Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 2000 Sep 15;527(Pt 3):593–599. doi: 10.1111/j.1469-7793.2000.00593.x

Developmental changes in plasma catecholamine concentrations during normoxia and acute hypoxia in the chick embryo

A L M Mulder *, J M C G van Golde *, A A C van Goor *, D A Giussani *, C E Blanco *
PMCID: PMC2270098  PMID: 10990543

Abstract

  1. In the mammalian fetus, the cardiovascular responses to acute hypoxaemia include a redistribution of the cardiac output away from the periphery towards the adrenal, myocardial and cerebral circulations. A component of the peripheral vasoconstriction is mediated by increased release of catecholamines into the fetal circulation during acute hypoxaemia. Previously, we have shown that the chick embryo also shows an increase in peripheral vascular resistance during acute hypoxaemia and that this response becomes progressively larger towards the end of the incubation period. However, the ontogeny of the catecholaminergic response to acute hypoxaemia has not been investigated in this species.

  2. Fertilised chicken eggs were studied on days 10, 13, 16 and 19 of incubation (hatching is at 21 days). At each stage of incubation, blood samples were obtained from the chorioallantoic artery of the chick embryos during normoxia and after 5 min of hypoxaemia for measurement of plasma concentrations of adrenaline and noradrenaline by HPLC.

  3. Basal plasma adrenaline and noradrenaline concentrations by the end of the incubation period were much higher in the chick embryo than values reported for mammalian fetuses during late gestation. During normoxia, basal plasma noradrenaline concentration remained unchanged during development but plasma adrenaline concentration showed a developmental increase from < 25.1 pmol l−1 at day 10 to 3 nmol l−1 at day 19 of incubation. Acute hypoxaemia caused an increase in plasma noradrenaline and adrenaline from day 13 and day 16 of incubation, respectively. In addition, the increase in plasma adrenaline and noradrenaline and in the ratio of plasma adrenaline to noradrenaline during acute hypoxaemia became progressively larger by the end of the incubation period.

  4. These data show an ontogenic increase in basal plasma catecholamines and in the catecholaminergic response to acute hypoxaemia in the chick embryo during the last third of the incubation period.

In the adult animal, maintenance of cardiovascular function is totally dependent on intact adrenal glands (Addison, 1855; Brown-Sequard, 1856). However, the role of the adrenal gland in fetal cardiovascular function and, more importantly, its contribution to the development of fetal cardiovascular responses to acute stress remain uncertain. Previous studies in the acutely exteriorised sheep fetus showed that the increase in adrenal amine release, in response to electrical stimulation of either the adrenal gland or the peripheral end of the splanchnic nerves, became progressively larger with increasing gestational age and rose exponentially in the last days of pregnancy (Comline & Silver, 1961). A progressive increase in the fetal plasma catecholaminergic response during gestation has been confirmed in the chronically instrumented sheep fetus during acute hypoxaemia (Iwamoto et al. 1989; Cheung, 1990).

In response to acute hypoxaemia, the sheep fetus initiates cardiovascular responses that have neural and endocrine components (Hanson, 1988; Giussani et al. 1994). Acute hypoxaemia stimulates a chemoreflex, initiated by the peripheral arterial chemoreceptors, particularly those located in the carotid arteries. Their activation mediates both an increase in efferent vagal activity to the fetal heart, resulting in bradycardia, and an increase in sympathetic outflow, which produces vasoconstriction in the peripheral circulation and contributes to an increase in fetal arterial blood pressure (Giussani et al. 1993). After this initial carotid chemoreflex response, slower incoming endocrine mechanisms are stimulated, in particular the release of catecholamines (Cohen et al. 1984) and vasopressin (Rurak, 1978), which maintain the peripheral vasoconstriction during the hypoxaemic challenge (Perez et al. 1989; Giussani et al. 1993). As a consequence, cardiac output is redistributed towards the heart, the brain and the adrenal glands, away from the kidneys, the intestines and the rest of the body (Cohn et al. 1974; Peeters et al. 1979).

The redistribution of the cardiac output in response to acute hypoxaemia has also been documented in the chick embryo in the last third of the incubation period (Mulder et al. 1998). In addition, previous work from our laboratory has shown that the cardiovascular responses to acute hypoxaemia in the chick embryo also show a developmental pattern since peripheral vasoconstriction in response to hypoxaemia became progressively larger by day 19 of incubation (Mulder et al. 1998). However, the ontogeny of the catecholaminergic response to acute hypoxaemia has not been investigated in this species.

