Perinatal cardiopulmonary adaptation to the thin air of the Alto Andino by a native Altiplano dweller, the llama.

Most mammals have a poor tolerance to hypoxia, and prolonged O2 restriction can lead to organ injury, particularly during fetal and early postnatal life. Nevertheless, the llama (Lama Glama) has evolved efficient mechanisms to adapt to acute and chronic perinatal hypoxia. One striking adaptation is the marked peripheral vasoconstriction measured in the llama fetus in response to acute hypoxia, which allows efficient redistribution of cardiac output toward the fetal heart and adrenal glands. This strong peripheral vasoconstrictor tone is triggered by a carotid body reflex and critically depends on α-adrenergic signaling. A second adaptation is the ability of the llama fetus to protect its brain against hypoxic damage. During hypoxia, in the llama fetus there is no significant increase in brain blood flow. Instead, there is a fall in brain O2 consumption and temperature, together with a decrease of Na+-K+-ATPase activity and Na+ channels expression, protecting against seizures and neuronal death. Finally, the newborn llama does not develop pulmonary hypertension in response to chronic hypoxia. In addition to maintaining basal pulmonary arterial pressure at normal levels the pulmonary arterial pressor response to acute hypoxia is lower in highland than in lowland llamas. The protection against hypoxic pulmonary arterial hypertension and pulmonary contractile hyperreactivity is partly due to increased hemoxygenase-carbon monoxide signaling and decreased Ca2+ sensitization in the newborn llama pulmonary vasculature. These three striking physiological adaptations of the llama allow this species to live and thrive under the chronic influence of the hypobaric hypoxia of life at high altitude.

Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures.

Hypoxia induces several responses at cardiovascular, pulmonary and reproductive levels, which may lead to chronic diseases. This is relevant in human populations exposed to high altitude (HA), in either chronic continuous (permanent inhabitants) or intermittent fashion (HA workers, tourists and mountaineers). In Chile, it is estimated that 1.000.000 people live at highlands and more than 55.000 work in HA shifts. Initial responses to hypoxia are compensatory and induce activation of cardioprotective mechanisms, such as those seen under intermittent hypobaric (IH) hypoxia, events that could mediate preconditioning. However, whenever hypoxia is prolonged, the chronic activation of cellular responses induces long-lasting modifications that may result in acclimatization or produce maladaptive changes with increase in cardiovascular risk. HA exposure during pregnancy induces hypoxia and oxidative stress, which in turn may promote cellular responses and epigenetic modifications resulting in severe impairment in growth and development. Sadly, this condition is accompanied with an increased fetal and neonatal morbi-mortality. Further, developmental hypoxia may program cardio-pulmonary circulations later in postnatal life, ending in vascular structural and functional alterations with augmented risk on pulmonary and cardiovascular failure. Additionally, permanent HA inhabitants have augmented risk and prevalence of chronic hypoxic pulmonary hypertension, right ventricular hypertrophy and cardiopulmonary remodeling. Similar responses are seen in adults that are intermittently exposed to chronic hypoxia (CH) such as shift workers in HA areas. The mechanisms involved determining the immediate, short and long-lasting effects are still unclear. For several years, the study of the responses to hypoxic insults and pharmacological targets has been the motivation of our group. This review describes some of the mechanisms underlying hypoxic responses and potential therapeutic approaches with antioxidants such as melatonin, ascorbate, omega 3 (Ω3) or compounds that increase the nitric oxide (NO) bioavailability.

Fetal and postnatal pulmonary circulation in the Alto Andino.

Lowland mammals at high altitude constrict the pulmonary vessels, augmenting vascular resistance and developing pulmonary arterial hypertension. In contrast, highland mammals, like the llama, do not present pulmonary arterial hypertension. Using wire myography, we studied the sensitivity to norepinephrine (NE) and NO of small pulmonary arteries of fetal llamas and sheep at high altitudes. The sensitivity of the contractile responses to NE was decreased whereas the relaxation sensitivity to NO was augmented in the llama fetus compared to the sheep fetus. Altogether these data show that the fetal llama has a lower sensitivity to a vasoconstrictor (NE) and a higher sensitivity to a vasodilator (NO), than the fetal sheep, consistent with a lower pulmonary arterial pressure found in the neonatal llama in the Andean altiplano. Additionally, we investigated carbon monoxide (CO) in the pulmonary circulation in lowland and highland newborn sheep and llamas. Pulmonary arterial pressure was augmented in neonatal sheep but not in llamas. These sheep had reduced soluble guanylate cyclase and heme oxygenase expression and CO production than at lowland. In contrast, neonatal llamas increased markedly pulmonary CO production and HO expression at high altitude. Thus, enhanced pulmonary CO protects against pulmonary hypertension in the highland neonate. Further, we compared pulmonary vascular responses to acute hypoxia in the adult llama versus the adult sheep. The rise in pulmonary arterial pressure was more marked in the sheep than in the llama. The llama pulmonary dilator strategy may provide insights into new treatments for pulmonary arterial hypertension of the neonate and adult.

