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2-receptor
function in vascular adrenergic nerves of adult and fetal
sheep
1 Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda 92350; and 2 Department of Pharmacology, College of Medicine, University of California, Irvine, California 92697
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The
impact of development and chronic high-altitude hypoxia on the function
of prejunctional 
2-adrenoceptors was studied by
measuring norepinephrine release in vitro from fetal and adult sheep
middle cerebral and facial arteries. Blockade of prejunctional 2-adrenoceptors with idazoxan significantly increased
stimulation-evoked norepinephrine release in normoxic arteries. This
effect was eliminated after chronic hypoxia in cerebral arteries, with
a tendency to decline in fetal facial arteries. After chronic hypoxia,
the capacity to release norepinephrine declined in fetal middle
cerebral arteries with a similar trend in facial arteries.
Norepinephrine release was maintained in adult arteries. During
development, stimulation-evoked norepinephrine release from middle
cerebral and facial arteries was higher compared with adult arteries.
In fetal arteries, adrenergic nerve function declined after chronic
hypoxia. However, in adult arteries, adrenergic nerves adapted to
chronic hypoxia by maintaining overall function. This differential
adaptation of adrenergic nerves in fetal arteries may reflect
differences in fetal distribution of blood flow in response to chronic
hypoxic stress.
sympathetic nerve function
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SYMPATHETIC NERVES ORIGINATING from the superior cervical ganglia amply innervate cerebral blood vessels (5). These nerves do not appear to play a major role in the control of cerebral blood flow under normal conditions, inasmuch as autoregulatory mechanisms maintain overall cerebrovascular tone (5). However, cerebrovascular adrenergic nerves have been shown to influence cerebral blood flow in the case of hypertension or hypoxia (1, 5, 12, 33). Other reports have shown an increase in adrenergic nerve activity during physiological stress. During acute hypercapnia, plasma catecholamines rise, reflecting elevated sympathetic nerve activity that is believed to protect vital organs (heart and brain) from damage (8). Thus potentially damaging consequences of hypertensive or hypoxic stress in the cerebral vasculature and peripheral organs may be attenuated by sympathetic nerve activation, suggesting that sympathetic nerves play a "protective" role during physiological stress (5, 30).
Acute hypoxia in isolated rabbit thoracic aortic strips inhibits contractile responses to adrenergic nerve stimulation to a greater extent than responses to exogenously applied norepinephrine (18), and stimulation-evoked norepinephrine release declines during acute hypoxia (19). In contrast, acute exposure to hypoxia in conscious dogs elevates circulating catecholamines, suggesting that acute hypoxia may elevate adrenergic nerve activity in vivo (27). In humans, acute hypoxia during exercise has been shown to increase release of cardiac norepinephrine along with the cotransmitter neuropeptide Y (14).
It is well known that release of norepinephrine from sympathetic nerves
is inhibited via feedback activation of 2-adrenoceptors and subsequent reduction of calcium influx through N-type calcium channels (7, 29). Activation of
2-adrenoceptors has been shown to reduce the
consequences of stress during severe acute hypoxia (17).
In another study using isolated atrial tissue from humans, acute anoxia
resulted in a decline in the effect of the
2-adrenoceptor agonist UK-14304 as well as the
antagonist yohimbine (25). Thus a decline in the function
of prejunctional 2-adrenoceptors may be one mechanism
for enhanced sympathetic nerve activity during acute hypoxic stress.
High-altitude hypoxia during pregnancy has been associated with an elevated incidence of cerebrovascular morbidity in the fetus. Infants exposed to hypoxia during the prenatal period show a higher incidence of intraventricular hemorrhage (16). Although there is evidence that sympathetic nerves may play a role in adaptation to chronic hypoxia, still very little is known about the effect of hypoxia on sympathetic nerve function. Long-term hypoxia has been shown to increase dopamine, but not norepinephrine, turnover in rat sympathetic ganglia (6). More recent studies in fetal and adult sheep showed that norepinephrine release is positively modulated by nitric oxide (NO) released from NO synthase (NOS)-containing nerves in the middle cerebral artery (4, 24). During chronic hypoxia at high altitude, the function of NOS nerves declined. However, despite the loss of this positive modulation of sympathetic nerves, stimulation-evoked norepinephrine release was not altered by chronic hypoxia (4). These data suggest that sympathetic nerves may adapt to chronic hypoxic stress to maintain overall function. However, these studies on the effects of chronic hypoxia do not address the full range of mechanisms that can modulate norepinephrine release at the neuroeffector junction.
