Cerebral glucose deficiency versus oxygen deficiency in neonatal encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) in newborn infants is generally considered to result from decreased arterial oxygen content or cerebral blood flow. Cerebral injury similar to that of HIE has been noted with hypoglycemia. Studies in fetal lambs have shown that ventilation with 3% oxygen did not change cerebral blood flow, but ventilation with 100% oxygen resulted in marked reduction in cerebral blood flow, glucose delivery and glucose consumption. Blood glucose concentration falls markedly after birth; this, associated with the fall in cerebral blood flow, greatly reduces glucose supply to the brain. In preterm infants, blood glucose levels tend to be very low. Also persistent patency of the ductus arteriosus may reduce cerebral flow in diastole, thus exaggerating the decrease in glucose supply. I propose that glycopenic-ischemic encephalopathy is a more appropriate term for the cerebral insult. We should consider more aggressive management of the low blood glucose concentrations in the neonate, and particularly in preterm infants. Administration of high levels of oxygen in inspired air should be avoided to reduce the enhancement of cerebral vasoconstriction and decreased flow that normally occurs after birth.

Cardiac output and blood flow redistribution in fetuses with D-loop transposition of the great arteries and intact ventricular septum: insights into pathophysiology.

OBJECTIVES: Although the postnatal physiology of D-loop transposition of the great arteries with intact ventricular septum (D-TGA/IVS) is well established, little is known about fetal D-TGA/IVS. In the normal fetus, the pulmonary valve (PV) is larger than the aortic valve (AoV), there is exclusive right-to-left flow at the foramen ovale (FO) and ductus arteriosus (DA), and the left ventricle (LV) ejects 40% of combined ventricular output (CVO) through the aorta, primarily to the brain. In D-TGA/IVS, the LV ejects oxygen-rich blood to the pulmonary artery, theoretically leading to pulmonary vasodilation, increased branch pulmonary artery flow and reduced DA flow. In this study, we tested the hypothesis that D-TGA/IVS anatomy results in altered cardiac valve sizes, ventricular contribution to CVO, and FO and DA flow direction. METHODS: Seventy-four fetuses with D-TGA/IVS that underwent fetal echocardiography at our institution between 2004 and 2015 were included in the study. AoV, PV, mitral valve and tricuspid valve sizes were measured and Z-scores indexed to gestational age were generated. Ventricular output was calculated using Doppler-derived velocity-time integral, and direction of flow at the FO and DA shunts was recorded in each fetus using both color Doppler and flap direction. Measurements in the D-TGA/IVS fetuses were compared with data of 222 controls, matched for gestational-age range, from our institutional normal fetal database. RESULTS: The LV component of CVO was higher in D-TGA/IVS fetuses than in controls (50.7% vs 40.2%; P < 0.0001), with no difference in the total CVO. Flow was bidirectional at the FO in 56 (75.7%) and at the DA in 24 (32.4%) D-TGA/IVS fetuses. Only 21.6% fetuses had normal right-to-left flow at both shunts. Bidirectional shunting was more common in third-trimester fetuses than in second-trimester ones (P < 0.03). AoV and PV diameters were nearly identical in D-TGA/IVS in contrast to control fetuses, hence AoV Z-score was higher than PV Z-score (1.13 vs -0.65, P < 0.0001) in D-TGA/IVS. CONCLUSIONS: In fetuses with D-TGA/IVS there is loss of the normal right-sided dominance, as each ventricle provides half of the CVO, with a relatively large AoV diameter and a small PV diameter, and high incidence of bidirectional FO and DA flow. This may support the theory that high pulmonary artery oxygen content reduces pulmonary vascular resistance, thereby increasing branch pulmonary artery flow and venous return, which results in increased LV preload and output. Pulmonary sensitivity to oxygen is thought to increase later in gestation, which may explain the higher incidence of bidirectional shunting. Consequences of these flow alterations include increased aortic and, most likely, brain flow, perhaps in an attempt to compensate for the substrate deficiency observed in D-TGA/IVS. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Congenital cardiovascular malformations and the fetal circulation.

