Pulmonary vascular response to prostacyclin in fetal lambs.

Eighteen prostacyclin injections (19.4 +/- 1.5 micrograms/kg) were performed in five chronically instrumented, intact fetal lambs in order to study the effects on pulmonary blood flow. These resulted in a brief period of bradycardia followed by a more prolonged period of increased pulmonary blood flow. In this latter phase, pulmonary blood flow increased from a baseline value of 49 +/- 4 ml/(kg min) to 122 +/- 10 ml/(kg min). Systolic/diastolic pulmonary arterial pressure simultaneously fell from 73 +/- 2/48 +/- 1 to 68 +/- 2/42 +/- 1 mm Hg. Flow through the ductus arteriosus was unchanged and right ventricular output increased to account for the increased pulmonary blood flow. Thus, prostacyclin causes pulmonary vasodilation in intact fetal lambs and may participate in the control of fetal pulmonary blood flow and the circulatory adjustments to extra-uterine life.     

Mechanisms of stimulation of pulmonary prostacyclin synthesis at birth

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O₂ and decreased CO₂. Ventilation with fetal gas (3%O₂, 5%CO₂) increased net pulmonary prostacyclin (as 6-keto-PGF_1α production from −5.1 ± 4.4 to +12.6 ± 7.6 ng/kg·min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous P_O2 and decreased P_O2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing P_O2 or decreasing P_CO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had P_O2 and P_CO2 similar to fetal blood, blood with elevated O₂, and blood that had P_O2 and P_CO2 values similar to arterial blood of newborn animals. Neither increased O₂ nor decreased CO₂ in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.     

Surgery increases fetal plasma prostacyclin

Pulmonary arterial prostacyclin (as 6-keto-PGF_1α) concentrations of near term, fetakl lambs and goats were determined following fetal surgery and 24, 48, and 72 hrs later. Blood gases, pH, and arterial pressure were determined also. At the end of 2.5 hrs of surgery including exteriorization of the uterus and fetal thorocotomy, pulmonary arterial concentrations of 6-keto-PGF_1α was 948 ± 92 (SEM) pg/ml of blood. Twenty-four hrs later it had fallen to 435 ± 92 pg/ml and remained constant for the duration of monitoring. Maternal arterial 6-keto-PGF_1α concentration was much lower (105 ± 20 pg/ml of blood). No significance changes in fetal Pa_O2, Pa_CO2, pH, or arterial pressure were observed, although Pa_CO2 appeared to be elevated and pH reduced following surgery. These values normalized within 24 hrs. We conclude that surgical perturbation increases fetal arterial prostacyclin concentration. Increased prostacyclin levels are transient, reaching stable values within 24 hrs following completion of extensive surgery.     

Mechanism of stimulation of pulmonary prostacyclin synthesis at birth

In order to investigate the mechanism behind ventilation-induced pulmonary prostacyclin production at birth, chloralose anesthetized, exteriorized, fetal lambs were ventilated with a gas mixture that did not change blood gases (fetal gas) and unventilated fetal lungs were perfused with blood containing increased O2 and decreased CO2. Ventilation with fetal gas (3%O2, 5%CO2) increased net pulmonary prostacyclin (as 6-keto-PGF1 alpha) production from -5.1 +/- 4.4 to +12.6 +/- 7.6 ng/kg X min. When ventilation was stopped, net pulmonary prostacyclin production returned to nondetectable levels. Ventilation with gas mixtures which increased pulmonary venous PO2 and decreased PCO2 also stimulated pulmonary prostacyclin production, but did not have greater effects than did ventilation with fetal gas. In order to determine if increasing PO2 or decreasing PCO2 could stimulate pulmonary prostacyclin production independently from ventilation, unventilated fetal lamb lungs were perfused with blood that had PO2 and PCO2 similar to fetal blood, blood with elevated O2, and blood that had PO2 and PCO2 values similar to arterial blood of newborn animals. Neither increased O2 nor decreased CO2 in the blood perfusing the lungs stimulated pulmonary prostacyclin synthesis. We conclude that the mechanism responsible for the stimulation of pulmonary prostacyclin production with the onset of ventilation at birth is tissue stress during establishment of gaseous ventilation and rhythmic ventilation.     