Hence, the aims of the present study were to determine: (1) the plasma concentrations of adrenaline and noradrenaline during the development of chick embryos from day 10 of incubation and (2) the effect of increasing incubation time on the chick embryo catecholaminergic response to an episode of acute hypoxaemia.

METHODS

Fertilised eggs of White Leghorn chickens were incubated in a commercial incubator at 38°C and 60 % humidity. Eggs were rotated constantly to avoid adhesions between the embryo and the membranes (Tazawa, 1981). In the present study we used chick embryos on days 10, 13, 16 and 19 of incubation (hatching is at 21 days), which correspond to stages 36, 39, 42 and 45, respectively, according to Hamburger & Hamilton (1951). For each day of incubation a separate group of chick embryos was studied; 60 chick embryos were used in total. Forty embryos were used for the measurement of plasma catecholamine levels at different incubation times (n = 10 each on days 10, 13, 16 and 19). On each day plasma catecholamine levels were measured during normoxia in five embryos and during hypoxaemia in five other embryos. Twenty chick embryos were used for blood gas analyses during normoxia (n = 12) or hypoxaemia (n = 8) between days 13 and 15 of incubation in order to document the magnitude and nature of the hypoxaemic event. All experiments complied with Dutch law on animal experiments.

Preparation

All blood samples were obtained from punctures in the chorioallantoic artery, between the embryo's umbilicus and the chorioallantoic membrane, where gas exchange takes place. The procedure was performed inside a clinical infant incubator provided with a light microscope (WILD 3M; magnification, × 10). Temperature and humidity were maintained constant at 38°C and 60 %, respectively. The eggs were opened at the air cell side and placed in a holder within a Plexiglas box. The oxygen concentration in the box was changed by supplying different warmed and humidified mixtures of N2 and O2 at a constant flow of 5 l min−1. A small incision was made in the chorioallantoic membrane avoiding damage to the chorioallantoic vessels, and a dark red pulsating chorioallantoic artery was identified. The embryo was then left for 15 min to recover before samples were taken.

Protocol

Blood samples were obtained by lifting the chorioallantoic artery using forceps followed by puncture of the artery with a 25 or 27 gauge needle. Samples were withdrawn in pre-heparinised syringes. For measurement of plasma catecholamine concentrations, blood samples (0.2–1.0 ml) were taken from chick embryos on days 10, 13, 16 and 19 of incubation. Samples were taken from two separate groups: (a) at the fifth minute of normoxia (21 % O2 in the Plexiglas box) and (b) at the fifth minute of hypoxaemia (100 % of N2 in the Plexiglas box).

In order to document the magnitude and nature of the hypoxaemic challenge, blood samples (0.2 ml) were taken from a separate group of chick embryos between days 13 and 15 of incubation for measurement of arterial blood gases and pH (corrected for the temperature of 38°C). Twelve embryos were sampled after 5 min of normoxia and eight embryos after 5 min of hypoxaemia.

Immediately after the experiment the chick embryos were killed by decapitation.

Measurements

Blood gases

Blood samples (0.2 ml) were collected in pre-heparinised syringes and analysed at 38°C using a Radiometer ABL3 blood gas analyser (Copenhagen).

Catecholamines

Blood samples (0.2–1.0 ml) were collected in pre-heparinised syringes. Blood was drawn into test tubes filled with 25 μl of glutathione–heparin solution (10 mg ml−1 glutathion, 5000 IU ml−1 heparin). Samples were centrifuged (8°C, 2400 g) for 15 min and the plasma stored at –35°C. Plasma concentrations of adrenaline and noradrenaline were measured using fluorescence HPLC, which has previously been described in detail (van der Hoorn et al. 1989). The lower limit of detection of the assay was 0.46 pg ml−1 for adrenaline and 0.98 pg ml−1 for noradrenaline.

Data analyses

All data were processed using SigmaStat 2.0 software (Jandel Scientific Corporation). Data are expressed as the median and interquartile range (IQR, 25th to 75th percentile). For statistical comparison, plasma concentrations of catecholamines that were below the lower detection limit of the assay were assigned the value for the lower limit of detection. The Mann-Whitney rank sum test for independent samples was applied for analyses of changes in plasma catecholamine concentration between groups.

