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Circulation Research. 1997;81:438-447

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(Circulation Research. 1997;81:438-447.)
© 1997 American Heart Association, Inc.

Articles

Left Ventricular Norepinephrine and Epinephrine Kinetics at Birth in Lambs

Joseph J. Smolich, Helen S. Cox, Philip J. Berger, Adrian M. Walker, Graeme Eisenhofer, , Murray D. Esler

From the Institute of Reproduction and Development (J.J.S., P.J.B., A.M.W.), Monash University, Clayton, Victoria, Australia; Baker Medical Research Institute (H.S.C., M.D.E.), Prahran, Victoria, Australia; and the Clinical Neuroscience Branch (G.E.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.

Correspondence to Dr J.J. Smolich, Institute of Reproduction and Development, Level 5, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria, Australia 3168. E-mail joe.smolich{at}med.monash.edu.au


*    Abstract
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 *Abstract
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 down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
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Abstract Little is known about the changes in the left ventricular (LV) kinetics of the catecholamines norepinephrine and epinephrine occurring at birth and their relationship to perinatal alterations in LV function and whole-body catecholamine kinetics. To address this issue, whole-body and LV catecholamine kinetics (radiotracer dilution methodology) and fetal LV output and myocardial blood flow (radioactive microspheres) were measured in chronically instrumented near-term fetuses and in the same animals 1 and 4 hours after birth. Between fetal and 1-hour lambs, LV external work increased 115% (P<.005); carotid arterial plasma norepinephrine concentration, 148% (P<.01); carotid arterial plasma epinephrine concentration, 546% (P<.005); LV norepinephrine spillover, a measure of LV sympathetic activity, 4.1-fold (P<.005); LV epinephrine spillover, 3-fold (P<.05); total-body spillover of norepinephrine, 52% (P<.025); and total-body spillover of epinephrine, 460% (P<.005). Arterial catecholamine concentrations and total-body catecholamine spillovers were unchanged between 1- and 4-hour lambs, but LV external work fell (P<.05) to a level still 77% greater than in fetal lambs (P<.005); LV norepinephrine spillover returned to near-fetal levels, and LV epinephrine spillover became undetectable. These results suggest that (1) a transient increase in LV sympathetic activity occurs at birth and may contribute to the immediate postnatal augmentation of LV performance, (2) organ differences in the pattern of sympathetic activation occur at birth, and (3) birth-related increases in LV sympathetic activity are accompanied by release of epinephrine from the heart.


Key Words: fetus • newborn • norepinephrine • epinephrine • spillover


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMaterials and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The transition from the fetal to the newborn state is characterized by a marked augmentation of left ventricular (LV) pumping performance.1 2 3 Because the sympathetic nervous system, via release of the principal neurotransmitter norepinephrine, has major stimulatory effects in both the adult4 and newborn heart5 and because birth is associated with activation of the sympathetic nervous system,6 it is tempting to presume that cardiac sympathetic nerve activity increases with birth and that this increase contributes to the perinatal rise in LV performance. However, morphological,7 histochemical,7 8 9 10 11 and biochemical studies8 in a wide range of species indicate that cardiac sympathetic innervation is incompletely developed in the fetus and newborn. Moreover, studies of isolated cardiac muscle preparations suggest that this incomplete structural development of cardiac sympathetic elements is accompanied by a functional immaturity, manifested as diminished12 13 or even absent14 norepinephrine uptake as well as reduced norepinephrine release.14 Indeed, the lack of effect of in utero chemical sympathectomy with 6-hydroxydopamine on postnatal hemodynamics15 would appear to discount any significant role for cardiac sympathetic activity in birth-related rises in LV performance. However, no study has specifically examined the changes in cardiac sympathetic nerve activity that accompany birth or their relation to postnatal alterations in LV function.

The lack of knowledge about the activity of cardiac sympathetic nerves in the developing heart is in part related to the relative inaccessibility of these structures for direct neural recording. However, information about organ sympathetic function can be obtained with isotope radiotracer methodology.16 Use of this approach in the adult has demonstrated that the heart avidly clears norepinephrine from the circulation,17 18 19 20 predominantly via a neuronal uptake mechanism,17 18 20 and that, consistent with the presence of a tonic cardiac sympathetic discharge, significant spillover of norepinephrine from the heart into the circulation is evident under baseline conditions.19 20 21 Moreover, the divergent changes in whole-body and cardiac norepinephrine spillover rates occurring with stimuli that activate the sympathetic nervous system indicate that such activation is not generalized but is instead region specific.16 The adult heart also removes epinephrine from the circulation, principally by extraneuronal mechanisms.18 20 Furthermore, recent observations indicate that epinephrine is coreleased with norepinephrine from cardiac sympathetic nerves, a phenomenon that is most readily detected during increases in cardiac sympathetic activity20 22 23 24 25 and that may subserve a modulatory role during sympathetic neurotransmission.20 26 However, no information is available about norepinephrine or epinephrine extraction or spillover in the in situ fetal heart, the changes in LV norepinephrine or epinephrine kinetics that accompany birth, or the relation of the latter to perinatal alterations in whole-body norepinephrine or epinephrine kinetics.