After birth, gas exchange is achieved in the lung, whereas prenatally it occurs in the placenta. This is associated with differences in blood flow patterns in the fetus as compared with the postnatal circulation. Congenital cardiovascular malformations are associated with haemodynamic changes in the fetus, which differ from those occurring postnatally. Obstruction to cardiac outflow may alter myocardial development, resulting in progressive ventricular hypoplasia. Alteration of oxygen content may profoundly influence pulmonary vascular and ductus arteriosus responses. Interference in blood flow and oxygen content may affect cerebral development as a result of inadequate oxygen or energy substrate supply. The circulatory effects may be gestational dependent, related to maturation of vascular responses in different organs. These prenatal influences of congenital cardiac defects may severely affect immediate, as well as longterm, postnatal prognosis and survival. This has stimulated the development of techniques for palliation of disturbed circulation during fetal life.

Group cohesion and working alliance: prediction of treatment outcome in cardiac patients receiving cognitive behavioral group psychotherapy.

BACKGROUND: Various definitions of both group cohesion and working alliance are used in theories on group psychotherapy, making the study of their relative contribution to the treatment outcome difficult. In this study, two different, nonoverlapping questionnaires were used to explore the relationship between group cohesion, working alliance and treatment outcome in a time-limited, structured cognitive behavioral group psychotherapy aiming at the reduction of coronary risk factors. METHODS: After having undergone percutaneous transluminal coronary angioplasty, 42 patients were treated with the aim to reduce exhaustion, anxiety, hostility and depression. The newly developed Group Cohesion Questionnaire (GCQ) and the Helping Alliance Questionnaire (HAQ-II, measuring the bond between individual patients and the group psychotherapist) were administered after the fifth and tenth treatment session. Exhaustion, quality of life, anxiety, blood pressure and heart rate were measured before and after treatment. To test the relationship between the GCQ, the HAQ-II and outcome variables, Pearson Product-Moment correlations and hierarchical regression was applied. RESULTS: Principal Component Analysis of the GCQ yielded two dimensions, the bond with the group as a whole and the bond with other group members. Hierarchical regression showed that both the bond with other group members and working alliance contributed significantly and independently to the prediction of posttreatment systolic and diastolic blood pressure as well as posttreatment quality of life (confidence). CONCLUSIONS: Conceptually and empirically, group cohesion and the working alliance may be considered to represent different relationships in a psychotherapy group, contributing in different ways to the treatment outcome in cardiac patients receiving cognitive behavioral group psychotherapy.

Myocardial growth before and after birth: clinical implications.

Perinatal changes in myocardial growth have recently evoked considerable interest with regard to cardiac chamber development with congenital cardiac lesions and to myocardial development in preterm infants. It is suggested that cardiac chamber development is influenced by blood flow. Experimental pulmonary stenosis in fetal lambs may induce either greatly reduced or markedly increased right ventricular volume. Ventricular enlargement appears to be associated with a large ventricular volume load resulting from tricuspid valve regurgitation. A small competent tricuspid valve is associated with reduced flow through the ventricle due to outflow obstruction and a small right ventricle. Postnatal growth of the ventricles in congenital heart disease is discussed. Increase in myocardial mass prenatally is achieved by hyperplasia, both during normal development and when myocardial mass is increased by right ventricular outflow obstruction. Postnatally, increases in myocardial mass with normal growth, as well as with ventricular outflow obstruction, are largely due to hypertrophy of myocytes. Myocardial capillary numbers do not increase in proportion with myocyte numbers in ventricular myocardium in association with outflow obstruction. The postnatal effects of these changes in congenital heart lesions are considered. Studies in fetal lambs suggest that the late gestational increase in blood cortisol concentrations is responsible for the change in the pattern of myocardial growth after birth. The concern is raised that prenatal exposure of the premature infant to glucocorticoids, administered to the mother to attempt to prevent hyaline membrane disease in the infant, may inhibit myocyte proliferation and result in a heart with fewer than normal myocytes. This would necessitate that each myocyte would have to hypertrophy abnormally to achieve a normal cardiac mass postnatally.

Perinatal myocardial DNA and protein changes in the lamb: effect of cortisol in the fetus.