Low-dose inhaled carbon monoxide reduces pulmonary vascular resistance during acute hypoxemia in adult sheep.

Carbon monoxide (CO) is produced by the action of the heme oxygenase (HO) complex through the oxidation of heme. CO, like nitric oxide (NO), is a molecular gas that among other actions stimulates guanylyl cyclase and increases cGMP levels in smooth muscle cells, regulating the vascular tone. Acute hypoxia generates pulmonary hypertension and increases the expression of inducible HO isoform (HO-1) in the vascular endothelium. Inhaled NO causes a potent pulmonary vasodilation. We hypothesized that inhaled CO might produce similar actions as NO on pulmonary vascular resistance (PVR). To test our contention, we studied the effects of inhaled CO (40 ppm) in the augmented PVR observed during hypoxemia. Five chronically instrumented German Merino sheep were submitted to a protocol consisting of 20 min of normoxemia (N), 20 min of isocapnic hypoxemia (H20), 20 min of isocapnic hypoxemia plus CO 40 ppm (H40), and 20 min of recovery (R). In the control protocol, we did not administer inhaled CO. Arterial gases and pH, percentage of carboxyhemoglobin (COHb), systemic and pulmonary arterial pressure, systemic and pulmonary vascular resistance, and cardiac output were measured during each period. During H20 period, there was a significant increase in cardiac output and PVR in sheep submitted to both protocols. The sheep treated with inhaled CO (H40 + CO) showed a modest but significant decrease (16%) in the elevated PVR. Our data indicate that inhaled CO decreases pulmonary vascular resistance associated with acute hypoxemia in adult sheep.

Nitric oxide synthase activity in brain tissues from llama fetuses submitted to hypoxemia.

The fetal llama (Lama glama; a species adapted to live in chronic hypoxia in the highlands of the Andes) did not increase cerebral blood flow and reduce the brain oxygen uptake during hypoxemia. Although nitric oxide (NO) is a normal mediator in the regulation of vascular tone and synaptic transmission, NO overproduction by hypoxemia could produce neuronal damage. We hypothesized that nitric oxide synthase (NOS) activity is either maintained or reduced in the central nervous system of the llama fetuses submitted to chronic hypoxemia. Approximately 85% of the Ca(2+)-dependent NOS activity was soluble, at least 12% was associated with the mitochondrial fraction, and less than 5% remains associated with microsomes. To understand the role of NO in chronic hypoxemia, we determined the effect of 24-h hypoxemia on NOS activity in the central nervous system. No changes in activity or the subcellular distribution of NOS activity in brain tissues after hypoxemia were found. We proposed that the lack of changes in NOS activity in the llama under hypoxemia could be a cytoprotective mechanism inherent to the llama, against possible toxic effects of NO.

Cardiovascular responses to arginine vasopressin blockade during acute hypoxemia in the llama fetus.

The fetal llama has a marked increase in the peripheral vascular resistance and no augmentation of brain blood flow during hypoxemia. In spite of the substantial plasma arginine-vasopressin (AVP) increase during hypoxemia, up to 8 times greater than in fetal sheep, there are no changes of carotid and femoral blood flows during hypoxemia with a V1 receptor blockade, as is seen in the fetal sheep. The aim of this study was to assess the role of AVP function in mediating the combined ventricular output and organ blood flow in the hypoxemic llama fetus. Six fetal llamas at 0.65 of gestation were instrumented under general anesthesia, and cardiorespiratory responses and blood flows determined under normoxemic and hypoxemic conditions. The AVP effect was determined using a V1 antagonist during normoxemic and hypoxemic conditions. Organ blood flows were measured with the radioactive microsphere technique. No significant differences in organ blood flow or in their vascular resistances were seen between the control and treated fetuses during hypoxemia. We conclude that V1 blockade did not have any important role in the cardiovascular response to acute hypoxemia in the llama fetus, in contrast with lowland fetuses. AVP may be playing a role in other regions, possibly in kidney or lung, during hypoxemia.