RESULTS

Baseline catecholamine concentrations

Plasma adrenaline increased significantly from non-detectable concentrations at day 10 to 3.0 nmol l−1 (IQR, 1.09–6.60) at day 19. In contrast, plasma noradrenaline concentration did not increase with incubation time (Table 1).

Table 1.

Plasma catecholamine concentrations in chick embryo from day 10 to day 19 of incubation

Day 10 Day 13 Day 16 Day 19
Normoxia (n = 5) Hypoxia (n = 5) Normoxia (n = 5) Hypoxia (n = 5) Normoxia (n = 5) Hypoxia (n = 5) Normoxia (n = 5) Hypoxia (n = 5)
Adrenaline 2.51 × 10−3 0.82 2.51 × 10−3 3.17 0.33 26.09 *‡ 3.00 † 227.49 *‡
(2.51 × 10−3–0.22) (0.22–2.02) (2.51 × 10−3–2.29) (1.96–8.79) (0.22–5.57) (12.44–42.90) (1.09–6.60) (92.24–302.15)
Noradrenaline 34.70 247.14 176.96 543.10* 29.85 477.02 63.78 806.97*‡
(12.18–170.24) (170.65–323.27) (82.40–200.38) (526.61–694.01) (27.13–285.62) (278.64–792.25) (43.98–183.54) (480.45–1195.74)
Open in a new tab

Values are expressed (in nmol l−1) as the median and 25th to 75th percentile (in parentheses) during normoxia and after 5 min of hypoxia. Significant differences (P < 0.05) are as follows:

*

normoxia vs. hypoxia

†

vs. normoxia group at day 10

‡

vs. hypoxia group at day 10.

Response to acute hypoxaemia

Exposure of the chick embryo to 100 % N2 resulted in significant falls in arterial PO2 (Pa,O2) and PCO2 (Pa,CO2) (Table 2). The median Pa,O2 in the control group (21 % O2) was 37.7 mmHg (IQR, 30.5–46.8 mmHg). At the fifth minute of hypoxaemia the median Pa,O2 had declined to 8.7 mmHg (6.7–10.6 mmHg). Similarly, the median Pa,CO2 in the control group (21 % O2) was 34.6 mmHg (IQR, 30.3–41.5 mmHg). At the fifth minute of hypoxaemia the median Pa,CO2 had decreased to 23.9 mmHg (22.5- 28.7 mmHg). Although there was a trend for arterial pH to increase during the acute hypocapnic hypoxaemic challenge, this trend did not reach significance (Table 2).

Table 2.

Arterial blood gases and pH in chick embryos between days 13 and 15 of incubation

Normoxia (n = 12) Hypoxia (n = 8)
Arterial pH 7.35 (7.32–7.42) 7.42 (7.41–7.44)
Pa,CO2 (mmHg) 34.6 (30.3–41.5) 23.9 (22.5–28.7)*
Pa,O2 (mmHg) 37.7 (30.5–46.8) 8.7 (6.7–10.6)*
Open in a new tab

Values are expressed as the median and 25th to 75th percentile (in parentheses) during normoxia and after 5 min of hypoxia.

*

Significant difference (P < 0.05) for normoxia vs. hypoxia.

Plasma adrenaline concentration was significantly elevated during acute hypoxaemia from day 16 of incubation (Table 1 and Fig. 1A). Plasma adrenaline concentration increased from 0.33 nmol l−1 (IQR, 0.22–5.57 nmol l−1) in normoxia to 26.09 nmol l−1 (IQR, 12.44–42.90 nmol l−1) during hypoxia at day 16 and from 3.00 nmol l−1 (IQR, 1.09–6.60 nmol l−1) to 227.49 nmol l−1 (IQR, 92.24–302.15 nmol l−1) at day 19 of incubation. Similarly, plasma noradrenaline concentration increased from 176.96 nmol l−1 (IQR, 82.40–200.38 nmol l−1) in normoxia to 543.10 nmol l−1 (IQR, 526.61–694.01 nmol l−1) during hypoxia at day 13, from 29.85 nmol l−1 (IQR, 27.13–285.62 nmol l−1) to 477.02 nmol l−1 (IQR, 278.64- 792.25 nmol l−1) at day 16, and from 63.78 nmol l−1 (IQR, 43.98–183.54 nmol l−1) to 806.97 nmol l−1 (IQR, 480.45- 1195.74 nmol l−1) at day 19 of incubation. However the increase in plasma noradrenaline at day 16 of incubation did not reach significance (P = 0.056; Fig. 1B).

