Myocardial Function

Cardiac output is determined by the interrelationships of preload, afterload, myocardial

contractility, and heart rate.
Preload (ventricular filling pressure) reflects the initial muscle
length, which by the Frank-Starling principle influences the
development of myocardial force. Afterload (the impedance to
ejection from the ventricles) is reflected basically by arterial
pressure. Contractility reflects the intrinsic inotropic capability
of the myocardium.Studies of fetal myocardium show immaturity of structure,
function, and sympathetic innervation relative to the adult
myocardium.16-20 At all muscle lengths along the curve of length
versus tension, the active tension generated by fetal myocardium
is lower than that generated by adult myocardium.16 In
addition, resting, or passive, tension is higher in fetuses than in
adults, suggesting lower compliance of fetal myocardium.
Studies in chronically instrumented intact fetal lambs
showed that after volume loading by the infusion of blood or
saline, the right ventricle is unable to increase stroke work or
output to the same extent as in the adult.17 This is particularly
true in less-mature fetuses, in whom right ventricular enddiastolic
pressure is markedly elevated without any obvious
change in right ventricular stroke work. Similar results are
found for both the left and right ventricles but with some ability
to increase output or work at lower pressures, between 2 and
5mmHg.18-20 Limitations in the increase in stroke work with
increasing filling pressure have been shown to be afterload
dependent and, for the left ventricle, are probably affected by
right ventricular mechanical constraint.21,22
Fetal and adult sarcomeres have equivalent lengths,23 but
there are major ultrastructural differences between fetal myocardium
and adult myocardium. The diameter of the fetal cells
is smaller, and perhaps more importantly, the proportion of
noncontractile mass (i.e., of nuclei, mitochondria, and surface
membranes) to the number of myofibrils is significantly greater
than in the adult. In the fetal myocardium, only about 30% of
the muscle mass consists of contractile elements; in the adult,
the proportion is about 60%. These ultrastructural differences
are probably responsible for the age-dependent differences in
performance.16
In newborn lambs, stroke volume is decreased at afterload
levels that would be considered low for adult animals.24 Gilbert20
showed that in fetal animals, an increase in arterial pressure
of about 15mmHg, produced by methoxamine infusion,
depresses the cardiac function curve so that cardiac output
averages 25% to 30% less than normal. The extent of shortening
is less in the fetus compared with the adult at any level of
tensiona potential explanation for the effects of afterload on
stroke volume.16
In chronically instrumented fetal lambs, there is a close relationship
between cardiac output and heart rate. Spontaneous
and induced changes in heart rate are associated with corresponding
changes in left or right ventricular output. Increasing
heart rate from the resting level of about 180 up to 250 to 300
beats/min increases cardiac output by 15% to 20%. Likewise,
decreasing heart rate below the resting level significantly

decreases ventricular output.

