Myocardial FunctionCardiac output is determined by the interrelationships of preload, afterload, myocardial contractility, and heart rate.Preload (ventricular filling pressure) reflects the initial musclelength, which by the Frank-Starling principle influences thedevelopment of myocardial force. Afterload (the impedance toejection from the ventricles) is reflected basically by arterialpressure. Contractility reflects the intrinsic inotropic capabilityof the myocardium.Studies of fetal myocardium show immaturity of structure,function, and sympathetic innervation relative to the adultmyocardium.16-20 At all muscle lengths along the curve of lengthversus tension, the active tension generated by fetal myocardiumis lower than that generated by adult myocardium.16 Inaddition, resting, or passive, tension is higher in fetuses than inadults, suggesting lower compliance of fetal myocardium.Studies in chronically instrumented intact fetal lambsshowed that after volume loading by the infusion of blood orsaline, the right ventricle is unable to increase stroke work oroutput to the same extent as in the adult.17 This is particularlytrue in less-mature fetuses, in whom right ventricular enddiastolicpressure is markedly elevated without any obviouschange in right ventricular stroke work. Similar results arefound for both the left and right ventricles but with some abilityto increase output or work at lower pressures, between 2 and5╯mm╯Hg.18-20 Limitations in the increase in stroke work withincreasing filling pressure have been shown to be afterloaddependent and, for the left ventricle, are probably affected byright ventricular mechanical constraint.21,22Fetal and adult sarcomeres have equivalent lengths,23 butthere are major ultrastructural differences between fetal myocardiumand adult myocardium. The diameter of the fetal cellsis smaller, and perhaps more importantly, the proportion ofnoncontractile mass (i.e., of nuclei, mitochondria, and surfacemembranes) to the number of myofibrils is significantly greaterthan in the adult. In the fetal myocardium, only about 30% ofthe muscle mass consists of contractile elements; in the adult,the proportion is about 60%. These ultrastructural differencesare probably responsible for the age-dependent differences inperformance.16In newborn lambs, stroke volume is decreased at afterloadlevels that would be considered low for adult animals.24 Gilbert20showed that in fetal animals, an increase in arterial pressureof about 15╯mm╯Hg, produced by methoxamine infusion,depresses the cardiac function curve so that cardiac outputaverages 25% to 30% less than normal. The extent of shorteningis less in the fetus compared with the adult at any level oftension—a potential explanation for the effects of afterload onstroke volume.16In chronically instrumented fetal lambs, there is a close relationshipbetween cardiac output and heart rate. Spontaneousand induced changes in heart rate are associated with correspondingchanges in left or right ventricular output. Increasingheart rate from the resting level of about 180 up to 250 to 300beats/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 ofits cardiac function curve. An increase in heart rate results inonly a modest increase in output; however, bradycardia canreduce output significantly. At an atrial filling pressure greaterthan approximately 8╯mm╯Hg, there is little or no increase inoutput because the length-to-tension relationship has reacheda plateau. In addition, the fetal heart is sensitive to changes inafterload.SYMPATHETIC AND PARASYMPATHETICINNERVATIONIsolated 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 directβ-adrenergic agonist that is not taken up and stored in sympatheticnerves, has similar effects on fetal and adult myocardium,the supersensitivity of fetal myocardium to norepinephrine isprobably the result of incomplete development of sympatheticinnervation in fetal myocardium. Myocardial concentrations ofnorepinephrine in the fetus within several weeks of term aresignificantly lower than in newborn animals, and activity oftyrosine hydroxylase, the intraneuronal enzyme responsible forthe first transformation in catecholamine biosynthesis, is alsoreduced.16 In contrast, adrenal gland tyrosine hydroxylase activityat the same gestational age is not suppressed, possiblybecause the decrease in myocardial activity is related to delayedsympathetic innervation rather than to a generalizedimmaturity.Monoamine oxidase, the enzyme responsible for oxidativedeamination of norepinephrine, is also present in lower concentrationsin the fetal heart than in the adult. Histochemicalevaluation of the development of sympathetic innervationusing the monoamine fluorescence technique has further substantiatedthe delayed development of sympathetic innervationof the fetal myocardium. At term, sympathetic innervation isincomplete. Patterns of staining indicate a progression of innervation,starting at the area of the sinoatrial node and progressingtoward the left ventricular apex.25,26Although sympathetic nervous innervation appears to begindeveloping in the fetal heart by about 0.55 of term, β-adrenergicreceptors seem to be present much earlier and can be stimulatedby appropriate agonists before 0.4 of term.27 Before about 0.55of term (80 days of gestation in the lamb), fetal myocardiummay be affected by circulating catecholamines, but local reflexactivity through the sympathetic nervous system is not likely toplay 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 amodest increase in fetal heart rate,28 indicating that vagal innervationis present by this stage of development. Histochemicalstaining for acetylcholinesterase in close-to-term fetuses hasshown that the concentrations of this enzyme, which is responsiblefor metabolism of acetylcholine, are similar to those foundin adults.ENERGY METABOLISM

