Download LACK OF PERIPHERAL SYMPATHETIC CONTROL OF UTERINE

LACK OF PERIPHERAL SYMPATHETIC CONTROL OF
UTERINE BLOOD FLOW DURING ACUTE HEAT STRESS 1
D. E. Brown 2 and P. C. Harrison
University of Illinois3 , Urbana 61801
Summary
Peripheral Q- and 3-adrenergic control of
uterine blood flow (UBF) during acute heat
stress of the gravid ewe was investigated. An
electromagnetic blood flow probe was surgically
implanted around the left miduterine artery
and catheters inserted in the left carotid artery
and right jugular vein in ewes between d 120
and 130 of gestation. Four or more days
postsurgery, ewes were fitted with instruments
to measure rectal temperature (Tr), heart rate
(HR), respiratory rate (RR), blood pressure
(BP) and UBF. One-half hour after instrument
calibration, a 15-rain thermoneutral control
period was initiated with carotid artery blood
samples taken at 5-rain intervals for pH and
PCO2 determinations. Ewes were then subjected
to a heat challenge that reached 40 C at 2 h. All
physiological data were recorded every 5 min
as l-rain mean values. In seven experiments on
five ewes, an tY-adrenergic blocking drug,
phenoxybenzamine (PB) was infused at 1
rag/rain for 15 rain subsequent to maximum
depression of UBF. A /3-adrenergic blocking
drug, propranolol (PR) was infused at .35
rag/rain for 15 min in eight experiments on five
ewes. Analysis of variance comparisons were
made between the control period and heat
stress infusion periods within the PB and PR
experiments. Further comparisons were made
between the start and 5, 10 or 15 min of PB or
PR infusion in order to test drug effects during
an acute heat stress. Rectal temperature HR,
RR and arterial pH were higher (P<.05) at the
start of PR and PB infusions than during the
thermoneutral control period. By th~ start of
PB and PR infusions, both PCO2 and UBF were
depressed (P<.05) from their respective thermoneutral control period values. The 15-rain
infusions of PB or PR did not increase UBF
during heat stress. The UBF of PB-treated ewes
remained depressed (P<.05) at the end of
infusion without a change in uterine vascular
resistance (UVR). The PR blocked tachycardia
(P<.05) without a depression in systemic
BP. These data indicate that peripheral ~- or
~adrenergic mediated vasoconstriction do not
appear to be responsible for the heat stressinduced depression of UBF. Alternate mechanisms are proposed for the phenomenon.
(Key Words: Sheep, Uterine Blood Flow,
Phenoxybenzamine, Propranolol, Sympathetic
Nervous System.)
Introduction
Intrauterine growth retardation (IUGR) is a
consequence of heat stress during late gestation
in sheep (Yeates, 1953, Shelton, 1964a,b).
Growth retarded lambs are proportionally small
rather than achondroplastic dwarfs (Brown et
al., 1977) and occur independent of ewe
nutrition. Ewes at thermoneutrality restricted
to the feed intake of heat-stress ewes produce
normal birth weight lambs (Cartwright and
Thwaites, 1976; Brown et al., 1977, 1979).
However, heat stress-induced growth retardation
may be a result of altered uterine blood flow
(UBF). The UBF provides organic substrates,
02 and water to the fetus (Barron, 1970).
Increased uterine uptake of substrates is due
almost entirely to increased UBF as gestation
proceeds (Comline and Silver, 1976; Clapp,
1The authors express appreciation of Ms. Sharon
1978; Ferrell and Ford, 1980). Because Oakes
Sittler and Mrs. Kathy Fry for their technical assistance.
et al. (1976a), Roman-Ponce et al. (1978a,b),
2Present address: Anita. Sci. Dept., Univ. of and Brown and Harrison (1981) have found
Nevada, Reno 89557.
that UBF is comprised during heat stress, it is
3 Dept. of Anim. Sci.
reasonable to suggest that heat stress-induced
Received August 31, 1983.
Accepted January 17, 1984.
IUGR may be mediated through altered UBF.
182
JOURNAL OF ANIMAL SCIENCE, Vol. 59, No. 1, 1984
UTERINE BLOOD FLOW CONTROL DURING HEAT STRESS
Estrogens and progesterone are major
regulators of UBF during pregnancy (Griess and
Anderson, 1970; Huckabee et al., 1970; Caton
et al., 1974). However, Roman-Ponce et al.
(1978a,b) have shown heat stress reduces the
magnitude of estrogen-induced increases in
UBF. The uterine vasculature is also sensitive to
adrenergic vasoconstriction (Barton et al.,
1974; Rosenfeld et al., 1976). In an earlier
study, Brown and Harrison (1981) have shown
that compromised UBF during heat stress is
insensitive to central sympathetic blockade.