The fetal heart normally appears to operate near the top of
its cardiac function curve. An increase in heart rate results in
only a modest increase in output; however, bradycardia can
reduce output significantly. At an atrial filling pressure greater
than approximately 8mmHg, there is little or no increase in
output because the length-to-tension relationship has reached
a plateau. In addition, the fetal heart is sensitive to changes in
afterload.
SYMPATHETIC AND PARASYMPATHETIC
INNERVATION
Isolated fetal cardiac tissue has a lower threshold of response to the inotropic effects of
norepinephrine than does adult cardiac tissue and is more sensitive to norepinephrine
throughout the dose-response curves.16 Because isoproterenol, a direct
-adrenergic agonist that is not taken up and stored in sympathetic
nerves, has similar effects on fetal and adult myocardium,
the supersensitivity of fetal myocardium to norepinephrine is
probably the result of incomplete development of sympathetic
innervation in fetal myocardium. Myocardial concentrations of
norepinephrine in the fetus within several weeks of term are
significantly lower than in newborn animals, and activity of
tyrosine hydroxylase, the intraneuronal enzyme responsible for
the first transformation in catecholamine biosynthesis, is also
reduced.16 In contrast, adrenal gland tyrosine hydroxylase activity
at the same gestational age is not suppressed, possibly
because the decrease in myocardial activity is related to delayed
sympathetic innervation rather than to a generalized
immaturity.
Monoamine oxidase, the enzyme responsible for oxidative
deamination of norepinephrine, is also present in lower concentrations
in the fetal heart than in the adult. Histochemical
evaluation of the development of sympathetic innervation
using the monoamine fluorescence technique has further substantiated
the delayed development of sympathetic innervation
of the fetal myocardium. At term, sympathetic innervation is
incomplete. Patterns of staining indicate a progression of innervation,
starting at the area of the sinoatrial node and progressing
toward the left ventricular apex.25,26
Although sympathetic nervous innervation appears to begin
developing in the fetal heart by about 0.55 of term, -adrenergic
receptors seem to be present much earlier and can be stimulated
by appropriate agonists before 0.4 of term.27 Before about 0.55
of term (80 days of gestation in the lamb), fetal myocardium
may be affected by circulating catecholamines, but local reflex
activity through the sympathetic nervous system is not likely to
play a major role in circulatory regulation.
Vagal stimulation at about 0.85 of term produces bradycardia.
Administration of atropine at 0.55 of term produces a
modest increase in fetal heart rate,28 indicating that vagal innervation
is present by this stage of development. Histochemical
staining for acetylcholinesterase in close-to-term fetuses has
shown that the concentrations of this enzyme, which is responsible
for metabolism of acetylcholine, are similar to those found
in adults.
ENERGY METABOLISM

In the normal unstressed fetus, myocardial blood flow is about

180mL/min per 100g of tissue, approximately 80% greater
than in the adult. Fetal myocardial oxygen consumption, as
measured in the left ventricular free wall, is about 400mM/min
per 100g, similar to that in the adult. In adult sheep, free fatty
acids provide the major source of energy for the myocardium,
and carbohydrate accounts for only about 40% of myocardial
oxygen consumption.29 In fetal sheep under normal conditions,
however, free fatty acid concentrations are extremely low, and
almost all the oxygen consumed by the left ventricular wall can
be accounted for by carbohydrate metabolism: 33% by glucose,
6% by pyruvate, and 58% by lactate metabolism.
Adenosine triphosphatase (ATPase) activity in fetal myocardium
is equal to that in adult myocardium, suggesting that
energy utilization by the contractile apparatus is similar in the
two tissues.16 Mitochondria from fetal myocardium demonstrate
higher oxidative phosphorylation than those from adultmyocardium.
The higher oxygen consumption in fetal mitochondria
uncoupled by deoxyribonucleoprotein suggests that
the augmented respiratory rate in mitochondria is a reflection
of increased electron transport.16 This is consistent with the
greater cytochrome oxidase activity in fetal mitochondria.

Control of the Cardiovascular System

Maintenance of normal cardiovascular function, blood pressure,

heart rate, and distribution of blood flow represents a
complex interrelationship among local vascular and reflex
effects. These effects are initiated by the stimulation of various
receptors, and they are mediated through the autonomic
nervous system as well as through hormonal influences.
Although some information is available about how these mechanisms
affect the circulation after stress, little is known about
their role in normal fetal cardiovascular homeostasis. To complicate
the situation, other factors, such as sleep state, electrocortical
activity, and uterine activity, transiently affect the
circulation. As a result, this area of fetal physiology is difficult
to study, and the data are difficult to interpret.
LOCAL REGULATION
As the oxygen content of blood perfusing the fetus falls, blood
flow to the brain, myocardium, and adrenal glands increases;
on the other hand, pulmonary blood flow falls as oxygen content
of the blood decreases. Local effects of changes in oxygen environment
are less clearly established for other organs.
Many adult organs exhibit autoregulation, the ability to
maintain constant blood flow over a fairly wide range of perfusion
pressures. In the fetus, the umbilical-placental circulation
does not exhibit autoregulation, and blood flow changes in relation
to changes in arterial perfusion pressure.30 On the other
hand, the cerebral circulation in fetal lambs does show autoregulatory
capability.31
BAROREFLEX REGULATION
In chronically instrumented fetal lambs, the fetal heart rate
slows after an acute increase in systemic arterial pressure.32,33
This baroreflex response, although present by 0.55 of term (80
days of gestation), is poorly developed early on; the sensitivity
of the reflex to induced changes in pressure increases with