Myocardial growth during fetal life is accomplished by proliferation of the number of myocytes (hyperplasia). Shortly after birth, normal growth of the heart is predominantly due to increase in cell size (hypertrophy), and myocytes largely lose the capability to replicate. This change is characterized by a decrease in myocardial DNA concentration and an increase in protein/DNA concentration ratio. Among many of the events associated with birth is an increase in plasma cortisol concentrations in the few days before delivery of the fetus. To determine the possible role of cortisol in the postnatal change in myocardial growth, we measured DNA and protein concentrations in the free walls of the left (LV) and right (RV) ventricles in normal fetal lambs, normal newborn lambs, and in fetal lambs in which cortisone was infused for 72-80 h into the left coronary artery, which we showed does not perfuse the RV free wall. Normally, fetal RV DNA is higher than LV DNA concentration, and DNA/protein ratio is lower in RV than in LV. It is suggested that this could be related to the greater load on the RV. Postnatally, protein concentrations increase progressively, but DNA remains the same in both ventricles, and protein/DNA ratios increase. Cortisol, infused to achieve normal prenatal levels in LV myocardium, markedly decreases LV DNA without affecting RV DNA concentrations. The present study indicates that cortisol inhibits myocyte replication and that cortisol simulates the change in myocardial growth pattern normally occurring after birth. It raises concerns regarding prenatal administration of glucocorticoids to mothers to mature the fetal lungs before preterm delivery.

Congenital obstructive lesions of the right aortic arch.

BACKGROUND: In the setting of normal cardiac situs, a right-sided aortic arch is uncommon. When a right arch does occur, it is typically in conjunction with other congenital cardiovascular anomalies, especially defects with abnormal right ventricular outflow. Congenital obstruction of a right arch, caused by coarctation, interruption, or cervical arch, is extremely rare. METHODS: We reviewed our experience and all reported cases of right aortic arch with coarctation of the aorta, interrupted arch, or obstruction of a cervical arch in the setting of normal cardiac situs and topology. RESULTS: Since 1992, 4 such patients have undergone repair at our institution, including 1 with interrupted arch, 1 with coarctation of a mirror image arch, and 2 with obstruction of a cervical arch. In addition to these 4 patients, 38 others have been described in the published reports: 15 with interrupted arch, 19 with coarctation, and 4 with obstruction of a cervical arch. Associated cardiac defects were uncommon, except for ventricular septal defect in patients with interrupted arch, but abnormalities of the brachiocephalic vessels were frequent. Except for most of the patients with interrupted right arch, the majority of patients described have undergone successful surgical repair. CONCLUSIONS: Although obstructive arch lesions are often grouped together, the etiologies of coarctation of the aorta, interrupted arch, and cervical arch with obstruction almost certainly differ. The rarity of such lesions among patients with right aortic arch may be explained in part by the fact that the fetal hemodynamic conditions associated with persistence of a right arch do not facilitate flow-related arch obstruction. In this review, we discuss these issues in detail, along with specific surgical considerations in the management of obstruction lesions of the right aortic arch.

Effect of beta-adrenergic stimulation on oxygen metabolism in the fetal lamb.

Catecholamines, which are released into the circulation during stress, increase fetal metabolism. This effect appears to be related to beta-adrenoreceptor stimulation. We examined the effect of isoproterenol infusion on umbilical blood flow, oxygen delivery and consumption, and glucose and lactate uptake in late-gestation fetal lambs. Isoproterenol increased umbilical blood flow, but oxygen delivery to the fetus did not increase. Umbilical venous oxygen content fell linearly with the increase in umbilical blood flow. It is proposed that oxygen delivery to the sheep fetus is at or near a maximum and that oxygen delivery cannot be raised by increasing umbilical blood flow because oxygen diffusion at the placental site is limited. Fetal oxygen consumption increased initially but returned to control levels with an increase in infusion rate. Blood glucose concentration increased during isoproterenol infusion; this was due to release of glucose and not because of increased placental uptake. Fetal blood pH values fell in association with elevated lactate levels. It is proposed that elevated glucose concentrations resulted in increased metabolism of glucose, and because oxygen delivery could not be enhanced, increased anaerobic glycolysis caused lactate concentration to rise.

Mechanisms of adrenomedullin-induced increase of pulmonary blood flow in fetal sheep.

Mechanisms of adrenomedullin-induced increases in fetal pulmonary blood flow were examined in 19 near-term fetal sheep using four key blocker drugs: nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine), calcitonin gene-related peptide (CGRP) receptor blocker, ATP-dependent potassium (K(ATP)) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin). Catheters were inserted into the left pulmonary artery and superior vena cava to administer drugs and into the main pulmonary and carotid arteries to measure pressures and heart rate. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. Adrenomedullin (mean 1.06 microg/kg) was injected into the left pulmonary artery before and after infusion of N(omega)-nitro-L-arginine (mean 96.5 mg/kg, n = 6), glibenclamide (mean 11.8 mg/kg, n = 6), CGRP receptor blocker (mean 312.0 microg/kg, n = 6), and indomethacin (mean 1.7 mg/kg, n = 8). Blockade was confirmed by appropriate agonist injection. The adrenomedullin-induced response in left pulmonary artery blood flow was inhibited by N(omega)-nitro-L-arginine (inhibition rate 99%) and significantly attenuated by glibenclamide (inhibition rate 44%); however, no significant changes were found with CGRP receptor blocker or indomethacin (inhibition rate 0 and 17%, respectively). The responses of the main pulmonary and carotid arterial pressures were similarly affected by those blockers. Our data suggest that in the fetal pulmonary circulation, the adrenomedullin-induced increase in pulmonary blood flow depends largely on nitric oxide release and partly on K(ATP) channel activation, and does not involve the CGRP receptor or a cyclooxygenase-mediated mechanism.