Accordingly, the present study had five major aims: (1) to evaluate norepinephrine and epinephrine removal processes in the fetal sheep heart and to determine if these processes were altered by birth; (2) via calculation of LV norepinephrine spillover, to evaluate fetal LV sympathetic nerve activity and its alterations after birth; (3) to examine the temporal relation between changes in LV pump function and any alterations in LV norepinephrine spillover in the immediate postnatal period; (4) by comparison of LV and total-body norepinephrine spillover patterns, to establish if regional differences in sympathetic activation occurred at birth; and (5) by computation of LV epinephrine spillover, to establish whether, as in the adult,20 22 23 24 25 sympathetic nerve activity in either the fetal or newborn heart was accompanied by LV epinephrine release. Studies were performed in chronically instrumented near-term fetal lambs and in the same animals 1 and 4 hours after cesarean section delivery.


*    Materials and Methods
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 up arrowIntroduction
 *Materials and Methods
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All animal experiments were performed in accord with guidelines set by the National Health and Medical Research Council of Australia. Seven fetuses with known breeding dates were chronically instrumented under aseptic conditions at 133 to 134 days of gestation (term, 147 days) as previously described.2 3 6 Fasted Border-Leicester cross ewes were anesthetized with intravenous propofol (5 mg/kg) and intubated with a cuffed endotracheal tube. Anesthesia was maintained by mechanical ventilation with 1% to 3% halothane and a 2:1 nitrous oxide/oxygen mixture. The uterus was exposed through a midline laparotomy and incised over the fetal hindlimbs. Polyvinyl catheters (inner diameter, 1 mm; outer diameter, 1.5 mm) were inserted into a fetal posterior tibial artery and lateral saphenous vein and advanced into the abdominal aorta and inferior vena cava, respectively. The fetal head, forelimbs, and upper thorax were delivered through a second hysterotomy, and a thoracotomy was performed in the third left interspace. After incision of the pericardium, a polytetrafluoroethylene cannula was inserted through an adventitial purse-string suture into the distal part of the pulmonary trunk and connected to a polyvinyl catheter. A polyvinyl catheter was inserted into the left atrial cavity through the left atrial appendage. The left hemiazygos vein was ligated, and a silastic catheter (inner diameter, 0.8 mm; outer diameter, 1.7 mm) was passed through its proximal portion into the origin of the coronary sinus.3 27 The pericardium was then loosely closed, the ribs were reapposed, and overlying muscle layers were repaired. After a midline neck incision, a nonocclusive polytetrafluoroethylene cannula was introduced into the left carotid artery and attached to a polyvinyl catheter. A polyvinyl catheter was also inserted through the left external jugular vein into the superior vena cava. Both catheters were passed to the chest incision through a subcutaneous tunnel. In all fetuses, a silastic catheter (inner diameter, 0.8 mm; outer diameter, 1.7 mm) was introduced into the upper part of the trachea via an intercartilaginous space and exteriorized through the cephalic end of the neck incision for later withdrawal of lung liquid. Last, a wide-bore catheter was sutured to the anterior chest wall for measurement of amniotic fluid pressure. The fetus was returned to the uterus, and all incisions were closed.

After completion of the fetal surgery, the vascular catheters were filled with sodium heparin solution (1000 IU/mL), tunneled subcutaneously to the ewe's right flank, and secured with elastic netting. After surgery, vascular catheters were flushed every second day and refilled with sodium heparin. Antibiotics (500 mg streptomycin and 5x106 U penicillin) were instilled into the amniotic cavity at the time of surgery and then administered daily, either as an intramuscular injection to the ewe or directly into the amniotic cavity during flushing of vascular catheters.

Experimental Protocol
The experiment protocol, which was performed 7 days after surgery (ie, at a gestation of 140 to 141 days), comprised a fetal and a newborn study. During the fetal study, ewes stood unrestrained in a mobile laboratory cart and were allowed free access to feed and water. To measure total-body and cardiac catecholamine kinetics, [3H]norepinephrine and [3H]epinephrine were simultaneously infused into the fetal hindlimb venous catheter for 30 minutes.6 Hemodynamics were then recorded, and blood samples were collected anerobically from the carotid artery for hemoglobin and hematocrit determination, as well as for blood gas analysis. After removal of twice the catheter dead space volume, 2.5 mL of blood was simultaneously withdrawn from the carotid artery, pulmonary trunk, abdominal aorta, and coronary sinus for catecholamine analysis. Subsequently, fetal LV and right ventricular (RV) outputs and major regional and LV myocardial blood flows were measured with radioactive microspheres using the reference-sample method.28 The tritiated catecholamine infusion was then stopped, and low spinal anesthesia was produced in the ewe with an intrathecal injection of 3 to 5 mL of 0.5% bupivacaine. After removal of between 10 and 40 mL of lung liquid to facilitate the rapid establishment of pulmonary gas exchange after birth,29 the fetus was quickly delivered by cesarean section, the tracheal catheter was removed, and the umbilical cord was clamped and cut. After delivery, the ewe was immediately killed with an intravenous overdose of pentobarbitone sodium.