In the normal unstressed fetus, myocardial blood flow is about180╯mL/min per 100╯g of tissue, approximately 80% greaterthan in the adult. Fetal myocardial oxygen consumption, asmeasured in the left ventricular free wall, is about 400╯mM/minper 100╯g, similar to that in the adult. In adult sheep, free fattyacids provide the major source of energy for the myocardium,and carbohydrate accounts for only about 40% of myocardialoxygen consumption.29 In fetal sheep under normal conditions,however, free fatty acid concentrations are extremely low, andalmost all the oxygen consumed by the left ventricular wall canbe accounted for by carbohydrate metabolism: 33% by glucose,6% by pyruvate, and 58% by lactate metabolism.Adenosine triphosphatase (ATPase) activity in fetal myocardiumis equal to that in adult myocardium, suggesting thatenergy utilization by the contractile apparatus is similar in thetwo tissues.16 Mitochondria from fetal myocardium demonstratehigher oxidative phosphorylation than those from adultmyocardium. The higher oxygen consumption in fetal mitochondriauncoupled by deoxyribonucleoprotein suggests thatthe augmented respiratory rate in mitochondria is a reflectionof increased electron transport.16 This is consistent with thegreater cytochrome oxidase activity in fetal mitochondria.Control of the Cardiovascular SystemMaintenance of normal cardiovascular function, blood pressure,heart rate, and distribution of blood flow represents acomplex interrelationship among local vascular and reflexeffects. These effects are initiated by the stimulation of variousreceptors, and they are mediated through the autonomicnervous system as well as through hormonal influences.Although some information is available about how these mechanismsaffect the circulation after stress, little is known abouttheir role in normal fetal cardiovascular homeostasis. To complicatethe situation, other factors, such as sleep state, electrocorticalactivity, and uterine activity, transiently affect thecirculation. As a result, this area of fetal physiology is difficultto study, and the data are difficult to interpret.LOCAL REGULATIONAs the oxygen content of blood perfusing the fetus falls, bloodflow to the brain, myocardium, and adrenal glands increases;on the other hand, pulmonary blood flow falls as oxygen contentof the blood decreases. Local effects of changes in oxygen environmentare less clearly established for other organs.Many adult organs exhibit autoregulation, the ability tomaintain constant blood flow over a fairly wide range of perfusionpressures. In the fetus, the umbilical-placental circulationdoes not exhibit autoregulation, and blood flow changes in relationto changes in arterial perfusion pressure.30 On the otherhand, the cerebral circulation in fetal lambs does show autoregulatorycapability.31BAROREFLEX REGULATIONIn chronically instrumented fetal lambs, the fetal heart rateslows after an acute increase in systemic arterial pressure.32,33This baroreflex response, although present by 0.55 of term (80days of gestation), is poorly developed early on; the sensitivityof the reflex to induced changes in pressure increases with