advancing gestation. Carotid denervation partially inhibits the

response, and combined carotid and aortic denervation abolishes
it. Parasympathetic blockade with atropine also abolishes
the reflex. Although the existence of the arterial baroreflex is
established, Dawes and associates34 suggested that the threshold
for fetal baroreflex activity is above the range of the normal fetal
arterial blood pressure and that this reflex is not important in
controlling cardiovascular function in utero.
Carotid sinus and vagus nerve activity are synchronous with
the arterial pulse, suggesting continuous baroreceptor activity.
35,36 Marked fluctuations in arterial blood pressure and heart
rate are observed after sinoaortic denervation, although the
average arterial blood pressure and heart rate are not different
from those in controls.37
The baroreflex in fetal animals requires fairly marked changes
in pressure to produce relatively minor responses. Sinoaortic
denervation increases heart rate and blood pressure variability,
however. Under normal circumstances, therefore, baroreceptor
function acts to stabilize the heart rate and blood pressure. In
the fetus, as in the adult, baroreflex control is also influenced
by hormonal systems.38
CHEMOREFLEX REGULATION
In general, chemoreceptor stimulation by sodium cyanide
injection induces hypertension and bradycardia.39,40 Central or
carotid chemoreceptor stimulation causes hypertension and
mild tachycardia with increased respiratory activity, whereas
aortic chemoreceptor stimulation produces bradycardia with
modest increases in arterial blood pressure. Because the carotid
chemoreceptors are less sensitive than the aortic chemoreceptors,
hypertension and bradycardia usually result. In chronically
instrumented fetal lambs, sodium cyanide produces bradycardia
with variable blood pressure changes, responses that are
abolished by sinoaortic denervation.41 Fetal hypoxia produces
bradycardia and hypertension, which are abolished by carotid
sinus denervation.42
AUTONOMIC NERVOUS SYSTEM AND
ADRENAL MEDULLA
As described earlier, sympathetic innervation of the heart is not
complete until term or, in some species, until after delivery. In
contrast, cholinergic innervation, as measured by the presence
of acetylcholinesterase, appears to be fully developed during
fetal life. The innervation of other vascular beds also appears to
proceed at different rates during gestation.43
Adrenergic receptors are present in the fetus and have been
demonstrated in myocardium.4446 Receptor populations that
have been studied in the fetus exhibit characteristics similar to
those in adults.47,48 The fetus possesses mature adrenergic receptors
fairly early in gestation, but the concentration of receptors
is different from that in adult organs.44 The fetal concentration
of receptors can be altered by administration of thyroid
hormone or isoxsuprine to the mother.
Injection of cholinergic or adrenergic agonists into fetal
sheep produces responses at as early as 0.4 of term (60 days
of gestation).27,49 -Adrenergic stimulation with methoxamine