Adrenergic and vasopressinergic contributions to the cardiovascular response to acute hypoxaemia in the llama fetus.

1. The effects of fetal intravenous treatment with phentolamine or a vasopressinergic V1-receptor antagonist on the fetal cardiovascular responses to acute hypoxaemia in the llama were investigated. 2. Six llama fetuses were surgically prepared between 60 and 70 % of gestation under general halothane anaesthesia with vascular catheters and transit-time ultrasonic flow probes around a carotid artery and a femoral artery. At least 4 days after surgery all fetuses were subjected to a 3 h experiment: 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery while on slow i.v. infusion with saline. On separate days this experiment was repeated with fetal i.v. treatment with either phentolamine or a V1-receptor antagonist dissolved in saline. 3. During saline infusion all llama fetuses responded to acute hypoxaemia with intense femoral vasoconstriction. Phentolamine during normoxia produced hypotension, tachycardia and vasodilatation in both the carotid and the femoral circulations. During hypoxaemia, fetuses treated with phentolamine did not elicit the pronounced femoral vasoconstriction and all died within 20 min of the onset of hypoxaemia. A V1-receptor antagonist produced a femoral vasodilatation during normoxia but did not affect the fetal cardiovascular responses to acute hypoxaemia. 4. In conclusion, alpha-adrenergic and V1-vasopressinergic mechanisms contribute to a basal vasoconstrictor tone in the femoral circulation in the llama fetus. The enhanced femoral vasoconstriction during acute hypoxaemia in the llama fetus is not mediated by stimulation of V1-vasopressin receptors, but is dependent on alpha-adrenergic receptor stimulation. Such alpha-adrenergic efferent mechanisms are indispensable to fetal survival during hypoxaemia in the llama since their abolition leads to cardiovascular collapse and death.

Repeated doses of the perfluorocarbon FC-100 improve lung function of preterm lambs.

Intratracheal administration of a single dose of the perfluorocarbon FC-100 improves lung function in surfactant-deficient animals. In this study we compared the response to repeated doses of FC-100 (3 mL/kg 3% solution, n = 5) with that observed after administration of Exosurf (5 mL/kg, n = 5) to mechanically ventilated preterm lambs of 125 d of gestation. The initial dose of FC-100 rapidly increased arterial PO2, decreased arterial PCO2, and improved arterial pH. Also dynamic lung compliance markedly improved with this agent. Administration of an additional dose of FC-100 resulted in relatively similar changes, albeit of lesser magnitude than those observed with the initial dose. In contrast, Exosurf did not improve these variables even after three doses. All lambs treated with FC-100 survived the 6-h study period, whereas one of the five Exosurf-treated lambs survived (p < 0.05). Mean arterial blood pressure and heart rate decreased in those lambs that received FC-100, but not in surviving lambs that received Exosurf. Our data demonstrate that repeated intratracheal administration of the perfluorocarbon FC-100 improves lung function and survival of surfactant-deficient lambs better than the synthetic surfactant Exosurf. We speculate that tensio-active agents with properties different from surfactant, such as FC-100, might improve lung function in preterm neonates with diseases due to surfactant deficiency.

Carotid blood flow changes with behavioral states in the late gestation llama fetus in utero.

This study tested the hypothesis that in the llama fetus changes in cerebral blood flow are closely associated with changes in cerebral oxidative metabolism such as occur during transitions between electrocortical states. For the first time reported in any species, instantaneous changes in common carotid blood flow, employed as a continuous index of cerebrovascular perfusion, were related to instantaneous changes in electrocortical activity. Three late gestation fetal llamas were surgically prepared under general anesthesia with vascular catheters, a tracheal and amniotic catheter, and with electrodes implanted to monitor the fetal electrocorticogram (ECoG). In addition, Transonic flow probes were placed around a common carotid artery and a femoral artery. At least 4 days after surgery fetal arterial blood, amniotic and tracheal pressures, carotid and femoral blood flows and the fetal ECoG were recorded continuously. Our results suggest a close association between increases in common carotid blood flow and low voltage ECoG in the llama fetus. Close coupling between instantaneous changes in carotid blood flow and electrocortical states together with the lack of an increase in brain blood flow without increased cerebral oxygen extraction during hypoxemia in the llama fetus supports a fall in cerebral oxidative metabolism in this species during hypoxemic episodes.

