B. Nuwayhid

Development of neurohumoral control of fetal, neonatal, and adult cardiovascular functions

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.

Comparison of maternal and fetal cardiovascular functions in acute and chronic experiments in the sheep

Abstract 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 animals 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.

Effects of estrogens on systemic and regional circulations in normal and renal hypertensive sheep

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-17 beta. 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.

Nitroprusside-induced hemodynamic alterations in normotensive and hypertensive pregnant sheep☆☆☆

It has been suggested that sodium nitroprusside, a potent vasodilator, be used in the management of an acute hypertensive crisis during pregnancy. The present study was designed to evaluate the hemodynamic effects of this agent in the same group of chronically instrumented, unanesthetized pregnant sheep during two experimental periods: (a) normotension with intact kidneys, and (b) one-kidney hypertension. The results demonstrate that (1) nitroprusside is a potent vasodilator which lowers mean arterial pressure; (2) nitroprusside-induced tachycardia was greater in the hypertensive animal; (3) uterine blood flow decreased with the development of hypertension; (4) the hypertensive-induced reduction in uterine blood flow was increased by the infusion of nitroprusside.

Systemic and Pulmonary Hemodynamic Responses to Adrenergic and Cholinergic Agonists during Fetal Development

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 the occuring in the lung. Both fetal systemic and pulmonary vascular beds are under alpha-adrenergic control whereas the fetal heart is under beta-adrenergic control.

Autonomic control of the pelvic circulation: In vivo and in vitro studies in pregnant and nonpregnant sheep

Pregnancy alters the autonomic control of the peripheral circulation. Present in vivo and in vitro studies were designed to investigate the mechanisms of these alterations. In the in vivo studies, pelvic and systemic circulatory responses to intra-arterial and intravenous injections of agonists were monitored in unanesthetized pregnant and nonpregnant ewes. In in vitro studies, a comparison was made of responses to transmural nerve stimulation (TNS) and to norepinephrine (NE) of different blood vessels obtained from pregnant and nonpregnant ewes. The results were the following: (1) Pelvic vascular response to all vasoactive stimuli was considerably more depressed during pregnancy than was systemic circulatory response. (2) In vitro reactivity to alpha-adrenergic stimulation with NE of different blood vessels obtained from pregnant animals was similar to that of vessels from nonpregnant animals. (3) The response to TNS of blood vessels obtained from pregnant ewes was less than that of vessels from nonpregnant ewes. The conclusions were that (a) probably largely related to dilution of a given dose of the stimulus in the greater blood volume and flow; and (b) the increased neurogenic tone of the peripheral circulation during pregnancy is most likely related to increased nerve firing rather than neural density in the vessel walls.

Mechanisms of beat-to-beat variability in the heart rate of the neonatal lamb

The contributions of the intrinsic, beta-adrenergic, and cholinergic systems to the mechanisms of beat-to-beat variability of the heart rate were investigated in chronically instrumented, unanesthetized newborn lambs from the first week to the eighth week of neonatal life. During this period of neonatal growth, the resting heart rate decreased spontaneously every week; the decrease was not related to alterations in the sympathetic and parasympathetic tones but rather to changes in the intrinsic mechanisms of heart rate control. Despite the weekly decrease in the resting heart rate of the neonatal lamb, the long and short-term beat-to-beat variabilities did not change significantly. This finding suggests an absence of a significant influence of the intrinsic mechanisms of heart rate control on the genesis of beat-to-beat variability. The results obtained with the various modes of adrenergic and cholinergic blockades and stimulation seem to indicate that the autonomic nervous system contributes significantly to the appearance of beat-to-beat variability. However, the influences of the adrenergic and cholinergic systems differ from week to week of neonatal growth and the patterns of changes are not the same for the long-term and short-term variabilities. The implication of these studies in terms of physiologic and hemodynamic significance of beat-to-beat variability in heart rate is discussed.

Circulatory and renal effects of β-adrenergic-receptor stimulation in pregnant sheep

The effects of beta-adrenergic-receptor stimulation with ritodrine on systemic and pulmonary hemodynamics and on renal handling of water and electrolytes were studied in unanesthetized, chronically instrumented pregnant sheep. Each animal was studied during control, ritodrine, and recovery periods, each lasting 60 minutes, with the use of three different modes of hydration. beta-receptor stimulation produced a significant increase in heart rate and cardiac output and a decrease in systemic vascular resistance. Pulmonary arterial and wedge pressures tended to increase. These circulatory effects were similar for the three types of hydration and they persisted after cessation of infusion. In terms of its renal effects, beta-receptor stimulation elicited a profound decrease in urine flow and in the excretions of sodium and potassium, irrespective of the mode of hydration. The antidiuresis and antinatriuresis were accompanied by no changes in plasma osmolality and sodium concentration, whereas plasma potassium levels decreased. All of these effects persisted for 60 minutes after the cessation of infusion. In the water-loaded experiments, the antidiuresis seemed to be related to increased antidiuretic hormone secretion; in the saline-loaded experiments, however, both the antidiuresis and antinatriuresis appeared to be related to increased renal reabsorption. The changes in renal hemodynamics seemed to have an insignificant role. The amount of fluid retained in the body was greater when ritodrine was infused with saline solution than with dextrose solution. These cardiovascular and renal studies suggest that a circulatory overload may be the major factor in the pathogenesis of pulmonary edema observed during beta-adrenergic-receptor stimulation.

The contribution of the β-adrenergic system to the cardiovascular response to hypovolemia

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 beta-adrenergic system (saline solution), beta-adrenergic blockage (propranolol), and beta-adrenergic stimulation (isoxsuprine). With an intact beta-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 beta-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 beta-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 beta-adrenergic system is minor during hypovolemia. When pharmacologically activated, it might play a significant role in the posthypovolemia compensatory mechanisms.

Renal hypertension and pregnancy in the sheep: I. Behavior of uteroplacental vasomotor tone during mild hypertension

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.