Figure 1. Developmental changes in plasma concentration of catecholamines in response to acute hypoxaemia in the chick embryo.

Figure 1

Open in a new tab

Values are expressed as box plots representing the 10th percentile, 25th percentile, median, 75th percentile and 90th percentile for plasma adrenaline (A) and noradrenaline (B) at the fifth minute of acute hypoxaemia on days 10, 13, 16 and 19 of incubation. * Significant difference (P < 0.05) vs. day 10 of incubation.

Ratio of plasma adrenaline to noradrenaline

Baseline plasma catecholamine concentrations showed an increase in the ratio of adrenaline to noradrenaline from 1.7 × 10−4 at day 10 to 3.0 × 10−2 at day 19; however, this increase fell below the significance level (Fig. 2A). In contrast, a significant increase in the ratio of plasma adrenaline to noradrenaline in response to acute hypoxaemia occurred during development, from 4.7 × 10−3 at day 10 to 0.24 at day 19 (Fig. 2B).

Figure 2. Developmental changes in the ratio of plasma concentrations of adrenaline to noradrenaline.

Figure 2

Open in a new tab

Values are expressed as box plots representing the 10th percentile, 25th percentile, median, 75th percentile and 90th percentile for the ratio of plasma adrenaline to noradrenaline during normoxia (A) and at the fifth minute of acute hypoxaemia (B) on days 10, 13, 16 and 19 of incubation. * Significant difference (P < 0.05) vs. day 10 of incubation.

DISCUSSION

The present study describes baseline plasma catecholamine concentrations in the chick embryo during the second half of the incubation period and the catecholaminergic response to an acute hypoxaemic event.

Catecholamines seem to be important during embryonal development since knockout mouse embryos for endothelial PAS domain protein 1 (EPAS1), a hypoxia-inducible transcription factor expressed in endothelial cells and sympatho-adrenal cells, and knockout mouse embryos for tyrosine hydroxylase, which are both unable to synthesise catecholamines, die at mid-gestation of cardiovascular failure (Zhou et al. 1995; Kobayashi et al. 1995; Tian et al. 1998). In contrast, previous studies in fetal sheep during late gestation showed no significant effect on basal fetal heart rate or arterial blood pressure of adrenalectomy (Ray et al. 1988; Unno et al. 1999) or of adrenal demedullation by pharmacological treatment (Jones et al. 1987). In combination, these findings suggest that the presence of catecholamines early in gestation is indispensable for the normal development of cardiovascular function and, in contrast, late in gestation circulating catecholamines from the adrenal medulla do not contribute to basal cardiovascular function. Extra-adrenal sources for catecholamine production may develop late in gestation, since para-aortic chromaffin tissue becomes hypertrophic following adrenalectomy (Jones et al. 1987). In addition, catecholamines do play an important role late in gestation in the response to an acute hypoxaemic insult, in redistributing the cardiac output away from the periphery to the vital organs, as described in the Introduction.

In the chick embryo, the adrenal medullary cells arise from the sympathetic chains on the fourth day of incubation (Sanchez-Montesinos et al. 1996) and catecholamines have been detected in very small amounts from day 5 in allantoic fluid (Boucek & Bourne, 1962). Although the chick embryo heart does not have sympathetic innervation before day 5 of incubation (Romanoff, 1960), catecholamines can be detected in the heart from day 3 of incubation. At that time, catecholamines appear to be accumulated in the yolk and maternal in origin (Ignarro & Shideman, 1968). After day 14–16 of incubation, adrenergic axons to the heart can release sufficient transmitter to influence right ventricular function (Higgins & Pappano, 1981). Innervation of the adrenal glands starts at day 8 of incubation with the formation of chromaffin cells, and seems to become functional at day 10 of incubation (Fujita et al. 1976). In the adrenal gland, the adrenaline concentration is relatively low until day 15, after which time it increases markedly towards hatching (Wassermann & Bernard, 1970). Detection of catecholamines in plasma has been reported for the chick embryo at days 10 and 14 of incubation, as has an increase in the plasma concentration of noradrenaline in response to asphyxia at day 14 (Epple et al. 1992). This sympatho-adrenal development in the second half of gestation resembles that in fetal lamb and fetal human in contrast to the sympatho-adrenal development in fetal rat and fetal rabbit, which is later in gestation and partly postnatal (Lagercrantz, 1998). The present study confirms a developmental increase in baseline plasma adrenaline concentration in the chick embryo and extends previous findings to report a developmental increase in the catecholaminergic response to episodes of acute hypoxaemia.