Mounting evidence suggests that sympathetic nerve function is important
for survival during acute hypoxia and possibly for adaptation to
chronic hypoxic stress. Thus we set out to study the effects of chronic
hypoxia on sympathetic nerve function in fetal and adult middle
cerebral and facial arteries of sheep. Two discrete parameters
controlling stimulation-evoked norepinephrine release were
investigated. First, we used the 2-adrenoceptor antagonist idazoxan to examine the impact of development and chronic hypoxia on prejunctional 2-adrenergic modulation of
norepinephrine release. Second, adrenergic uptake blockers,
deoxycorticosterone (Doc) and cocaine (Coc), were used to study the
impact of development and chronic hypoxia on the function of
norepinephrine reuptake. Using norepinephrine release in vitro as an
index of adrenergic nerve function along with selective pharmacological
agents enables further investigation of the impact of chronic hypoxia
on function of an important control mechanism in the cerebral circulation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Sixteen pregnant and sixteen nonpregnant ewes of mixed breed were obtained from a single supplier (Nebeker Ranch, Lancaster, CA). These animals were randomly separated into control normoxic (8 pregnant and 8 nonpregnant) and long-term hypoxic groups (8 pregnant and 8 nonpregnant). Animals in the control group remained at Nebeker Ranch (718 m). At 30 days gestation, animals in the hypoxic group (pregnant and nonpregnant) were transported to the Barcroft Laboratory, White Mountain Research Station (Bishop, CA; altitude 3,820 m). At 138-142 days gestation, pregnant and nonpregnant normoxic and hypoxic animals were transported to the Department of Perinatal Biology at Loma Linda University where they underwent immediate study.
In the case of hypoxic ewes awaiting study, immediately after arrival at the Department of Perinatal Biology, a nonocclusive tracheal catheter was surgically implanted (11) so that N2 gas could be administered to maintain the arterial PO2 at ~60 Torr. Arterial blood gases in the adults were measured in 0.5-ml samples (ABL300; Radiometer, Copenhagen, Denmark). Mean PO2 values were 101 ± 3 and 61 ± 2 Torr for normoxic and hypoxic adults, respectively. On the experimental day, ewes were euthanized by administration of 100 mg/kg iv pentobarbital sodium, and near-term fetuses were delivered by cesarean section. Fetal arterial PO2 values were 22.4 ± 0.4 and 19.1 ± 0.8 Torr for normoxic and hypoxic fetuses, respectively. Fetal weights were unaffected by hypoxia. Weights were 3,965 ± 103 (n = 8) and 4,033 ± 372 (n = 8) g for control and hypoxic fetuses, respectively. The facial arteries and brain were removed from both adults and fetuses and immediately placed in separate beakers containing ice-cold Krebs solution. Dissection of middle cerebral arteries followed. Krebs solution contained (in mM) 118 NaCl, 4.8 KCl, 1.6 CaCl2, 1.2 KH2PO4, 25 NaHCO3, 1.2 MgSO4, 0.3 ascorbic acid, and 11.5 glucose.
Tissue preparation. Segments of middle cerebral and facial arteries (3-4 cm) were cannulated at both ends with polyethylene tubing and mounted in a low-volume perfusion system as previously described (3). The middle cerebral artery segment used was the main branch from the circle of Willis. Middle cerebral artery diameters ranged from 0.8 to 1.1 mm, while facial artery diameters were from 1 to 1.4 mm. Arteries were perfused at a rate of 1.0 ml/min, creating a perfusion pressure of ~55-65 mmHg in either artery type. The entire perfusion assembly was immersed in a circulating water bath and kept at 37°C. Tissues were perfused with aerated (95% O2-5% CO2) Krebs solution throughout the experiment.
Norepinephrine release.
