Pulmonary metabolism during diving: conditioning blood for the brain.

During experimental diving by the awake Weddell seal, blood glucose concentration falls consistently. A large fraction of the glucose consumed from the central circulating blood appears as lactate. During diving, the lung utilizes blood lactate in preference to blood glucose as a source of both carbon and energy, and it is able to release glucose into pulmonary venous blood to supplement the supply available for brain metabolism.

Seal lungs collapse during free diving: evidence from arterial nitrogen tensions.

Arterial blood nitrogen tensions of free-diving Weddell seals (Leptonychotes weddelli) were measured by attaching a microprocessor-controlled blood pump and drawing samples at depth to determine how these marine mammals dive to great depths and ascend rapidly without developing decompression sickness. Forty-seven samples of arterial blood were obtained from four Weddell seals during free dives lasting up to 23 minutes to depths of 230 meters beneath the sea ice of McMurdo Sound, Antarctica. Peak arterial blood nitrogen tensions of between 2000 and 2500 millimeters of mercury were recorded at depths of 40 to 80 meters during descent, indicating that the seal's lung collapses by 25 to 50 meters. Then arterial blood nitrogen tensions slowly decreased to about 1500 millimeters of mercury at the surface. In a single dive, alveolar collapse and redistribution of blood nitrogen allow the seal to avoid nitrogen narcosis and decompression sickness.

Breathing pattern, CO2 elimination and the absence of exhaled NO in freely diving Weddell seals.

UNLABELLED: Weddell seals undergo lung collapse during dives below 50 m depth. In order to explore the physiological mechanisms contributing to restoring lung volume and gas exchange after surfacing, we studied ventilatory parameters in three Weddell seals between dives from an isolated ice hole on McMurdo Sound, Antarctica. METHODS: Lung volumes and CO(2) elimination were investigated using a pneumotachograph, infrared gas analysis, and nitrogen washout. Thoracic circumference was determined with a strain gauge. Exhaled nitric oxide was measured using chemiluminescence. RESULTS: Breathing of Weddell seals was characterized by an apneustic pattern with end-inspiratory pauses with functional residual capacity at the end of inspiration. Respiratory flow rate and tidal volume peaked within the first 3 min after surfacing. Lung volume reductions before and increases after diving were approximately 20% of the lung volume at rest. Thoracic circumference changed by less than 2% during diving. The excess CO(2) eliminated after dives correlated closely with the duration of the preceding dive. Nitric oxide was not present in the expired gas. CONCLUSION: Our data suggest that most of the changes in lung volume during diving result from compression and decompression of the gas remaining in the respiratory tract. Cranial shifts of the diaphragm and translocation of blood into the thorax rather than a reduction of thoracic circumference appear to compensate for lung collapse. The time to normalise gas exchange after surfacing was mainly determined by the accumulation of CO(2) during the dive. These findings underline the remarkable adaptations of the Weddell seal for restoring lung volume and gas exchange after diving.

Protein binding of plasma cortisol in the foetal lamb near term.

Binding of cortisol to plasma proteins was studied in the foetal lamb by equilibrium dialysis at 37 degrees C. At 122 days of pregnancy the mean level of transcortin expressed as cortisol-binding capacity was 28 +/- 6 (S.D.) ng cortisol/ml plasma. During the last 14 days of pregnancy there was a progressive increase in transcortin-binding capacity to 85 +/- 14 ng cortisol/ml plasma. A sharp increase in the concentration of both protein-bound and unbound cortisol was observed over the same period. A rise in the concentration of total cortisol from around 3 to 42 ng/ml was associated with an increase in unbound cortisol from 0-2 to a maximum of 2-1 ng/ml. The concentration of albumin-bound cortisol was approximately equal to that of unbound cortisol. The mean value for the transcortin-cortisol affinity constant was 1-15 x 10(8) l/mol. It is concluded that an increase in transcortin-binding capacity is partly responsible for the prepartum increase of corticosteroid levels observed in normal foetal lambs.

