Placental oxygen transport in sheep with different
hemoglobin types
R. B. Wilkening, R. D. Molina and G. Meschia
Am J Physiol Regulatory Integrative Comp Physiol 254:585-589, 1988.
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Placental oxygen transport in sheep
with different hemoglobin types
RANDALL
Departments
University
B. WILKENING,
RICHARD
D. MOLINA,
AND GIACOMO
of Pediatrics, Obstetrics and Gynecology, and Physiology, Division
of Colorado School of Medicine,
Denver, Colorado 80262
placenta;
RANDALL
oxyhemoglobin
dissociation
curve
ADULT SHEEP carry two hemoglobin types (A hemoglobin
and B hemoglobin) that are controlled by two autosomal
codominant genes (10). The blood of hemoglobin A carriers (A sheep) has markedly higher 0, affinity than the
blood of hemoglobin B carriers (B sheep) (17). In the
erythrocytes of heterozygotes both hemoglobins are present in equimolar concentrations (17) and confer to blood
an oxyhemoglobin dissociation curve that is intermediate
to the curves of the homozygotes (17, 23).
The frequency of each hemoglobin type in any given
flock varies widely according to breed and location. In
general, the reproductive success of A and B sheep is
similar (11). However, the selection of A hemoglobin
seems to be favored by cold, harsh environments (24).
Theoretical models of placental O2 transfer (14, 16), as
well as experimentally induced changes in the oxyhemoglobin dissociation curve of maternal blood in sheep
(27) and rats (5, 13), have led to the conclusion that an
increase in the O2 affinity of maternal hemoglobin is, by
itself, a hindrance to fetal oxygenation and growth (5,
13). Therefore the good reproductive performance of A
sheep suggests the hypothesis of chronic compensatory
0363-6119/88
$1.50 Copyright
Medicine,
mechanisms preventing the development of fetal hypoxia
in ewes with high 0, affinity hemoglobin. The experiments described in this paper were designed to compare
fetal oxygenation in A and B ewes that carry a single
fetus and to verify the hypothesis of compensatory differences in the mechanisms of fetal O2 delivery,
MATERIALS
AND METHODS
Selection of animals. The ewes for this study were
selected over a Z-year period from a group of 250 Rambouillet-Columbia sheep raised on the Nebeker Ranch,
Santa Monica, CA, (elevation 800 m) and transported to
our laboratory in Denver, CO (elevation 1,500 m) at -80
days of gestation. The maternal hemoglobin type was
determined at arrival by means of paper electrophoresis
(23). Each of eight A sheep was paired with B sheep of
similar age, body weight, parity, and length of gestation.
The ewes of each pair were operated on consecutive days
and studied at the same interval after surgery (5 to 7
days).
Surgery and animal care. The ewes were fasted for 48
h before surgery. Under general intravenous pentobarbital sodium anesthesia and 1% tetracaine hydrochloride
spinal anesthesia (lo-12 mg)Y polyvinyl catheters (1.4
mm OD) for blood sampling were placed in a maternal
femoral artery with the catheter tip positioned in an
external iliac artery, in the uterine veins draining the
two uterine horns with the catheter tip positioned 4 cm
below the level of the ovary, in a fetal hindlimb artery
with the catheter tip positioned in the external iliac
artery, and in an umbilical vein with the catheter tip
positioned in the common umbilical vein. A polyvinyl
catheter for infusion was placed in a fetal hindlimb vein
with the catheter tip positioned in the external iliac vein.
A catheter was also placed in the amniotic fluid cavity
for instillation of antibiotic.
The animals recovered promptly from surgery and
were standing and feeding in their individual pens within
6 h. Antibiotic was administered and catheters maintained as previously described (31). The ewes were given
water and fed ad libitum with a standard alfalfa pellet
diet. On the day of the study a solution of ethanol in
normal saline was delivered to the fetus via the hindlimb
venous catheter at a constant rate (0.1 ml/min) by means
of a syringe pump. The ethanol concentration in the
infusate was adjusted based on estimates of fetal size and
placental clearance to give a fetal arterial ethanol con-
0 1988 the American Physiological
Society
R585
Downloaded from ajpregu.physiology.org on January 21, 2007
B., RICHARD
D. MOLINA,
AND GIAPlacental oxygen transport in sheep with different hemoglobin types. Am. J. Physiol. 254 (Regulatory Integrative Comp. Physiol. 23): R585-R589,
1988.-To
study the
effect of genetic differences in the maternal oxyhemoglobin
dissociation curve on fetal O2 supply, we compared eight pregnant ewes homozygous for high O2 affinity hemoglobin (A) with
eight pregnant ewes homozygous for low O2 affinity hemoglobin
(B). Each ewe carried a single fetus. Fetal weights were not
significantly different (A, 3,000 t 170 g; B, 3,070 t 270 g). The
A ewes had significantly
higher arterial O2 saturation
(95 vs.