After delivery, all lambs spontaneously began respiratory movements and rapidly assumed a regular rhythmic breathing pattern. Lambs were dried and placed on a heated table, and newborn studies were performed 1 hour and 4 hours after cord clamping. As in the fetus, [3H]norepinephrine and [3H]epinephrine were infused into the hindlimb venous catheter, beginning 30 minutes before each study. With the [3H]catecholamine infusion continuing, hemodynamics were then recorded; blood samples were taken for hematocrit, blood gas, and catecholamine analysis; and LV output and LV myocardial blood flow were measured with radioactive microspheres. To determine the neuronal and extraneuronal components of LV norepinephrine and epinephrine removal in the perinatal period, the [3H]catecholamine infusion was continued after the 4-hour newborn study in a subgroup of five animals, while catecholamine neuronal uptake was blocked with intravenous desipramine hydrochloride (Sigma Chemical Co), injected at a dose of 2 mg/kg.18 20 Carotid arterial and coronary sinus blood samples were withdrawn 30 minutes after desipramine administration to obtain the LV fractional extraction of [3H]norepinephrine and [3H]epinephrine. At the end of the experiment, lambs were killed with an intravenous overdose of pentobarbital sodium, and in the subgroup of animals that received desipramine, tissue samples (30 to 100 mg wet weight) were rapidly excised from the basal, mid, and apical regions of the left ventricle for catecholamine analysis.

Physiological Measurements
Abdominal aortic and amniotic fluid pressures were monitored with strain-gauge pressure transducers (model 1280B, Hewlett-Packard) that were calibrated against a water manometer before each experiment. Mean vascular pressures were obtained electronically and referenced to amniotic fluid pressure in fetal lambs and to atmospheric pressure at the midchest position in newborn lambs. Heart rate was measured with a tachometer triggered by a systemic arterial pulse. All signals were displayed on an eight-channel paper recorder (model 7758A, Hewlett-Packard, or model 800Z, Neomedix Systems).

Blood pH, PO2, PCO2, and base excess were determined at 39°C in fetuses and at the measured rectal temperature in lambs with a blood gas analyzer (model 168, Corning Medical). Blood hemoglobin content and oxygen saturation were determined in duplicate with a hemoximeter (model OSM2, Radiometer).

Radiotracer Infusions
Approximately 50 µCi aliquots of the stock solutions of radiolabeled norepinephrine (levo-[3H]2,5,6-norepinephrine, New England Nuclear) and epinephrine (levo-N-methyl-[3H]epinephrine, New England Nuclear), dissolved in 0.2 mol/L acetic acid containing 1 mg/mL sodium ascorbate, were stored at -80°C. Before the study, an aliquot of each radiotracer was thawed and mixed in 40 mL of 0.9% sodium chloride. The diluted and combined radiotracers were infused using a syringe pump at a rate of 0.18 mL/min, which corresponded to an infusion rate of 46.2±4.3 nCi · kg-1 · min-1 for [3H]norepinephrine and 55.2±5.7 nCi · kg-1 · min-1 for [3H]epinephrine. A sample of the infusate was stored at -80°C for subsequent norepinephrine and epinephrine assay.

Assay of Catecholamines in Blood and Tissue Samples
Blood samples withdrawn during fetal and newborn studies were transferred to tubes containing EDTA and immediately centrifuged. The plasma fraction was initially stored on dry ice and then in a -80°C freezer until assay. The red blood cell fraction was resuspended in a plasma substitute (Haemaccel, Behring) and used to replace blood removed during subsequent blood sampling. LV tissue samples obtained at the end of the experiment were immediately frozen in liquid nitrogen, weighed, and stored at -80°C until assay. Tissue samples were later homogenized in 1 mL of 0.4 mol/L perchloric acid containing 100 µmol/L EDTA and 100 µmol/L sodium ascorbate and centrifuged, and the supernatant was assayed for catecholamine content.

Endogenous and tritiated catecholamines were extracted from 1 mL plasma and 50 µL tissue supernatant using alumina adsorption. After separation with high-performance liquid chromatography, norepinephrine and epinephrine concentrations in plasma, tissue supernatant, and 10-µL infusate samples were quantified by electrochemical detection.6 20 Timed collection of the eluant leaving the electrochemical cell allowed fractionation of 3H-labeled catecholamines into scintillation vials for subsequent counting by liquid scintillation spectroscopy. The within-assay coefficient of variation for measurement of endogenous catecholamine levels with this technique, determined from a pooled plasma sample, was 4.2% for norepinephrine and 6.2% for epinephrine. Endogenous levels of norepinephrine and epinephrine were not corrected for the contribution of exogenous 3H-labeled catecholamines because infused [3H]norepinephrine constituted only 0.07±0.01% of the endogenous norepinephrine level in fetal lambs, 0.05±0.01% in 1-hour newborn lambs, and 0.06±0.02% in 4-hour newborn lambs, whereas infused [3H]epinephrine contributed 1.9±0.5%, 0.4±0.1%, and 0.3±0.1% to the endogenous epinephrine concentration in fetal, 1-hour, and 4-hour lambs, respectively.

Radioactive Microsphere Technique
Radioactive microspheres, 15 µm in diameter and labeled with one of five gamma-emitting isotopes (141Ce, 113Sn, 85Sr, 95Nb, or 46Sc; New England Nuclear) were ultrasonicated for 10 to 15 minutes and then injected over 30 to 45 seconds with 10 mL isotonic saline. In fetuses, two different microsphere labels were injected simultaneously, one into the left atrium and the other into a vascular stream passing predominantly into the right ventricle (either the superior vena cava or coronary sinus). For both regimens, {approx}0.5 to 1x106 microspheres were injected per microsphere label, while reference samples were drawn simultaneously from the pulmonary trunk, carotid artery, and descending aorta. In newborn lambs, microspheres were injected into the left atrium, and reference samples were obtained from the carotid artery and the descending aorta. All reference samples were drawn at a rate of 4.1 mL/min with a mechanical pump (model 901A, Harvard Apparatus). Reference sample collection was begun 5 to 10 seconds before injection and continued for an additional 75 seconds after the end of injection. Blood withdrawn in the reference samples was simultaneously replaced with a 1:1 mixture of a plasma substitute (Haemaccel, Behring) with either fetal or newborn lamb blood.