Because exogenous epinephrine depressed UBF
(Roman-Ponce et al., 1978a) and catecholamines
are elevated during heat stress in cattle (Alvarez
and Johnson, 1973; Davis et al., 1978), this
experiment was initiated to determine if
depressed UBF of pregnant ewes during heat
stress is mediated through peripheral a- and
/3-adrenergic receptors.
Experimental Procedure
Seven ewes of mixed breeding were bred at
synchronized estrous periods. Silastic implants
containing progesterone were inserted sc on the
brisket for 14 d. Each ewe was given 500 IU of
pregnant mare serum gonadotropin after
implant removal. Breeding dates were determined by using rams with grease paint applied
to the region of the sternum.
Ewes were placed in a plexiglass calorimetry
chamber between d 120 and 130 of pregnancy.
A polyvinyl chloride catheter was sutured into
the left carotid artery and an indwelling catheter 4 was inserted through the skin into the left
jugular vein. An electromagnetic blood flow
transducer s was implanted around the left
miduterine artery as described previously
(Brown and Harrison, 1981). All factorycalibrated blood flow probes were recalibrated
in vitro. The regression coefficients of actual
blood flow into a graduated cylinder on blood
flow measured b y the blood flow probes
4E-Z cath, 8"-18ga, Desert Pharmaceutical Co.,
Sandy, UT.
SModel ER 416, Carolina Medical Electronics,
King, NC.
6 Model 1203, Harvard Apparatus, Dover, MA.
SYSI 47, Yellow Springs Instrument Co., Yellow
Springs, OH.
8Model 501, Carolina Medical Electronics, King,
NC.
9Micro 13, Instrumentation Labs, Lexington, MA.
183
have been reported (Brown and Harrison,
1981).
Beginning 4 d after surgery, five ewes were
utilized for seven heat exposure episodes in
which phenoxybenzamine (PB), an a-adrenergic
antagonist (Furchgott, 1959), was infused and
five ewes were utilized in eight trials in which
propranolol (PR), a /3-adrenergic antagonist
(Furchgott, 1959), was infused. Constant rate
infusions of PB (2mg/ml) and PR (.7mg/ml) in
the jugular vein at .5 ml/min for 15 min were
made using an infusion pump 6 when UBF had
remained at a minimum depressed level for 5
rain. All heat-stress episodes were separated by
at least 48 h at 20 to 22 C. Three of the ewes
received both PB and PR in a completely
randomized design experiment.
On the morning of a heat-stress episode,
ewes were fitted with instruments as previously
described (Brown and Harrison, 1981). Catheter
and transducer cables were exteriorized through
a chamber porthole. The ewes were thus
untouched during a heat-stress episode. Chamber
air temperature (Ta) and rectal temperature
(Tr) at a depth of 6 cm were recorded from a
telethermometer 7. Respiratory rate (RR), heart
rate (HR), carotid artery blood pressure (BP)
and UBF from a blood flow meter s were
recorded on a polygraph. Carotid artery blood
samples were collected into heparinized glass
syringes and stored on ice. Partial pressure of
CO2 (PCO2) and pH were measured on a blood
gas analyzer 9 within 10 min of blood sample
collection. At least 30 rain after instrument
calibration, a 15-min thermoneutral control
period began in which all functions were
monitored. Blood samples were taken initially
and three times at 5-rain intervals. Control
period mean values of all functions were the
average of the four recordings spanning the
15-rain thermoneutral period. Uterine vascular
resistance (UVR) was calculated as the ratio of
BP to UBF.
After the thermoneutral control period, a
58-cm, 600 W radiant heat tube was turned on
and Ta allowed to reach 40 C at an air exchange
rate of 160 liters/rain. Fifteen-minute infusions
of PB and PR began at the time of maximum
depression in UBF.
Data were analyzed by analysis of variance
(Steel and Torrie, 1980). Physiological functions
measured at the start of PB or PR infusions and
5, 10 and 15 rain from the start of infusions
were analyzed for differences from the thermoneutral control period. In order to test drug
184
BROWN AND HARRISON
effects during heat stress, changes in all functions between the start and 5, 10 and 15 rain of
infusion were analyzed for both PB and PR
experiments. In all analyses, among and within
ewe variances were separated because some
ewes in both treatments received PB or PR on
two separate occasions. Treatment mean
squares were evaluated by using the appropriate
among-ewe mean square for the F test.
+1
+1
Results and Discumion
increased during heat exposure from 19.6 + 1.0
to 40.0 -+ .~ C and from 20.6 + 1.1 to 37.9 -+
.8 C in 75 -+ $ and 78 + 4 rain for PB and PR
treatments, respectively. In response to heat
stress, ewe Tr increased 2.0 and 2.3 (P<.05) for
PB and PR treatments, respectively (table 1 and
2). Rectal temperature responses were higher
than the 1.5 C rise previously reported for ewes
subjected to identical heat episodes (Brown and
Harrison, 1981 ).
