determined concentration ratios of (3H)-3-O-methyl-D-glucose at various times
after a bolus injection into blood
Lens
Ocular Humor
Time (min)
n
8.1 ±0.1
11.4 ±0.2
19.4 ± 0.2
30.2 ± 0.3
45.1 ±0.3
60.6 ± 0.8
101.2 ± 1.0
120.3 ± 2.0
4
8
7
6
2
4
3
2
0.24
0.31
0.49
0.68
0.82
0.94
1.01
1.02
Steady state
estimate
± 0.03*
±0.04
± 0.04
± 0.05
± 0.04
± 0.04
± 0.03
± 0.04
cL/cP
cA/cF
Cy/CP
0.54
0.62
0.79
0.89
0.96
0.98
1.02
1.01
± 0.07
± 0.06
± 0.03
± 0.03
± 0.02
± 0.03
± 0.04
±0.03
0.15
0.21
0.34
0.50
0.65
0.72
0.83
0.85
1.0
1.0
Cornea
cL/cA
±0.01
± 0.012
± 0.02
± 0.03
± 0.03
± 0.05
± 0.04
± 0.04
0.28
0.34
0.43
0.56
0.68
0.73
0.81
0.84
1.0
± 0.02
± 0.03
± 0.03
± 0.06
± 0.04
± 0.06
±0.03
± 0.07
1.0
Cc/CP
CC/CA
0.659 ±0.110
0.866 ±0.121
1.11 ±0.14
1.29 ±0.17
1.56 ± 0.20
1.50 ±0.21
1.73 ±0.25
1.67 ±0.22
.22 ±0.21
.38 ± 0.28
.41 ±0.16
.45 ±0.19
.63 ±0.31
.63 ±0.15
.70 ±0.21
1.65 ±0.16
1.80
1.80
Mean ± SDM.
premise that transport into the lens or corneal water
compartments was uniformly accessible to the labeled
glucoses. Simplefirst-orderkinetics was assumed, and
the previously estimated steady state values were used.
In lens, the entry constant for mD-glu is significantly
higher than for L-glu, which, along with the fact that
the steady state ratio CL/C A approaches 1.0, suggests
evidence of a facilitated diffusion mechanism.
The entry of both L-glu and mD-glu into cornea is
very fast (faster than mD-glu entry in lens or aqueous
humor), and both steady state ratios are greater than
1.0. Transport of these test glucoses into cornea does
not appear to be either by simple or facilitated diffusion
nor by a stereospecific active transport mechanism.
much slower than that of mD-glu and demonstrates
a steady state ratio approaching 1.0, which is suggestive
of a simple diffusion mechanism.
Labeled L-glu concentrations in lens appears to level
off at a steady state concentration that is less than that
of aqueous humor, suggesting that if L-glu enters the
lens by simple diffusion, as is thought to be the case,
then a portion of the total lens water is inaccessible
to L-glu or else entry into a relatively inaccessible compartment is very slow. By contrast, the mD-glu concentration ratio CL/C A rises much faster than that of
L-glu and appears to be approaching 1.0, which is
indicative of a facilitated diffusion mechanism as previously suggested.6
Corneal steady state concentrations of both L-glu
and mD-glu are higher than in either plasma or aqueous
humor from which they are thought to have originated
via the endothelium. This is indicative of some transport mechanism other than simple or facilitated diffusion.
Table 4 reports the calculated results obtained with
the transport model from the various raw data of Tables
2 and 3. The rate constants were calculated on the
Discussion
The experimental data shown in Tables 1 and 2
along with the calculated rate constants in Table 3
demonstrate that L-glu entry into lens tissue is slow
and restricted. The fact that the mean L-glu concentration in lens water does not reach the concentration
in the aqueous may indicate that part of the lens is
not accessible to this passively transported marker. A
Table 3. Determined concentration ratios of (14C)-L-glucose at various times after a bolus injection into blood
Lens
Ocular Humors
Time (min)
n
8.1
11.4
19.9
30.2
45.1
60.6
101.2
120.3
4
8
7
6
2
±0.1
±0.2
± 0.2
± 0.3
±0.3
± 0.8
± 1.0
± 2.0
Steady state
estimate
4
3
2
cja
Cy/Cp
0.14
0.16
0.23
0.29
0.36
0.42
0.49
0.55
±0.02*
±0.03
± 0.03
± 0.04
± 0.04
± 0.03
± 0.04
± 0.06
0.18
0.238
0.351
0.462
0.580
0.667
0.815
0.862
1.0
Mean ± SDM.