At the end of the experiment, the lamb and placenta were placed in formalin fixative for 7 to 10 days. The lamb carcass was then divided into upper and lower body segments at the site of the previous thoracotomy.27 The LV free wall and left half of the interventricular septum were removed from the heart and dissected free of fat, large coronary vessels, and valve leaflets. The lungs and the placenta were placed in aluminum pans and carbonized in a vented box furnace at 280°C. The carbonized tissue was ground into a coarse powder and, together with the LV myocardium, was packed into plastic counting vials to a height of <2 cm. The radioactivity of the blood reference samples and the tissue vials was counted in a gamma counter (model 1282 CompuGamma, LKB-Wallac) using appropriate window settings, and the photopeaks of individual isotopes were separated by an on-line computer program.

Calculation of Blood Flows and LV Pump Function
Radioactive microsphere blood flow measurements were obtained from the general relation QTissue=[QReference · RTissue]/RReference, where Q is flow (mL/min) and R is radioactivity (counts/min). Fetal and newborn LV output (QLV) was calculated as [QReference · RLA]/RLACA, where RLA is the radioactivity of the label injected into the left atrial cavity and RLACA is the radioactivity of the same label collected in the carotid arterial reference sample. Fetal RV output (QRV) was computed as [QReference · RRV]/RVPT, where RRV is the radioactivity of the venous label passing into the right ventricle, calculated as the injected radioactivity of the venous label minus that portion crossing the foramen ovale to appear in the LV outflow, and RVPT is the radioactivity of the venous label in the pulmonary reference sample.27

Because infusion of tritiated catecholamines into the fetal circulation may be associated with regional differences in the systemic concentrations of these radiotracers,6 blood flows to the three major fetal vascular compartments (the upper body, the lungs, and the combined lower fetal body and placenta) were computed to calculate mean systemic catecholamine levels and to thereby derive an accurate estimate of fetal whole-body catecholamine clearance and spillover. Fetal lung blood flow was obtained directly using the measured radioactivities in the pulmonary arterial reference sample and lung tissue, but determination of the upper fetal body and the combined lower fetal body and placental flows required calculation of the aortic isthmus flow. The latter, which was obtained from measured variables using previously derived equations,27 was computed as (QRV-QL)(RLAAA)/(RLACA-RLAAA), where QL is lung blood flow (mL/min), and RLACA and RLAAA are the radioactivities of the left atrial microsphere label in carotid and abdominal aortic reference samples, respectively. Fetal upper body flow (QUB) was then equal to QLV-[(QRV-QL)(RLAAA)/(RLACA-RLAAA)]; the combined fetal lower body and placental flow (QLBP) was equivalent to [QRV-QL][1+(RLAAA)/(RLACA-RLAAA)].

Changes in LV performance between the fetal and newborn periods were evaluated by calculating LV external work (g · m · min-1 · kg-1) as (0.0136 · MAP · LVO)/BW, where MAP is mean systemic arterial pressure (mm Hg), LVO is LV output (mL/min), and BW is body weight (kg).

Total-Body Catecholamine Kinetics
Total-body plasma catecholamine clearance and spillover rates were obtained using previously described formulas.16 20 21 Thus, the total-body plasma clearance of catecholamines (TBCl) was calculated as IR/([3H]CatA · BW), where IR is the infusion rate of 3H-labeled catecholamine (dpm/min), [3H]CatA is the steady state mean systemic arterial plasma concentration of 3H-labeled catecholamine (dpm/mL), and BW is the body weight (kg). The total-body fractional extraction (TBFx) of either catecholamine was computed as TBCl/[CO · (1-Hct)], where CO (mL/min/kg) is the combined LV and RV output in the fetal circulation and LV output in the newborn circulation, and Hct is the hematocrit. The total-body spillover rate of catecholamines into plasma (TBSp) was computed as TBCl · CatA, where CatA (pg/mL) is the arterial plasma concentration of norepinephrine or epinephrine.

In fetuses, the mean systemic concentration of either endogenous or tritiated catecholamines6 was calculated as [(QUB · CatCA)+(QLBP · CatAA)+(QL · CatPT)]/[QUB+QL+QLBP], where CatCA, CatAA, and CatPT are the levels of endogenous or tritiated catecholamine in the carotid artery (which is representative of ascending aortic blood), abdominal aorta, and pulmonary trunk, respectively, and QUB, QL, and QLBP are as defined above. To obtain an accurate measure of total-body norepinephrine and epinephrine clearance in newborn lambs, the infusion rate of 3H-labeled catecholamine was corrected for any pulmonary catecholamine extraction.30 The systemic catecholamine level after birth was obtained from the average of carotid arterial and abdominal aortic samples.

LV Catecholamine Kinetics
The LV norepinephrine or epinephrine fractional extraction (LVFx) was calculated as ([3H]CatCA-[3H]CatCS)/[3H]CatCA, the LV catecholamine clearance was calculated as [(LVFx · CatCA)] · [QLV · (1-Hct)], and the LV catecholamine spillover was calculated as [(LVFx · CatCA)+(CatCS-CatCA)] · [QLV · (1-Hct)],17 21 where CatCA and CCS are the catecholamine concentrations (pg/mL) in carotid arterial and coronary sinus plasma, [3H]CatCA and [3H]CatCS are the steady state concentrations of 3H-labeled catecholamine (dpm/mL) in carotid arterial and coronary sinus plasma, respectively, and QLV is the blood flow to the LV free wall and left half of the septum (mL · m-1 · g-1), which was converted to LV myocardial plasma flow from knowledge of Hct, the hematocrit.