advancing gestation. Carotid denervation partially inhibits theresponse, and combined carotid and aortic denervation abolishesit. Parasympathetic blockade with atropine also abolishesthe reflex. Although the existence of the arterial baroreflex isestablished, Dawes and associates34 suggested that the thresholdfor fetal baroreflex activity is above the range of the normal fetalarterial blood pressure and that this reflex is not important incontrolling cardiovascular function in utero.Carotid sinus and vagus nerve activity are synchronous withthe arterial pulse, suggesting continuous baroreceptor activity.35,36 Marked fluctuations in arterial blood pressure and heartrate are observed after sinoaortic denervation, although theaverage arterial blood pressure and heart rate are not differentfrom those in controls.37The baroreflex in fetal animals requires fairly marked changesin pressure to produce relatively minor responses. Sinoaorticdenervation increases heart rate and blood pressure variability,however. Under normal circumstances, therefore, baroreceptor

function acts to stabilize the heart rate and blood pressure. Inthe fetus, as in the adult, baroreflex control is also influencedby hormonal systems.38CHEMOREFLEX REGULATIONIn general, chemoreceptor stimulation by sodium cyanideinjection induces hypertension and bradycardia.39,40 Central orcarotid chemoreceptor stimulation causes hypertension andmild tachycardia with increased respiratory activity, whereasaortic chemoreceptor stimulation produces bradycardia withmodest increases in arterial blood pressure. Because the carotidchemoreceptors are less sensitive than the aortic chemoreceptors,hypertension and bradycardia usually result. In chronicallyinstrumented fetal lambs, sodium cyanide produces bradycardiawith variable blood pressure changes, responses that areabolished by sinoaortic denervation.41 Fetal hypoxia producesbradycardia and hypertension, which are abolished by carotidsinus denervation.42AUTONOMIC NERVOUS SYSTEM ANDADRENAL MEDULLAAs described earlier, sympathetic innervation of the heart is notcomplete until term or, in some species, until after delivery. Incontrast, cholinergic innervation, as measured by the presenceof acetylcholinesterase, appears to be fully developed duringfetal life. The innervation of other vascular beds also appears toproceed at different rates during gestation.43Adrenergic receptors are present in the fetus and have beendemonstrated in myocardium.44–46 Receptor populations thathave been studied in the fetus exhibit characteristics similar tothose in adults.47,48 The fetus possesses mature adrenergic receptorsfairly early in gestation, but the concentration of receptorsis different from that in adult organs.44 The fetal concentrationof receptors can be altered by administration of thyroidhormone or isoxsuprine to the mother.Injection of cholinergic or adrenergic agonists into fetalsheep produces responses at as early as 0.4 of term (60 daysof gestation).27,49 α-Adrenergic stimulation with methoxamine

produces an increase in arterial blood pressure, a small decreasein cardiac output, an increase in blood flow to the lungs, and amarked decrease in kidney and peripheral blood flow at as earlyas 0.5 of term. β-Adrenergic stimulation by isoproterenol causesa response earlier in gestation and an increase in heart rate withlittle 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 andheart rate and increases pulmonary blood flow markedly, particularlyin fetuses close to term.Although receptor affinity is well developed during fetal life,the response to a specific agonist is blunted relative to that inthe adult. The maximal constrictor response to norepinephrineor nerve stimulation increases throughout the latter part ofgestation, and even more after birth.50 The increase might resultfrom gestational differences in neurotransmitter release in thefetus. During the last trimester of gestation, there is a progressiveincrease in maximal pressor response to ephedrine, whichexerts its effect indirectly through neurotransmitter release;phenylephrine has a direct pressor effect.51 In addition, neurotransmitterreuptake in sympathetic nerve terminals is notfully mature in the fetus.48 Similarly, the differences between