Phasic flow events at the aortic isthmus-ductus arteriosus junction and branch pulmonary artery evaluated by multimodal ultrasonography in fetal lambs.

OBJECTIVES: We assessed the phasic flow and interaction between the pulmonary trunk and aortic isthmus flow at their junction in the lamb fetus in late gestation and also assessed the interaction of the left pulmonary artery branch. STUDY DESIGN: With echocardiographic and Doppler ultrasonographic and saline-contrast techniques, we studied 7 fetal lambs with arterial and venous catheters in place to assess direction, velocity, and timing of flow at the aortic isthmus, ductus arteriosus, and proximal left pulmonary artery. RESULTS: At the isthmus-ductus junction, ductus systolic flow occurred later (0.048 +/- 0.006 second, mean +/- SD) and accelerated more slowly than isthmus flow but with higher velocities (peak 70.7 +/- 7.1 vs 63.1 +/- 6.3 cm/s, velocity time integral 5.7 +/- 1.2 vs 4.5 +/- 1.3 cm, respectively; P <.001). There was a small degree of late systolic flow reversal and admixture from both sources. Signals from the left pulmonary arterial branch showed a sharp, brief systolic forward flow with a peak velocity of 48.8 +/- 9.1 cm/s, followed by late systolic and diastolic flow reversal with a peak velocity of 23.5 +/- 8.7 cm/s. CONCLUSION: The differences in the flow timing may be the result of different timing of ventricular contraction, resistances in the vascular beds, and ductus constriction, both anatomic and physiologic.

Perinatal regulation of the cerebral circulation: role of nitric oxide and prostaglandins.

Nitric oxide (NO) influences cerebral vascular tone both in the normal fetus and in the hypoxemic fetus, but during postnatal life this regulating role of NO seems less prominent. It is therefore possible that under conditions when arterial oxygen content is at postnatal levels NO exerts no action on smooth muscle. We therefore examined the impact of NO on cerebral blood flow and vascular resistance in five near-term lamb fetuses during intrauterine ventilation and oxygenation. Four additional fetuses were pretreated with indomethacin to investigate a possible additional regulatory role of prostaglandins on cerebral vascular resistance. Cerebral blood flow (Qbrain) was measured using radionuclide-labeled microspheres. A tracheal tube was inserted to ventilate the fetus. After recovery, Qbrain and resistance in the cerebral vascular bed (Rcer) were measured during the following subsequent conditions: before and after increasing fetal arterial O2 content by ventilation with air, after inhibition of NO production with N(omega)-nitro-L-arginine during and after cessation of ventilation, and finally after infusion of L-arginine to increase nitric oxide production. Ventilation decreased Qbrain (95 +/- 18 to 47 +/- 15 mL/100 g/min) and increased Rcer. N(omega)-Nitro-L-arginine did not alter Qbrain (52 +/- 13 mL/100 g/min) or Rcer during ventilation and oxygenation, indicating no modulating role of NO during higher arterial oxygen content. On cessation of ventilation, PO2 returned to fetal levels and Qbrain increased significantly, but did not return to baseline fetal values (83 +/- 7 mL/min). Infusion of L-arginine increased Qbrain to baseline fetal levels (116 +/- 30 mL/min). However, indomethacin pretreatment prevented the rise in cerebral blood flow after cessation of ventilation and after additional L-arginine infusion (Qbrain 53 +/- 20 and 52 +/- 4 mL/100 g/min. respectively). These studies indicate that, during postnatal levels of arterial oxygen content, NO does not exert an action on smooth muscle cells of the cerebral resistance vessels as it does at lower arterial (fetal) oxygen content. They further show that prostaglandins are important in facilitating the full expression of NO-induced vasodilation.