89.4%), uterine blood flow per kilogram of fetus (464 vs. 374
ml/min), uterine venous O2 saturation
(78.1 vs. 67.5%), and
placental-to-fetal
weight ratio (0.107 vs. 0.085). Uterine venous
Pop was significantly
less in A ewes (41.7 vs. 47.6 Torr), but
umbilical
venous and arterial Paz and fetal O2 uptake were
virtually equal in the two groups. We conclude that the difference in O2 affinity between A and B hemoglobins
is fully
compensated for by differences in arterial O2 saturation, in the
rate of perfusion of the pregnant uterus, and in the degree of
Paz equilibration
between the uterine and umbilical circulations so that the single fetuses of A and B hemoglobin carriers
have equal levels of oxygenation.
WILKENING,
COMO MESCHIA.
MESCHIA
of Perinatal
R586
FETAL
OXYGENATION
0 2 = (Hb x So2/100)
+ 0.00131 Po2
where 0.00131 is the O2 solubility coefficient at 39.5OC
and Po2 is in Torr. Po2, Pco~, and pH were analyzed at
39.5”C with a Radiometer
BMS 3 MK 2 instrument
(Radiometer,
Copenhagen).
Umbilical and uterine blood flows were calculated by
application of the Fick principle to the steady-state
diffusion of the test molecule (either ethanol or tritiated
water) across the placenta (20,30). Uterine 0, extraction
was calculated as the A-V/A 0, content ratio.
Uterine and fetal O2 uptakes were calculated from the
blood flow and O2 content data by application of the Fick
principle to the uterine and umbilical circulations
(20,
30). The rate of O2 delivery to the pregnant uterus was
calculated as the uterine blood flow (ml/min) times arterial O2 content (mol/ml) product (31).
Ethanol placental clearance (C; ml/min)
was calcu-
lated as
C = Q/(a - A)
where & is the rate of ethanol transfer
from fetus to
mother and (a - A) is the ethanol concentration
difference between umbilical arterial and maternal arterial
blood (7).
Statistics. The significance
(P < 0.05) of differences
between the eight A sheep and the eight B sheep was
determined using unpaired Student’s t test analysis and
14 degrees of freedom.
RESULTS
Maternal, fetal, and placental weights. The two groups
did not differ significantly with respect to maternal
weight and gestational age (Table 1). Mean fetal weights
were virtually identical, but the weight of the placental
cotyledons was significantly higher in the A sheep. The
placental to fetal weight ratio was also significantly
higher (0.107 vs. 0.085, P c 0.05).
Maternal circulation data. The O2 saturation of arterial
blood was significantly higher in the A sheep (95.0% vs.
89.4%, P < O.OOl), whereas O2 capacity, arterial Po2,
Pco~, and pH were not significantly different (Table 2).
Mean arterial 0, content was 8% higher in the A sheep
but not significantly so. In A sheep the uterine venous
O2 saturation was significantly higher (78.1 vs. 67.5, P <
O.OOl), and the Pop significantly lower (41.7 vs. 47.6, P
< 0.001) than in B sheep (Fig. 1). Mean uterine 0,
uptakes were similar in the two groups, whereas uterine
blood flow per kilogram of fetus and uterine O2 delivery
rate were significantly higher in A sheep.
The mean uterine arteriovenous difference of 0, content was 24% higher in B sheep (1.47 vs. 1.19 mM, P <
0.01). Because 0, arteriovenous differences represent the
reciprocal of blood flow per millimole of 0, uptake, this
finding implies that for equ.al values of uterine 0, requirements, uterine blood flow was 24% higher in A
sheep. Similarly, mean uterine O2 extraction was 36%
higher in B sheep (0.247 vs. 0.182, P c O.OOl), implying
a 36% higher 0, delivery rate in A sheep. The measurements of absolute flows and 02 delivery rate gave comparable results. Mean uterine blood flow and mean O2
delivery rate were 21 and 31% higher, respectively, in the
A sheep group.