Statistics
Results are reported as mean±SE. Perinatal hemodynamic, blood gas, blood flow, and catecholamine variables were analyzed with repeated-measures one-way ANOVA.31 The sums of squares were partitioned into individual degrees of freedom to evaluate changes among the fetal, 1-hour, and 4-hour lambs using, as appropriate, the Bonferroni procedure for multiple tests.32 A value of P<.05 was considered significant.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMaterials and Methods
 *Results
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Blood Gases, Hemodynamic Variables, and LV Pump Function
Between fetal and 1-hour newborn lambs, hemoglobin oxygen saturation rose by 37.7±3.1% (P<.005); oxygen tension, by 27.9±3.7 mm Hg (P<.005); systemic blood pressure, by 13±3 mm Hg (P<.005); heart rate, by 56±12 bpm (P<.005); and LV output, by 137±18 mL · min-1 · kg-1 (P<.005). In the same period, pH fell by 0.075±0.009 unit (P<.005), and LV myocardial plasma flow did not change significantly (Table 1Down). In the interval between 1 and 4 hours after birth, hemoglobin oxygen saturation rose by 7.0±1.7% (P<.025), and oxygen tension rose by 18.4±3.8 mm Hg (P<.005), while LV myocardial plasma flow fell by 0.42±0.09 mL · min-1 · g-1 (P<.05, Table 1Down).


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  		Table 1. Hemodynamics and Ascending Aortic Blood Gas Variables Before and After Birth

Between fetal and 1-hour lambs, LV external work increased by 115%, from 136±8 to 292±17 g · m · min-1 · kg-1 (P<.005), and then fell to 241±16 g · m · min-1 · kg-1 in 4-hour lambs (P<.05). However, LV external work in 4-hour lambs was still 77% higher than in fetal lambs (P<.005, Fig 1Down).



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  		Figure 1. Left ventricular external work in fetal lambs (F), 1-hour newborn lambs (1 HR NB), and 4-hour newborn lambs (4 HR NB).

Endogenous Plasma Catecholamines
Plasma norepinephrine concentration increased from 1049±168 to 2253±434 pg/mL (P<.01) in the carotid artery and from 909±200 to 2233±401 pg/mL (P<.005) in the coronary sinus between fetal and 1-hour lambs. Carotid arterial plasma norepinephrine concentration was unchanged between 1- and 4-hour lambs but fell to 1522±280 pg/mL in the coronary sinus (P<.05). When the carotid artery and coronary sinus were compared, plasma norepinephrine concentrations were not significantly different in fetal (P>.25) and 1-hour lambs (P>.8), but the carotid arterial norepinephrine concentration was 715±51 pg/mL greater in 4-hour lambs (P<.005, Fig 2ADown).



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  		Figure 2. Plasma norepinephrine concentration (A) and epinephrine concentration (B) in the carotid artery (solid bars) and coronary sinus (open bars) of fetal lambs (F), 1-hour newborn lambs (1 HR NB), and 4-hour newborn lambs (4 HR NB). *P<.025 and ***P<.005 for carotid artery vs coronary sinus.

Between fetal and 1-hour lambs, plasma epinephrine concentration increased 5.5-fold in the carotid artery (from 50±14 to 323±66 pg/mL, P<.005) and 3.5-fold in the coronary sinus (from 46±10 to 208±37 pg/mL, P<.005), but neither changed significantly between 1- and 4-hour lambs. Carotid arterial and coronary sinus plasma epinephrine concentrations were similar in fetal lambs, but the carotid arterial epinephrine concentration was 115±38 pg/mL (P<.025) and 153±31 pg/mL (P<.005) greater in 1-hour and 4-hour lambs, respectively (Fig 2BUp).

Total-Body Catecholamine Clearance, Fractional Extraction, and Spillover
The total-body clearance rate of norepinephrine decreased by 33±5% (P<.005) and that of epinephrine decreased by 35±4% (P<.005) between fetal and 1-hour lambs but did not change significantly between 1- and 4-hour lambs. By contrast, norepinephrine and epinephrine total-body fractional extractions remained essentially constant among fetal, 1-hour, and 4-hour lambs. Norepinephrine total-body spillover increased by 52±16% (P<.025) and epinephrine total-body spillover increased by 460±124% (P<.005) between fetal and 1-hour lambs, but neither changed significantly between 1- and 4-hour lambs (Table 2Down).


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  		Table 2. Norepinephrine and Epinephrine Total-Body Clearance, Fractional Extraction, and Spillover in Fetal and Newborn Lambs

LV Catecholamine Fractional Extraction and Clearance
LV norepinephrine fractional extraction did not change significantly among fetal (0.45±0.05), 1-hour (0.47±0.04), and 4-hour (0.54±0.02) lambs (Fig 3ADown). By contrast, because of the marked postnatal rise in the plasma norepinephrine concentration, LV norepinephrine clearance increased from 713±116 to 1921±429 pg · min-1 · g-1 of myocardium between fetal and 1-hour lambs (P<.01) and was similar in 4-hour lambs. LV epinephrine fractional extraction also did not differ significantly among fetal (0.39±0.03), 1-hour (0.46±0.07), and 4-hour (0.50±0.04) lambs (Fig 3BDown). However, LV epinephrine clearance increased 8.3-fold at birth, from 28±6 pg · min-1 · g-1 in fetuses to 259±68 pg · min-1 · g-1 in 1-hour lambs (P<.005), and was not significantly different in 4-hour lambs. No difference was apparent between LV norepinephrine and epinephrine fractional extractions, and neither the LV norepinephrine nor LV epinephrine fractional extraction differed significantly from the corresponding total-body fractional extraction in fetal or newborn lambs (Table 2Up).