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±
±
±
±
±
±
±
±
1.0
CJCP
0.012
0.018
0.015
0.021
0.022
0.017
0.012
0.024
0.029
0.040
0.067
0.116
0.151
0.187
0.236
0.260
±0.011
± 0.008
± 0.009
±0.019
±0.021
±0.024
±0.031
± 0.030
0.31
Cornea
cL/cA
0.16
0.17
0.19
0.25
0.26
0.28
0.29
0.30
±0.02
±0.02
±0.03
± 0.04
± 0.03
± 0.03
± 0.02
± 0.03
0.31
Cc/Cp
0.923
1.09
1.55
2.14
2.41
2.74
3.10
3.05
±0.041
±0.051
±0.082
±0.10
±0.11
±0.18
±0.29
± 0.26
3.1
CC/CA
1.71
1.75
1.96
2.41
2.51
2.80
3.04
3.02
±0.23
±0.31
± 0.32
±0.40
±0.43
± 0:30
±0.41
±0.31
3.1
164
INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / February 1984
Table 4. (3H)-3-O-methyl-D-glucose and
(14C)-L-glucose calculated rate constants for
transport into lens and cornea
f\
Kj(Wllft J
Ko(f7lin
Lens
L-glucose
3-O-methyl-D-glucose
19
19
0.021 ±0.003*
0.061 ± 0.006
0.069 ± 0.008
0.061 ±0.006
Cornea
L-glucose
3-O-methyl-D-glucose
19
19
0.498 ± 0.045
0.423 ±0.031
0.161 ±0.013
0.235 ±0.018
• Mean ± SDM.
possible explanation being that L-glu entry into inferior
fiber cells is more restricted than entry into epithelium
cells or extracellular space. This is supported by previous reports, 36 as well as observations made by us
whereby the radiolabeled L-glu was found to be confined to the capsule and outer regions of the sectioned
lens. No doubt transport into lens is more complex
than the two-compartment model may suggest. By
contrast, D-glucose entry into lens is significantly faster
than L-glu and does not reach levels higher than in
aqueous humor. This indicates the presence of a transport-facilitating mechanism, which demonstrates a
clear stereospecific preference for mD-glu. Although
there are presently conflicting reports 31516 on the
mechanism for glucose transport into lens, the present
work gives clear in vivo support to previous in vitro
studies that have suggested a facilitated diffusion
mechanism. From our work, it remains unclear at
what level the facilitation of transport is occurring. Is
the lens epithelium demonstrating selectivity, or do
individual lens fibers selectively take up the required
D-glucose as has been previously suggested?3'6 By what
mechanism does D-glucose travel to the interior fibers?
Procion dye was found to travel from cell to cell via
gap junctions 17 and therefore, so may D-glucose, although it is an uncharged molecule.
The model used by us to calculate transport constants for in vivo transport from plasma to aqueous
and from aqueous to lens assumes that all the fluid
compartments are equally accessible to the molecular
species of interest. This approximation is more valid
for mD-glu than for L-glu. Further work is required
in more clearly determining unsteady state local concentration profiles of L and D-glucose entry into lens
to make this type of modeling more generally applicable.
Our data clearly indicates that L-glucose entry into
cornea is fast and unrestricted. By 10 min, the concentration of tracer in corneal water has reached the
plasma concentration and is 70% higher than the Lglucose concentration in the aqueous humor bathing
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Vol. 25
the endothelium. Simple or facilitated diffusion mechanisms cannot explain these results. In addition, mDglu transport into cornea is also fast. Although mDglu transport constants reported in Table 3 are somewhat lower than L-glucose constants, there is no clear
statistical difference between groups; moreover, this
difference, if real, may be related to spatial consideration concerning the extra methyl group of mD-glu.
Thus, there appears to be little, if any, difference in
transport rates for L and D isomers of glucose, which
suggests a mechanism of transport that is not stereospecific. Therefore, a direct active transport of D-glucose is not likely. A possible mechanism that might
explain these results could involve convective bulk
flow. That is, aqueous humor could enter across the
corneal endothelium, bringing with it all dissolved
molecular components, and water could be actively
returned into the aqueous via the endothelium, as has
been previously suggested and measured.19"22 In fact,
a model of corneal endothelial water transport 23 with
a pattern of water recirculation has been suggested and
could support our results with glucose. Whether this
recirculation mechanism could proceed fast enough
to explain our glucose results is not clear. Moreover,
when aqueous fluid enters the corneal extracellular
space, would not the removal of only water lead to an
accumulation of molecules dissolved in aqueous humor? Most likely, the results we obtained represent
the net results of a number of equilibrium processes
that could exchange sugar molecules with the extracellular space. The mechanism by which both L-glu
and mD-glu enter the cornea thus remains unclear.
Our work suggests that this mechanism is too fast to
be simple diffusion and does not appear to demonstrate
the stereospecific behavior that facilitated diffusion or
active transport mechanisms would require.
Key words: glucose transport, lens, cornea, endothelium, Lglucose, 3-O-methyl-D-glucose
Acknowledgments
The technical expertise of Mr. Jack Streitman is gratefully
noted. Sincere thanks to Dr. J. Friend and Dr. L. Liebovitch
for helpful discussions of our results. The author thanks Dr.
J. A. Zadunaisky for support and assistance and Ms. J. E.
Bates for help in processing this manuscript.
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