Effect of ventilation on pulmonary blood volume of the fetal lamb.

Blood volume changes in the fetal lung following the onset of ventilation were studied by isotopic measurement of red blood cell and plasma volume in rapidly frozen lungs of ten near term fetal lambs. Total pulmonary blood volumes of fetal lambs ventilated with 3% O2 and 7% CO2 in nitrogen (so that blood gas levels were little changed from fetal values), or with air, were compared with measurements in unventilated lambs. Regional correlations of blood volume and blood flow (measured with isotope-labeled microemboli) within the lungs were also examined. Total pulmonary blood volume averaged 5.6 ml/kg body weight in unventilated fetal lambs and was approximately 43% greated in fetal lambs after 5-20 min of air ventilation, but not significantly different in lambs ventilated with 3% O2 and 7% CO2 in nitrogen. Thus it is ventilation with air, rather than the introduction of gas into the alveoli, which enlarges the fetal pulmonary vascular bed. Regional pulmonary blood volume and blood flow were correlated, though poorly, in air-ventilated lungs, but not in lungs ventilated with 3% O2 and 7% CO2 in nitrogen; this suggests that a common factor may operate to increase both blood flow and blood volume in the fetal lung following the introduction of air.     

Prostacyclin does not change during an oxygen induced increase in pulmonary blood flow in the fetal lamb

The role of prostacyclin in mediating the increase in pulmonary blood flow caused by an increase in oxygen tension in the fetal lamb was investigated. Plasma concentrations of 6-keto-PGF1 alpha, the hydrolysis product of prostacyclin, were measured during an increase in pulmonary blood flow caused by a rise in oxygen tension in eight intrauterine fetal lambs. Fetal oxygen tension was increased by placing the pregnant ewes in a hyperbaric chamber and having them breathe 100% oxygen at three atmospheres absolute pressure. This increased fetal PaO2 from 27 +/- 3 to 60 +/- 6 torr (mean +/- S.E., p less than or equal to 0.0001) and increased the proportion of right ventricular output distributed to the fetal lungs from 6 +/- 2 to 45 +/- 7% (mean +/- S.E., p less than or equal to 0.001). However, the fetal plasma concentration of 6-keto-PGF1 alpha did not change, 186 +/- 26 to 208 +/- 40 pg/ml (mean +/- S.E.). Indomethacin decreased plasma concentrations of 6-keto-PGF1 alpha in each of three fetuses but did not decrease the proportion of right ventricular output distributed to their lungs. The increase in pulmonary blood flow caused by an increase in oxygen tension in the fetal lamb is not associated with an increase in plasma concentrations of 6-keto-PGF1 alpha. Prostacyclin does not appear to be involved in the increase in pulmonary blood flow caused by the increase in oxygen tension at birth.     

NO supports right ventricular flow dominance and whole body O(2) utilization in midgestation fetal lambs

It is unknown if nitric oxide (NO) modulates the relative levels of left (LV) and right (RV) ventricular output, fetal O2 consumption, or blood flow distribution between the body and placenta at midgestation. To address these questions, six fetal lambs were instrumented at 89-96 days gestation (term 147 days), and blood flows were measured with radioactive microspheres 3-4 days later at baseline and after inhibition of NO synthesis with 10 mg/kg (L-NNA10) and 25 mg/kg (L-NNA25) N(omega)-nitro-L-arginine. LV output fell by 74 +/- 15 ml. min(-1). kg(-1) at L-NNA10 (P < 0.005), whereas RV output decreased by 90 +/- 18 ml. min(-1). kg(-1) at L-NNA10 (P < 0.02) and by a further 80 +/- 22 ml. min(-1). kg(-1) at L-NNA25 (P < 0.05). As a result, RV output exceeded LV output at baseline (P = 0.03) and L-NNA10 (P < 0.02) but not at L-NNA25. Fetal body blood flow fell by 95 +/- 25 ml. min(-1). kg(-1) at L-NNA10 (P < 0.01), but because placental blood flow decreased by 70 +/- 22 ml. min(-1). kg(-1) at L-NNA10 (P < 0.01) and a further 71 +/- 21 ml. min(-1). kg(-1) at L-NNA25 (P < 0.01), the fetal body-to-placental blood flow ratio was near unity at baseline and L-NNA10 but rose to 1.5 +/- 0.3 at L-NNA25 (P < 0.05). In association with these flow changes, fetal O2 consumption declined by 1.4 +/- 0.3 ml. min(-1). kg(-1) at L-NNA10 (P < 0.05) and by a further 1.5 +/- 0.6 ml. min(-1). kg(-1) at L-NNA25 (P < 0.02). These findings suggest that, in midgestation fetal lambs, NO supports an RV flow dominance, whole body O2 utilization, and the maintenance of a near-equal fetoplacental blood flow distribution.     