fetal and adult myocardium with respect to threshold and sensitivityto norepinephrine indicate an immature reuptakemechanism for norepinephrine in the fetus.16As gestation progresses, these variable rates of maturation ofdifferent components of the autonomic nervous system modifycontrol mechanisms relating to the autonomic nervous system.The role of β-adrenergic stimulation in resting circulatory regulationhas been evaluated by pharmacologic blockade ofβ-adrenergic receptors with propranolol. This component ofthe sympathetic nervous system exerts a positive influence overfetal heart rate that first appears at about 0.6 of term (80 to 90days),28 but this influence is relatively small.52 During stress suchas hypoxia or hemorrhage, however, β-adrenergic activityappears to be increased because propranolol produces muchgreater changes in heart rate.α-Adrenergic control of the circulation has a somewhatclearer developmental pattern. α-Adrenergic blockade withphentolamine or phenoxybenzamine reduces arterial bloodpressure very little, if at all, before 0.75 of term (100 to 110days); thereafter, there is a progressive increase in response,indicating a progressive increase in resting vascular tone attributedto α-adrenergic nervous activity. The parasympatheticnervous system exerts an inhibitory influence over fetal heartrate that is present by 0.55 of term (80 days).28,52 Parasympatheticblockade with atropine produces small changes at thisage, and there is a progressive increase in parasympatheticcontrol as gestation advances. After approximately 0.85 of term(120 to 130 days), no further increase is evident.Hypoxemia or asphyxia increases circulating plasma catecholamineconcentrations in fetal sheep.53–55 In fetuses youngerthan about 120 days’ gestation, when the adrenal gland becomesinnervated, extremely low fetal blood oxygen concentrations are

required to stimulate the adrenal gland; thereafter, catecholaminesecretion can be induced by more moderate hypoxemia.53Infusing catecholamines to reach plasma concentrations thatmimic those observed during hypoxemia produces circulatorychanges similar to those seen during hypoxemia.56 Adrenalmedullary responses to stress appear to play a role in circulatoryadjustments; whether catecholamine secretion exerts a continuousregulatory function is not clear.HORMONAL REGULATION OF THE CIRCULATIONRENIN-ANGIOTENSIN SYSTEMThe renin-angiotensin system is important in regulating thenormal fetal circulation and its response to hemorrhage. Thejuxtaglomerular apparatus in the kidneys is well developed infetuses and is present by 0.6 of term (90 days).57 Plasma reninactivity, as well as circulating angiotensin II, is present in fetalplasma as early as about 0.6 of term.58-60 The effects of fetalstress (e.g., hemorrhage, hypoxia) on the renin-angiotensinsystem are not absolutely clear. In some studies, small amountsof hemorrhage increased plasma renin activity,57,58 but otherstudies have shown little effect.61 Similarly, the effects of hypoxemiaon 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 concentrationssimilar to those that occur after a moderate (15% to 20%)hemorrhage, there are broad cardiovascular effects.62 Arterialblood pressure increases markedly, and after an initial abruptbradycardia, heart rate increases. Combined ventricular outputincreases, as does blood flow to the lungs and myocardium

Renal blood flow decreases, but umbilical placental flow isunchanged; this latter phenomenon indicates vascular constrictionin the umbilical-placental circulation because arterialblood pressure increases but flow does not. The increase inmyocardial blood flow is probably caused by an increase instroke work, and the large increase in pulmonary blood flowprobably reflects the release of some other local pulmonaryvasodilating substance, such as one of the prostaglandins.63Inhibition 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 anda slight decrease in heart rate occur.59 Combined ventricularoutput 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, andmyocardium increases. During hemorrhage, the effects of saralasinare markedly accentuated and result in profound hypotensionand bradycardia.Under normal resting conditions, endogenous angiotensinII appears to exert a tonic vasoconstriction on the peripheralvascular bed, thereby maintaining systemic arterial bloodpressure and umbilical-placental blood flow. In response tohemorrhage, angiotensin II is released; it produces more vasoconstrictionin the periphery and has other cardiovasculareffects, thereby maintaining systemic arterial blood pressureand umbilical blood flow.

