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Neurohumoral control of fetal, neonatal, and adult cardiovascular functions have been reviewed. Resting fetal heart rate remains fairly constant but neonatal heart rate declines progressively, reaching adult levels within six to eight weeks; systemic arterial pressure rises while pulmonary pressure falls to adult levels within the first week after birth. Sympathetic and parasympathetic control of circulatory functions matures at different rates during fetal and neonatal development; the sympathetic system becomes active earlier in fetal life than does the parasympathetic system. After birth, the parasympathetic tone of the resting heart rate rises to adult levels while adrenergic tone decreases. Despite changing autonomic activities, resting heart rate is set at given levels through alterations in intrinsic control. In the fetus, peripheral circulation is under neurohumoral tone of increasing magnitude; after birth, neurohumoral tone declines progressively, reaching levels comparable to those of adult nonpregnant sheep. Fetal cardiovascular response to neurotransmitters increases with age because of maturation of the effector system. The pulmonary bed responds primarily to acetylcholine whereas the systemic circulation responds to norepinephrine. After birth, the neonatal cardiovascular system becomes four to five times more sensitive to the action of neurotransmitters mainly because of closure of vascular shunts and elimination of umbilicoplacental circulation. In the neonate and adult, the pulmonary vascular bed loses its reactivity to neurotransmitters.

The progressive changes in arterial pressure and uteroplacental hemodynamics were studied in 13 pregnant sheep from about the eightieth gestational day. All animals were followed to term. The results revealed a progressive increase in uteroplacental blood flow as the pregnancy progressed in the seven control animals. In six of the animals, mild hypertension was induced by unilateral renal artery constriction at about the one hundred fifteenth day. Following the induction of mild hypertension, there was a transient increase in uteroplacental vascular resistance and a reduction in uteroplacental blood flow. The arterial pressure remained significantly increased throughout the remainder of the gestation.

Blood volume (BV), plasma volume (PV), red cell volume (RCV), cardiac output (CO), and organ blood flows were measured in nonpregnant (Group I), 10 to 19 days’ pregnant (Group II), and 20 to 30 days’ pregnant (Group III) rabbits. BV, PV, and RCV increased throughout pregnancy, with maximum increase during the second third of gestation. CO peaked during the second third of gestation and then decreased. Mean arterial pressure and systemic vascular resistance decreased. Total reproductive blood flow increased throughout pregnancy but when calculated per unit of weight it did not change. Redistribution of blood flow within the reproductive organs occurred, with ovarian and placental flow per unit of weight increasing and myometrial flow/unit of weight decreasing. Splenic flow decreased significantly; liver flow decreased. The flow to the lungs and kidneys remained unchanged. The data suggest that major hemodynamic changes occur during the first two thirds of gestation and this period appears to test the competency of the maternal organism to adapt to the needs of pregnancy. The last one third of gestation is characterized by the fetoplacental unit interaction.

Chronically instrumented, near-term pregnant sheep were subjected to autonomic blockade with spinal anesthesia. Systemic arterial pressure, heart rate, and uterine blood flow decreased and uterine vascular resistance increased during the spinal blockade. Infusion of dopamine during the spinal hypotension corrected the disturbed circulatory parameters. These data provide evidence that: (1) the peripheral circulation of the near-term pregnant sheep is as sensitive as that of pregnant women to autonomic blockade, (2) the sensitivity is probably related to factors other than the changes in venous pressure in areas below the pelvis, and (3) dopamine represents a useful agent in the management of spinal hypotension.

Comparative studies have been made of various maternal and fetal circulatory functions and blood respiratory gases and pH obtained from pregnant sheep under acute experimental condition and from chronically instrumented animals. The maternal and fetal values observed in pregnant animals studied under pentobarbital anesthesia were compared to those observed in ewes studied under spinal anesthesia. In addition, the impact of various anesthetic agents on the behavior of maternal and fetal vasomotor tones and regional circulation was investigated. The data show that anesthetic agents affect cardiovascular functions in different ways. Some anesthetic agents abolish totally or partially maternal and fetal neural reflexes controlling circulatory functions; they also alter the vascular responses to vasoactive substances. Despite these alterations, the values for maternal and fetal circulatory functions in the acute anesthetized animal were not significantly different from those observed in the chronically instrumented, unanesthetized animal. In terms of research objectives, the data was used to discuss: (a) the criteria for defining the animal's health condition; (b) knowledge of the effects of anesthesia on a given maternal and fetal function; (c) the place of the acute and the chronic experimental preparation; and (d) the care to be observed in comparing data with the published literature.