Fetal and maternal blood oxygen affinity: a comparative study in llamas and sheep.

We compared blood oxygen affinity (P50) and hemoglobin concentration among fetal and maternal llamas and sheep, as respective examples of species native to high and low altitudes. P50, hemoglobin concentration and blood oxygen content were determined at sea level in 16 pregnant llamas, 6 pregnant sheep and their respective fetuses. P50 was similar in fetal llamas and sheep, but maternal llamas had higher blood oxygen affinity than maternal sheep. As a consequence, the P50 difference between mother and fetus was less in llamas than in sheep. Fetal llamas had higher hemoglobin concentrations than fetal sheep. In contrast, the maternal hemoglobin concentrations were similar. The blood oxygen content was higher in fetal and maternal llamas than in fetal and maternal sheep. We conclude that the llama, a species native to the altiplano, has a higher blood oxygen content than the sheep, as determined in the fetus by a high hemoglobin concentration and in the mother by a low P50.

Chemoreflex and endocrine components of cardiovascular responses to acute hypoxemia in the llama fetus.

We tested the hypothesis that the llama fetus has a blunted cardiovascular chemoreflex response to hypoxemia by investigating the effects of acute hypoxemia on perfusion pressure, heart rate, and the distribution of the combined ventricular output in 10 chronically instrumented fetal llamas at 0.6-0.7 gestation. Four llama fetuses had the carotid sinus nerves sectioned. In the intact fetuses, there was a marked bradycardia, an increase in perfusion pressure, and a pronounced peripheral vasoconstriction during hypoxemia. These cardiovascular responses during hypoxemia in intact fetuses were accompanied by a pronounced increase in plasma vasopressin, but not in plasma angiotensin II concentrations. Carotid denervation prevented the bradycardia at the onset of hypoxemia, but it did not affect the intense vasoconstriction during hypoxemia. Plasma vasopressin and angiotensin II levels were not measured in carotid-denervated fetuses. Our results do not support the hypothesis that the carotid chemoreflex during hypoxemia is blunted in the llama fetus. However, they emphasize that other mechanisms, such as increased vasopressin concentrations, operate to produce an intense vasoconstriction in hypoxemia. This intense vasoconstriction in the llama fetus during hypoxemia may reflect the influence of chronic exposure to the hypoxia of high altitude on the magnitude and gain of fetal cardiovascular responses to a superimposed acute episode of hypoxemia.

Cardiovascular responses to graded degrees of hypoxaemia in the llama fetus.

The fetal llama exposed to an intense degree of hypoxaemia did not increase cerebral blood flow, but showed a marked peripheral vasoconstriction. The same cardiovascular response is observed in fetal sheep submitted to a extremely severe hypoxaemia, when the initial compensatory vasodilatory mechanisms in brain and heart fail. To investigate whether the fetal llama responses to acute hypoxaemia are adaptive, or whether they are the result of a breakdown of mechanisms of blood flow redistribution that favours the central nervous system, we studied seven fetal llamas (0.6-0.7 of gestation) chronically-catheterized during 1 h of graded and progressive hypoxaemia. Fetal ascending aorta blood gases and fetal cardiac output and its distribution (radiolabelled-microspheres) were measured after 60 min of normoxaemia (B) and at the end of 20 min (H20), 40 min (H40) and 60 min (H60) of hypoxaemia. Data were analysed by ANOVA and Newman-Keuls tests. Each treatment resulted in a lower (P < 0.05) percentage of haemoglobin saturation than hypoxaemia; H40 was lower than H20, and H60 was lower than H20 and H40. No statistical difference was observed among treatments for cardiac output or cerebral blood flow. These results demonstrate that fetal cardiac output and brain blood flow are maintained at all degrees of hypoxaemia, indicating that these cardiovascular responses are an adaptive response in the llama fetus, rather than an index of cardiorespiratory decompensation.

Maternal administration of glucocorticoid and thyrotropin-releasing hormone enhances fetal lung maturation in undisturbed preterm lambs.