Comparison of the effects of prostaglandin E2, prostacyclin and 1-24 adrenocorticotrophin on plasma cortisol levels of fetal sheep.

The changes in plasma cortisol levels in response to intravenous infusions of prostaglandin E2 (PGE2), prostacyclin and 1-24 ACTH have been studied in chronically catheterized fetal sheep during the last third of gestation. All three drugs increased plasma cortisol levels with prostacyclin being sigificantly more potent than either PGE2 or 1-24 ACTH. No interaction between the steroidogenic actions of 1-24 ACTH and either PGE2 or prostacyclin could be demonstrated. The steroidogenic action of PGE2 was not significantly modified by fetal hypophysectomy. It is concluded that neither PGE2 nor prostacyclin is likely to be involved in the enhanced adrenal responsiveness to 1-24 ACTH observed in fetal sheep in the period immediately before birth.

On the origin of dehydroepiandrosterone sulphate in the blood of fetal sheep.

Total sulphoconjugated and unconjugated dehydroepiandrosterone (DHA) and total oestrone were measured in plasma of intact sheep fetuses, fetuses hypophysectomized at 104-112 days and fetuses bilaterally adrenalectomized at 98-101 days. At 120-127 days, the mean concentrations of total DHA and oestrone in intact fetuses (n = 13) were 29.7 +/- 4.2 (S.E.M.) nmol/l and 14.3 +/- 2.8 nmol/l respectively. At term, the values for total DHA and oestrone in hypophysectomized fetuses (n = 13) of 18.0 +/- 1.9 nmol/l and 9.1 +/- 2.0 nmol/l were significantly (P less than 0.05) lower than the intact group whereas in the adrenalectomized fetuses (n = 8) total DHA (80.8 +/- 13.0 nmol/l) was higher (P less than 0.05) and total oestrone values were similar to the intact animals. Intrafetal infusion of cortisol at term (1 mg/h for 84 h) raised levels of total oestrone in intact (n = 6; 12.3 +/- 2.9 vs 31.6 +/- 8.5 nmol/l) and adrenalectomized (n = 4; 14.2 +/- 2.6 vs 190.6 +/- 53.0 nmol/l) fetuses and of total DHA in hypophysectomized fetuses (n = 7; 16.0 +/- 1.9 vs 31.6 +/- 8.5 nmol/l) while infusion of ACTH (1-24) (5 micrograms/h) was without significant effect in any group. It is concluded that the ovine fetal adrenal in late pregnancy makes no significant contribution either to the high circulating concentrations of DHA sulphate or to the substrates for placental oestrogen synthesis.

Serum somatomedin C concentrations in the fetal sheep increase markedly during gestation.

Serum somatomedin C concentrations in fetal sheep and pregnant ewes from days 51 to 149 of gestation were determined by specific radioimmunoassay. In the fetus (n = 61 samples) serum somatomedin C concentrations, fitted to a regression curve, increased significantly with advancing gestation from 0.44 units/ml at 51 days to 3.99 units/ml at 149 days, an increase of 806% (P less than 0.001). In the pregnant ewes (n = 14 samples), serum somatomedin C did not change during gestation. The temporal relationship between the marked increase in fetal somatomedin C concentrations and the acceleration of fetal growth is consistent with the hypothesis that somatomedin is important in the stimulation of fetal growth.

Prostaglandins: current therapeutic status in obstetrics.