VasopressinArginine vasopressin (antidiuretic hormone) has been detectedat as early as 0.4 of term (60 days) in fetal lambs.64 Althoughhypoxia and hemorrhage, as well as many other stimuli such ashypotension and hypernatremia, induced a marked increase inplasma vasopressin concentrations,64,65 it is unlikely that vasopressinplays a major role in normal circulatory regulation.Maximal antidiuresis in adults occurs with vasopressin concentrationsthat have no discernible effects on systemic blood pressure.Fetal vasopressin concentrations are below this level.Infusing vasopressin into fetal sheep to produce concentrationssimilar to those observed during fetal hypoxemia produceshypertension and bradycardia.60 Combined ventricularoutput decreases slightly, but the proportion distributed to thegastrointestinal tract and peripheral circulations falls, whereasthat distributed to the umbilical-placental, myocardial, andcerebral circulations increases. These findings indicate thatvasopressin probably participates in fetal circulatory responsesto stress not only directly but also by enhancing pressorresponses to other vasoactive substances. Under resting conditions,however, vasopressin apparently has little regulatoryfunction.Natriuretic PeptidesAtrial natriuretic peptide (ANP) and B-type natriuretic peptide(BNP) belong to a potent volume-regulating family of cardiachormones released from the atria and ventricles in response tomyocyte stretch and other stimuli such as α-agonist stimulation,endothelin 1 (ET-1), and cytokines.66 These peptides havepotent vasodilatory, diuretic, natriuretic, and growth inhibitoryactions via the secondary messenger, cyclic guanosine monophosphate(cGMP). The natriuretic system appears to be functionalby mid-gestation, and it is able to regulate systemic andpulmonary blood pressures as well as salt and water balance inthe fetus. In addition, these peptides are regulated during heart

development, suggesting an important role for the natriureticpeptides in the developing cardiovascular system. Finally, bothANP and BNP have potent vasodilating properties in the placentaand therefore may be important regulators of placentalblood flow.67,68Arachidonic Acid MetabolitesAlthough prostaglandins typically are locally active substancesthat do not normally circulate in adult blood, relatively highconcentrations do normally circulate in the fetus.69,70 It is likelythat these prostaglandins are derived from the placenta. Thefetal vasculature is also capable of producing prostaglandins,and the umbilical vessels, ductus arteriosus, and aorta producesignificant amounts of prostaglandin E (PGE) and prostacyclin(also known as PGI2).Prostaglandins administered to the fetus have diverse andextensive cardiovascular effects. PGE1 and PGE2 constrict theumbilical-placental circulation.71,72 PGF2α and thromboxanealso cause constriction, whereas PGI2 dilates the umbilicalplacentalcirculation. PGE1, PGE2, PGI2, and PGD2 producepulmonary vasodilatation in the fetus, whereas PGF2α produces