Basal plasma catecholamine concentrations in the chick embryo are very high compared with data obtained from the mammalian fetus. Compared with the sheep fetus near term (Cheung, 1990; Fowden et al. 1998), baseline plasma noradrenaline concentration was 60-fold higher, and baseline plasma adrenaline concentration was 5-fold higher in the chick embryo on day 19 of incubation. Other reports on plasma catecholamine concentrations in the chick embryo show comparatively high circulating concentrations (Wittmann & Prechtl, 1991; Epple et al. 1992). In addition, plasma catecholamine concentrations in the adult chicken have been reported to be much higher than those in adult mammals (Kamimura et al. 1995).

In the present study, there was a developmental increase in baseline plasma adrenaline concentration, but not in baseline plasma noradrenaline concentration, from day 10 to day 19 of incubation in the chick embryo. High circulating levels of noradrenaline early in incubation in the chick embryo may be from extra-adrenal sources such as the para-aortic chromaffin tissue, which has been described in the human fetus (Lagercrantz & Slotkin, 1986) and from sympathetic nerve endings. It is not known to what extent these sources contribute to plasma catecholamine concentrations. That the developmental increase in baseline catecholamine concentration is primarily due to an increase in adrenaline, but not noradrenaline, concentration has also been described in the sheep fetus (Fowden et al. 1998). Similarly, while basal output of noradrenaline from fetal sheep adrenal glands in vitro did not change with increasing gestation time, basal output of adrenaline showed an exponential rise by the end of gestation (Butler et al. 1995). In sheep, the increase in plasma adrenaline concentration during gestation parallels the pre-partum increase in fetal plasma cortisol concentration (Fowden et al. 1998). It is possible that the pre-parturient increase in fetal plasma cortisol leads to an increase in phenylethanolamine N-methyltransferase (PNMT; Bohn et al. 1981; Padbury, 1989; Adams et al. 1998), the enzyme responsible for the last step of adrenaline synthesis, the conversion of noradrenaline to adrenaline.

Additional data reported in the present manuscript suggest that the chick embryo is able to increase plasma noradrenaline and adrenaline concentrations in response to an episode of acute hypoxaemia from day 13 and day 16 of incubation, respectively. Furthermore, these catecholaminergic responses to acute hypoxaemia mature with incubation time in the chick embryo, as evidenced by a progressive increase in the plasma concentrations of adrenaline and noradrenaline, and in the ratio of plasma adrenaline to noradrenaline during acute hypoxaemia. These developmental changes in the ability of the chick embryo to mount a significant catecholaminergic response to an episode of acute stress are similar to those previously reported in the sheep fetus. Iwamoto et al. (1989) and Padbury et al. (1989) reported that the sheep fetus is able to release catecholamines into its circulation at 0.6 of gestation. Similarly, fetal sheep and fetal calf plasma concentrations of adrenaline and noradrenaline in response to acute hypoxaemia become progressively larger with increasing gestation time (Comline & Silver, 1961; Widmark et al. 1989). In the sheep and the calf fetus, adrenal medulla adrenaline release may be regulated by sympathetic stimulation of the splanchnic nerves (Comline & Silver, 1961) and by the direct action of hypoxia on the adrenal gland (Comline & Silver, 1961,1966a, b; Cheung, 1990; Rychkov et al. 1998). The latter group of studies also showed that the direct effect of hypoxia on adrenaline release from the adrenal gland becomes less important towards term, when functional innervation of the adrenal gland is completed.

The present study reports that plasma noradrenaline concentrations in response to acute hypoxaemia become significantly elevated at day 13 of incubation in the chick embryo. In contrast, plasma adrenaline levels in response to acute hypoxaemia only rise significantly after day 16 of incubation and show a marked response by day 19. These findings suggest that noradrenaline release in response to acute hypoxaemia at day 13 of incubation is likely to be the result of direct stimulation of chromaffin cells by hypoxia in the chick embryo. In contrast, the exponential increase in plasma adrenaline concentration during acute hypoxaemia after day 16 of incubation parallels the rapid increase in the adrenaline content of the adrenal glands in the chick embryo (Wassermann & Bernard, 1970), and is likely to reflect the development of neural sympathetic stimulation of the adrenal glands during acute hypoxaemia.

