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The relationship between the changes in the uteroplacental circulation and those occurring in the maternal systemic circulation have been discussed. The uteroplacental vascular bed acts as a low-resistance system that lowers the maternal systemic resistance and attenuates the action of vasoactive stimuli. The controlling mechanisms of the uteroplacental hemodynamics have been discussed, including the effects of the beta- and alpha-adrenergic systems. The metabolic and renal effects of the beta agonists have been listed with an appeal that they should be kept in mind when these agents are used to arrest labor. Finally, the behavior of the uteroplacental circulation during the hypertensive diseases of pregnancy has been described; the implication of these findings in the management of these diseases is emphasized.

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Circulatory responses to progressive hypovolemia, hypotensive shock, blood reinfusion, and recovery were studied in pregnant and nonpregnant sheep with an intact or pharmacologically ablated sympathetic nervous system produced by administration of 6-hydroxydopamine. These studies also provided an opportunity to assess the contribution of the sympathetic nervous system to the maintenance of vasomotor tone in the pregnant animal at rest. The results show the following: (1) Although there were some differences in the circulatory adjustments to the initial period of blood loss between intact and "sympathectomized" animals, the overall circulatory responses to progressive hypovolemia, shock, blood reinfusion, and recovery were not significantly different in animals with intact or ablated sympathetic nervous systems whether or not they were pregnant. (2) The reasons for the similarity of cardiovascular responses to hypovolemia are the marked increase in catecholamine outputs by the adrenal medulla, which was not affected by 6-hydroxydopamine, and the supersensitivity of the systemic vascular beds of the sympathectomized animal to catecholamines. (3) The contribution of the sympathetic nervous system to the maintenance of the resting vasomotor tone is considerably enhanced during pregnancy, as demonstrated by the chronic effects of adrenergic ablation on the resting arterial pressure. (4) The circulation of the pregnant uterus possesses the ability of autoregulation during chronic changes of perfusing pressure as demonstrated by the differences in the arterial pressure and uteroplacental vascular resistance between intact and sympathectomized animals.

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Heat flux (conductive and convective heat) and oxygen consumption of the pregnant uterus and its content were measured simultaneously in the same group of pregnant ewes during the acute postoperative period, during a chronic resting period, and during alpha- and beta-adrenergic-receptor stimulation with norepinephrine and ritodrine. Results indicated four conclusions. First, an excellent correlation existed between heat flux and oxygen consumption in the acute and chronic resting condition as well as during increasing uteroplacental vascular resistance and decreasing blood flow produced by norepinephrine infusion; the correlation was not as good during ritodrine infusion. Second, during rest, about 85% of heat generated by the pregnant uterus is eliminated through the uteroplacental circulation while the remaining heat diffuses through the myometrium. Third, during decreasing uteroplacental blood flow and elevated resistance, the pregnant uterus is able to maintain a normal thermostasis by widening the temperature difference in the blood entering and leaving the uterus and by increasing the myometrial heat exchange; oxygen consumption also is maintained at normal level through increase in oxygen extraction. Fourth, with the exception of uteroplacental circulation, the circulatory, metabolic, and thermal conditions of the pregnant ewe are not different after 5 hours from 5 to 7 days after the surgical procedure.

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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.

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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.

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Circulatory effects of chemical sympathectomy with 6-hydroxydopamine (6-HD), including changes in vascular sensitivity to neurotransmitters, were investigated in chronically instrumented unanesthetized fetal, neonatal, and adult sheep. In all animals acute response to 6-HD consisted of hypertension and tachycardia, which lasted 2-3 h. Chronic phase of sympathetic ablation then followed during which arterial pressure and heart rate of sympathectomized fetus and neonate returned to and remained at levels observed in intact animals, whereas adult sheep were slightly hypotensive throughout this period. In all animals supersensitivity of peripheral circulation to norepinephrine occurred, but only the fetus exhibited supersensitivity to acetylcholine and isoproterenol. Our conclusions are as follows: 1) acute phase of chemical sympathectomy in fetal, neonatal, and adult sheep simulates strong adrenergic stimulation; 2) absence of significant alteration in arterial pressure of fetus and neonate during the chronic phase of sympathectomy suggests a minor role for the adrenergic system in the maintenance of resting tone of peripheral circulation; and 3) on the basis of present and previous data, we postulate that the supersensitivity of fetal circulation to acetylcholine and isoproterenol may be secondary to changes occurring in pulmonary vascular bed.

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A basic requirement for using indicators for measuring blood flow is adequate mixing of the indicator with blood prior to sampling the site. This requirement has been met by depositing the indicator in the heart and sampling from an artery. Recently, authors have injected microspheres into veins and sampled from venous sites. The present studies were designed to investigate the mixing problems in sheep and rabbits by means of Cardio-Green and labeled microspheres. The indicators were injected at different points in the circulatory system, and blood was sampled at different levels of the venous and arterial systems. Results show the following. (a) When an indicator of small molecular size (Cardio-Green) is allowed to pass through the heart chambers, adequate mixing is achieved, yielding accurate and reproducible results. (b) When any indicator (Cardio-Green or microspheres) is injected into veins, and sampling is done at any point in the venous system, mixing is inadequate, yielding flow results which are inconsistent and erratic. (c) For an indicator or large molecular size (microspheres), injecting into the left side of the heart and sampling from arterial sites yield accurate and reproducible results regardless of whether blood is sampled continuously or intermittently.

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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.

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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 two resistance system of placental circulation, and (3) the effect of progesterone on the vascular smooth muscle.

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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.

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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 instrumental 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 decrease the flow in both vessels proportionately. Angiotensin in doses less than 0.16 micrograms/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.

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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.

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The effects of acute hypoxia on the resting arterial pressure as well as on heart rate and its beat-to-beat variability were studied in chronically instrumented, unanesthetized newborn lambs at 2 to 8 weeks of neonatal life. Lung ventilation with a gas mixture containing 10% oxygen and 3% carbon dioxide decreased arterial blood PO2 by about 50% in all animals regardless of age without significantly altering blood pH and PCO2. This degree of hypoxia produced a mild pressor response, accompanied by a significant tachycardia; the pattern of these changes, however, differed somewhat according to neonatal growth. The impact of hypoxia on beat-to-beat variability of the neonatal heart rate also varied with age. When the lambs were 2 to 3 weeks old, both the long- and short-term variabilities decreased progressively during hypoxia and the decrement reached a maximum at 10 minutes of oxygen deprivation. As the lambs became older, however, there was some initial and transient increase in the long- and short-term variabilities in the early period of hypoxia but thereafter the changes were inconsistent. The significance of these observations is discussed in terms of our knowledge of the pathophysiologic alterations in the cardiovascular system produced by acute hypoxia.

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Nonpregnant and pregnant sheep at 110 to 140 days' gestation were chronically instrumented for measurement of mean arterial pressure, heart rate, cardiac output, common internal iliac artery blood flow, and middle uterine artery blood flow. Systemic and regional vascular resistances were calculated from pressure/flow data. Either isoxsuprine, 10 microgram/kg/min, or terbutaline, 0.40 microgram/kg/min, was infused continuously for a period of one hour. The above-mentioned parameters were monitored during control, infusion, and postinfusion periods. The findings show that: (a) isoxsuprine had greater effects on the mean arterial pressure, heart rate, and cardiac output than did terbutaline; (b) both agents had minimal effects on the common internal iliac artery blood flow of pregnant ewes, but isoxsuprine decreased the middle uterine artery blood flow significantly; and (c) with isoxsuprine, a marked vasodilatation occurred in the common internal iliac vascular bed of nonpregnant ewes, in contrast to the insignificant changes in the pregnant ewes. The conclusions drawn were that: (1) the more pronounced effects of isoxsuprine are most probably related to a greater beta 1 stimulation; (2) contiguous regional vascular beds respond differently to pharmacologic stimuli; and (3) the state of a given vascular bed during the resting state determines its response to vasoactive agents.

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The circulatory responses to progressively increasing doses of angiotensin II were studied in the same group of chronically instrumented unanesthetized pregnant sheep during three consecutive periods: a) normotensive with intact kidneys; b) normotensive with unilateral nephrectomy; and c) one-kidney hypertension. The results show that 1) the pressor response to a given dose of angiotensin was significantly greater in the normotensive than in the hypertensive condition; 2) uterine blood flow decreased markedly with the development of hypertension; 3) uterine circulatory response to angiotensin depended on the dosage; the response was less the the hypertensive than in the normotensive condition; 4) renal blood flow decreased and renal vascular resistance increased during angiotensin infusion, but the response was less in the hypertensive than in the normotensive condition; the response of the renal circulation decreased with increasing doses of angiotensin. These observations suggest a generalized vascular refractoriness to exogenous angiotensin II in the pregnant ewe with experimental renal hypertension.

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The cardiovascular effects of endotoxin in the unanesthetized chronically instrumented sheep were investigated. The observations were extended to include the response to intravenous infusions of dopamine to the same sheep at the height of endotoxin action. When the cardiovascular effects of endotoxin in the unanesthetized and anesthetized sheep were compared, there were distinct differences. Unanesthetized sheep tolerated considerably greater dosages of endotoxin. In anesthetized sheep, the compensatory stimulation of the sympathoadrenal system seems to have been blunted and all of the circulatory parameters deteriorate rapidly, ending in death within three hours. In the absence of anesthesia, there was clear evidence of a compensatory sympathoadrenal stimulation, as reflected by the return of most of the circulatory parameters to normal values, and furthermore, the sheep recovered from the effects of endotoxin. The exact mechanism by which anesthesia altered the response of the sheep to endotoxin was not clear. Depression of the baroreceptor and neurohumoral compensatory mechanisms was suggested. The present data indicated that dopamine was a useful agent in correcting the cardiovascular changes brought about by endotoxin.

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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.

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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.

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