PIP: Recent research suggests that the action of prostaglandins on the pregnant uterus is more complex than that of oxytocin. Despite the fact that prostaglandins, like oxytocin, may fall short of the ideal, preliminary work makes it apparent that prostaglandins have attributes for induction of labor that will ultimately rank them as far superior to oxytocin. A 1st sign that prostaglandins might be more than just oxytocic agents came from the discovery of the effectiveness of prostaglandin F2alpha (PGF2alpha) and prostaglandin E2 (PGE2) in inducing mid-trimester abortion. For a long time it has been known that oxytocin seldom causes abortion of a normal pregnancy. Prostaglandins cause rapid dilatation of the cervix and expulsion of the conceptus despite a lesser degree of measurable uterine activity than that induced by oxytocin. Prostaglandins do something more, either to the quality of uterine contractions or to the cervix. A major problem associated with the pharmacological use of prostaglandins has been a high incidence of unpleasant side-effects when given by routes that are associated with substantial systemic uptake. In general, doses of prostaglandins that are oxytocic result in nausea, vomiting and diarrhea when administered by the intravenous, oral or intravaginal routes. The intra-amniotic and extra-ovular routes of administration for induction of mid-trimester abortion, as described by Doctors Karim and Hillier, are examples of the successful application of the principle that prostaglandins can be effective without side-effects when they are delivered close to the site of action. Prostaglandins appear particularly well suited to induction of labor in women with prolonged fetal death, anencephaly or hydatidiform mole.^ieng

Collagen content of human amniotic membranes: effect of gestation length and premature rupture.

The collagen content of amniotic membranes was measured in samples obtained at delivery from patients with and without premature rupture of the membranes (PROM). In samples from patients with PROM the collagen content (343 microgram/mg) was significantly lower than in samples from patients without PROM (373 microgram/mg) (P less than .005). The collagen content decreased between 32 and 40 weeks' gestation from 446 to 362 microgram/mg (r = .588; P less than .001) in patients without PROM and from 393 to 332 microgram/mg (r = -.362; P less than .05) in patients with PROM. The latent period between membrane rupture and delivery was not associated with a decrease in collagen content. The changes in amnion collagen during gestation and the differences observed with PROM suggest that weakening of the amnion in preparation for rupture may be determined partly by factors controlling the synthesis and degradation of collagen.

System for predicting spontaneous preterm birth.

The authors performed a prospective analysis of the value of a system for scoring the risk of preterm delivery (RPD). The RPD system predicts that approximately 10% of patients will have preterm labor and delivery. Although only one third of these patients deliver before term, they account for approximately two thirds of all preterm births. The discrimination of the RPD system is better for multigravid patients than for primigravid patients, and rescoring at 26 to 28 weeks' gestation improves the accuracy of prediction.

Synergism of cortisol and thyrotropin-releasing hormone in lung maturation in fetal sheep.

The effects of fetal infusions of cortisol and thyrotropin-releasing hormone (TRH) singly and together on pressure-volume relationships and saturated phosphatidylcholine (SPC) concentrations in the lungs were studied in 28 fetal sheep delivered at 128 days of gestation. Four groups each of 7 fetuses were infused with either saline (for 156 h), TRH (25 micrograms/h in 60-s pulses for 156 h), TRH (for 156 h) combined with cortisol (1 mg/h for 84 h), or cortisol (for 84 h). Cortisol had no effect on SPC concentrations, whereas both TRH and cortisol plus TRH increased the concentration of SPC in lavage fluid but not lung tissue. Neither cortisol nor TRH significantly affected lung distensibility [V40; 0.64 +/- 0.04 and 0.57 +/- 0.10 (SE) ml/g, respectively, vs. 0.41 +/- 0.03 ml/g in controls] or stability (V5; 0.24 +/- 0.01 and 0.35 +/- 0.07 ml/g vs. 0.24 +/- 0.03 ml/g), whereas treatment with a combination of the two hormones was associated with a fourfold increase in V40 (1.70 +/- 0.16 ml/g) and V5 (1.03 +/- 0.15 ml/g). Since raised concentrations of cortisol, triiodothyronine, and estradiol-17 beta (treatment with cortisol) had no effect on V40 and V5, whereas similar hormonal changes associated with elevated prolactin levels (treatment with cortisol plus TRH) had marked effects, we conclude that prolactin plays an essential part in the synergism of cortisol and TRH.

Synergistic hormonal effects on lung maturation in fetal sheep.