In response to an episode of acute hypoxaemia, the sheep fetus (Cohn et al. 1974) and the chick embryo (Mulder et al. 1998) show a marked peripheral vasoconstriction which aids the redistribution of the cardiac output towards the adrenal, myocardial and cerebral circulations. In the sheep fetus, peripheral vasoconstriction during acute hypoxaemia is triggered by a carotid chemoreflex (Giussani et al. 1993) and is maintained by the release of humoral vasoconstrictors such as catecholamines into the fetal circulation (Cohen et al. 1984). The ontogenic increase in the peripheral vasoconstriction during acute hypoxaemia previously reported for the chick embryo (Mulder et al. 1998) parallels the maturation of the catecholaminergic response to acute hypoxaemia in the chick embryo reported in the present study. Hence, the maturation of the catecholaminergic response to acute hypoxaemia in the chick embryo may reflect the development of an important defence mechanism which helps to redistribute cardiac output away from the periphery towards important circulations during situations of acute stress.

In conclusion, the data reported in the present manuscript show that baseline plasma catecholamine concentrations in the chick embryo are high compared with those of other species. While plasma noradrenaline concentration remains unchanged from baseline, plasma adrenaline concentration shows a marked increase by the end of the incubation period. In addition, the chick embryo is able to increase plasma adrenaline and noradrenaline concentrations in response to acute hypoxaemia from day 13 of incubation. This catecholaminergic response to acute hypoxaemia matures during incubation since the increases in plasma adrenaline, plasma noradrenaline and the ratio of plasma adrenaline to noradrenaline all become progressively larger as the chick embryo approaches hatching.