Fetal and uteroplacental data. In contrast to the uterine
circulation data, umbilical arterial and venous 0, satuTABLE
1. Gestational age and weight data
Maternal wt,kg
Gestational
age, days
Fetal wt, g
Placental
wt, g
No. of placental
cotyledons
Mean wt of placental
cotyledons
Placental/fetal
wt
A Sheep
B Sheep
P*
46.6k2.0
131.022.0
3,000~170
312H6
79.1rt3.6
3.97t0.16
0.107t0.007
48.1t1.8
133.0t1.0
3,070&270
255&19
79.3t2.3
3.2o-co.19
0.085~0.005
NS
NS
NS
co.05
NS
co.02
co.05
Values are means & SE. See text for definitions.
difference
between
A and B means (unpaired
t test).
P > 0.05 were considered
NS.
* Significance
of
Differences
with
Downloaded from ajpregu.physiology.org on January 21, 2007
centration not exceeding 10 mg/dl at the conclusion of
the experiment. Tritiated water in normal saline rather
than ethanol was infused into fetuses of one pair of ewes
as the test molecule.
Approximately
60 min after starting the test molecule
infusion, blood samples for test molecule concentration
(1.0 ml in EDTA-coated
syringes), for hemoglobin concentration and 0, saturation (0.5 ml into heparin-coated
capillaries),
and for yOZ, Pco~, and pH (0.5 ml into
heparin-coated
capillaries)
were drawn simultaneously
from the maternal arterial (A), uterine venous (V), fetal
arterial (a), and umbilical venous (v) catheters.
Four
such sample sets were drawn at 20- to 30-min intervals.
At the end of each study the animals were killed by an
injection of euthanasia solution, at which time the condition and placement of the catheters were verified, fetal
and placental weights were measured, and the number
of cotyledons counted.
Analytical methods and calculations. Blood ethanol was
measured in triplicate using the enzymatic conversion of
ethanol to acetaldehyde (Sigma Reagents) (7). The radioactivity
due to tritiated
water was determined
on
plasma samples in triplicate with the Packard Tri-Carb
460C liquid scintillation
system and converted to counts
per milliliter of blood as previously described (29).
The PO, and Pco2 electrodes were calibrated with two
gas mixtures having the composition
95% Nz-5% CO,
and 83% Nz-10% CO,-7% 02, respectively.
Blood hemoglobin concentration
expressed as O2 capacity (Hb, mM) and oxyhemoglobin
saturation (So2, %)
were measured in duplicate by an a,utomatic, direct reading spectrophotometer
(OSM-2,
Radiometer,
Copenhagen). The 0, capacity reading was calibrated by means
of fully oxygenated blood whose hemoglobin content had
been measured in a Beckman DU-7 spectrophotometer
at wavelength
540 nm after conversion to cyanomethemoglobin. The molar extinction
coefficient used in the
cyanomethemoglobin
measurement
was 11.0 per millimolar solution of l-cm thickness.
The 100 and 0% saturation readings were calibrated separately for A sheep, B
sheep, and fetal blood. Blood O2 content (mM) was
calculated as
FETAL
TABLE
2. Maternal circulation data
--.w-._--
A Sheep
_-.-
BSheep
P*
6.77-r-0.19
6.62-cO.24
NS
95.0t0.4
6.53t0.19
71.5Ikl.l
35.8ti.Q
7.45z!zo.O09
89.4k0.6
6.02zkO.24
71.7s.4
34.3-cl.2
7.47&0.004
~0.003
NS
NS
NS
NS
78.1*0.5
5.34kO.16
41.7t0.6
39.1t0.8
7.43kO.011
67.5+1.4
4.55-c-0.24
47.6-F-0.8
38.6t1.3
7.44kO.006
4u-nl
~0.02
60.001
NS
NS
16.9t0.5
1.19~0.85
18.2~0.5
1,374+93
464k34
21.9t1.3
1.47H.07
24.7k1.4
1,132&83
374&E
co.01
co.01
<O.OOl
NS
co.05
8.90t0.50
1.6lkO.09
6.81M.55
1.65t0.13
~8.02
Ns
Values are means t SE. See text for definitions.
difference
between A and B means (unpaired
t test).
P > 0.05 were considered
NS.