Cortisol has minimal effects on lung maturation in fetal sheep before 130 days gestation. To test whether there is enhancement of cortisol action by other hormones, cortisol (F), triiodothyronine (T3), epinephrine (E), prolactin (PRL), and epidermal growth factor (EGF), alone or in combination, were infused into fetal sheep for 84 h between 124 and 128 days gestation. A mixture of F + T3 + PRL, but not any combination of two hormones, increased both distensibility [1.71 +/- 0.12 (SE) ml of air/g wet wt at 40 cmH2O, V40] and stability (1.16 +/- 0.09 ml of air per g wet wt at 5 cmH2O, V5) to near full-term values, above values resulting from treatment with F alone (0.91 +/- 0.12 and 0.43 +/- 0.09 ml/g, P less than 0.01). Only F had an effect when given alone, V40 increasing (P less than 0.05). Treatment with F + T3 (0.81 +/- 0.18 ml/g) and F + E (0.77 +/- 0.07 ml/g) increased V5 above values obtained with F alone (P less than 0.05). Alveolar saturated phosphatidylcholine (SPC) was higher after treatment with F + T3 (161 +/- 52 micrograms/g), F + T3 + PRL (156 +/- 53 micrograms/g, P less than 0.05), and F + E (113 +/- 40 micrograms/g, P = 0.07) than after F (12 +/- 3 micrograms/g). We conclude that F, T3, and PRL have a synergistic effect on the development of distensibility and stability of the ovine fetal lung.

Sympathectomy and beta-adrenergic blockade during lung maturation stimulated by TRH and cortisol in fetal sheep.

To test whether beta-adrenergic mechanisms and the sympathetic nervous system are involved in the synergistic action of thyrotropin-releasing hormone (TRH) and cortisol on lung maturation, fetal sheep (n = 32) were infused from 121 to 128 days of gestation with saline, TRH + cortisol, TRH + cortisol + beta-adrenergic blocker, or TRH + cortisol after chemical sympathectomy with 6-hydroxydopamine. TRH + cortisol increased lung distensibility and stability and alveolar concentrations of saturated phosphatidylcholine two- to threefold over control fetuses. beta-Adrenergic blockade prevented the increase in distensibility in response to TRH + cortisol. Sympathectomy did not impair the increase in distensibility and stability in response to TRH + cortisol but inhibited the increase in alveolar total phospholipids. Tissue concentrations of saturated phosphatidylcholine increased in TRH + cortisol-treated fetuses after either sympathectomy or beta-adrenergic blockade. We concluded that during lung maturation by TRH + cortisol 1) sympathetic mechanisms are requisite for surfactant release, 2) nonneurogenic beta-adrenergic mechanisms are requisite for the maturation of the mechanical properties of the lung and 3) stimulation of surfactant synthesis is independent of beta-adrenergic action and the sympathetic nervous system.

Hemoglobin concentrations and blood gas tensions of free-diving Weddell seals.

Arterial blood gas tensions, pH, and hemoglobin concentrations were measured in four free-diving Weddell seals Leptonychotes weddelli. A microprocessor-controlled sampling system enabled us to obtain 24 single and 31 serial aortic blood samples. The arterial O2 tension (PaO2) at rest [78 +/- 13 (SD) Torr] increased with diving compression to a maximum measured value of 232 Torr and then rapidly decreased to 25-35 Torr. The lowest diving PaO2 we measured was 18 Torr just before the seal surfaced from a 27-min dive. A consistent increase of arterial hemoglobin concentrations from 15.1 +/- 1.10 to 22.4 +/- 1.41 g/100 ml (dives less than 17 min) and to 25.4 +/- 0.79 g/100 ml (dives greater than 17 min) occurred during each dive. We suggest that an extension of the sympathetic outflow of the diving reflex possibly caused profound contraction of the Weddell seal's very large spleen (0.89% of body wt at autopsy), although we have no direct evidence. This contraction may have injected large quantities of red blood cells (2/3 of the total) into the seal's central circulation during diving and allowed arterial O2 content to remain constant for the first 15-18 min of long dives. The increase of arterial CO2 tensions during the dive and the compression increase of arterial N2 tensions were also moderated by injecting red blood cells sequestered at ambient pressure. After each dive circulating red blood cells are oxygenated and rapidly sequestered, possibly in the spleen during the first 15 min of recovery.