Adrenomedullin increases pulmonary blood flow in fetal sheep.

We studied the effects of exogenously administered adrenomedullin on fetal pulmonary arterial blood flow in near-term fetal sheep. The hemodynamic effects of a single injection of adrenomedullin into the left pulmonary artery were compared with those of acetylcholine; the effects of repeated injections of adrenomedullin were also studied. In seven unanesthetized fetal sheep, catheters were inserted into the left pulmonary artery to administer drugs, and into the main pulmonary and carotid arteries to measure pressures. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. A single 5-microgram injection of adrenomedullin (1.90 +/- 0.35 micrograms/kg of fetal weight) increased pulmonary arterial blood flow significantly, from 17 +/- 10 to 120 +/- 21 mL/min (p < 0.001). Two micrograms of acetylcholine (0.74 +/- 0.14 microgram/kg of fetal weight) also increased left pulmonary arterial blood flow, from 18 +/- 16 to 113 +/- 37 mL/min, but the effect of adrenomedullin on flow was more prolonged than was that of acetylcholine. Additionally, adrenomedullin and acetylcholine similarly decreased mean pulmonary arterial pressure by 11 and 16%, respectively, but adrenomedullin did not decrease mean carotid arterial pressure to the same degree as acetylcholine (2 versus 19%, respectively). Five sequentially repeated injections of adrenomedullin, once every 5 min, increased left pulmonary arterial blood flow significantly in a stepwise manner without significantly changing heart rate or mean pulmonary and carotid arterial pressures. We conclude that exogenously administered adrenomedullin is a pulmonary vasodilator in fetal sheep and has the ability to increase pulmonary blood flow significantly; there is less effect on the systemic circulation. This finding might be important in considering the therapeutic use of this peptide in the management of persistent pulmonary hypertension in the perinatal period.

Developmental biology of the heart: is there a role for the physiologist?

Support for physiological research has generally declined, as interest in cellular and molecular investigation has assumed ascendancy. However, there are many important issues relating to cardiovascular development that require a systems approach to study of the circulation. Examples are mechanisms of circulatory response to hypoxia during fetal life; changes in myocardial growth in response to loading before and after birth, and resultant cardiac function; and prenatal and postnatal development of the great vessels with altered circulatory patterns in congenital heart lesions. These issues are of great concern in considerations for potential fetal cardiovascular surgery.

Assessment of flow events at the ductus venosus-inferior vena cava junction and at the foramen ovale in fetal sheep by use of multimodal ultrasound.

BACKGROUND: Previous techniques for the study of the fetal circulation did not permit assessment of phasic events associated with the cardiac cycle. We used multimodal ultrasound techniques to examine flow events that occur in the major veins and across the foramen ovale in the circulation of the fetal lamb. METHODS AND RESULTS: We studied eight fetal lambs instrumented with catheters in the superior and inferior venae cavae and a peripheral umbilical vein and performed ultrasound studies that included M-mode and two-dimensional imaging, pulsed and Doppler color flow ultrasound, and contrast echocardiography to evaluate flow in the ductus venosus, in both venae cavae, and through the foramen ovale. Two blood streams of different flow velocities were identified within the cephalic portion of the inferior vena cava. The stream that originated from the narrowed ductus venosus had a higher velocity than that from the caudal inferior vena cava (mean velocity, 57 +/- 13 versus 16 +/- 3 cm/s; P < .0002). Facilitated by the eustachian valve and the septum primum, the ductus venosus stream preferentially passed through the foramen ovale to the left atrium. This flow occurred during most of the cardiac cycle, except for 19.6 +/- 2.3% of the cycle when the foramen ovale was closed during atrial contraction. Superior vena cava flow passed almost exclusively into the right atrium and tricuspid valve; a small amount that was refluxed from the right atrium into the inferior vena cava subsequently passed through the foramen into the left atrium. CONCLUSIONS: Visualization of fetal circulatory streaming at the venous sites by ultrasound techniques aids in understanding the function of the fetal circulation and may be helpful in detecting the human fetus that is hemodynamically compromised.

Effect of drugs on chemoreceptor responsiveness in fetal sheep.