Acute hypoxia alters eicosanoid production of perfused pulmonary artery endothelial cells in culture

Hypoxia alters vascular tone which regulates regional blood flow in the pulmonary circulation. Endothelial derived eicosanoids alter vascular tone and blood flow and have been implicated as modulators of hypoxic pulmonary vasoconstriction. Eicosanoid production was measured in cultured bovine pulmonary endothelial cells during constant flow and pressure perfusion at two oxygen tensions (hypoxia: 4% O₂, 5% CO₂, 91% N₂; normoxia: 21% O₂, 5% CO₂, 74% N₂). Endothelial cells were grown to confluence on microcarrier beads. Cell cartridges (N=8) containing 2 ml of microcarrier beads ( 5 × 10⁶ cells) were constantly perfused (3 ml/min) with Krebs' solutions (pH 7.4, T 37°C) equilibrated with each gas mixture. After a ten minute equilibration period, lipids were extracted (C₁₈ Sep Pak®) from twenty minute aliquots of perfusate over three hours (nine aliquots per cartridge). Eicosanoids (6-keto PGF_1α; TXB₂; and total leukotriene [LT - LTC₄, LTD₄, LTE₄, LTF₄]) were assayed by radioimmunoassay. Eicosanoid production did not vary over time. 6-keto PGF_1α production was increased during hypoxia (normoxia 291 ± 27 vs hypoxia 395 ± 35 ng/min/gm protein; p < 0.01). Thromboxane production (normoxia 19 ± 2 vs hypoxia 20 ± 2 ng/min/gm protein) and total leukotriene production (normoxia 363 ± 35 vs hypoxia 329 ± 29 ng/min/gm protein) did not change with hypoxia. These data demonstrated that oxygen increased endothelial prostacyclin production but did not effect thromboxane or leukotriene production.     

The effects of prostacyclin and thromboxane analogue (U46619) on the fetal circulation and umbilical flow velocity waveforms

In placental insufficiency and pre-eclampsia the relative production rates of prostacyclin and thromboxane by the placenta and umbilical vessels are altered and the Doppler umbilical flow velocity waveform shows a high resistance pattern. To investigate the control of umbilical placental blood flow by those eicosanoids either prostacyclin (10 micrograms/min), or the thromboxane analogue U46619 (10 ng/min) was infused into the distal aorta of 12 chronically catheterized fetal lambs at day 125. Thromboxane produced a rise in mean arterial pressure and a rise in the systolic diastolic ratio of the umbilical artery flow waveform (2.6 to 3.1; P less than 0.05). Umbilical blood flow did not change and there was no evidence of altered flow to other organs. Prostacyclin caused a fall in fetal mean arterial pressure and a decrease in the umbilical artery systolic diastolic ratio (2.9 to 2.4; P less than 0.05). Prostacyclin produced a three-fold increase in lung perfusion (and the onset of fetal breathing movements) and this was associated with a 90% reduction in muscle blood flow (hindlimb muscle flow reduced from 12.5 to 1.1 ml.min-1 100g-1; P less than 0.01). We conclude that the local release of thromboxane in the fetal placental vascular bed could account for the rise in systolic diastolic ratio seen in umbilical placental insufficiency.     