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  		Figure 3. Left ventricular norepinephrine (A) and epinephrine (B) fractional extraction in fetal lambs (F), 1-hour newborn lambs (1 HR NB), and 4-hour newborn lambs (4 HR NB).

After neuronal uptake blockade with desipramine, LV norepinephrine fractional extraction in newborn lambs decreased from 0.52±0.03 to 0.23±0.03 (P<.001), and LV epinephrine fractional extraction decreased from 0.48±0.05 to 0.39±0.07 (P<.05) (Fig 4Down). Comparison of desipramine-sensitive and desipramine-resistant fractional extractions indicated that neuronal and extraneuronal uptake contributed a similar portion of LV norepinephrine removal (P=.25), whereas extraneuronal uptake accounted for 81% of LV epinephrine clearance (P<.05). Furthermore, comparison of the desipramine-induced reductions in the LV fraction extraction of norepinephrine (0.29±0.02) and epinephrine (0.09±0.03) indicated that neuronal uptake of norepinephrine was 3.2-fold more efficient than that of epinephrine (P<.005). By contrast, comparison of LV catecholamine fractional extractions after desipramine indicated that extraneuronal uptake of epinephrine was 70% more efficient than that of norepinephrine (P<.05).



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  		Figure 4. Fractional extraction of [3H]norepinephrine and [3H]epinephrine in left ventricle before (solid bars) and after (open bars) desipramine in 4-hour lambs.

LV Catecholamine Spillover
LV norepinephrine spillover increased from 476±155 to 1962±426 pg · min-1 · g-1 of myocardium between fetal and 1-hour lambs (P<.005) but then fell to 630±167 pg · min-1 · g-1 in 4-hour lambs (P<.01, Fig 5ADown). This pattern of LV norepinephrine spillover differed from the perinatal change in total-body norepinephrine spillover in two major respects. First, the increase in LV norepinephrine spillover between fetal and 1-hour lambs (414±81%) exceeded that of the total-body norepinephrine spillover (52±16%, P<.005). Second, the reduction in LV norepinephrine spillover between 1-hour and 4-hour lambs (-65±5%) was more pronounced (P<.005) than the insignificant decline in norepinephrine total-body spillover (-10±11%). As a result of these divergent changes, LV norepinephrine spillover constituted 0.7±0.2% of the total-body norepinephrine spillover in fetuses, but this increased to 1.8±0.3% in the 1-hour lambs (P<.005) and then fell to 0.8±0.2% in 4-hour lambs (P<.005).



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  		Figure 5. Left ventricular norepinephrine (A) and epinephrine (B) spillover in fetal lambs (F), 1-hour newborn lambs (1 HR NB), and 4-hour newborn lambs (4 HR NB).

Significant LV epinephrine spillover (P<.02) was detectable in fetal lambs, averaging 24±7 pg · min-1 · g-1 of myocardium. After birth, LV epinephrine spillover increased 3-fold to 73±22 pg · min-1 · g-1 in 1-hour lambs (P<.05) but then fell to 3±15 pg · min-1 · g-1 in 4-hour lambs (P<.025), a value not significantly different from zero (Fig 5BUp). LV epinephrine spillover was less than LV norepinephrine spillover (P<.005), with, on average, one epinephrine molecule released into the circulation for every 23 molecules of norepinephrine in fetuses and 29 molecules of norepinephrine in 1-hour lambs. The pattern of total-body (Table 2Up) and LV epinephrine spillovers also differed in the perinatal period, with the contribution of LV epinephrine spillover to total-body epinephrine spillover falling progressively from 1.2±0.4% in fetuses to 0.2±0.2% in 4-hour lambs (P<.025).

LV Tissue Catecholamine Concentrations
No significant differences in norepinephrine or epinephrine concentrations were evident between the LV basal, mid, and apical regions in 4-hour lambs. The pooled LV tissue norepinephrine concentration was 440±98 pg/mg of wet tissue weight, and epinephrine concentration was 16.1±3.6 pg/mg, indicating that LV myocardium contained, on average, one molecule of epinephrine for every 30 molecules of norepinephrine.