This study was designed to examine the effects of the drugs ketamine, morphine, pentobarbital, and propranolol on fetal chemoreceptor responsiveness. Eleven fetal lambs (gestational age 125-133 d) were chronically instrumented with a catheter in a hindlimb artery and vein and a forelimb artery; a carotid arterial oximeter catheter was placed in six of these fetuses. An inflatable cuff occluder was placed around the maternal hypogastric artery. Acute fetal hypoxemia was induced repeatedly by reducing uterine blood flow. Fetal heart rate, arterial pressure, and carotid arterial oxygen saturation were monitored continuously before and after administering ketamine, morphine, pentobarbital, or propranolol to the fetus. The ratio delta heart rate/delta O2 saturation has been shown previously to be a reproducible index of chemoreflex response. The differences in baseline values and changes with drugs were compared by multiple regression analysis coded by effects. Chemoreflex response was markedly attenuated by ketamine and morphine but not by pentobarbital or propranolol. Because the cardiovascular response to hypoxemia is blunted by some drugs, caution should be exercised in interpreting heart rate responses to hypoxemia in the fetus when these drugs have been administered to the mother.

Effect of indomethacin on cerebral blood flow and oxygenation in the normal and ventilated fetal lamb.

Indomethacin lowers fetal and neonatal brain blood flow and may reduce the risk of periventricular-intraventricular hemorrhage. However, concerns have been raised that cerebral O2 metabolism may be compromised at lower cerebral perfusion pressures. In 17 near-term lamb fetuses, changes in brain blood flow and cerebral O2 metabolism (CMRO2) were measured at mean carotid arterial pressures (MCBP) ranging from 8 to 70 mm Hg. MCBP was adjusted by inflating balloon occluders around the aortic isthmus and brachiocephalic trunk. This was done before and during intrauterine pulmonary ventilation and oxygenation. Nine fetuses were pretreated with indomethacin (1 mg/kg i.v.); eight served as control. Changes in brain blood flow were assessed from carotid arterial blood flow (Qcar, mL/min) measured with flow transducers. In 15 animals, brain blood flow was also measured intermittently by radionuclide-labeled microspheres (Qbrain). Qcar correlated closely with Qbrain (r = 0.94, p < 0.0001); this relationship was not altered by indomethacin or by ventilation with oxygen. In the nonventilated fetuses, indomethacin decreased Qcar at pressures above the lower limit of cerebral autoregulation (43 mm Hg). However, at MCBP below 44 mm Hg, Qcar with indomethacin was not significantly different from controls. CMRo2 fell when MCBP was decreased below 30 mm Hg (range 8-29 mm Hg), but there was no significant difference between control and indomethacin-pretreated fetuses. In the ventilated fetuses, indomethacin reduced the slope of the pressure-flow relationship above the lower limit of cerebral autoregulation (43 mm Hg), suggesting improved cerebral autoregulation. When MCBP was decreased below 44 mm Hg (range 10-43 mm Hg), indomethacin did not lower Qcar or CMRO2 as compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of nitric oxide in the regulation of the cerebral circulation in the lamb fetus during normoxemia and hypoxemia.

The influence of nitric oxide (NO) blockade on resting tone and on hypoxia-induced vasodilatation of the cerebral vascular bed was examined in chronically instrumented lamb fetuses. Total (Qbrain-tot) and regional brain blood flow were measured using radioactive microspheres. NO blockade was achieved by N omega-nitro-L-arginine (NNLA) infusion into the carotid artery via a lingual artery. Fetal cerebral blood flow and cerebral vascular resistance (Rcer) were determined during normoxemia and hypoxemia and before and during infusion of L-arginine. During normoxemia, the brain blood flow decreased, and the resistance increased significantly after NNLA infusion (Qbrain-tot from 129 +/- 25 to 89 +/- 26 ml/100 g/min, p < 0.05; Rcer from 0.46 +/- 0.03 to 0.80 +/- 0.09 mm Hg/ml/100 g/min, p < 0.05). During hypoxemia before NNLA infusion, Qbrain-tot increased (from 129 +/- 25 to 187 +/- 56 ml/100 g/min, p < 0.05), and Rcer decreased (from 0.46 +/- 0.03 to 0.39 +/- 0.07 mm Hg/ml/100 g/min, p < 0.05). This vasodilatory response was largely blocked after NNLA (Qbrain-tot 143 +/- 45 ml/100 g/min; Rcer 0.58 +/- 0.07 mm Hg/ml/100 g/min). The response to hypoxemia was restored after infusion of L-arginine (Qbrain-tot 180 +/- 47 ml/100 g/min). The resting tone of the cerebral vascular bed of the lamb fetus is under NO control, and NO mediates the cerebral vasodilatory response to hypoxia in the lamb fetus.