produces an increase in arterial blood pressure, a small decrease

in cardiac output, an increase in blood flow to the lungs, and a
marked decrease in kidney and peripheral blood flow at as early
as 0.5 of term. -Adrenergic stimulation by isoproterenol causes
a response earlier in gestation and an increase in heart rate with
little or no change in arterial blood pressure and cardiac output.
Blood flow to both the myocardium and the lungs is increased.
Administration of acetylcholine decreases blood pressure and
heart rate and increases pulmonary blood flow markedly, particularly
in fetuses close to term.
Although receptor affinity is well developed during fetal life,
the response to a specific agonist is blunted relative to that in
the adult. The maximal constrictor response to norepinephrine
or nerve stimulation increases throughout the latter part of
gestation, and even more after birth.50 The increase might result
from gestational differences in neurotransmitter release in the
fetus. During the last trimester of gestation, there is a progressive
increase in maximal pressor response to ephedrine, which
exerts its effect indirectly through neurotransmitter release;
phenylephrine has a direct pressor effect.51 In addition, neurotransmitter
reuptake in sympathetic nerve terminals is not
fully mature in the fetus.48 Similarly, the differences between
fetal and adult myocardium with respect to threshold and sensitivity
to norepinephrine indicate an immature reuptake
mechanism for norepinephrine in the fetus.16
As gestation progresses, these variable rates of maturation of
different components of the autonomic nervous system modify
control mechanisms relating to the autonomic nervous system.
The role of -adrenergic stimulation in resting circulatory regulation
has been evaluated by pharmacologic blockade of
-adrenergic receptors with propranolol. This component of
the sympathetic nervous system exerts a positive influence over
fetal heart rate that first appears at about 0.6 of term (80 to 90
days),28 but this influence is relatively small.52 During stress such
as hypoxia or hemorrhage, however, -adrenergic activity
appears to be increased because propranolol produces much
greater changes in heart rate.
-Adrenergic control of the circulation has a somewhat
clearer developmental pattern. -Adrenergic blockade with
phentolamine or phenoxybenzamine reduces arterial blood
pressure very little, if at all, before 0.75 of term (100 to 110
days); thereafter, there is a progressive increase in response,
indicating a progressive increase in resting vascular tone attributed
to -adrenergic nervous activity. The parasympathetic
nervous system exerts an inhibitory influence over fetal heart
rate that is present by 0.55 of term (80 days).28,52 Parasympathetic
blockade with atropine produces small changes at this
age, and there is a progressive increase in parasympathetic
control as gestation advances. After approximately 0.85 of term
(120 to 130 days), no further increase is evident.
Hypoxemia or asphyxia increases circulating plasma catecholamine
concentrations in fetal sheep.5355 In fetuses younger
than about 120 days gestation, when the adrenal gland becomes
innervated, extremely low fetal blood oxygen concentrations are

required to stimulate the adrenal gland; thereafter, catecholamine

secretion can be induced by more moderate hypoxemia.53
Infusing catecholamines to reach plasma concentrations that
mimic those observed during hypoxemia produces circulatory
changes similar to those seen during hypoxemia.56 Adrenal
medullary responses to stress appear to play a role in circulatory
adjustments; whether catecholamine secretion exerts a continuous
regulatory function is not clear.
HORMONAL REGULATION OF THE CIRCULATION
RENIN-ANGIOTENSIN SYSTEM
The renin-angiotensin system is important in regulating the
normal fetal circulation and its response to hemorrhage. The
juxtaglomerular apparatus in the kidneys is well developed in
fetuses and is present by 0.6 of term (90 days).57 Plasma renin
activity, as well as circulating angiotensin II, is present in fetal
plasma as early as about 0.6 of term.58-60 The effects of fetal
stress (e.g., hemorrhage, hypoxia) on the renin-angiotensin
system are not absolutely clear. In some studies, small amounts
of hemorrhage increased plasma renin activity,57,58 but other
studies have shown little effect.61 Similarly, the effects of hypoxemia
on the renin-angiotensin system in the fetus are controversial,
but most likely hypoxemia is of little consequence.
When angiotensin II is infused to achieve plasma concentrations
similar to those that occur after a moderate (15% to 20%)
hemorrhage, there are broad cardiovascular effects.62 Arterial
blood pressure increases markedly, and after an initial abrupt
bradycardia, heart rate increases. Combined ventricular output
increases, as does blood flow to the lungs and myocardium
Renal blood flow decreases, but umbilical placental flow is
unchanged; this latter phenomenon indicates vascular constriction
in the umbilical-placental circulation because arterial
blood pressure increases but flow does not. The increase in
myocardial blood flow is probably caused by an increase in
stroke work, and the large increase in pulmonary blood flow
probably reflects the release of some other local pulmonary
vasodilating substance, such as one of the prostaglandins.63
Inhibition of the action of angiotensin II by specific inhibitors,
such as saralasin, has somewhat variable effects. In general,
in unstressed fetal animals, a fall in mean arterial pressure and
a slight decrease in heart rate occur. 59 Combined ventricular
output is unaltered, but umbilical-placental blood flow falls,
probably in association with the fall in systemic arterial pressure.
Blood flow to the peripheral tissues, adrenal glands, and
myocardium increases. During hemorrhage, the effects of saralasin
are markedly accentuated and result in profound hypotension
and bradycardia.
Under normal resting conditions, endogenous angiotensin
II appears to exert a tonic vasoconstriction on the peripheral
vascular bed, thereby maintaining systemic arterial blood
pressure and umbilical-placental blood flow. In response to
hemorrhage, angiotensin II is released; it produces more vasoconstriction
in the periphery and has other cardiovascular
effects, thereby maintaining systemic arterial blood pressure
and umbilical blood flow.