*    Discussion
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 *Discussion
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This is the first study to have examined alterations in LV norepinephrine and epinephrine kinetics occurring at birth, as well as their relationship to alterations in LV function and whole-body catecholamine kinetics. An important feature of our experimental design was that measurements were performed in chronically instrumented fetal sheep in which hemodynamics and blood gases were within normal limits2 3 6 27 33 34 and which, after cesarean section delivery and the onset of spontaneous respiration, underwent hemodynamic and blood gas changes typically seen in the transition from the fetal to the newborn state.33 34 35 In recent years, the use of this type of experimental preparation has provided new insights into the circulatory and cardiac changes occurring at birth. These insights include the recognition that (1) the increase in LV output that occurs at birth can be entirely accounted for by an extension of the LV perfusion territory to encompass systemic tissues perfused by the right ventricle in utero, without any significant change in overall flow to body tissues,2 and (2) the increase in LV pumping performance occurring at birth is accompanied by a substantial elevation in LV myocardial oxygen consumption, which is underpinned by an enhanced LV arteriovenous oxygen extraction rather than any significant rise in LV myocardial blood flow.3

In the sheep, sympathetic innervation of the heart starts after about two thirds of the gestational term9 and is still incompletely developed in near-term fetal and newborn lambs, with sparse nerve varicosities evident on monoamine fluorescence9 and with only one third of the myocardial stores of norepinephrine found in adult sheep.8 The present study indicates that in association with this incomplete structural development of cardiac sympathetic elements, only 45% to 54% of circulating norepinephrine was extracted by fetal and newborn hearts, a proportion substantially lower than the 64% to 80% measured in adult hearts of other species.17 19 20 25 By contrast, the corresponding LV fractional epinephrine extraction (39% to 50%) lay within the lower part of the range of 38% to 62% measured in adult hearts.18 20 23 25 Consequently, although cardiac norepinephrine extraction exceeds epinephrine extraction in the adult heart,18 20 no difference was evident between perinatal LV norepinephrine and epinephrine extractions, implying that postnatal growth is accompanied by a preferential rise in LV norepinephrine uptake. Given that norepinephrine is mainly removed by neuronal uptake (Fig 4Up), the latter is presumably related to the increase in myocardial sympathetic innervation occurring in the initial weeks after birth.8 9

The presence of LV norepinephrine spillover in utero (Fig 5AUp) indicates that cardiac sympathetic nerves were tonically active in the fetal heart. However, fetal LV norepinephrine spillover constituted only 0.7% of total-body norepinephrine spillover, a value substantially less than the 1.3% to 3% reported in adult human and animal studies.17 19 20 The most likely basis for this low fetal LV–to–total-body norepinephrine spillover ratio relates to histochemical36 and biochemical evidence,12 which suggests that sympathetic innervation of the heart lags behind that of other tissues (eg, intestine and spleen) during fetal and postnatal development. The possibility that the low fetal LV–to–total-body norepinephrine spillover ratio was due to organ-related differences in the degree of reuptake of norepinephrine after its release at neuroeffector sites16 can be discounted because of the similarity between total-body and LV norepinephrine fractional extractions (Table 2Up and Fig 3AUp).

After delivery, LV norepinephrine spillover rose >4-fold in 1-hour lambs and then fell to near-fetal levels in 4-hour lambs, indicating that LV sympathetic nerve activity increased after birth but that this increase was transitory in nature. The latter conclusion is founded on the proportionality that exists between organ norepinephrine spillover and sympathetic nerve firing rates16 and is dependent on the maintenance of a similar matching between LV norepinephrine spillover and sympathetic nerve firing rates in fetal and newborn animals. This matching may be altered by hemodynamic and neuronal factors, such as a rise in organ perfusion16 or a reduction in norepinephrine extraction,24 which both increase the proportion of norepinephrine released by sympathetic nerves that spills over into the circulation. However, changes in LV plasma flow were either absent or minor (Table 1Up), whereas LV norepinephrine fractional extraction was similar in fetal and newborn lambs (Fig 3Up), suggesting that perinatal changes in LV norepinephrine spillover principally reflected alterations in LV sympathetic nerve activity in the present study.

Given that cardiac sympathetic nerve stimulation augments the function of newborn lamb hearts,5 it is likely that the increase in LV sympathetic activity occurring between fetal and 1-hour lambs in the present study contributed to the accompanying increase in LV pumping performance. However, the finding of only a minor reduction in LV external work after the subsequent return of LV norepinephrine spillover to near-fetal levels in 4-hour lambs suggests that any such contribution was of relatively small magnitude. This proposition is thus in accord with findings obtained during the increased sympathetic activation associated with the circulatory stress of hypoxemia, which indicate that adrenergic regulation of the newborn lamb heart is mainly mediated by circulating catecholamines, with only a minor contribution from developing cardiac sympathetic elements.37 Our conclusion about the potential role of LV sympathetic activity in the changes in LV performance at birth therefore differs from the study of Agata et al,15 who observed that in utero sympathectomy with 6-hydroxydopamine had no significant effect on alterations in heart rate, blood pressure, and cardiac output in ventilated and paralyzed lambs in the first 4 hours after cesarean section delivery. Presumably, the difference is at least in part due to the restoration of circulatory hemodynamics to near-normal values that accompanies chemical sympathectomy with 6-hydroxydopamine15 38 39 as a result of the emergence of compensatory mechanisms, such as rises in the circulating levels of vasoactive humoral agents40 and hyperresponsiveness to circulating adrenergic agonists.38 41