constriction.73 Infusion of PGE1 into fetal sheep has no effecton cardiac output or systemic pressure, but, in addition to areduction in umbilical-placental blood flow, there are increasesin flow to the myocardium, adrenals, gastrointestinal tract, andperipheral tissues.74Of great interest is the role of prostaglandins in maintainingpatency of the ductus arteriosus in the fetus. Circulating prostaglandins,as well as PGE2 and PGI2 produced locally in theductus arteriosus, play a major role in maintaining the ductusarteriosus in a dilated state in utero.75–77 Details of the overallphysiologic regulation of the ductus arteriosus are discussed ina later section.The role of endogenous prostaglandin production in regulatingother fetal vascular beds has been elucidated by administeringinhibitors of prostaglandin synthesis to the fetus.Although PGE2 produces umbilical-placental vasoconstriction,inhibition of prostaglandin synthesis has little effect onumbilical-placental vascular resistance, suggesting that prostaglandinsdo not normally regulate the umbilical-placentalcirculation. When prostaglandin synthesis is inhibited, the proportionof blood flow to the gastrointestinal tract, kidneys, andperipheral circulation decreases, indicating an increase in vascularresistance in these tissues. Vascular resistances in othertissues are essentially unchanged.Although prostaglandins do not appear to be central to regulationof the resting fetal pulmonary circulation, PGI2 may act tomodulate tone and thereby maintain pulmonary vascular resistancerelatively constant. However, leukotrienes, also metabolitesof arachidonic acid and potent smooth muscle constrictors, mayplay an active role in maintenance of the normally high fetalpulmonary vascular resistance. In newborns,78 leukotriene inhibitionattenuates hypoxic pulmonary vasoconstriction. In fetallambs, leukotriene receptor blockade79 or inhibition of leukotrienesynthesis80 increases pulmonary blood flow about eightfold,suggesting a role for leukotrienes in maintenance of the normallyhigh fetal pulmonary vascular resistance; the presence of leukotrienesin fetal tracheal fluid supports this hypothesis.81Endothelial-Derived Factors and EndothelinIn addition to PGI2, vascular endothelial cells can be stimulatedto produce other important vasoactive factors, including potent

vasoconstrictors such as ET and potent vasodilators such asendothelium-derived nitric oxide (NO).82 NO is produced bymost endothelial cells in response to various stimuli, usuallyinvolving specific receptors or changes in shear stress. Smoothmuscle relaxation is produced through several messengersystems, such as guanylyl cyclase/cGMP, K channels, or PGI2/cyclic adenosine monophosphate. In the human fetus, NO isproduced by umbilical vascular endothelium83,84; nitroso- compoundsreduce umbilical vascular resistance in vitro,85 and NOmodulates resting umbilical vascular tone in fetal sheep inutero.86 Disturbances in normal NO production may also beinvolved in the genesis of preeclampsia87 and persistent pulmonaryhypertension of the newborn (PPHN).88NO clearly is involved in regulation of vascular tone in the

fetal pulmonary circulation, although it plays a far more importantrole in the postnatal transition to air breathing.89 Superfusedfetal sheep pulmonary arteries release endotheliumderivedrelaxing factor when stimulated with bradykinin.90In fetal lambs, the vasodilating effects of bradykinin are attenuatedby methylene blue, and resting tone increases with Nω-nitro-l-arginine, an inhibitor of NO that is synthesized by NOsynthase from precursor l-arginine,91 suggesting that a cGMPdependentmechanism, such as NO production, continuouslymodulates or offsets the increased tone of the resting fetal pulmonarycirculation. Inhibition of endothelial-derived NO synthesisalso blocks the pulmonary vasodilatation with oxygenationof fetal lungs in utero and markedly attenuates the increase inpulmonary blood flow with ventilation at birth.91,92ET-1, a 21-amino-acid polypeptide also produced by vascularendothelial cells, has potent vasoactive properties.93 Thehemodynamic effects of ET-1 are mediated by at least two distinctreceptor populations, ETA and ETB, the densities of whichare different depending on the vascular bed studied. The ETAreceptors are located on vascular smooth muscle cells andmediate vasoconstriction, whereas the predominant subpopulationof ETB receptors is located on endothelial cells and mediatesvasodilation.94–96 However, a second subpopulation of ETBreceptors is located on smooth muscle cells and mediates vasoconstriction.97 The vasodilating effects of ET-1 are associatedwith the release of NO and potassium channel activation.98-102The vasoconstricting effects of ET-1 are associated with phospholipaseactivation, the hydrolysis of phosphoinositol toinositol-1,4,5-triphosphate and diacylglycerol, and the subsequentrelease of Ca2+.103 In addition to its vasoactive properties,ET-1 has mitogenic activity on vascular smooth muscle cellsand may participate in vascular remodeling.104The predominant effect of exogenous ET-1 in the fetal andnewborn sheep pulmonary circulation is vasodilation, mediatedvia ETB receptor activation and NO release. However, thepredominant effect in the juvenile and adult pulmonary circulationsis vasoconstriction, mediated via ETA receptor activation.In fetal lambs, selective ETA receptor blockade produces smalldecreases in resting fetal pulmonary vascular resistance. Thissuggests a potential minor role for basal ET-1–induced vasoconstrictionin maintaining the high fetal pulmonary vascularresistance.99,101 Although plasma and urinary concentrations ofET-1 are increased at birth,105,106 in vivo studies suggest thatbasal ET-1 activity does not play an important role in mediatingthe transitional pulmonary circulation.107 ET-1 causes fetalrenal vasodilation108 and therefore may be involved in the regulationof fetal renal blood flow. An upregulation of ET-1 hasbeen implicated in PPHN.109