Vasopressin
Arginine vasopressin (antidiuretic hormone) has been detected
at as early as 0.4 of term (60 days) in fetal lambs.64 Although
hypoxia and hemorrhage, as well as many other stimuli such as
hypotension and hypernatremia, induced a marked increase in
plasma vasopressin concentrations,64,65 it is unlikely that vasopressin
plays a major role in normal circulatory regulation.
Maximal antidiuresis in adults occurs with vasopressin concentrations
that have no discernible effects on systemic blood pressure.
Fetal vasopressin concentrations are below this level.
Infusing vasopressin into fetal sheep to produce concentrations
similar to those observed during fetal hypoxemia produces
hypertension and bradycardia.60 Combined ventricular
output decreases slightly, but the proportion distributed to the
gastrointestinal tract and peripheral circulations falls, whereas
that distributed to the umbilical-placental, myocardial, and
cerebral circulations increases. These findings indicate that
vasopressin probably participates in fetal circulatory responses
to stress not only directly but also by enhancing pressor
responses to other vasoactive substances. Under resting conditions,
however, vasopressin apparently has little regulatory
function.
Natriuretic Peptides
Atrial natriuretic peptide (ANP) and B-type natriuretic peptide
(BNP) belong to a potent volume-regulating family of cardiac
hormones released from the atria and ventricles in response to
myocyte stretch and other stimuli such as -agonist stimulation,
endothelin 1 (ET-1), and cytokines.66 These peptides have
potent vasodilatory, diuretic, natriuretic, and growth inhibitory
actions via the secondary messenger, cyclic guanosine monophosphate
(cGMP). The natriuretic system appears to be functional
by mid-gestation, and it is able to regulate systemic and
pulmonary blood pressures as well as salt and water balance in
the fetus. In addition, these peptides are regulated during heart
development, suggesting an important role for the natriuretic
peptides in the developing cardiovascular system. Finally, both
ANP and BNP have potent vasodilating properties in the placenta
and therefore may be important regulators of placental
blood flow.67,68
Arachidonic Acid Metabolites
Although prostaglandins typically are locally active substances
that do not normally circulate in adult blood, relatively high
concentrations do normally circulate in the fetus. 69,70 It is likely
that these prostaglandins are derived from the placenta. The
fetal vasculature is also capable of producing prostaglandins,
and the umbilical vessels, ductus arteriosus, and aorta produce
significant amounts of prostaglandin E (PGE) and prostacyclin
(also known as PGI2).
Prostaglandins administered to the fetus have diverse and
extensive cardiovascular effects. PGE1 and PGE2 constrict the
umbilical-placental circulation.71,72 PGF2 and thromboxane
also cause constriction, whereas PGI2 dilates the umbilicalplacental
circulation. PGE1, PGE2, PGI2, and PGD2 produce
pulmonary vasodilatation in the fetus, whereas PGF2 produces