Birth is characterized by a surge in circulating norepinephrine levels, which occurs after interruption of the umbilical circulation42 and is therefore not due to the maternal-to-fetal transplacental passage of norepinephrine.43 Although this norepinephrine surge has been considered to be due to a generalized activation of the sympathoadrenal system,44 a considerable body of evidence now indicates that changes in plasma norepinephrine concentrations constitute an imprecise and indirect measure of sympathetic nerve activity.16 This is particularly evident at birth because then only {approx}45% of the increment in plasma norepinephrine results from increased norepinephrine spillover secondary to sympathetic activation.6 More important, the results of the present study point to birth-related differences in the regional pattern of the increases in sympathetic discharge. Thus, the greater increase in LV compared with total-body norepinephrine spillover between fetal and 1-hour lambs indicates that the rise in LV sympathetic activity exceeded that in the remainder of the body, whereas the marked fall in LV norepinephrine spillover with unaltered total-body norepinephrine spillover apparent between 1 and 4 hours after birth indicates that LV sympathetic nerve firing fell even though overall sympathetic activity was maintained. Taken together, these findings imply that birth is accompanied by an organ-specific rather than a generalized activation of the sympathetic nervous system, a notion also supported by the report of a divergence between postnatal changes in renal nerve electrical activity and circulating norepinephrine levels after cesarean section delivery in lambs.45

A novel finding of the present study was that epinephrine was released from the near-term fetal lamb heart under resting conditions. This epinephrine could have originated from the uptake of circulating epinephrine into intraneuronal stores and its subsequent release during sympathetic neurotransmission,26 a scenario that appears to account for the release of epinephrine from the heart of anesthetized dogs,20 healthy young adults undergoing strenuous aerobic exercise,23 and healthy elderly subjects at rest.24 However, although fetal LV epinephrine spillover in the present study (24 pg · min-1 · g-1) was of similar magnitude to LV epinephrine clearance (28 pg · min-1 · g-1), administration of desipramine revealed that only {approx}20% of the LV epinephrine clearance (ie, 5 to 6 pg · min-1 · g-1) occurred by a neuronal process, implying that most of the epinephrine released from the fetal heart was synthesized within the myocardium itself. Although never previously examined in the fetus, the concept of myocardial epinephrine synthesis is supported by catecholamine kinetic studies performed in pathophysiological conditions, such as cardiac failure,23 25 and by evidence that the heart contains the epinephrine-synthesizing enzymes phenylethanolamine N-methyltransferase46 47 and a nonspecific N-methyltransferase.46 Present data suggest that, within the myocardium, epinephrine is synthesized in an extraneuronal location and is then sequestered into cardiac sympathetic nerves.46 Two presumptive sites of myocardial epinephrine synthesis have thus far been identified. The first is "small intensely fluorescent" cells, which occur predominantly in the atria and atrioventricular node48 49 and which are known to be abundant in the developing heart.50 The second is the recently described "intrinsic cardiac adrenergic" cells, which are distributed throughout the atria and ventricles.47

The similar increases in the magnitudes of the LV norepinephrine and epinephrine spillovers between fetal and 1-hour lambs and the marked reduction in the LV spillover of these catecholamines between 1- and 4-hour lambs in the present study are consistent with the notion that perinatal release of epinephrine occurred from LV sympathetic nerves. However, in contrast to fetal lambs, LV neuronal uptake of epinephrine in 1-hour lambs ({approx}50 pg · min-1 · g-1; ie, the desipramine-sensitive portion of the LV epinephrine clearance of 259 pg · min-1 · g-1) constituted approximately two thirds of the LV epinephrine spillover (73 pg · min-1 · g-1), indicating that enhanced neuronal uptake of circulating epinephrine could have accounted for most of the rise in LV epinephrine spillover occurring at birth. Our present results cannot provide a definitive explanation for the lack of any measurable LV epinephrine spillover in 4-hour lambs. However, the latter is more likely to be related to the technical limitation of detecting a low level of organ epinephrine spillover in the presence of markedly elevated circulating epinephrine concentrations rather than a neonatal depletion of myocardial epinephrine stores, because the myocardial epinephrine-to-norepinephrine ratio in 4-hour lambs (1:30) was even higher than the ratio of 1:67 measured in anesthetized adult dogs exhibiting significant baseline cardiac epinephrine release.20

The precise physiological role of epinephrine released from the fetal and newborn heart remains to be elucidated. Potentially, such epinephrine may act directly on ß1-adrenoceptors or the abundant {alpha}-adrenoceptors present on fetal and newborn myocytes51 to increase cardiac contractility. However, two ß2-adrenoceptor actions of epinephrine are also likely to have relevance in the developing heart. First, epinephrine released into myocardial neuroeffector junctions may indirectly increase cardiac contractility by acting on presynaptic ß2-adrenoceptors to facilitate release of norepinephrine and thereby increase the amount of norepinephrine released per nerve impulse.26 However, the extent to which prejunctional modulation of norepinephrine release by epinephrine exists in the fetal and newborn heart is unknown; indeed, results from the canine saphenous vein suggest that such modulation emerges during postnatal growth.52 Second, neonatal ventricular myocytes appear to exhibit an exaggerated contractile response to ß2-adrenergic stimulation,53 raising the possibility that locally released epinephrine may act on postjunctional ß2-adrenoceptors to directly increase myocardial contractility.

In summary, we have studied LV norepinephrine and epinephrine kinetics before and after cesarean section in chronically instrumented fetal lambs. Our results suggest that birth is accompanied by a transient rise in LV sympathetic activity, that LV sympathetic activation may contribute to the immediate but not the sustained augmentation of LV performance after birth, that organ differences in the pattern of sympathetic activation occur at birth, and that birth-related increases in LV sympathetic activity are accompanied by release of epinephrine from the heart.


*    Acknowledgments
 
We acknowledge the valuable technical assistance of Ann Oates, Vojta Brodecky, Jennene Wild, and Karyn Forster.

Received January 13, 1997; accepted June 20, 1997.


*    References
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