* Significance
of
Differences
with
mbilicol
Vein
8o
?O
“B 0
.O
0
0
0
Maternal
z
0
---I--~
3. Fetal and uteroplacental data
--.--..“.--
-OZ capacity
of fetal blood, mM
Umbilical
venous blood
0, saturation,
%
0, content,
mM
Po2, Torr
Pco~, Torr
PH
Umbilical
arterial
blood
O2 saturation,
%
O2 content,
mM
Po2, Torr
Pco~, Torr
PM
Umbilical
blood flow, ml/min
Umbilical
blood flow/kg
fetus,
ml/min
Umbilical
O2 uptake,
mrnol/min
Umbilical
O2 uptake/kg
fetus,
mmol/min
Uteroplacental
OP consumption,
mmol/min
Placental
ethanol clearancet,
ml/min
Uterine-umbilical
venous PoB
difference,
Torr
A Sheep
---6.7OdzO.22
BSheep
P*
7.14k0.26
NS
81.2kl.5
5.46t0.14
27.5kO.9
42.3-t-0.9
7,411kO.O06
79.7Hi.O
5.74-t0.28
27.ls.4
42,0-c-1.1
7.4ldI.009
NS
NS
NS
NS
NS
56.1t1.7
3.78-1-0.17
19.2-r-0.6
47.421.1
7.38t0.006
634-+20
216-i-11
54.9k2.4
3.95t0.25
18.8tl.O
47.9-1.2
7.38t0.009
571k40
189rslO
NS
NS
NS
NS
NS
NS
NS
1.06&0.05
0.359t0.020
1.02t0.09
0.329zkO.006
NS
NS
0.55kO.06
0.63;610.06
NS
362210
296*21
<O.OZ
14.2-t-1.2
20.4zkl.2
co.01
--Values are means * SE. See text for definitions,
* Significance
of
difference
between A and B means (unpaired
t test). Differences
with
P > 0.05 were considered
NS. t Seven observations
per group.
IOO90-
TABLE
1
P < 0.01). Estimates of uteroplacental 0, consumption
(i.e., the difference between uterine and umbilical uptakes) were variable and not significantly different between the two groups. Placental ethanol clearance was
significantly higher in A sheep, reflecting a higher level
of placental perfusion in this group (7).
Artery
c
a70K
2
DISCUSSION
:: 60-
Uterine
Vein
0”
lJmbilica1
Artery
I
10
I
I
20
30
I
40
Po2 (TORR)
I
50
1
I
I
60
70
80
FIG. 1. Plot of maternal
and fetal blood O2 saturation
vs. Paz in 8
pregnant
ewes homozygous
for high O2 affinity
adult hemoglobin
A (a)
and 8 pregnant
ewes homozygous
for low 02 affinity
adult hemoglobin
B (0). Adult blood of A sheep has an oxyhemoglobin
dissociation
curve
to the left of B sheep adult blood curve. Fetuses of A and B sheep have
overlapping
oxyhemoglobin
dissociation
curves because at gestational
age of study most hemoglobin
present in fetal blood is fetal hemoglobin.
ration, O2 content, and Paz values were similar in both
groups (Table 3 and Fig. 1). Umbilical O2 uptakes were
also similar. Mean umbilical blood flow per kilogram of
fetus was 14% higher in A sheep, but this difference did
not attain the level of statistical significance. The Po2
difference between uterine venous and umbilical venous
blood was significantlv less in A sheep (14.2 vs. 20.4 Torr.
In sheep the uterine and umbilical circulations form
an exchange system that tends to equilibrate uterine and
umbilical venous Po2 and PCO~ (12, 14, 31). Even under
normal physiological conditions, however, full equilibration is not attained, so that the venous concentrations
of the diffusing molecules are consistently higher in the
donor than in the recipient blood stream (7, 18, 31).
Given this relatively ineffective system of respiratory
exchange and the importance of the maternal oxyhemoglobin dissociation curve in determining uterine venous
Po2, it may seem reasonable to assume that the level of
fetal oxygenation is critically dependent on the 02 affinity of maternal blood. Contrary to this assumption, the
present study demonstrates that in ewes with two widely
different oxyhemoglobin dissociation curves fetal 02
pressures are equal and that several mechanisms contribute to this equality.