constriction.73 Infusion of PGE1 into fetal sheep has no effect

on cardiac output or systemic pressure, but, in addition to a
reduction in umbilical-placental blood flow, there are increases
in flow to the myocardium, adrenals, gastrointestinal tract, and
peripheral tissues.74
Of great interest is the role of prostaglandins in maintaining
patency of the ductus arteriosus in the fetus. Circulating prostaglandins,
as well as PGE2 and PGI2 produced locally in the
ductus arteriosus, play a major role in maintaining the ductus
arteriosus in a dilated state in utero.7577 Details of the overall
physiologic regulation of the ductus arteriosus are discussed in
a later section.
The role of endogenous prostaglandin production in regulating
other fetal vascular beds has been elucidated by administering
inhibitors of prostaglandin synthesis to the fetus.
Although PGE2 produces umbilical-placental vasoconstriction,
inhibition of prostaglandin synthesis has little effect on
umbilical-placental vascular resistance, suggesting that prostaglandins
do not normally regulate the umbilical-placental
circulation. When prostaglandin synthesis is inhibited, the proportion
of blood flow to the gastrointestinal tract, kidneys, and
peripheral circulation decreases, indicating an increase in vascular
resistance in these tissues. Vascular resistances in other
tissues are essentially unchanged.
Although prostaglandins do not appear to be central to regulation
of the resting fetal pulmonary circulation, PGI2 may act to
modulate tone and thereby maintain pulmonary vascular resistance
relatively constant. However, leukotrienes, also metabolites
of arachidonic acid and potent smooth muscle constrictors, may
play an active role in maintenance of the normally high fetal
pulmonary vascular resistance. In newborns,78 leukotriene inhibition
attenuates hypoxic pulmonary vasoconstriction. In fetal
lambs, leukotriene receptor blockade79 or inhibition of leukotriene
synthesis80 increases pulmonary blood flow about eightfold,
suggesting a role for leukotrienes in maintenance of the normally
high fetal pulmonary vascular resistance; the presence of leukotrienes
in fetal tracheal fluid supports this hypothesis.81
Endothelial-Derived Factors and Endothelin
In addition to PGI2, vascular endothelial cells can be stimulated
to produce other important vasoactive factors, including potent
vasoconstrictors such as ET and potent vasodilators such as
endothelium-derived nitric oxide (NO).82 NO is produced by
most endothelial cells in response to various stimuli, usually
involving specific receptors or changes in shear stress. Smooth
muscle relaxation is produced through several messenger
systems, such as guanylyl cyclase/cGMP, K channels, or PGI2/
cyclic adenosine monophosphate. In the human fetus, NO is
produced by umbilical vascular endothelium83,84; nitroso- compounds
reduce umbilical vascular resistance in vitro,85 and NO
modulates resting umbilical vascular tone in fetal sheep in
utero.86 Disturbances in normal NO production may also be
involved in the genesis of preeclampsia87 and persistent pulmonary
hypertension of the newborn (PPHN).88
NO clearly is involved in regulation of vascular tone in the

fetal pulmonary circulation, although it plays a far more important

role in the postnatal transition to air breathing.89 Superfused
fetal sheep pulmonary arteries release endotheliumderived
relaxing factor when stimulated with bradykinin.90
In fetal lambs, the vasodilating effects of bradykinin are attenuated
by methylene blue, and resting tone increases with Nnitro-l-arginine, an inhibitor of NO that is synthesized by NO
synthase from precursor l-arginine,91 suggesting that a cGMPdependent
mechanism, such as NO production, continuously
modulates or offsets the increased tone of the resting fetal pulmonary
circulation. Inhibition of endothelial-derived NO synthesis
also blocks the pulmonary vasodilatation with oxygenation
of fetal lungs in utero and markedly attenuates the increase in
pulmonary blood flow with ventilation at birth.91,92
ET-1, a 21-amino-acid polypeptide also produced by vascular
endothelial cells, has potent vasoactive properties.93 The
hemodynamic effects of ET-1 are mediated by at least two distinct
receptor populations, ETA and ETB, the densities of which
are different depending on the vascular bed studied. The ETA
receptors are located on vascular smooth muscle cells and
mediate vasoconstriction, whereas the predominant subpopulation
of ETB receptors is located on endothelial cells and mediates
vasodilation.9496 However, a second subpopulation of ETB
receptors is located on smooth muscle cells and mediates vasoconstriction.
97 The vasodilating effects of ET-1 are associated
with the release of NO and potassium channel activation.98-102
The vasoconstricting effects of ET-1 are associated with phospholipase
activation, the hydrolysis of phosphoinositol to
inositol-1,4,5-triphosphate and diacylglycerol, and the subsequent
release of Ca2+.103 In addition to its vasoactive properties,
ET-1 has mitogenic activity on vascular smooth muscle cells
and may participate in vascular remodeling.104
The predominant effect of exogenous ET-1 in the fetal and
newborn sheep pulmonary circulation is vasodilation, mediated
via ETB receptor activation and NO release. However, the
predominant effect in the juvenile and adult pulmonary circulations
is vasoconstriction, mediated via ETA receptor activation.
In fetal lambs, selective ETA receptor blockade produces small
decreases in resting fetal pulmonary vascular resistance. This
suggests a potential minor role for basal ET-1induced vasoconstriction
in maintaining the high fetal pulmonary vascular
resistance.99,101 Although plasma and urinary concentrations of
ET-1 are increased at birth,105,106 in vivo studies suggest that
basal ET-1 activity does not play an important role in mediating
the transitional pulmonary circulation.107 ET-1 causes fetal
renal vasodilation108 and therefore may be involved in the regulation
of fetal renal blood flow. An upregulation of ET-1 has
been implicated in PPHN.109
Other factors, such as calcitonin generelated peptide and a
related substance, adrenomedullin, have vasodilatory effects on
the fetal pulmonary circulation and may play a role in the regulation
of pulmonary vascular tone in the fetus.110,111 The effects
of these substances probably also are mediated by NO release. 112