References

  1. Adams MB, Phillips ID, Simonetta G, McMillen IC. Differential effects of increasing gestational age and placental restriction on tyrosine hydroxylase, phenylethanolamine N-methyltransferase, and proenkephalin A mRNA levels in the fetal sheep adrenal. Journal of Neurochemistry. 1998;71:394–401. doi: 10.1046/j.1471-4159.1998.71010394.x. [DOI] [PubMed] [Google Scholar]
  2. Addison T. On the Constitutional and Local Effects of the Suprarenal Capsules. London: S. Highley; 1855. [Google Scholar]
  3. Bohn MC, Goldstein M, Black IB. Role of glucocorticoids in expression of the adrenergic phenotype in rat embryonic adrenal gland. Developmental Biology. 1981;82:1–10. doi: 10.1016/0012-1606(81)90423-1. [DOI] [PubMed] [Google Scholar]
  4. Boucek RJ, Bourne B. Catecholamines of the allantoic fluid in the developing chick embryo. Nature. 1962;193:1181–1182. doi: 10.1038/1931181a0. [DOI] [PubMed] [Google Scholar]
  5. Brown-Sequard CE. Recherches experimentales sur la physiologie et la pathologie des capsules surrenales. Comptes Rendus de l'Academie des Sciences. 1856;43:422–425. [Google Scholar]
  6. Butler TG, Simonetta G, Roberts ML, McMillen IC. Impact of gestational age on the catecholamine responses of the fetal sheep adrenal to cholinergic stimulation in vitro. Experimental Physiology. 1995;80:767–777. doi: 10.1113/expphysiol.1995.sp003885. [DOI] [PubMed] [Google Scholar]
  7. Cheung CY. Fetal adrenal medulla catecholamine response to hypoxia — direct and neural components. American Journal of Physiology. 1990;258:R1340–1346. doi: 10.1152/ajpregu.1990.258.6.R1340. [DOI] [PubMed] [Google Scholar]
  8. Cohen WR, Piasecki GJ, Cohn HE, Young JB, Jackson BT. Adrenal secretion of catecholamines during hypoxemia in fetal lambs. Endocrinology. 1984;114:383–390. doi: 10.1210/endo-114-2-383. [DOI] [PubMed] [Google Scholar]
  9. Cohn HE, Sacks EJ, Heymann MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. American Journal of Obstetrics and Gynecology. 1974;120:817–824. doi: 10.1016/0002-9378(74)90587-0. [DOI] [PubMed] [Google Scholar]
  10. Comline RS, Silver M. The release of adrenaline and noradrenaline from the adrenal glands of the foetal sheep. The Journal of Physiology. 1961;156:424–44. doi: 10.1113/jphysiol.1961.sp006685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Comline RS, Silver M. Development of activity in the adrenal medulla of the foetus and new-born animal. British Medical Bulletin. 1966a;22:16–20. doi: 10.1093/oxfordjournals.bmb.a070430. [DOI] [PubMed] [Google Scholar]
  12. Comline RS, Silver M. The development of the adrenal medulla of the foetal and new-born calf. The Journal of Physiology. 1966b;183:305–340. doi: 10.1113/jphysiol.1966.sp007868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Epple A, Gill TS, Nibbio B. The avian allantois: a depot for stress-released catecholamines. General and Comparative Endocrinology. 1992;85:462–476. doi: 10.1016/0016-6480(92)90091-w. [DOI] [PubMed] [Google Scholar]
  14. Fowden AL, Mundy L, Silver M. Developmental regulation of glucogenesis in the sheep fetus during late gestation. The Journal of Physiology. 1998;508:937–947. doi: 10.1111/j.1469-7793.1998.937bp.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fujita H, Tanizawa Y, Hiura M. Ontogenesis of granule formation in adrenal chromaffin cells of the chick. In: Coupland RE, Fujita T, editors. Chromaffin, Enterochromaffin and Related Cells. Amsterdam: Elsevier Scientific Publishing Company; 1976. pp. 1–12. [Google Scholar]
  16. Giussani DA, Spencer JA, Moore PJ, Bennet L, Hanson MA. Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. The Journal of Physiology. 1993;461:431–449. doi: 10.1113/jphysiol.1993.sp019521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Giussani DA, Spencer JAD, Hanson MA. Fetal cardiovascular reflex responses to hypoxaemia. Fetal and Maternal Medicine Review. 1994;6:17–37. [Google Scholar]
  18. Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. Journal of Morphology. 1951;88:49–92. [PubMed] [Google Scholar]
  19. Hanson MA. The importance of baro- and chemoreflexes in the control of the fetal cardiovascular system. Journal of Developmental Physiology. 1988;10:491–511. [PubMed] [Google Scholar]
  20. Higgins D, Pappano AJ. Development of transmitter secretory mechanisms by adrenergic neurons in the embryonic chick heart ventricle. Developmental Biology. 1981;87:148–162. doi: 10.1016/0012-1606(81)90068-3. [DOI] [PubMed] [Google Scholar]
  21. Ignarro LJ, Shideman FE. Norepinephrine and epinephrine in the embryo and embryonic heart of the chick: uptake and subcellular distribution. Journal of Pharmacology and Experimental Therapeutics. 1968;159:49–58. [PubMed] [Google Scholar]
  22. Iwamoto HS, Kaufman T, Keil LC, Rudolph AM. Responses to acute hypoxemia in fetal sheep at 0.6–0.7 gestation. American Journal of Physiology. 1989;256:H613–620. doi: 10.1152/ajpheart.1989.256.3.H613. [DOI] [PubMed] [Google Scholar]
  23. Jones CT, Roebuck MM, Walker DW, Lagercrantz H, Johnston BM. Cardiovascular, metabolic and endocrine effects of chemical sympathectomy and of adrenal demedullation in fetal sheep. Journal of Developmental Physiology. 1987;9:347–367. [PubMed] [Google Scholar]