In all experiments, a Grass S-48 model stimulator (Grass Instruments,
Quincy, MA) delivered electrical field stimulation to perivascular
nerves through a pair of platinum electrodes. The parameters for
stimulation were 8 Hz, 60 V, 1-ms duration, and 480 pulses (1-min
stimulation). In Fig. 1, actual data from
one middle cerebral artery are shown to illustrate the experimental protocol. In each experiment, one middle cerebral artery and one facial
artery served as time controls. In addition to sympathetic nerves, the
cerebral vasculature has been shown to contain NOS-containing nerves,
which release NO on stimulation (31, 32). We recently showed that NO released from NOS-containing nerves augments
stimulation-evoked norepinephrine release (4, 24).
Therefore, to remove the influence of NOS nerves, tissues were
continuously exposed to an inhibitor of NOS,
N
-nitro-L-arginine methyl ester
(L-NAME; 10 µM), throughout all experiments.
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5 M Doc and
105 M Coc (Doc+Coc) for 20 min to block extraneuronal and
neuronal norepinephrine uptake. Once again, nerves were activated for 1 min (S2) followed by a 30-min equilibration. After S2, tissues were
exposed to Doc+Coc together with the 2-adrenoceptor
antagonist idazoxan (1 µM). Again nerves were activated for 1 min (S3).
Measurement of norepinephrine. The perfusate was collected at the start of each stimulation period until 5 ml was collected. Basal norepinephrine release was monitored by collecting 5 ml of perfusate before each stimulation. Perfusates were extracted with alumina and quantified with dihydroxybenzylamine (DHBA) as an internal standard (300 pg). This has been fully described previously (3). A 100-µl sample of extracted amines was then injected into an ESA coulochem II high-pressure liquid chromatograph (ESA, Bedford, MA) and separated on an ESA reverse-phase C18 column with ESA MD-TM aqueous mobile phase. The mobile phase contained (in mM) 75 Na2H2P04, 500 sodium dodecyl sulfate, 0.025 EDTA, 20% acetonitrile, and 5% methanol. The following formula was used to calculate the amount of norepinephrine in the injected sample: pg NE = (NE peak Ht sample/NE peak Ht standard) · 100 pg DHBA · (DHBA peak Ht standard/DHBA peak Ht sample), where NE is norepinephrine and Ht is peak height. Recovery varied from 85 to 98%.
To quantify the tissue norepinephrine content, arteries were homogenized at the end of each experiment in 0.1 N perchloric acid followed by centrifugation. A 300-µl aliquot of the supernatant was taken, and norepinephrine was extracted in a similar manner as the perfusate. Norepinephrine content was used to calculate stimulation-evoked fractional norepinephrine release: fractional NE release = pg NE released/pg NE tissue content · number of stimulation pulses.Statistical analysis. The impact of development and hypoxia on norepinephrine content and release was analyzed by two-way ANOVA and Fisher's protected least-significant difference test. Effect of treatments within the groups was analyzed by Student's paired t-test. The level of significance chosen was P < 0.05.
Drugs used. Coc, Doc, and L-NAME were obtained from Sigma Chemicals (St. Louis, MO). Idazoxan was obtained from Research Biochemicals (Natick, MA).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of idazoxan on norepinephrine release.
As shown in Fig. 2, application of
the 2-adrenoceptor antagonist idazoxan significantly
elevated norepinephrine release in all normoxic arteries studied: fetal
and adult middle cerebral and facial arteries. In arteries from animals
exposed to chronic hypoxia, the effect of idazoxan to increase
stimulation-evoked norepinephrine release was markedly lower, and this
was found in all arteries studied with the exception of adult facial
arteries. In middle cerebral arteries from hypoxic fetuses or adults,
the application of idazoxan no longer significantly increased
norepinephrine release (Fig. 2, A and B). In
facial arteries from hypoxic fetuses, the enhancement of
stimulation-evoked norepinephrine release by idazoxan was attenuated;
however, the effect of idazoxan was still statistically significant
(Fig. 2C). In contrast, in the adult facial artery, after
chronic hypoxia the effect of idazoxan was not altered compared with
facial arteries from normoxic animals (Fig. 2D).
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Effect of uptake blockade.
When extraneuronal and neuronal uptake of norepinephrine was blocked
with Doc and Coc, stimulation-evoked norepinephrine overflow was
significantly elevated in all groups studied (Fig.