The cerebral critical oxygen threshold of ventilated preterm lambs and the influence of antenatal inflammation

Perinatal inflammation is associated with adverse neurodevelopmental outcomes, which may be partly due to changes in the cerebral oxygen delivery/consumption relationship. We aimed to determine the critical oxygen delivery threshold of the brain of preterm, ventilated lambs and to determine whether the critical threshold is affected by exposure to inflammation in utero. Pregnant ewes received intra-amniotic injection of lipopolysaccharide or saline at 125 or 127 days of gestation. Pulmonary and systemic flow probes and catheters were surgically positioned in the fetus immediately before delivery at 129 days of gestation. After delivery, lambs were ventilated for 90 min using a positive end-expiratory pressure recruitment strategy. Cardio-respiratory variables and blood gases were measured regularly. Systemic and cerebral oxygen delivery, consumption (Fick), and extraction were calculated, and the relationship between cerebral delivery and consumption analyzed. Linear regression was used to define the transition or "critical" oxygen threshold as the point at which the slope of the oxygen delivery/consumption curve changed to be > 10°. Four subgroups were defined according to the calculated critical threshold. A total of 150 measurements were recorded in 18 lambs. Fetal cerebral oxygen consumption was increased by antenatal lipopolysaccharide (P < 0.05). The postnatal critical oxygen threshold was 3.6 ml·kg?1·min?1, corresponding to cerebral oxygen consumption of 0.73 ml·kg?1·min?1. High oxygen delivery and consumption were associated with increased pulmonary and carotid blood flow and systemic extraction compared with low oxygen delivery and consumption. No postnatal effect of antenatal inflammation was observed. Inflammation in utero increases fetal, but not postnatal, cerebral oxygen consumption. Adverse alterations to pulmonary blood flow can result in reduced cerebral blood flow, oxygen delivery, and consumption. Regardless of exposure to inflammation, there is a consistent postnatal relationship between cerebral oxygen delivery and consumption.     

Hemodynamic effects of postpulmonary administration of prostaglandin D2 in fetal animals

Dose-response relationships in pulmonary vascular resistance (PVR), mean systemic arterial pressure (SAP), and heart rate (HR) to left atrial administration of prostaglandin D2 (PGD2) were determined in five fetal lambs. Fetuses were delivered by cesarean section from chloralose anesthetized ewes with the umbilical circulation maintained intact. Fetuses were prevented from breathing thus maintaining pulmonary vascular tone in the elevated fetal state. Blood was withdrawn from the inferior vena cava and pumped at constant flow into the lower left lobe of the fetal lung. Postpulmonary infusions of PGD2 brought about dose-dependent decreases in pulmonary vascular resistance. Heart rate tended to increase in fetal lambs. Mean systemic arterial pressure increased in the fetal lambs at all doses tested except for the largest dose (44.14 micrograms/kg X min), which produced slight hypotension. These data demonstrate that exposure to the systemic circulation prior to entering the pulmonary vasculature does not alter the preferential dilator action of PGD2 on fetal pulmonary vessels nor does it produce significant systemic hypotension.     

Abolition of ventilatory response to caffeine in chemodenervated lambs

In this study we have evaluated the role of the peripheral chemoreceptors in the ventilatory response to caffeine at a dose currently used in human infants for treatment of central apneas (10 mg/kg). Twelve lambs were studied; six had carotid body denervation (CBD) and six had a sham denervation (intact). The denervation was done the 2nd wk of life, and the study of the response to caffeine infusion was carried out at a mean age of 82 days. The awake and nonsedated animals received 10 mg/kg of caffeine, and caffeine blood levels were, respectively, 8.8 and 9.0 mg/l in the intact and in the CBD lambs. The intact lambs responded to caffeine by a significant immediate increase in minute ventilation (VE) of 46% from 274 to 400 ml X min-1 X kg-1 (P less than 0.001), 1 min after caffeine infusion. This response rapidly faded, but VE was still increased at 2 h, 314 ml X min-1 X kg-1. The increase in ventilation was brought about by a change in mean inspiratory flow (VT/TI), which increased from 9.9 to 14.0 ml X s-1 X kg-1 within 1 min (P less than 0.01); VT/TI was still increased at 11.2 ml X s-1 X kg-1 2 h later. In contrast, for the CBD lambs there was no response to caffeine infusion as measured by VE or VT/TI. We conclude that bolus caffeine infusion produces a rapid response in VE followed by a fall in VE that remained above base line until at least 2 h postinfusion, and the intact chemoreceptor function appears as an essential mediator for these increases in ventilation, since the peripheral chemodenervation has completely abolished the VE response to this particular dose of caffeine.     