The high O2 affinity hemoglobin carriers (A sheep)
have some advantage in the uptake of O2 via the pulmonary circulation. At Denver altitude (1,500 m above
sea level) arterial O2 saturation was higher in the A sheep
with no significant differences in arterial Po2 and 02
capacity. Previous studies, which include observations at
sea level as well as higher elevations, have also shown
Downloaded from ajpregu.physiology.org on January 21, 2007
O2 capacity of maternal
blood, mM
Maternal
arterial blood
0, saturation,
%
0, content,
mM
PO,, Torr
Pco~, Torr
PH
Uterine
venous blood
O2 saturation,
%
0, content,
mM
PO,, Torr
Pco~, Torr
PH
Uterine
arteriovenous
differences
0, saturation
difference,
%
0, content difference,
mM
Uterine
O2 extraction,
%
Uterine
blood flow, ml/min
Uterine
blood flow/kg
fetus, ml/
min
Uterine
0, delivery,
mmol/min
Uterine
O2 uptake,
mmol/min
R587
OXYGENATION
R588
FETAL
OXYGENATION
19, 27) have not demonstrated
the large decrease in
uterine-umbilical
venous Po2 difference that should occur if this difference were caused by umbilical vascular
shunts and uneven perfusion (27). Furthermore,
neither
a countercurrent
nor a concurrent
model of placental
exchange agree with histological evidence (28) and with
the observation
(21) that, in th.e ovine placenta artificially perfused via the umbilical circulation,
reversing
the direction of the perfusion does not change the clearance of NzO (26). Although shunts and uneven perfusion
must contribute
to the ineffectiveness
of placental O2
exchange, we cannot exclude the possibility that placental 0, diffusing capacity is an important
factor in determining the degree of equilibration
between uterine and
umbilical venous 0, pressures and that the smaller uterine-umbilical
venous Paz difference in A sheep results
from a greater placental O2 diffusing capacity. In favor
of this suggestion is the finding that placental weight
and the placental to fetal weight ratio were significantly
greater in the A sheep. An increase in placental size is
likely to imply an increase in diffusing capacity.
It is interesting to note that the development of a high
level of uterine perfusion and a small Paz gradient between maternal and fetal blood, which appear to be
necessary for normal fetal oxygenation
in A sheep, is
inhibited in hot environments.
Pregnant sheep exposed
to high ambient temperatures
from 45 to 120 days gestation had abnormally
low uterine blood flows, small
placentas, significantly
larger uterine-umbilical
venous
Po2 differences, and fetal hypoxia and hypoglycemia (6).
This suggests that different frequencies of ovine hemoglobins in different climates may result in part from the
effect of environmental
temperature
on placental function.
In humans, maternal blood with high O2 affinity hemoglobin is compatible with normal fetal development
and growth (8, 22, 25), thus suggesting the presence of
adaptive mechanisms similar to those observed in sheep.
In apparent contrast to the evidence in sheep and humans are two studies in rats showing that maternal
exchange transfusion
with high 0, affinity carbamylated
blood resulted in fetal growth retardation
(5, 13). A
possible explanation
of this discrepancy
is that the inheritance of high O2 affinity hemoglobins is linked with
the inheritance
of other traits that promote the growth
of a well-perfused
placenta with a relatively
high O2
diffusing capacity. An alternative explanation, however,
is suggested by a comparison
of the two rat studies. In
one study (5), exchange transfusion
at day 19 of gestation
resulted in an 18% reduction in fetal weight and no
change in placental weight at day 21; whereas in the
other study (13), exchange transfusion
at day 9 resulted
in a smaller decrease in fetal weight (10%) and a 20%
increase in placental weight at day 21. These quantitatively different results suggest that placental O2 transfer
mechanisms
are capable of physiological
adaptation to
experimentally
induced changes in the maternal oxyhemoglobin dissociation
curve if sufficient time is allowed
for the adaptation to develop.
Figure 1 demonstrates
that all fetuses had similar
oxyhemoglobin
dissociation
curves, in marked contrast
to the difference in 0, affinity between A and B ewes. In
Downloaded from ajpregu.physiology.org on January 21, 2007
greater O2 saturations
in the arterial blood of A sheep
(3, 9). The comparison
of 0, capacities has yielded less
consistent results. Although no significant difference was
present in our study, other investigations
have indicated
that higher 0, affinity tends to be associated with a
higher mean hemoglobin content (1, 17).
In relation to the problem of maintaining
a high uterine venous Paz, the higher arterial 0, saturation
of A
sheep could not fully compensate
for the greater 0,
affinity of A hemoglobin. On the basis of the data in Fig.