3). Chronic hypoxia did not appear to
significantly influence the effectiveness of uptake blockade in fetal
cerebral arteries or fetal and adult facial arteries (Fig. 3,
A, C, and D). The effect of treatment with Doc and Coc tended to be greater in middle cerebral arteries from
hypoxic, compared with normoxic, adults (Fig. 3B). However, this difference was not statistically significant.
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Effect of development.
As shown in Fig. 5, in normoxic
animals there were no statistically significant developmental
differences in vascular norepinephrine content in either middle
cerebral or facial arteries. In contrast, there are distinct
developmental differences in stimulation-evoked fractional
norepinephrine release in both vessels. When extraneuronal and neuronal
norepinephrine uptake were blocked, stimulation-evoked norepinephrine
release was greater in both middle cerebral and facial arteries from
normoxic fetuses compared with normoxic adults (Fig. 2, A
and C). This effect of development persisted when idazoxan was added, so that stimulation-evoked norepinephrine release remained greater in normoxic fetal arteries compared with normoxic adult (Fig.
2, A and C).
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Effect of hypoxia.
Chronic hypoxia resulted in a tendency for norepinephrine content to be
lower in both middle cerebral and facial arteries (Fig. 5). However,
this only reached statistical significance in the adult middle cerebral
artery. Stimulation-evoked norepinephrine release in the presence of
both uptake and prejunctional 2-adrenoceptor antagonists
can be taken as a measure of the total capacity of adrenergic nerves to
release norepinephrine. Under these conditions, stimulation-evoked
norepinephrine release from the hypoxic fetal middle cerebral artery
was significantly lower compared with arteries from normoxic fetuses
(Fig. 2A). In contrast to the fetus, despite the lack of
effect of idazoxan on norepinephrine release, in the presence of
idazoxan there was no statistically significant difference in
stimulation-evoked norepinephrine release between adult middle cerebral
arteries from hypoxic and normoxic animals (Fig. 2B).
Basal norepinephrine release.
Effects of treatments, development, and chronic hypoxia on basal
norepinephrine release are shown in Table
1. There were no statistically
significant effects of development or chronic hypoxia on basal,
unstimulated norepinephrine release in middle cerebral or facial
arteries from adult or fetus. Furthermore, drug treatments did not
significantly alter basal norepinephrine release in any of the groups
studied.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Successful adaptation to environmental stress such as chronic hypoxia appears to depend on sympathetic nerve reactivity (5). The fetus is exposed to a lowered O2 environment and adapts in two ways: high cardiac output and high fetal oxygen consumption (22). When norepinephrine is infused into the fetus in utero to simulate stress conditions, fetal oxygen consumption increases by redistribution of fetal blood flow to the placenta; this serves, in part, to maintain fetal blood gas levels (22).
The model of maternal and fetal hypoxia in this study (pregnant sheep maintained at 3,820 m) is thought to be one of moderate well-adapted hypoxia. There appears to be a "threshold" level of oxygen, which depends on the oxygen level and duration of exposure (21). Beyond this threshold level of oxygen, detrimental effects can occur. During pregnancy at 3,820 m, adult and fetal arterial PO2 values fall significantly, arterial pH remains unchanged, and hemoglobin rises to increase oxygen extraction (15). Hypoxic fetuses continue normal weight gains during gestation with near-term fetal weights comparable to control fetuses maintained at 718 m. Furthermore, fetal mortality, morbidity, and abortion do not increase during the hypoxic exposure period. Animals in this study were exposed to the same degree of hypoxic stress reported in previous studies, and arterial PO2 values in adult and near-term fetuses were nearly equivalent to previously reported values (4, 15, 35). Thus this model serves as one of moderate chronic hypoxia in which adaptive responses can be successfully studied.
Hypoxia and function of prejunctional
2-adrenoceptors.
The most significant finding in this study is that chronic hypoxia
caused a significant reduction in the effect of the
2-adrenoceptor antagonist idazoxan in both fetal
and adult middle cerebral as well as in the fetal facial artery. These
data suggest that acclimatization at high altitude reduces negative
feedback inhibition via 2-adrenoceptors. Prejunctional
2-adrenoceptors normally modulate
stimulation-evoked norepinephrine release by decreasing calcium
influx into sympathetic nerve terminals (7, 13, 29). Thus
the current data suggest that during chronic hypoxia, cerebrovascular
sympathetic nerves lose feedback modulation of stimulation-evoked
calcium influx.