The heart and respiratory rate responses of
the pregnant ewes to an acute 40 C heat stress
are comparable with results of previous research
in our laboratory. The maximum heart rates of
147 beats/min (table 1) and 151 beats/rain
(table 2) for PB and PR treatments, respectively,
are similar to the maximum heart rate of 146
beats/min of a previous group of mixed breed
ewes (Brown and Harrison, 1981). Infusion of
PR resulted in blockade of 3-receptor stimulation
during heat stress within the 1~ rain of infusion
period. The HR of 118 beats/rain after 15 rain
of PR infusion was decreased (P<.05) from the
maximum HR of 151 beats/rain at the start of
infusion (table 2) and was similar to the control
period rate of 119 beats/min. Thus, all heat
stress induced cardiac sympathetic tone was
effectively blocked with the dose o f PR administered. Tachycardia persisted during PB infusion
(table 1) as would be anticipated from the
absence of cardiac a-adrenergic receptors
(Furchgott, 1959). Hyperpnea during hyperthermia was present at the initiation and
persisted throughout infusions of both PB and
PR (tables 1 and 2). Panting was above three
times the resting RR after 15 rain of PB and
PR, suggesting that heat stress-induced panting
is not primarily controlled by peripheral
sympathetic neurons. Both Voile and Koelle
(1970) and Brown and Harrison (1981) found
no decrease in RR upon blocking central sym-
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pathetic transmission with hexamethonium,
further suggesting that panting is not a result of
increased sympathetic tone. Harrison et al.
(1972) have shown that panting during heat
stress in the Coturnix quail is a parasympathetic
vagal reflex. A dose of atropine large enough to
block heat stress-induced bradycardia in quail
was sufficient to reduce the RR from 250 to 50
breaths/min 9
Blood Gas and pH Change. The hypocapnia
and alkalosis observed in both PB- and PRtreated ewes is similar to heat-stress data in a
previous report from this laboratory (Brown
and Harrison, 1981) and other acute heat-stress
experiments (Hales, 1973 ; Oakes et al., 1976a).
The PCO2 decreased from 24.8 to 16.2 mm
Hg (P<.05), while blood pH increased from
7.57 to 7.76 (P<.05) at the start of PB (table
1). Blood PCO2 decreased from 26.6 to 11.0
mm Hg (P<.05) in PR treatment ewes, while
blood pH increased (P<.05) from 7.56 to 7.88
(table 2). In both PB and PR experiments, a
new blood pH buffer equilibrium was established
by the start of drug infusions as neither PCO2
nor pH continued to change further (tables 1
and 2) . The lack of blood gas change during
the 15-min PB or PR infusions would be
expected from the failure of either PB or PR to
alter respiratory rate during heat stress.
Uterine Vascular Cbanges. Systemic blood
pressure did not decrease during the acute heat
stress of either PB- or PR-treated ewes, which is
in disagreement with a previous report from
this laboratory (Brown and Harrison, 1981)9
However, the control period PB of 81 and 83
mm Hg for PB and PR ewes, respectively, was 9
and 7 m m Hg lower than the resting BP of ewes
in the previous experiment (Brown and Harrison,
1981), suggesting mild hypotension may have
been present in the ewes of this experiment
before the application of heat stress. The uterus
of the pregnant ewe at thermoneutrality does
not maintain constant blood flow as pressure
decreases and is considered a passive vascular
bed (Greiss, 1966; Ladner et al., 1970)9 The
UBF decreased in both the PB and PR treatments, unaccompanied by significant changes in
BP, suggesting that autoregulation of the
uterine vasculature occurs during heat stress9
Maximum UBF depression occurred at 94 + 9
and 81 + 10 rain for PB and PR treatments,
respectively. These data are consistent with a
previous report of active vascular tone regulation
in heat-stressed, pregnant ewes (Brown and
Harrison, 1981). Adrenergic vasoconstriction of
186
BROWN AND HARRISON
has been reported previously that saline infusion
during the time of heat stress-depressed UBF
has no effect on the UBF or UVR in late
gestation ewes (Brown and Harrison, 1981).
Some a-adrenergic vasoconstriction cannot be
totally ruled out in the present experiment. The
ewes were not given exogenous NE subsequent to PB which would determine the degree
of adrenergic blockade 9 It also remains to be
tested whether PB administered before heat
stress would prevent depression of UBF.
However, reduced UBF should be reversed if PB
is administered to actively firing a-adrenergic
neurons of the uterine vascular bed (Vivaros et
al., 1968).