OBJECTIVE: We hypothesized that combined treatment with glucocorticoid plus thyrotropin-releasing hormone administered to pregnant ewes with preterm gestation accelerates fetal lung maturation of undisturbed lambs better than single hormonal treatment does. STUDY DESIGN: Twenty-five pregnant ewes at 123 days of gestation were randomized to receive (1) 0.9% sodium chloride (controls), (2) betamethasone (12 mg intramuscularly every 24 hours two times), (3) thyrotropin-releasing hormone (400 micrograms intravenously every 8 hours six times), or (4) thyrotropin-releasing hormone plus betamethasone. After delivery by cesarean section at 125 days fetal lamb lung compliance and alveolar lavage phospholipid content were determined. RESULTS: Betamethasone plus thyrotropin-releasing hormone significantly increased fetal lung compliance expressed as milliliters of air per gram of wet weight at 40 cm H2O and 5 cm H2O (0.82 +/- 0.13 and 0.35 +/- 0.10 ml/gm wet lung, respectively) versus betamethasone (0.37 +/- 0.02 and 0.07 +/- 0.02), thyrotropin-releasing hormone (0.38 +/- 0.02 and 0.14 +/- 0.03), and control (0.25 +/- 0.03 and 0.09 +/- 0.01) groups. Also, total phospholipids and saturated phosphatidylcholine concentrations in alveolar lavage were significantly higher in the combined betamethasone plus thyrotropin-releasing hormone group (27.3 +/- 4.9 and 16.9 +/- 4.3 micrograms/gm wet lung, respectively) versus betamethasone (10.9 +/- 3.5 and 6.7 +/- 2.1), thyrotropin-releasing hormone (15.2 +/- 5.6 and 7.3 +/- 2.0), and control (7.9 +/- 2.4 and 3.6 +/- 1.0) groups. CONCLUSION: Combined maternal administration of betamethasone plus thyrotropin-releasing hormone improves lung maturation in undisturbed fetal lambs at 125 days' gestation more than does either hormone given alone.

Effect of a melatonin implant on the circadian variation of plasma prolactin and rectal temperature in newborn sheep.

Plasma prolactin and rectal temperature show a circadian rhythm in newborn sheep raised under continuous light. Melatonin lowers the concentration of plasma prolactin but it is not known if it affects its circadian rhythm. To detect whether melatonin acts on the circadian system we studied the effect of a subcutaneous melatonin implant in the circadian rhythms of prolactin and rectal temperature in newborn lambs raised under continuous light. We placed catheters in the pedal artery and vein in 9 newborn lambs (2-5 days of age). A subcutaneous melatonin implant was placed in 4 of the lambs at 9-12 days of age. Blood samples and rectal temperature measurements were obtained hourly for a period of 24 h, 11-15 days after the implant, at 20-27 days of age. To avoid interferences of heparin in our melatonin assay, serum melatonin concentration was measured before and during the implant in three additional newborns. Prolactin and melatonin were measured by RIA. Melatonin concentrations were 52.8 +/- 45.9 pg/ml (day) and 315.5 +/- 77.0 pg/ml (night) before treatment (SEM, P less than 0.001), and increased to 594.1 +/- 54.5 pg/ml after placing the implant (there was no difference in melatonin concentration between day and night during the time that the implant was in place). Melatonin had no effect on rectal temperature or its rhythm, but decreased basal plasma prolactin concentration (control: 97.5 +/- 11.3 ng/ml; treated: 25.1 +/- 2.4 ng/ml, P less than 0.001) and abolished the prolactin circadian rhythm, (Cosinor analysis): control: log prolactin (ng/ml) = 1.8 + 0.26 cos 15 (t - 11.16), p = 0.05; treated: log prolactin (ng/ml) = 1.2 + 0.14 cos 15 (t - 9.43), P = 0.36.

The circadian variation of prolactin in fetal sheep is affected by the seasons.

Plasma PRL concentration shows a circadian variation in fetal and adult sheep. In the adult sheep the presence of this variation depends on the season. In this paper we investigated whether season affects the presence of the circadian variation of PRL in the fetal sheep. To that effect we measured plasma PRL concentration every 2 h for 24 h during summer, fall, and winter in three groups of fetal sheep whose gestational ages ranged from 125-133 days. Mean (+/- SEM) fetal plasma PRL concentrations were 352.8 +/- 65.0 ng/ml during summer (n = 6), 98.7 +/- 12.9 during fall (n = 8), and 10.5 +/- 2.6 during winter (n = 4). A 24-h variation of plasma PRL was detected during summer [PRL (ng/ml) = 352.8 + 85.2 cos 15 (t - 18.5); P = 0.007] and fall [PRL (ng/ml) = 98.7 + 26.6 cos 15 (t - 23.6); P = 0.041] but not during winter. The mesor and amplitude of the variation are higher in summer than in fall, and the acrophases differ by 5 h, taking place at dusk in summer and close to midnight in fall. These findings show that in fetal sheep, PRL responds to seasons in utero. The signal triggering this response is most likely photoperiod.