Bradykinin produces pulmonary vasodilation in fetal lambs: role of prostaglandin production

Bradykinin produces pulmonary vasodilation and also stimulates production of other pulmonary vasodilators, including prostaglandin I2 (PGI2) and endothelial-derived relaxing factor. In 12 chronically instrumented fetal lambs, we therefore investigated potential mediation of the bradykinin response by PGI2 or other cyclooxygenase products. A 15-min infusion of bradykinin (approximately 1 microgram/kg estimated fetal wt/min) increased fetal pulmonary blood flow by 522% (P less than 0.05) and decreased pulmonary vascular resistance by 86% (P less than 0.05); plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentration also increased (P less than 0.05). After cyclooxygenase inhibition by indomethacin (3 mg), bradykinin increased pulmonary blood flow by only 350% (P less than 0.05) and decreased pulmonary vascular resistance by 83% (P less than 0.05); plasma 6-keto-PGF1 alpha concentrations did not increase. The increase in pulmonary blood flow produced by bradykinin was greater before administration of indomethacin than after (P less than 0.05). These studies demonstrate that bradykinin produces fetal pulmonary vasodilation by at least two mechanisms, one dependent on and the other independent of PGI2 production, the latter mechanism predominating.     

Measurement of umbilical blood flow in fetal lambs in utero.

We continuously measured umbilical blood flow in fetal lambs in utero by placing an electromagnetic flow transducer around the common umbilical artery. Umbilical arteries originate from a short common segment as the terminal branches of the descending aorta. This segment was isolated by a retroperitoneal surgical approach and encircled with a specially constructed electromagnetic flow transducer. Catheters were also placed in fetal vessles to monitor pressure and derive flow values by the radionuclide-labeled microsphere technique. The fetus and ewe were allowed to recover for two days before studies were performed. Average umbilical blood flow obtained in 11 animals with the transducer was 199 ml/kg per min. In seven animals flow measurements obtained with the transducer were compared with those derived from microsphere injections. Paired measurements varied by an average of only 5.3%. This technique makes possible the accurate and instantaneous measurement of umbilical blood flow in fetal lambs in utero over a prolonged period.     

The effect of closing the ductus arteriosus on the pulmonary circulation of the fetal sheep

In the mammalian fetus the ductus arteriosus allows right ventricular output to be shunted away from the lungs to the systemic circulation. This study was performed to determine how closing the ductus arteriosus of the fetal sheep would affect the pulmonary circulation. Under halothane anaesthesia 6 near-term fetal sheep were delivered with the umbilical circulation intact. Catheters were placed in the right atrium, the pulmonary artery, and the aorta. Pulmonary blood flow was measured by injecting radioactive microspheres into the right atrium while a reference sample was withdrawn from the pulmonary artery. Closing the ductus arteriosus increased pulmonary arterial pressure by 22% from 51 +/- 3 to 62 +/- 3 mmHg and increased pulmonary blood flow disproportionately by 198% from 232 +/- 74 to 692 +/- 80 ml/min per 100g. Thus, pulmonary vascular resistance decreased by 75% from 0.451 +/- 0.65 to 0.095 +/- 0.010 mmHg 100g min/ml. These findings extend the observation that pressure and flow in the pulmonary circulation of the air-breathing lung do not have a linear relationship passing through the origin to include a striking example in the fluid-filled lung of the intact fetus. They also raise questions about the nature of the elevated vascular resistance in the fetal lung.     

Effects of uterine stimulant drugs on prostacyclin production by the pregnant rat myometrium. I. Oxytocin, bradykinin and PGF2α

The release of prostacyclin from chopped myometrial fractions of 18–20 day pregnant rats was assayed by inhibition of ADP-induced aggregation of citrated rabbit platelet-rich plasma. Preincubation of myometrial tissue with oxytocin 10 mU/ml increased prostacyclin generation from 2.25 ± 0.48 (control) to 3.75 ± 0.73 ng/mg over 15 minutes. Bradykinin 20 μg/ml also caused a significant increase in myometrial prostacyclin output from 2.26 ± 0.19 to 4.26 ± 0.64 ng/mg. PGF_2α 1 μg/ml did not increase prostacyclin release significantly. Pretreatment of myometrial tissue with the phospholipase inhibitor mepacrine significantly reduced the peptide-stimulated release of prostacyclin. The results suggest that prostacyclin production may play an important role in modulating the actions of oxytocin and bradykinin in the pregnant rat myometrium.     