Myoglobin saturation in free-diving Weddell seals.

Although the consumption of myoglobin-bound O2 (MbO2) stores in seal muscles has been demonstrated in seal muscles during laboratory simulations of diving, this may not be a feature of normal field diving in which measurements of heart rate and lactate production show marked differences from the profound diving response induced by forced immersion. To evaluate the consumption of muscle MbO2 stores during unrestrained diving, we developed a submersible dual-wavelength laser near-infrared spectrophotometer capable of measuring MbO2 saturation in swimming muscle. The probe was implanted on the surface of the latissimus dorsi of five subadult male Weddell seals (Leptonychotes weddelli) released into a captive breathing hole near Ross Island, Antarctica. Four seals had a monotonic decline of muscle O2 saturation during free diving to depths up to 300 m with median slopes of -5.12 +/- 4.37 and -2.54 +/- 1.95%/min for dives lasting < 17 and > 17 min, respectively. There was no correlation between the power consumed by swimming and the desaturation rate. Two seals had occasional partial muscle resaturations late in dives, indicating transfer of O2 from circulating blood to muscle myoglobin. Weddell seals partially consume their MbO2 stores during unrestrained free diving.

Splenic contraction, catecholamine release, and blood volume redistribution during diving in the Weddell seal.

The spleen of the Weddell seal (Leptonychotes weddelli) may contract and inject red blood cells (RBCs) into the peripheral circulation during diving, but evidence for this hypothesis is indirect. Accordingly, we measured splenic dimensions by ultrasonography, plasma catecholamine concentrations, hemoglobin concentration, and hematocrit in five Weddell seals before and after intravenous epinephrine during halothane anesthesia and while awake at the surface after voluntary dives. Spleen size was reduced immediately after epinephrine injection or after the seal surfaced. Within the first 2 min after the seal surfaced, cephalocaudal splenic length was 71 +/- 2% (mean +/- SD; P < 0.05) and splenic thickness was 71 +/- 4% (P < 0.05) of the maximal resting values. Splenic size increased (half-time = 6-9 min) after the seal surfaced and was inversely correlated with plasma epinephrine and norepinephrine concentrations. Hemoglobin concentration increased from 17.5 +/- 5.3 g/dl (measured during general anesthesia) to 21.9 +/- 3.7 g/dl (measured in the first 2 min after surfacing). At these same times, the hematocrit increased from 44 +/- 12 to 55 +/- 8%. These values decreased (half-time = 12-16 min) after the seal surfaced. We estimate 20.1 liters of RBCs were sequestered at rest, presumably in the spleen, and released either on epinephrine injection or during diving. Catecholamine release and splenic contraction appear to be an integral part of the voluntary diving response of Weddell seals.

Ultrasonic heating of the brain of the fetal sheep in utero.

The fetal sheep was used as a model to determine the extent of ultrasound-induced heating of brain tissue in procedures involving pulsed Doppler examination of fetal intracranial arteries. Temperature measurements were recorded in late-gestation fetuses insonated in utero. The centre frequency was 3.5 MHz and a pulse repetition rate of 6 to 10 kHz produced a power output of 0.6 or 2 W. The brain was insonated in the near field of a focussed beam where the -6-dB beam width was 1.7 cm for the 0.6-W transducers and 1.2 cm for the 2-W transducers. Mean (standard error) maximal temperature increases of 3.0 degrees C (0.3) and 12.5 degrees C (1.3), respectively, were recorded in dead fetuses. The mean values obtained in normally perfused living fetuses were lower by 43% and 30%, respectively, showing that vascular perfusion substantially limited ultrasonic heating in sheep fetal brain tissue. There were no changes in blood flow to the heated brain tissue as measured using radiolabelled microspheres.