Fetal prolactin levels respond to a maternal melatonin implant.

Seasonal PRL changes in adult sheep are controlled by photoperiod. The ability to detect photoperiod is mediated by the pineal gland through melatonin secretion. A rhythm in plasma melatonin has been described in fetal sheep. In this work we investigated whether the fetus responds to changes in circulating levels of melatonin. Fetal plasma PRL was measured every 2 h for 24 h, 7 days after the mother had received a sc Silastic implant containing approximately 1 g melatonin. Control fetuses received an empty implant. Melatonin is slowly released from implants, and it is known to cross the sheep placenta. Fetal plasma melatonin increased 10-fold after the implant. Plasma PRL in fetuses treated with melatonin was a third of that of control fetuses. Fetal plasma PRL concentrations were 56.6 +/- 5.7 ng/ml (mean +/- SE) in control and 18.1 +/- 2.7 ng/ml 7 days after the melatonin implant. We conclude from these data that the ability to respond to melatonin is present in sheep during fetal life.

Ontogeny of the circadian rhythm of cortisol in sheep.

In this work we investigated the ontogeny of the rhythm of plasma cortisol in sheep. Plasma cortisol was measured by radioimmunoassay in blood samples obtained every 1 or 2 h, for periods of 24 or 48 h, in 13 fetal sheep (124-140 days of gestation; 130.6 +/- 1.5, mean +/- SE) and in 23 newborn (5-39 days of age). To this end, indwelling polyvinyl catheters were implanted into the femoral artery and vein in all animals. The presence of rhythm was determined by Cosinor Analysis. Newborns were separated into four groups. Group 1, newborns younger than 15 days of age (7.9 +/- 0.7 days), and Group 2, newborns older than 15 days of age (25.4 +/- 2.3), were raised under nyctohemeral conditions (12L:12D). Group 3, newborns younger than 15 days of age (11.4 +/- 0.9 days), and Group 4, newborns older than 15 days of age (22.0 +/- 1.2 days), were raised under constant light conditions. A 24-h rhythm of plasma cortisol (F) was observed in newborns over 15 days of age under both nyctohemeral: F (ng/ml) = 16.1 + 7.6 cos [15 (t-12.9)], (p = 0.01, n = 8) and constant light conditions: F (ng/ml) = 17.1 + 3.9 cos [15 (t-7.9)], (p = 0.02, n = 5). No rhythm was observed in fetal sheep or in newborn sheep younger than 15 days of age under nyctohemeral or constant light conditions.

Arginine vasopressin mediates cardiovascular responses to hypoxemia in fetal sheep.

Acute hypoxemia results in hypertension, bradycardia, and cardiac output redistribution in fetal sheep. The blood flow redistribution is produced by differential changes in vascular resistance of various fetal organs. alpha-Adrenergic activity is one of the few vasoconstrictor mechanisms thus far identified in the hypoxemic fetal sheep. Arginine vasopressin (AVP) is a potent vasoconstrictor in adults. Since AVP administration to the normoxic fetus mimics some of the fetal cardiovascular responses to hypoxemia and fetal plasma AVP levels increase with hypoxemia, we examined the hypothesis that AVP modifies the fetal cardiovascular response to hypoxemia by changing the vascular resistance of some fetal vascular beds. To test this we determined fetal systemic arterial pressure and fetal cardiac output and its distribution during hypoxemia with and without the V1 AVP antagonist d(CH2)5-Tyr(Me)AVP. Fourteen fetal sheep (0.79-0.90 of gestation) were chronically catheterized. Five days after surgery fetal hypoxemia was induced by introducing a mixture of 95% N2-5% CO2 (10-20 l/min) into a maternal tracheal catheter. The hypoxemia was maintained for 40 min. Fetal heart rate, systemic arterial blood pressure, and combined ventricular output and its distribution (radiolabeled microspheres) were measured before hypoxemia, at 20 min of hypoxemia alone, and at 20 min of hypoxemia plus either AVP antagonist (n = 5) or NaCl 0.9% (n = 5, controls). Fetal hypertension and bradycardia were partially reversed after the AVP antagonist administration during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)