2-adrenoceptors in response to hypoxemia. In male humans
at high altitude (>4,400 m) for 15 days, the expression of platelet
2-adrenoceptors was reduced (36). In human
atrial tissue and rat skeletal arterioles, modulation of
stimulation-evoked norepinephrine release by prejunctional 2-adrenoceptors and the contribution of postjunctional
2-adrenoceptors to arteriolar tone declines during acute
hypoxia (20, 25). Taken together, these data suggest that
a decline in the function of pre- or postjunctional
2-adrenoceptors during acute or prolonged hypoxia may be
a common response to lowered arterial PO2.
The decline in function of these receptors in vascular sympathetic
nerves during chronic hypoxic acclimatization could be viewed as an
adaptation or a detrimental consequence of lowered oxygen tension.
2-Adrenoceptor agonists have been shown to increase the
latency for convulsion and death during severe hypoxia in mice and rats
(17). Ornithine decarboxylase activity, a rapid indicator
of acute hypoxic stress in the brain, was studied in newborn rats. The
2-adrenoceptor antagonist phenoxybenzamine attenuated
the rise in brain ornithine decarboxylase activity during acute hypoxic
stress (30). Thus during acute hypoxia, modulation of
central sympathetic nerves via prejunctional
2-adrenoceptors may be important to survival. However,
acute hypoxia may not represent the best comparison for the current
study, because the level of hypoxic stress at high altitude, although
prolonged, is not necessarily severe.
Hypoxia and function of adrenergic nerves. When uptake of norepinephrine and negative feedback inhibition are blocked, stimulation-evoked norepinephrine release represents the capacity of the sympathetic nerves to release norepinephrine. Under these conditions, stimulation-evoked norepinephrine release is maintained after chronic hypoxia in adult middle cerebral arteries but declines after hypoxia in fetal middle cerebral arteries. Thus cerebrovascular sympathetic nerves in the fetus and adult respond to chronic hypoxia in a very different manner, with maintained adrenergic nerve function in the adult but a decline in function in the fetus.
A similar trend is seen in the fetal facial artery during hypoxia. When reuptake of norepinephrine and2-adrenoceptors was blocked, there was a decline in stimulation-evoked norepinephrine release, which did not reach statistical significance. Again chronic hypoxia did not alter the capacity of the sympathetic nerves to release
norepinephrine in adult facial arteries.
During chronic high-altitude hypoxia, norepinephrine content tended to
decline in fetal and adult middle cerebral and facial arteries,
reaching statistical significance in adult middle cerebral arteries.
Despite the trend toward lower norepinephrine content in adult
arteries, the capacity to release norepinephrine was maintained during
chronic hypoxia. In the fetal middle cerebral artery, the small
decrease in norepinephrine content cannot explain the >50% decline in
stimulation-evoked norepinephrine release. Thus the decline in
stimulation-evoked norepinephrine release in hypoxic fetal middle
cerebral arteries would appear to be dependent on the sensitivity of
the release mechanism itself.
Effects of development.
In near-term normoxic fetal middle cerebral and facial arteries,
blockade of prejunctional 2-adrenoceptors causes an
increase in stimulation-evoked norepinephrine release that is
approximately the same as the increase caused by idazoxan in arteries
from the normoxic adult. Thus the function of vascular prejunctional
2-adrenoceptors appears to be similar in the near-term
fetus and adult. The expression of prejunctional
2-adrenoceptors develops rapidly in utero and parallels
sympathetic nerve innervation of the rat brain and sheep kidney and rat
peripheral blood vessels during prenatal development (10,
34). However, little is known about the impact of development on
function of prejunctional 2-adrenoceptors. Inhibition of
stimulation-evoked contractile responses with an
2-adrenoceptor antagonist in rat iris arterioles in
vitro was similar for animals near term and during postnatal
development (10-21 days; Ref. 28). In renal cortical
homogenates from near-term fetus, lamb, and adult, the density of
2-adrenoceptors is greatest in the near-term fetus and
decreases in the lamb followed by a leveling in the adult (10). Despite the decline in 2-adrenoceptor
expression during development, our data show robust function of
2-adrenoceptors in sympathetic nerves in the middle
cerebral and facial arteries from the fetus and adult.