The role of cortisol in preparing the fetus for birth.

The glucocorticoids, cortisol and corticosterone, have a unique function in the fetus in inducing a wide range of enzymes before birth that have little or no function during fetal life but on which survival after birth is dependent. The loss of the placenta at birth deprives the fetus of a source of oxygen, glucose and heat (among many other things) for which alternatives must be available immediately if survival is to be assured. In anticipation of these needs several organs undergo maturational changes in late pregnancy aimed at meeting these requirements. The lungs mature structurally and functionally, becoming distensible and capable of coping with high surface tension when air enters the alveoli with the first breath. In the liver, glycogen accumulates and gluconeogenesis is initiated to meet the demands for glucose until feeding begins. There is an increase in the production of tri-iodothyronine and catecholamines in preparation for the sharp increase in metabolic rate and thermogenesis associated with breathing and the cold environment. All these dramatic maturational events are regulated by cortisol as are numerous others in most organ systems that contribute to neonatal well-being but on which survival is less dependent. Pharmacological manipulation of these systems before birth has made a substantial contribution to improving human health.

Thyrotrophin-releasing hormone (TRH) and lung maturation.

Clinical trials of thyrotrophin-releasing hormone (TRH) in conjunction with antepartum glucocorticoid treatment in the prevention of respiratory distress syndrome is based on experimental evidence that fetal lung maturation is accelerated by exposure to raised concentrations of triiodothyronine (T3) in fetal plasma. Studies of fetal rat and rabbit lung in vitro show an inconsistent increase in surfactant synthesis in response to T3 and potentiation of the response to corticosteroid. Experiments with fetal rodents in vivo are difficult to interpret because of confounding effects of the procedures and the responses to T3 are variable. In fetal sheep, very high concentrations of T3 are without effect on lung maturation. These observations suggest that the action of TRH on the lung may be mediated at least in part by one of the numerous, non-hormonal pathways known to be stimulated by TRH, particularly the autonomic nervous system. Experiments in rats and sheep lend support to this possibility. It is concluded that available evidence is inadequate to determine the mechanism of action of TRH.

Changes in thoracic dimensions induced by breathing movements in fetal sheep.

The dimensions of the three major axes of the thorax (longitudinal, transverse and antero-posterior) were monitored in utero from the ultrasonic transit-time between pairs of piezo-electric transducers chronically implanted at opposite sides of the thorax in five fetal sheep at 119-122 days of gestation; tracheal and vascular catheters and diaphragmatic EMG electrodes were also implanted. To measure thoracic length, ultrasound transducers were implanted on the diaphragm and over the upper sternum and manubrium sterni. A pair was implanted on opposite sides of the chest to measure thoracic width, and another pair was implanted over the lower thoracic spine and lower sternum (antero-posterior dimension). The width of the thorax either decreased (mean 0.6 +/- 0.2 mm) or increased (mean 0.7 +/- 0.1 mm) during fetal breathing movements (FBM). The depth of the thorax (antero-posterior dimension) usually decreased (mean 0.9 +/- 0.1 mm) during FBM. The distance between the upper sternum and the diaphragm decreased by 1.0 +/- 0.1 mm (left side) and 1.6 +/- 0.3 mm (right side) during inspiratory efforts. The distance between the upper thorax and a fixed point on the lower thoracic spine decreased by a similar amount. Overall, fetal thoracic dimensions changed by 1-3%. The largest changes measured, and the most surprising, were reductions, rather than increases, in the separation between the dome of the diaphragm and the upper thorax; this suggests that, during inspiratory efforts, the upper thorax moves caudally by a greater distance than the diaphragm. FBM induce complex and variable changes in thoracic dimensions; these are likely to induce small alterations in the shape of the lungs that may act as a stimulus to lung growth.