Systemic and pulmonary hemodynamic responses to adrenergic and cholinergic agonists were investigated in fetal lambs between 60 days and term gestation. The cardiovascular response to these agents increases with fetal age, and the increase is related to maturation of the effector system rather than the vascular receptors. The fetal pulmonary vascular bed and the ductus arteriosus are the primary components responding to acetylcholine; the systemic response is secondary to that occurring in the lung. Both fetal systemic and pulmonary vascular beds are under α-adrenergic control whereas the fetal heart is under β-adrenergic control.

Effects of estrogen administration on systemic and regional circulation were studied in normotensive and renal hypertensive, chronically instrumented nonpregnant and pregnant ewes. Arterial pressure, cardiac output, and uterine, renal, superior mesenteric, and iliac blood flows, as well as uterine oxygen transfer, were monitored before and after intravenous administration of Premarin or estradiol-17β. The results show that: (1) estrogen administration produces a marked decrease in uterine vascular resistance and increase in uterine blood flow and oxygen transfer, lasting for about 2 hours; (2) arterial pressure, cardiac output, and other regional blood flows were not affected by estrogens; (3) the magnitude of uterine vasodilatation produced by estrogens was greater in the hypertensive than in the normotensive animals; it was also greater in the nonpregnant than in the pregnant state; these findings indicate that the magnitude of uterine vasodilatation depends on the status of the uterine vascular resistance in the resting state; (4) blockade of the autonomic nervous system at various levels, as well as administration of a mild antihistaminic agent, failed to alter the magnitude of the estrogen-induced uterine vasodilatation. These results indicate that estrogens act directly on the uterine vascular bed and produce a redistribution of flows and resistances in the body; the precise sites of this redistribution are not as yet determined.

The cardiovascular responses of the neonatal and adult sheep to autonomic agonists and antagonists were studied in the resting state and following adrenergic neuronal depletion with reserpine. Both the neonates and adults showed similar supersensitivity of the effector system of the peripheral circulation to alpha adrenergic stimulation with catecholamines. In addition, the neonates exhibited supersensitivity of the myocardial effector system to β-adrenergic stimulation. Unusual finding was a marked supersensitivity of the heart and peripheral circulation to cholinergic receptor blockade with atropine, the mechanisms of which are as yet unclear.

Unanesthetized, chronically instrumented, nonpregnant sheep were studied in periods of progressive blood withdrawal, hypovolemic shock, blood reinfusion, and recovery. Hemodynamic responses were recorded during experiments with an intact β-adrenergic system (saline solution), β-adrenergic blockade (propranolol), and β-adrenergic stimulation (isoxsuprine). With an intact β-adrenergic system, stepwise bleeding produced a progressive decrease in arterial pressure, stroke volume, and cardiac output and an increase in systemic vascular resistance; heart rate increased initially but fell when hypovolemia became severe. All circulatory parameters returned toward control valves during blood reinfusion and recovery. In animals deprived of β-adrenergic control, the hemodynamic response to progressive hypovolemia and blood reinfusion was not greatly different from that of control animals, despite abolition of tachycardia. During β-adrenergic stimulation, arterial pressure and cardiac output fell more rapidly than in control and tachycardia was relatively small; cardiac output and stroke volume rebounded strikingly during reinfusion and recovery. These results support findings of others that the role of the β-adrenergic system is minor during hypovolemia. When pharmacologically activated, it might play a significant role in the posthypovolemia compensatory mechanisms.

Previous studies suggest that women with asthma are at increased risk of preterm birth. Moreover, drugs (especially beta-agonists) used to treat asthma are also used to treat preterm labor. The authors carried out a case-control study of 555 women from three hospital centers with idiopathic preterm labor (< 37 weeks), including two overlapping (i.e., non-mutually exclusive) subsamples: cases with early idiopathic preterm labor (< 34 weeks) and cases with idiopathic recurrent preterm labor (< 37 weeks plus a previous history of preterm delivery or second-trimester miscarriage). Controls were matched to cases according to race and smoking history prior to and during pregnancy. All subjects responded in person to questions about atopic, respiratory, obstetric, and sociodemographic histories. Subjects in the early and recurrent preterm labor subsamples were also asked to undergo spirometric testing with methacholine challenge 6-12 weeks after delivery. Cases were significantly more likely to report histories of asthma symptoms and physician-diagnosed asthma (matched odds ratios of 2-3) than controls, particularly those cases with recurrent preterm labor. No significant associations were observed, however, with methacholine responsiveness. These results could not be explained by residual confounding by smoking or other variables, nor by selective recall of asthma symptoms and histories by cases. Women with asthma are at increased risk of idiopathic preterm labor. The fact that no such association was seen with methacholine responsiveness suggests that nonatopic, noncholinergic mechanisms may link bronchial and uterine smooth muscle lability.