Ductus Arteriosus

Patency of the fetal ductus arteriosus is regulated by both dilating

and contracting factors. The factors that promote ductus
arteriosus constriction in the fetus have yet to be fully identified.
The ductus arteriosus maintains a tonic degree of constriction
in utero that appears to be both dependent and independent of
extracellular calcium.113 ET-1 also appears to play a role in producing
the basal tone of the ductus arteriosus.114
The factors that oppose ductus arteriosus constriction in
utero are better understood. The vascular pressure within the
ductus arteriosus lumen opposes ductus arteriosus constriction.
115 Vasodilator prostaglandins appear to be the most important
factors opposing ductus arteriosus constriction in the latter
part of gestation.113,116 Inhibitors of prostaglandin synthesis
(e.g., indomethacin) constrict the fetal ductus arteriosus both
in vitro and in vivo.76,117,118 Their vasoconstrictive effects appear
to be most pronounced beyond 30 weeks gestation in humans.
Both the type 1 and type 2 isoforms of cyclooxygenase (COX)
are present within the fetal ductus arteriosus and are responsible
for synthesizing the prostaglandins that maintain ductus
arteriosus patency.119 Inhibitors of both COX-1 and COX-2
individually produce fetal ductus arteriosus constriction in
vivo.119 Conversely, PGE2 dilates the constricted ductus arteriosus
both in vitro and in vivo. PGE2 produces ductus arteriosus
relaxation by interacting with several of the PGE receptors (i.e.,
EP2, EP3, and EP4).120 The EP4 receptor appears to play a prominent
role in ductus arteriosus vasodilation.121,122 NO also is
made by the fetal ductus arteriosus and appears to play an
important role in maintaining ductus arteriosus patency in
rodent fetuses.116 Although NO is made in the ductus arteriosus
of larger species, its importance in maintaining ductus arteriosus
patency under normal conditions has not been conclusively
demonstrated.123
Although pharmacologic inhibition of prostaglandin synthesis
produces ductus arteriosus constriction in utero, genetic
interruptions of either prostaglandin synthesis (i.e., homozygous
combined COX-1 and COX-2 knockout mice)124 or signaling
(i.e., homozygous EP4 receptor knockout mice)122 do not
lead to ductus arteriosus constriction in utero. Contrary to
expectations, both of these genetic interruptions produce
newborn mice in which the ductus arteriosus fails to close after
birth. The mechanisms through which the absence of prostaglandins
early in gestation alters the normal balance of other
vasoactive factors in the ductus arteriosus have yet to be elucidated.
Pharmacologic inhibition of prostaglandin synthesis in
human pregnancy also is associated with an increased incidence
of patent ductus arteriosus after birth.125 When the fetus is
exposed to indomethacin in utero, the ductus arteriosus constricts.
Ductus arteriosus constriction in utero produces ischemic
hypoxia, increased NO production, and smooth muscle
cell death in the ductus arteriosus wall. These factors prevent
the ductus arteriosus from constricting normally after birth and
make it resistant to the constrictive effects of indomethacin
administered postnatally.125127