Prostaglandin-mediated hyperemia and renin-mediated hypertension during acute ureteral obstruction

Acute elevation of ureteral pressure to 100 mm Hg in anesthetized dogs (n=7) resulted in an increase (P<0.005) in systemic blood pressure from 151±7 to 163 ± 7 mm Hg, a transient (15 min) increase (P<0.05) in renal blood flow from 413 ± 27 to 465 ± 27 ml/min C and a rise (P<0.05) in plasma renin activity from 6.0 ± 1.6 to 10.3 ± 2.1 ng/ml/hr. Pretreatment with a competitive inhibitor of angiotensin II, i.e. sar¹gly⁸AII, abolished the hypertensive response to acute ureteral obstruction, and pretreatment with 2 mg/kg of either indomethacin (n=6) or meclofenamate (n=3), 15 min before obstruction, prevented the hyperemic response. These results suggest that acute ureteral obstruction leads to hypertension via activation of the renin-angiotensin system and hyperemia via a prostaglandin-initiated mechanism.     

Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension.

During the latter third of gestation, the number of resistance vessels in the lungs of the fetal sheep increases by 10-fold even after correction for lung growth. We measured pulmonary arterial pressure and blood flow directly and calculated total pulmonary resistance (pressure divided by flow) in intrauterine fetal lambs at 93-95 days and at 136 days of gestation (term is 145-148 days). In addition, we used a hyperbaric chamber to increase oxygen tension in the fetuses and measured the effect on the pulmonary circulation. When corrected for wet weight of the lungs, pulmonary blood flow did not change with advancing gestation (139 +/- 42 to 103 +/- 45 ml.100 g-1.min-1). Pulmonary arterial pressure increased (42 +/- 5 to 49 +/- 3 mmHg); thus total pulmonary resistance increased with advancing gestation from 0.32 +/- 0.12 to 0.55 +/- 0.21 mmHg.100 g.min.ml-1. If the blood flow is corrected for dry weight of the lungs, neither pulmonary blood flow nor total pulmonary resistance changed with advancing gestation. Increasing oxygen tension increased pulmonary blood flow 10-fold in the more mature fetuses but only 0.2-fold in the less mature fetuses. At the normal low oxygen tension of the fetus, pulmonary blood flow does not increase between these two points of gestation in the fetal lamb despite the increase in vessel density in the lungs. However, during elevated oxygen tension, pulmonary blood flow does increase in proportion to the increase in vessel density.     

Lung vascular permeability changes in lambs with hyaline membrane disease

To investigate the mechanism of pulmonary edema in hyaline membrane disease (HMD), lymph from the efferent duct of the mediastinal lymph node was collected in premature lambs before and after delivery by cesarean section. Mean lymph flow in 7 lambs with histologically verified HMD increased progressively over 4 h after delivery to 3 times the fetal value, while lymph flow in 7 lambs without HMD increased to 3.5 times at 1 h and decreased thereafter. At 4 h after birth, lung lymph flow was significantly higher in lambs with HMD than in lambs without HMD (0.70 +/- 0.15 (SEM) vs 0.43 +/- 0.07 ml.h-1.kg-1). Lymph/plasma concentration ratio for small endogenous protein fractions (effective molecular radius, 3.6 and 3.8 nm) was significantly higher in lambs with HMD than in lambs without HMD at 2-4 h. Postmortem extravascular lung water was significantly higher in lambs with HMD (6.1 +/- 0.5 vs 4.3 +/- 0.3 ml/g dry lung weight). It is concluded that lung water is high in lambs with HMD, which appears to be a result both of delayed absorption of fetal lung liquid and increased permeability of the pulmonary exchange vessels.