The responses of the common internal iliac artery and middle uterine artery of the pregnant horn to continuous infusions of graded doses of norepinephrine, epinephrine, dopamine, isoxsuprine, angiotensin and nitroprusside were investigated in chronically instrumented pregnant ewes. Norepinephrine progressively decreased the blood flow and increased the resistance in both vessels but the changes were more marked in the middle uterine artery. Isoxsuprine and epinephrine had an insignificant effect on the common internal iliac artery blood flow, but decreased that of the middle uterine artery. Nitroprusside decreased the flow in both vessels proportionately. Angiotensin in doses less than 0.16 µg/kg/min increased the flow in both arteries to the same extent, but higher doses decreased both flows. It is concluded that in the chronically instrumented pregnant ewe, the responses of contiguous vascular beds to different vasoactive agents may differ depending on the nature of the stimulus.

The systemic and uterine hemodynamic effects of dopamine were studied in nonpregnant and near-term pregnant, unanesthetized, chronically instrumented sheep. Dopamine was administered by constant intravenous infusion in doses ranging from 2 to 40 μg per kilogram per minute. A hypertensive effect was consistently observed when doses greater than 5 μg per kilogram per minute were given. The rise in pressure was accompanied by a rise in the systemic vascular resistance and an increase in the cardiac output; the increment in the latter was greater in the pregnant than in the nonpregnant animals. Uterine blood flow increased consistently despite some rise in uterine vascular resistance; uterine fraction of cardiac output either remained unchanged or increased slightly. Venomotor constriction, reflected by a rise in central venous pressure, occurred at all dose levels. These hemodynamic properties of dopamine may be explained partly on the basis of its combined beta- and alpha-mimetic action, as well as through redistributions of flows and resistances among various regional vascular beds.

Hemodynamic responses to hypovolemia were investigated in unanesthetized, unstressed fetal lambs and in acute fetal and neonatal preparations. The unstressed fetus tolerated twice the amount of blood loss of the acutely studied fetus or newborn lamb and with a lesser hypotension. Hemodynamic behavior of the newborn lamb and fetus anesthetized with pentobarbital during hypovolemia was markedly different from that of the fetus studied under spinal anesthesia or chronically. Besides tolerating greater blood loss, the unstressed fetus reversed the state of hypovolemic shock rapidly as contrasted to the stressed fetus which was unable to do so even with total blood reinfusion. All animals exhibited bradycardia in response to hypovolemia. The following conclusions were drawn: (a) cardiovascular response to hypovolemia in the perinatal period depends on the initial status of the animal, (b) the fetus tolerates a greater degree of blood loss than a newborn or adult animal, and (c) anesthesia and stress of surgery modify considerably circulatory behavior during blood loss.

The responses of different parts of the pelvic vascular bed to beta-adrenergic and cholinergic receptor stimulation were studied in chronically instrumented, unanesthetized pregnant and nonpregnant sheep. Isoproterenol and acetylcholine were administered intra-arterially in progressively increasing bolus injections, and dose-response curves were constructed for changes in blood flows, arterial pressure, and heart rate. Response to beta-adrenergic and cholinergic stimulation was measured before and after the agents reached the central circulation. In addition, data were obtained from the same animals before and after pharmacologic cardiac denervation. Results show: (1) Stimulation of beta-adrenergic and cholinergic receptors produced active vasodilatation in extrauterine vascular beds with minor changes in uterine blood flow of the pregnant horn; (2) the changes in uterine flow observed during beta-adrenergic and cholinergic stimulation were probably secondary and related to a shift of blood from the uterus to other vascular beds that were actively dilated; (3) the response of the pregnant animal to any given dose of the autonomic agonist was strikingly smaller to that of the nonpregnant animal. A number of physiologic factors peculiar to pregnancy may contribute to this difference; among these are: (1) dilution factor related to the greater volume flow; (2) near-maximal dilatation of some blood vessels and the presence of the low resistance system of placental circulation, and (3) the effect of progesterone on the vascular smooth muscle. (Am. J. Obstet. Gynecol. 141:599, 1981.)