Beta-adrenergic receptors are present in the
uterine circulation of sheep (Greiss and Pick,
1964), but do not affect UBF at thermoneutrality. Oakes et al. (1976b) found no
change in UBF or UVR during a 1-h infusion of
PR. The 3-adrenergic agonists ritodrine and
salbutamol have a biphasic effect on UBF. An
initial depression in UBF and UVR with ritodrine abated with time (Brennen et al., 1977).
The failure of PR to reverse ritodrine-induced
decreases in UVR (Ehrenkranz et al., 1976)
may be due to the passive nature of the uterine
vascular bed at thermoneutrality. Hyp0tension
persisted during the PR blockage of ritodrineinduced tachycardia.
In the present experiment, a PR dose sufficient to totally block heat stress-induced
tachycardia failed to alter UBF. The UBF
remained depressed despite a trend for UVR to
decrease in the presence of constant BP (table
2, figure 2). It appears that the decreased UBF
observed with maternal heat stress is neither
alleviated or heightened through 3-adrenergic
PHENOXYBE N Z A M I NE
receptors.
5 0 _.9
A number of alternate mechanisms exist that
II
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~ .E may be primary mediators of depressed UBF.
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The blood pH-PCO2 system has been implicated
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by Oakes et al. (1976a) as a mechanism of
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autoregulation. A 50% recovery from decreased
E
UBF during heat stress was observed in ewes
9 -25
rebreathing CO2 during respiratory alkalosis.
?
Hypocapnia at thermoneutrality in rabbits also
-3Z5
led to a 43% reduction in placental blood flow
(Leduc, 1972). Prostaglandin F 2 a ( P G F 2 a ) h a s
40
-30
20
20
10
0
I0
been shown to cause vasoconstriction in both
Time
from
Phenoxybenzomlnl
the uterine and umbilical circulations, while
Figure 1. The percentage change in uterine blood prostaglandin E series compounds are vasoflow (UBF) and uterine vascular resistance (UVR)
from the thermoneutral control period. The time dilators and depress adrenergic vasoconstriction
shown is from 40 rain before to 15 min after the on- in the uterine vasculature (Clark, 1977;
McLaughlin et al., 1978). Angiotension II
set of a 15-min phenoxybenzamine infusion.
the uterine vascular bed has been documented
(Barton et al., 1974; Rosenfeld et al., 1976;
Roman-Ponce et al., 1978a). Increased UVR
accompanied by decreased UBF after norepinephrine (NE) infusions in pregnant ewes has
been prevented with PB (Ladner et al., 1970),
demonstrating the presence of uterine a-adrenergic receptors. A 250 /ag/kg intraarterial dose
of PB totally blocked a 50% increase in UVR
induced by a norepinephrine (NE) injection of
2 /ag/kg. In the present experiment neither
decreased vascular resistance or increased UBF
occurred after infusion of 15 mg PB (200 to
250 /ag/kg) during acute heat stress (figure 1).
Because single doses of PB have a half-life of 24
h (Nickerson, 1970), the dose of PB given in
this experiment over 15 min is comparable
to the previously given injection of 250/ag/kg
(Ladner et al., 1970). The maximum nonequilibrium blockage of a-receptors by PB is not
obtained for up to 1 h but develops asymptotically and the persistent blockade should
initiate decreased resistance and increased
blood flow within minutes of infusion if strong
adrenergic tone is present during the acute heat
stress (Nickerson, 1970). Heat stress-induced
decrease in UBF is also an unlikely consequence
of increased a-adrenergic tone because UBF in
the pregnant heat-stressed ewes decreased
30% in the absence of increased UVR (table 1).
Vascular changes during infusion were compared
with the status at the start of infusions for drug
effect comparisons and were not compared
with a separate group of sham infused ewes. It
t
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T TIT
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UTERINE BLOOD FLOW CONTROL DURING HEAT STRESS
PROPRANOLOL
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Figure 2. The percentage change in uterine blood
flow (UBF) and uterine vascular resistance (UVR)
from the thermoneutral control period. The time
shown is from 40 rain before to 20 rain after the onset of a 15-min propranolol infusion.
increases U V R ( C o h e n et al., 1977) and appears
to f u n c t i o n i n d e p e n d e n t o f ~-adrenergic m e c h a nisms in t h e u t e r i n e vascular b e d ( A n d e r s o n et
al., 1978). H e a t s t r e s s - c o m p r o m i s e d UBF t h u s
a p p a r e n t l y o c c u r s b y m e a n s o t h e r t h a n adrenergic v a s o c o n s t r i c t i o n , b u t the actual c o n t r o l
m e c h a n i s m or m e c h a n i s m s remain t o b e elucidated.
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