2-adrenoceptors. These data suggest that adrenergic
nerve response to stimulation in the near-term fetus is greater
compared with the adult. During in utero and postnatal development,
density of adrenergic nerves in various tissues, including blood
vessels, has been shown to increase and resembles the adult pattern by
the sixth postnatal week (28). In the sheep,
cerebrovascular sympathetic nerve function is greater in the fetus
compared with the adult and increases further during parturition
(4). In general, the data from this study support other
studies demonstrating that the release of norepinephrine in the
near-term fetus is greater than in the adult.
Function of norepinephrine reuptake. To effectively focus on the impact of development and chronic hypoxia on reuptake of norepinephrine per se, fractional norepinephrine release under drug-free conditions was subtracted from release in the presence of Doc and Coc. When the data were analyzed in this manner, it was clear that in the fetus, chronic hypoxia increased the reuptake of norepinephrine in both middle cerebral and facial arteries. In contrast, hypoxia did not alter reuptake of norepinephrine in the adult middle cerebral or facial artery. To our knowledge, there have been no previous studies on the impact of long-term high-altitude hypoxia on norepinephrine reuptake. Thus our finding that chronic hypoxia increases adrenergic reuptake in fetal arteries is novel.
In contrast to our data in adult arteries that show no effect of hypoxia on combined uptake and metabolism, two reports in the adult rat and dog show a decline in uptake during hypoxia. Five-day hypoxic exposure in the adult rat resulted in a decline in the uptake of [3H]norepinephrine in right and left ventricles of the heart (23). Similarly, in the dog pulmonary artery, 14-day exposure to hypoxia significantly reduced the uptake of [3H]norepinephrine (26). One possibility for the difference in the present report in adult sheep and the two discussed above is that the duration of hypoxia in our study is much greater compared with either 5 or 14 days. Overall, our data suggest that during chronic hypoxia, the function of extraneuronal and neuronal norepinephrine uptake mechanisms is maintained in the adult but increases in fetal arteries. It is interesting that there is no significant developmental effect on norepinephrine reuptake in adrenergic nerves innervating the facial artery. This is in contrast to our findings in the fetal middle cerebral artery where reuptake of norepinephrine was significantly smaller compared with the adult. These data suggest that the impact of development on the function of norepinephrine reuptake mechanisms may be dependent on the vascular model. Indeed, this is consistent with data in the right atrium and salivary glands showing that [3H]norepinephrine uptake is fully developed soon after birth (9). Our data in middle cerebral arteries are consistent with other studies showing that during near-term and postnatal development the function of reuptake mechanisms increases in nerve terminals in the iris, spleen, heart, and adrenal glands (2, 9). In conclusion, in this model of well-adapted chronic hypoxia, the function of prejunctional2-adrenoceptors declines
compared with normoxic fetal and adult middle cerebral arteries, with a tendency to decline in fetal facial arteries as well. During chronic hypoxia, the capacity to release norepinephrine from fetal middle cerebral arteries declines but is maintained in adult arteries. A
similar trend is seen in the facial artery. Furthermore, during development, stimulation-evoked norepinephrine release from middle cerebral and facial arteries is higher compared with adult. These data
suggest that in fetal arteries, the function of adrenergic nerves
declines during chronic hypoxia. However, in adult arteries, adrenergic
nerves exhibit an adaptation to chronic hypoxia and maintain their
overall function. This differential adaptation of adrenergic nerves in
fetal arteries may possibly reflect differences in fetal distribution
of blood flow in response to chronic hypoxic stress.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge J. Sephus and C. Hewitt for technical expertise in the execution of these experiments.
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FOOTNOTES |
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This work was supported in part by a National Institute of Child Health and Human Development Grant P01-HD-13226.
Address for reprint requests and other correspondence: J. Buchholz, Dept. of Physiology and Pharmacology, Loma Linda Univ., School of Medicine, Loma Linda, CA 92350 (E-mail: jbuchholz{at}som.llu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 29 December 2000; accepted in final form 17 May 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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(No
Drug) divided by (Doc+Coc). Bars represent the means ± SE;
n = 6 to 8 arteries from each group. **Significantly
different from normoxic; +significantly different from adult by 2-way
ANOVA and Fisher's PLSD test. Level of significance is
P < 0.05.