  24. Kamimura K, Nishimura H, Bailey JR. Blockade of beta-adrenoceptor in control of blood pressure in fowl. American Journal of Physiology. 1995;269:R914–922. doi: 10.1152/ajpregu.1995.269.4.R914. [DOI] [PubMed] [Google Scholar]
  25. Kobayashi K, Morita S, Sawada H, Mizuguchi T, Yamada K, Nagatsu I, Hata T, Watanabe Y, Fujita K, Nagatsu T. Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice. Journal of Biological Chemistry. 1995;270:27235–27243. doi: 10.1074/jbc.270.45.27235. [DOI] [PubMed] [Google Scholar]
  26. Lagercrantz H. Sympathoadrenal mechanisms during development. In: Polin RA, Fox WW, editors. Fetal and Neonatal Physiology. Philadelphia: W. B. Saunders Company; 1998. pp. 220–225. [Google Scholar]
  27. Lagercrantz H, Slotkin TA. The ‘stress’ of being born. Scientific American. 1986;254:100–107. doi: 10.1038/scientificamerican0486-100. [DOI] [PubMed] [Google Scholar]
  28. Mulder ALM, van Golde JC, Prinzen FW, Blanco CE. Cardiac output distribution in response to hypoxia in the chick embryo in the second half of the incubation time. The Journal of Physiology. 1998;508:281–287. doi: 10.1111/j.1469-7793.1998.281br.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Padbury JF. Functional maturation of the adrenal medulla and peripheral sympathetic nervous system. Baillieres Clinical Endocrinology and Metabolism. 1989;3:689–705. doi: 10.1016/s0950-351x(89)80049-7. [DOI] [PubMed] [Google Scholar]
  30. Peeters LLH, Sheldon RE, Jones MDJ, Makowski EL, Meschia G. Blood flow to fetal organs as a function of arterial oxygen content. American Journal of Obstetrics and Gynecology. 1979;135:637–646. doi: 10.1016/s0002-9378(16)32989-1. [DOI] [PubMed] [Google Scholar]
  31. Perez R, Espinoza M, Riquelme R, Parer JT, Llanos AJ. Arginine vasopressin mediates cardiovascular responses to hypoxemia in fetal sheep. American Journal of Physiology. 1989;256:R1011–1018. doi: 10.1152/ajpregu.1989.256.5.R1011. [DOI] [PubMed] [Google Scholar]
  32. Ray ND, Turner CS, Rawashdeh NM, Rose JC. Ovine fetal adrenal gland and cardiovascular function. American Journal of Physiology. 1988;254:R706–710. doi: 10.1152/ajpregu.1988.254.4.R706. [DOI] [PubMed] [Google Scholar]
  33. Romanoff AL. The Avian Embryo. Structural and Functional Development. New York: The Macmillan Company; 1960. [Google Scholar]
  34. Rurak DW. Plasma vasopressin levels during hypoxaemia and the cardiovascular effects of exogenous vasopressin in foetal and adult sheep. The Journal of Physiology. 1978;277:341–357. doi: 10.1113/jphysiol.1978.sp012275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rychkov GY, Adams MB, McMillen IC, Roberts ML. Oxygen-sensing mechanisms are present in the chromaffin cells of the sheep adrenal medulla before birth. The Journal of Physiology. 1998;509:887–893. doi: 10.1111/j.1469-7793.1998.887bm.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sanchez-Montesinos I, Merida-Velasco JA, Espin-Ferra J, Scopsi L. Development of the sympathoadrenal system in the chick embryo: An immunocytochemical study with antibodies to pan-neuroendocrine markers, catecholamine-synthesizing enzymes, proprotein-processing enzymes, and neuropeptides. Anatomical Record. 1996;245:94–101. doi: 10.1002/(SICI)1097-0185(199605)245:1<94::AID-AR14>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  37. Tazawa H. Adverse effect of failure to turn the avian egg on the embryo oxygen exchange. Respiratory Physiology. 1981;41:137–142. doi: 10.1016/0034-5687(80)90047-x. [DOI] [PubMed] [Google Scholar]
  38. Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes and Development. 1998;12:3320–3324. doi: 10.1101/gad.12.21.3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Unno N, Wong CH, Jenkins SL, Wentworth RA, Ding XY, Li C, Robertson SS, Smotherman WP, Nathanielsz PW. Blood pressure and heart rate in the ovine fetus: ontogenic changes and effects of fetal adrenalectomy. American Journal of Physiology. 1999;276:H248–256. doi: 10.1152/ajpheart.1999.276.1.H248. [DOI] [PubMed] [Google Scholar]
  40. van der Hoorn FA, Boomsma F, Man in't Veld AJ, Schalekamp MA. Determination of catecholamines in human plasma by high-performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. Journal of Chromatography. 1989;487:17–28. doi: 10.1016/s0378-4347(00)83003-0. [DOI] [PubMed] [Google Scholar]
  41. Wassermann GF, Bernard EA. Adrenaline content of the chick embryo adrenal gland during development. Acta Physiologica Latino Americana. 1970;20:171–173. [PubMed] [Google Scholar]
  42. Widmark C, Hokegard KH, Lagercrantz H, Lilja H, Rosen KG. Electrocardiographic waveform changes and catecholamine responses during acute hypoxia in the immature and mature fetal lamb. American Journal of Obstetrics and Gynecology. 1989;160:1245–1250. doi: 10.1016/0002-9378(89)90204-4. [DOI] [PubMed] [Google Scholar]
  43. Wittmann J, Prechtl J. Respiratory function of catecholamines during the late period of avian development. Respiration Physiology. 1991;83:375–386. doi: 10.1016/0034-5687(91)90056-o. [DOI] [PubMed] [Google Scholar]
  44. Zhou QY, Quaife CJ, Palmiter RD. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature. 1995;374:640–643. doi: 10.1038/374640a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES