Reduction In Uterine Blood Flow Research Articles

Effect of prolonged uterine blood flow reduction on fetal growth in sheep.

The purpose of the present investigation was to study the effect of 7 days of uterine blood flow reduction on fetal growth. Reduction in uterine blood flow was accomplished by external occlusion of the terminal aorta in 20 pregnant sheep. Linear growth was monitored daily by means of a crown-rump length measuring device. The deliveries of oxygen, glucose, and lactate to the fetus, as well as their uptakes by the fetus, were determined before and after 7 days of uterine blood flow reduction and correlated with rates of fetal growth. Identical studies were conducted in nine control animals. Uterine blood flow reduction resulted in a significant decrease in fetal oxygen delivery and fetal arterial oxygen content. Linear growth rate decreased by 38% in the occluded animals during hypoxemia. In addition, there was a 20% reduction in daily weight gain in occluded animals compared with controls. There were no differences in the uptakes of oxygen, glucose, and lactate by the fetus. Positive correlations were found between linear growth rate and fetal arterial oxygen content (r2 = 0.25, P = 0.0001) and between linear growth rate and fetal oxygen delivery (r2 = 0.21, P = 0.0006). The correlations between linear growth rate and fetal oxygenation provide strong evidence of the central role of oxygen in the regulation of fetal growth.

Effect of prolonged catecholamine infusion on heart rate, blood pressure, breathing, and growth in fetal sheep.

Norepinephrine and epinephrine were infused into fetal sheep for 24 h to compare the effects on fetal heart rate, blood pressure, breathing movements, and tissue growth with those of prolonged reductions in uterine blood flow. Norepinephrine concentrations increased (p < 0.01) from 871 +/- 71 to 6831 +/- 1090 pg/mL (2 h) with norepinephrine infusion, and epinephrine concentrations increased from 310 +/- 95 to 1424 +/- 288 pg/mL (2 h) with epinephrine infusion. Fetal pH decreased (p < 0.01) from 7.37 +/- 0.01 to 7.29 +/- 0.02 at 0.5 h of the norepinephrine infusion and returned to control values by 2 h, whereas fetal lactate concentrations increased (p < 0.05) from 1.6 +/- 0.2 to 4.6 +/- 1.0 mmol/L at 2 h and remained elevated for 12 h. Lactate concentrations also increased with epinephrine infusion. Fetal heart rate increased (p < 0.05) from 176 +/- 5 to 246 +/- 6 and 220 +/- 6 beats/min in the 1st h of norepinephrine and epinephrine infusions, respectively, with a subsequent decline. Fetal blood pressure increased (p < 0.05) from 43 +/- 3 and 40 +/- 2 to 53 +/- 3 and 47 +/- 2 mmHg (1 mmHg = 133.3 Pa) during the 1st h of norepinephrine and epinephrine infusions, respectively, remaining elevated for 24 h. Fetal body weights were not different between the groups of animals, although liver/body weight ratio was less (p < 0.05) in epinephrine-infused fetuses (0.030 +/- 0.001) compared with vehicle-infused animals (0.036 +/- 0.002). There was no change in DNA synthesis rate in any of the fetal organs, despite changes in organ-specific DNA and protein content. Our results indicate that the changes in fetal cardiovascular and behavioural function, as well as tissue growth, that occur with prolonged reductions in uterine blood flow are not mediated solely by elevated circulating catecholamine concentrations.

Endocrine responses of fetal sheep to prolonged hypoxemia with and without acidemia: relation to urine production

Our aim was to examine the endocrine changes associated with alterations in fetal urine production during 24 h of hypoxemia induced by either reduced uterine blood flow (RUBF) or maternal N2 inhalation (N2). In contrast to RUBF, which caused a diuresis, N2 caused a transient antidiuresis; during both posthypoxemia periods (RUBF and N2), fetal urine production was increased. RUBF, but not N2, was associated with a transient acidemia. Fetal plasma arginine vasopressin (AVP) and atrial natriuretic factor (ANF) concentrations increased during RUBF and were inversely correlated to pH; there were no detectable AVP or ANF responses to N2. Fetal prostaglandin E2 (PGE2) increased during the hypoxemia and posthypoxemia periods induced by both methods, but RUBF caused the greater increase. AVP and PGE2 concentrations were positively correlated with urine production. Fetal arterial blood pressure increased during RUBF but not N2. During RUBF, the increases in AVP and PGE2 concentrations and/or fetal arterial blood pressure may have contributed to the diuresis. During N2, we suggest that low, but increased, levels of AVP may have caused the transient antidiuresis, whereas the diuresis observed during both posthypoxemia periods may have been mediated by elevated PGE2 concentrations and/or increased fetal arterial blood pressure.

Oxygen, glucose, and lactate uptake by fetus and placenta during prolonged hypoxemia

Our aim was to compare the effects of short (4 h) and prolonged (24 h) periods of reduced uterine blood flow (RUBF) on fetal and placental uptake of O2, glucose, and lactate. In pregnant sheep, uterine and umbilical blood flows were measured under normal conditions and after 4 and 24 h of RUBF. A 50% reduction in uterine blood flow caused a 56% reduction in fetal arterial O2 saturation (SaO2). Umbilical blood flow increased from 325 +/- 33 to 378 +/- 32 ml.min-1.kg-1 (P < 0.05) after 4 h but was not different from pre-RUBF values after 24 h. O2 uptake by the gravid uterus was not altered by RUBF, due to an increase (84%) in uterine O2 extraction. Similarly, uteroplacental and fetal O2 consumptions and fetal glucose uptake were not affected by RUBF, whereas uteroplacental glucose uptake was significantly reduced after 4 h (by 42%) and 24 h (by 58%) of RUBF. Fetal lactate uptake was greatly reduced from 78.7 +/- 15.5 to -167 +/- 57 mumol.min-1.kg-1 after 4 h and to -198 +/- 80 mumol.min-1.kg-1 after 24 h of RUBF; negative values indicate placental lactate uptake from the fetal circulation. Thus, although RUBF significantly reduced fetal SaO2, fetal and uteroplacental O2 consumptions did not change. In addition, although fetal glucose uptake was not altered by RUBF, during RUBF the placenta became a major site of lactate clearance from the fetal circulation.

Placental and fetal hepatic growth are selectively inhibited by prolonged reductions of uterine blood flow in pregnant sheep

Experiments were conducted in eight pregnant sheep to determine the effect on fetal growth of mechanical restriction of uterine blood flow (RUBF) between 120 days and 134 days gestation. Uterine blood flow measured in the middle uterine arteries was 40% less in RUBF animals compared with control animals at the end of the experimental period. There was no change in fetal blood gases, bodyweights, or organ weights between the two groups of animals. The rate of DNA synthesis in the right lobe of the liver was significantly less in RUBF animals (581 +/- 34 dpm micrograms-1 DNA) compared with control animals (845 +/- 44 dpm microgram-1 DNA). There was no difference in the rate of DNA synthesis in the left lobe of the liver or in any of the other organs examined. Autoradiographic examination of the placental cotyledons demonstrated that most DNA synthesis in the placenta was occurring in fetal trophoblastic cells and there was a 40% reduction in the nuclear-labelling index of placental trophoblast cells. These studies show that mild mechanical reductions in uterine blood flow in pregnant sheep results in the selective inhibition of growth in the right lobe of the fetal liver and the placental trophoblastic cells. The mechanism underlying this close association remains to be determined.

Pathophysiology, cellular and molecular mechanisms of foetal growth retardation.

In mammals, size at birth is the outcome of length of gestation and rate of foetal growth. In the absence of premature delivery, foetal size within species is determined principally by foetal growth rate which is dependent on both genetic and epigenetic factors. Failure of either of these mechanisms leads to foetal growth retardation. In mammals, including human infants, foetal growth retardation can occur naturally or pathologically. One major cause for natural foetal growth retardation or runting is the increase in litter size. In many cases, however, the cause of runting is unknown. Parental genotype or antigenic differences between the mother and the developing conceptus may be potential causes. Pathological foetal growth retardation or intrauterine growth retardation (IUGR) is due to genetic causes (chromosomal abnormalities or inherited syndromes) or epigenetic causes (intrauterine infections, toxins and chemicals, maternal diseases of pregnancy affecting the placenta). The underlying pathophysiological processes that occur at the cellular and molecular level in IUGR are still unknown. Reduction in the supply of substrates that are necessary for normal cellular function, and alteration in mediator molecules that regulate cellular growth and differentiation, are important mechanisms. A decrease in growth promoting factors or an increase in growth inhibitory factors may lead to growth failure. Growth factors and their receptors are expressed in the developing embryo (as early as the 1-2-cell stage), placenta and maternal uterine tissues, suggesting that these molecules may play a role in regulating normal growth and differentiation of the conceptus as well as maternal reproductive tissues. The local expression within developing tissues indicates that these factors act in either autocrine or paracrine mechanism. Recent studies using gene targeting to knock out one allele of insulin-like growth factor II (IGF II) gene in mice which resulted in growth retarded pups at birth, strongly support the importance of local IGF II in regulating tissue growth. Foetal growth retardation has also been induced experimentally in several species using one of the following methods: (i) maternal undernutrition, (ii) chronic hypoxia, (iii) prolonged reduction in uterine blood flow, (iv) reduction in placental size, and (v) endocrine alterations. These models provide useful information on the physiological mechanisms underlying a specific type of growth retardation. These in-vivo models and in-vivo tissue culture models can now be analysed by biochemical and molecular biological techniques to unravel the basic mechanisms that underlie foetal growth retardation.

Acute intrauterine hypoxia increases amniotic fluid prostaglandin F metabolites in the pregnant sheep

OBJECTIVE: Amniotic fluid infection promotes cytokine release, prostaglandin production, and premature labor. In several tissues local hypoxia also activates the secretion of cytokines. Many patients initially seen in premature labor carry small-for-gestational-age fetuses, a condition associated with intrauterine hypoxia. The purpose of our study was to determine whether a reduction in placental blood flow and subsequent acute hypoxia affects prostaglandin secretion by the placenta. STUDY DESIGN: We chronically catheterized six pregnant sheep at 120 days of gestation. We placed catheters in the maternal and fetal femoral arteries and in the amniotic fluid cavity. A flow probe and snare were placed around the common uterine artery. RESULTS: A 30-minute uterine circulation occlusion of 30% of its control value produced an increase in prostaglandin F metabolite from 790 ± 157 to 944 ± 184 pg/ml within 10 minutes ( p < 0.01). Additional uterine blood flow reduction to 60% of control increased the amniotic fluid prostaglandin F metabolites concentration to 894 ± 202 ( p < 0.05, analysis of variance). No increase in mean intrauterine pressure was detected ( p > 0.1). CONCLUSIONS: We speculate that the prostaglandin increase in amniotic fluid in response to intrauterine hypoxia could eventually lead to premature labor. Whether the increase in prostaglandins is mediated by changes in cytokines is unknown at the present time.

Effects of restricting uteroplacental blood flow on concentrations of corticotrophin-releasing hormone, adrenocorticotrophin, cortisol, and prostaglandin E2 in the sheep fetus during late pregnancy.

We have examined the effects of reduced uterine blood flow and prolonged fetal hypoxemia on the temporal relationship between changes in hormones associated with the activity of the pituitary-adrenal axis (corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), cortisol, and prostaglandin E2 (PGE2) in the ovine fetus at 120-125 days of pregnancy, and we sought evidence for placental secretion of CRH and ACTH during prolonged hypoxemia. Uterine blood flow was reduced by placing an adjustable Teflon clamp around the maternal common internal iliac artery to decrease fetal arterial oxygen saturation from mean values of 59.1 +/- 3.3 to 25.7 +/- 4.6% (+/- SEM, n = 10). There was a transient peak in immunoreactive (IR-) CRH at 1-2 h after reducing uterine blood flow. IR-ACTH rose to peak values at +2 h, then gradually decreased to control level by +12 h. Fetal plasma cortisol and PGE2 concentrations were elevated significantly by +2 and +4 h, respectively, and at 20-24 h. The identity of IR-CRH in fetal plasma and in ovine placental extracts was confirmed by HPLC, but there was no consistent umbilical vein--femoral arterial concentration difference for either IR-CRH or IR-ACTH during normoxemia or hypoxemia. We conclude that a sequence of endocrine changes involving CRH, ACTH, PGE2, and cortisol occurs in the fetus during a prolonged reduction in uterine blood flow. However, we did not obtain evidence, for placental secretion of either CRH or ACTH in response to this manipulation.

Effect of maternal oxygen administration on fetal oxygenation during graded reduction of umbilical or uterine blood flow in fetal sheep

Effects of maternal oxygen administration on fetal blood gases and on oxygen delivery and consumption during reduced uterine and reduced umbilical blood flows were examined. In eight pregnant sheep (gestational age 133 +/- 4 days) flow transducers were applied to a uterine and the common umbilical artery. Graded reductions in uterine and umbilical blood flows were achieved by a hypogastric artery snare and a balloon cuff encircling the umbilical cord. Fetal femoral arterial and umbilical venous oxygen contents and flows were measured at varying flow reductions with the ewe breathing air or oxygen. During 75% reduction in umbilical blood flow maternal oxygen administration significantly increased fetal oxygen delivery (6.4 +/- 2.5 to 7.7 +/- 2.3 ml/min/kg) and oxygen consumption (4.3 +/- 1.2 to 5.0 +/- 0.8 ml/min/kg). With similar reduction of uterine flow oxygen administration increased oxygen delivery from 8.3 +/- 2.4 to 12.3 +/- 3.6 and oxygen consumption from 3.3 +/- 0.8 to 4.7 +/- 1.6 ml/min/kg. Maternal oxygen inhalation improves fetal oxygenation during umbilical but especially during uterine blood flow reduction.

Hydralazine does not restore uterine blood flow during cocaine-induced hypertension in the pregnant ewe.

Cocaine abuse is widespread, and its use by the parturient has potential significant adverse effects in both the mother and the newborn. This study was undertaken in gravid ewes to determine the effects of treatment of cocaine-induced hypertension with hydralazine (Apresoline) on the maternal and fetal cardiovascular systems, catecholamine response, blood gas and acid-base status, and uterine blood flow (UBF). Twenty-one experiments were performed in 15 chronically instrumented ewes near term gestation. After a 30-min control period, cocaine was given intravenously to all ewes for 55 min to induce and maintain increased maternal mean arterial pressure (MMAP) and reduced UBF. The sheep were randomly assigned to receive either cocaine alone (n = 11, control group) or hydralazine (n = 10, treatment group), starting 15 min after the cocaine administration. Both drugs were discontinued 55 min after the start of the cocaine administration, followed by a 35-min recovery period. In the control group, cocaine administration resulted in a 31 +/- 13% (SD) increase in MMAP (P less than 0.05) and a 26 +/- 21% reduction in UBF (P less than 0.05). In the treatment group, the initial cocaine administration resulted in a similar increase in MMAP and decrease in UBF. Hydralazine therapy restored MMAP toward baseline after 20 min of administration, but UBF remained reduced (37 +/- 17%) throughout therapy (P less than 0.05) and recovery (18 +/- 13%) (P less than 0.05). The maternal heart rate increased maximally by 121 +/- 33% (P less than 0.05) after the administration of hydralazine, compared with a 14 +/- 21% increase (P less than 0.05) in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Das „Goldblatt-Phänomen am Uterus“ und die latente Nierenerkrankung als Ursache der schwangerschaftsinduzierten Hypertonie - Epidemiologie und therapeutische Konsequenzen*

The aetiology of pregnancy-induced hypertension (PIH) is at present unknown. Epidemiological data lead us to assume, that two main mechanisms could be responsible for the development of PIH. They are not well understood in their complexity, but result in the same pattern of signs and symptoms: Oedema, proteinuria and hypertension. 1. "Goldblatt-Phenomenon" in the uterus, as a result of a disturbed maternal immune response to the cytotrophoblast, followed by the reduction of uterine blood flow and the liberation of vasoactive substances from the placenta. 2. Renal factors, especially in elderly women, result in a manifestation of nephrotic diseases during pregnancy. No screening methods are at the present time available to diagnose PIH in advance. It is therefore necessary, to look at typical clinical manifestations, i.e. the development of hypertension. It is also important to estimate the weight gain and the occurrence of oedema before rising blood pressure demonstrates a general vasoconstriction in the maternal vascular system. The basic therapeutical concept is to reduce the peripheral vascular resistance, to prevent maternal complications and to reduce the uterine vascular resistance to improve foetal oxygenation. In many cases an improvement of the oxygen supply to the foetus is not possible, since irreversible alterations of the uterine arterial vascular bed have already taken place. For the treatment of PIH, different drugs are available which act on different targets. In cases of special medical history, the early application of magnesium and acetyl salicylic acid (ASA) should be included in the therapeutical concept of prophylaxis.

Effects of reduced uterine blood flow on fetal cardiovascular, renal, and lung function

Uterine blood flow (UBF) was reduced for 1 h by partially occluding the maternal aorta below the renal arteries in seven pregnant ewes (gestation age 126-134 days). Fetuses became hypoxic, acidemic, and hypercapnic. They developed hypertension (P less than 0.005) and a bradycardia (P less than 0.05). During restricted UBF, fetal hematocrit (Hct) rose (P less than 0.005) and blood volume fell in five of seven fetuses. After release of constriction, fetal Hct fell, and blood volume rose by 7.5 +/- 3.26% (P less than 0.05) relative to control. During reduced UBF, lung liquid and urine flow rates fell (P less than 0.025 and P less than 0.05, respectively). After the occluder was released, Na excretion (which did not fall significantly during reduced UBF) increased (P less than 0.05), and fractional reabsorption of Na fell (P less than 0.05). Changes in fetal blood volume (FBV) were directly related to changes in maternal lower body flow (r = 0.47, P = 0.01, n = 33), and changes in fetal Hct were inversely related to maternal flow (r = -0.635, P = 0.001). Fetal urinary Na excretion per kilogram body weight was directly related to FBV per kilogram (r = 0.44, P = 0.005, n = 40), whereas fractional reabsorption of Na was inversely related to FBV per kilogram body wt (r = 0.48, P less than 0.002, n = 39). It is concluded that reductions in UBF cause fetal hypoxemia and acidemia, which lead to changes in fetal cardiovascular function and in FBV.(ABSTRACT TRUNCATED AT 250 WORDS)

Fetal endocrine responses to prolonged hypoxemia in sheep

Our aim was to characterize the pattern of release of epinephrine, norepinephrine, arginine vasopressin (AVP), cortisol (hydrocortisone), and prostaglandin E2 (PGE2) into the fetal circulation during prolonged reductions in uterine blood flow (RUBF). In five sheep RUBF was induced for 24 h, whereas in another five sheep (controls) uterine blood flow was not reduced. Fetal arterial oxygen saturation was decreased from 60.5 +/- 3.6 to 20.3 +/- 1.6% after 2 h of RUBF and remained significantly reduced for the entire RUBF period. The incidence of fetal breathing movements (FBM) and fetal arterial pH were reduced from 36.7 +/- 4.5 min/h and 7.36 +/- 0.01 to 4.3 +/- 1.8 min/h and 7.13 +/- 0.02, respectively, after 2 h of RUBF, but both had returned to control levels after 14 h. Fetal plasma AVP and epinephrine concentrations were increased from 4.4 +/- 0.5 pg/ml and 0.19 +/- 0.05 ng/ml to 333.8 +/- 41.5 pg/ml and 1.5 +/- 0.6 ng/ml, respectively, after 2 h and then declined to near control levels after 12 h of RUBF. Fetal plasma norepinephrine and cortisol concentrations were increased from 1.3 +/- 0.4 and 4.0 +/- 2.2 ng/ml to 6.1 +/- 1.8 and 13.5 +/- 4.1 ng/ml, respectively, after 2 h of RUBF, and both remained significantly elevated throughout the remainder of the RUBF period. Fetal plasma PGE2 concentrations progressively increased (from 1.9 +/- 0.4 to 8.8 +/- 1.7 nmol/l at 12 h) as the duration of RUBF increased and were still significantly elevated after 24 h. The time course for the increase in PGE2 during RUBF was very similar to the increases in arterial pH and in the incidence of FBM.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Acute Uterine Ischemia on Fetal Circulation1

The effects of acute maternal hemorrhage on uterine blood flow and fetal circulation were investigated in pregnant sheep. Nine chronically instrumented pregnant sheep (114-128 d gestation), phlebotomized from the iliac artery at the point of origin of the uterine artery, were studied at baseline, after acute hemorrhage, and immediately and two h after replacement of the blood. Maternal hemorrhage caused a reduction in uterine blood flow as well as both fetal hypoxemia and acidemia. Changes in fetal organ blood flow measured by radionuclide-labeled microspheres showed that blood flow to the brain, heart, and adrenal glands increased (p less than 0.05), whereas blood flow to the other major organs did not change significantly. Rapid replacement of blood restored all parameters to baseline values. We conclude that acute maternal hemorrhage causes a reduction in uterine blood flow, fetal hypoxemia, and acidemia with a secondary increase in blood flow to the high priority organs. Rapid replacement of blood reverses these effects.

Effect of beta-adrenergic blockade on lung liquid secretion during fetal asphyxia

The hypothesis tested in this study was that beta-adrenergic stimulation is responsible for the inhibition of fetal lung liquid production during moderate fetal asphyxia. In chronically catheterized fetal sheep, net lung liquid production rates were measured over three consecutive periods: a control period, a period of reduced uterine blood flow (RUBF) or epinephrine infusion, and periods of RUBF or epinephrine infusion in the presence of the beta-adrenergic receptor antagonist propranolol. The net production rate of fetal lung liquid was decreased from a mean control value of 7.7 +/- 1.0 to 1.5 +/- 0.4 ml/h (P less than 0.001) by RUBF; the administration of propranolol had no further effect on these liquid production rates (1.1 +/- 0.5 ml/h). In other experiments epinephrine infusion reduced the net production rate of fetal lung liquid from a mean control value of 7.2 +/- 1.4 to 1.7 +/- 1.8 ml/h (P less than 0.025); the addition of propranolol reversed this inhibition (secretion rate 6.1 +/- 1.4 ml/h, P less than 0.005). We conclude that the inhibition of fetal lung liquid production induced by moderate fetal asphyxia does not solely result from catecholamine stimulation of pulmonary beta-receptors.

The effect of a single dose of oestradiol on tamoxifen-induced uterine hyperaemia and growth in the rat.

1. The effect of oestradiol on tamoxifen - (single doses of each agent) induced responses in the uterus of the mature ovariectomized rat was investigated. The parameters examined were uterine blood flow (measured by the microsphere technique), weight and oestrogen receptor concentrations. 2. Initially the addition of oestradiol to the tamoxifen regimen produced a reduction in uterine blood flow and dry weight which was reflected by a reduction in nuclear oestrogen receptor. However, as the tamoxifen response became more established from 48 h onwards the addition of oestradiol produced an additive effect. These changes were not mirrored by increases in nuclear oestrogen receptor. 3. The results suggest that tamoxifen and oestradiol may, in part, act via different mechanisms; the role of possible mediatory systems such as histamine release and eosinophil migration is discussed. Heterogeneous control systems may also be involved in the early and late uterine response.

Fetal and maternal endocrine responses to prolonged reductions in uterine blood flow in pregnant sheep

To examine the effects of sustained (48-hour) hypoxemia on fetal and maternal adrenocorticotropic hormone concentrations and on maternal progesterone, uterine blood flow was reduced in eight sheep at day 128 of pregnancy by means of an adjustable Teflon clamp placed around the maternal common internal iliac artery. Control measurements were made in four animals in which the vascular clamp was not adjusted. Fetal PaO2 fell from 20.6 +/- 1.1 mm Hg (mean +/- SEM) to 16.6 +/- 0.6 mm Hg within 1 hour after application of the clamp and remained suppressed during 48 hours. There was a transient acidemia at 1 to 2 hours that had corrected by 8 hours. Fetal adrenocorticotropic hormone levels rose from 24 +/- 6 to 1320 +/- 205 pg/ml at 2 hours but decreased by 16 hours. Measured by high-pressure liquid chromatography, more than 95% of immunoreactivity corresponded to adrenocorticotropic hormone1-39. Fetal cortisol levels rose by 6 hours and remained elevated through 48 hours. Maternal adrenocorticotropic hormone, cortisol, and progesterone levels were unchanged during the study period. We conclude that fetal hypoxemia-acidemia after restriction of uterine blood flow provokes fetal adrenocorticotropic hormone release, but the elevation in adrenocorticotropic hormone is not sustained. However, the level of fetal cortisol rises progressively, consistent with fetal adrenal activation.

Reduction of uterine blood flow by phenylephrine, an alpha-adrenergic agonist, in the day 11 pregnant rat: relationship to potentiation of acetazolamide teratogenesis.

We have demonstrated previously that phenylephrine, a selective postsynaptic alpha-1-adrenergic agonist, significantly potentiates the incidence of acetazolamide-induced right forelimb ectrodactyly in a dose-response manner. As reported herein, phenylephrine also decreases maternal uterine blood flow in a dose-response manner as measured by radioactive microsphere methodology. At the potentiative dose of 12.5 mg/kg phenylephrine decreases uterine blood flow by 86.8% when compared to control. In turn, pretreatment with prazosin, a selective postsynaptic alpha-1-adrenergic antagonist, prevents this large decrease in uterine blood flow and abolishes the potentiation of acetazolamide teratogenesis by phenylephrine. Although the effects of acetazolamide or acetazolamide + phenylephrine on uterine blood flow were not measured the data suggest a correlation between decreased uterine blood flow and potentiation of acetazolamide teratogenesis.

Fetal beta-endorphin levels in response to reductions in uterine blood flow.

Fetal beta-endorphin release has been associated with fetal hypoxia. The purpose of this study was to assess the degree of uterine blood flow reduction needed to elicit fetal beta-endorphin release in the sheep since there is a large reserve of oxygen supply to the fetus. Uterine blood flow was reduced by 26 +/- 2, 46 +/- 3 and 66 +/- 2%, producing fetal oxygen content concentrations of 5.7 +/- 0.6, 4.4 +/- 0.7 and 2.6 +/- 0.3 ml/dl, respectively. Although fetal oxygen concentrations were significantly decreased in the groups with a reduction in uterine blood flow of 46 and 66%, beta-endorphin was elevated only in the latter group. It is speculated that fetal beta-endorphin is released at a level of hypoxia which leads to a decrease in fetal oxygen consumption. A reduction in uterine blood flow of 66% appears to produce a stressful environment for the fetus as measured by fetal plasma beta-endorphin levels.

Maternal factors modulating nutrient transfer to fetus.

Current knowledge of the modulation of maternal-fetal transfer of metabolites is reviewed and new data on the actual placental transport of D-glucose, L-alanine and glycerol in the rat are presented. Twenty-one day pregnant rats were infused with the 14C-labelled substrates throughout the left uterine artery. Radioactivity appearing in fetuses was corrected by the specific dilution of the tracer at maternal arterial plasma and the uterine artery blood flow to estimate placental transfer. This parameter appeared to be 127 mumol X kg-1 fetal b.w. X min-1 for D-glucose, 23 for L-alanine, and 1 for glycerol--values which are much higher than those described for larger species. There is a parallelism between the magnitude of transfer to fetus and arterial concentration in mother for each studied metabolite and actually variations in their plasmatic levels affect this transport process. This is clearly seen in the case of glucose where placental transfer is reduced during fasting hypoglycemia and greatly increased in diabetes. Placental transfer of L-alanine and blood flow to the placenta were reduced in both 48-hour starved and streptozotocin-induced diabetic late pregnant rats. Results show the main role of maternal nutrient concentration as a modulator of their transfer to fetus, the deleterious effect of reductions of uterine blood flow on placental transport of amino acids as well as the small placental transfer of glycerol as compared to either glucose or alanine.