Other factors, such as calcitonin gene–related peptide and arelated substance, adrenomedullin, have vasodilatory effects onthe fetal pulmonary circulation and may play a role in the regulationof pulmonary vascular tone in the fetus.110,111 The effectsof these substances probably also are mediated by NO release.112

Ductus Arteriosus

Patency of the fetal ductus arteriosus is regulated by both dilatingand contracting factors. The factors that promote ductusarteriosus constriction in the fetus have yet to be fully identified.The ductus arteriosus maintains a tonic degree of constrictionin utero that appears to be both dependent and independent ofextracellular calcium.113 ET-1 also appears to play a role in producingthe basal tone of the ductus arteriosus.114The factors that oppose ductus arteriosus constriction inutero are better understood. The vascular pressure within theductus arteriosus lumen opposes ductus arteriosus constriction.115 Vasodilator prostaglandins appear to be the most importantfactors opposing ductus arteriosus constriction in the latterpart of gestation.113,116 Inhibitors of prostaglandin synthesis(e.g., indomethacin) constrict the fetal ductus arteriosus bothin vitro and in vivo.76,117,118 Their vasoconstrictive effects appearto 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 responsiblefor synthesizing the prostaglandins that maintain ductusarteriosus patency.119 Inhibitors of both COX-1 and COX-2individually produce fetal ductus arteriosus constriction invivo.119 Conversely, PGE2 dilates the constricted ductus arteriosusboth in vitro and in vivo. PGE2 produces ductus arteriosusrelaxation by interacting with several of the PGE receptors (i.e.,

EP2, EP3, and EP4).120 The EP4 receptor appears to play a prominentrole in ductus arteriosus vasodilation.121,122 NO also ismade by the fetal ductus arteriosus and appears to play animportant role in maintaining ductus arteriosus patency inrodent fetuses.116 Although NO is made in the ductus arteriosusof larger species, its importance in maintaining ductus arteriosuspatency under normal conditions has not been conclusivelydemonstrated.123Although pharmacologic inhibition of prostaglandin synthesisproduces ductus arteriosus constriction in utero, geneticinterruptions of either prostaglandin synthesis (i.e., homozygouscombined COX-1 and COX-2 knockout mice)124 or signaling(i.e., homozygous EP4 receptor knockout mice)122 do notlead to ductus arteriosus constriction in utero. Contrary toexpectations, both of these genetic interruptions producenewborn mice in which the ductus arteriosus fails to close afterbirth. The mechanisms through which the absence of prostaglandinsearly in gestation alters the normal balance of othervasoactive factors in the ductus arteriosus have yet to be elucidated.Pharmacologic inhibition of prostaglandin synthesis inhuman pregnancy also is associated with an increased incidenceof patent ductus arteriosus after birth.125 When the fetus isexposed to indomethacin in utero, the ductus arteriosus constricts.Ductus arteriosus constriction in utero produces ischemichypoxia, increased NO production, and smooth musclecell death in the ductus arteriosus wall. These factors preventthe ductus arteriosus from constricting normally after birth andmake it resistant to the constrictive effects of indomethacinadministered postnatally.125–127