I, we estimate tha.t equal uterine arteriovenous
differences of 0, saturation
in A and B sheep would have
resulted in a much lower uterine venous Po2 in the A
sheep (37.0 vs, 47.6 Torr). The A sheep combined higher
a.rterial O2 saturation with a higher rate of 0, delivery to
the pregnant uterus to produce a uterine venous 0,
saturation that was 10.5% greater than in B sheep (78.0
vs. 67.5%). Despite this greater venous O2 saturation, A
sheep failed to attain the uterine venous Paz of B sheep
(41.7 vs. 47.6 Torr). Note that the uterine venous blood
of A sheep would have required -85% saturation
to
attain the mean 47.6 Torr Paz of B sheep (Fig. 1).
Everything else being equal, the maintenance of an 85%
saturation in uterine venous blood would have entailed
a uterine blood flow of 2.3 l/min instead of the observed
mean flow of L4 l/min.
The significantly
lower uterine venous Po2 of A sheep
did not result in fetal hypoxia because their placenta was
more effective than the B sheep placenta in equilibrating
the 0, pressures of the uterine and umbilical circulations.
The mean uterine-umbilical
venous Po2 difference in B
sheep was 20.4 Torr. An equally large vein-to-vein
POT
difference in A sheep would have produced an umbilical
vein Po2 of 21.3 Torr (instead of 27.5 Torr) and a 68%
umbilical
venous 0, saturation
(instead
of 81.2%).
Therefore better equilibration
of uterine and umbilical
venous O2 pressures represents a third local mechanism
that combined with a greater arterial 0, saturation
and
a greater uterine O2 delivery rate to give as high a level
of fetal oxygenation in A sheep as in B sheep.
The exact nature of this third mechanism is unclear
because there is inadequate knowledge of the factors that
create the Paz difference between uterine and umbilical
venous blood. According to one hypothesis, maternal and
fetal O2 pressures are virtually equal at the venous end
of the placental capillaries,
and the uterine-umbilical
venous PO, difference results from a combination
of
vascular shunts and uneven maternal to fetal perfusion
ratios in different parts of the placenta (14, 16). If this
hypothesis is correct, the placenta of A sheep would have
less vascular shunting and a smaller degree of uneven
perfusion than the placenta of B sheep.
The major evidence in favor of the shunting-uneven
perfusion hypothesis
is that placental O2 diffusing capacity, estimated from studies of carbon monoxide placental transport,
is sufficiently
high to permit full equilibration of venous 0, pressures in a concurrent model of
placental exchange (15). Other observations,
however,
suggest caution in accepting the validity of this hypothesis. Experiments
designed to study placental Oz transport under conditions
of hypoxia (27, 31) and a right
shift in the fetal oxyhemoglobin
dissociation
curve (3,
FETAL
OXYGENATION
fetal sheep the rapid synthesis of adult hemoglobin begins after MO days of gestation, and very small amounts
of adult hemoglobin are actually present in fetal blood
at that age (2). Therefore, the similarity
of fetal oxyhemoglobin dissociation
curves shown in Fig. 1 is due to a
preponderance
of fetal hemoglobin at the age of study.
There is no evidence in our data suggesting that there
is a sharply defined maternal O2 affinity that is optimal
for fetal growth. The system of fetal 0, delivery seems
capable of adapting successfully
to a broad range of
maternal O2 affinities. It is noteworthy,
however, that
this adaptation does not involve any significant
change
in fetal blood O2 pressure. Although individual fetuses
can survive relatively large decreases in oxygenation,
it
seems likely that even small chronic changes in the fetal
internal environment
are not selectively neutral.
Received
24 August
1987; accepted
in final
form
3 November
and
R.
1987.
REFERENCES
N. S., J. V. EVANS,
AND J. ROBERTS.
Red blood cell
potassium
and haemoglobin
polymorphism
in sheep. A review.
Anim. Breed. Abstr. 40: 407-436,
1972.
BARD,
H., F. C. BATTAGLIA,
E. L. MAKOWSKI,
AND G. MESCHIA.
The synthesis
of fetal and adult hemoglobin
in sheep during the
perinatal
period. Proc. Sot. Exp. Biol. Med. 139: 1148-1150,
1972.
BATTAGLIA,
F. C., R. E. BEHRMAN,
C. W. DELANNOY,
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Downloaded from ajpregu.physiology.org on January 21, 2007
This work was supported
by National
Institute
of Child Health
Human Development
Grants HD-01866,
HD-00781,
and HD-20761;
D. Molina
was supported
by Training
Grant HD-07186.
R589