Lung liquid secretion, flow and volume in response to moderate asphyxia in fetal sheep

The effects of moderate fetal asphyxia, induced by constriction of the maternal common internal iliac artery, on lung liquid secretion, tracheal fluid efflux and lung liquid volume have been investigated in unanaesthetized fetal sheep (111-142 days) in utero. During periods of fetal asphyxia the percent oxygen saturation, PO2, pH, and PCO2 of fetal carotid arterial blood changed from 57.2 +/- 1.3% (mean +/- SEM), 22.9 +/- 0.6 mmHg, 7.35 +/- 0.01 and 45.6 +/- 1.0 mmHg to 26.3 +/- 0.5% (P less than 0.001), 14.7 +/- 0.2 mmHg (P less than 0.001), 7.28 +/- 0.02, (P less than 0.001) and 47.8 +/- 0.4 mmHg (P less than 0.02), respectively. Fetal asphyxia, over 6 h, decreased the efflux of tracheal fluid from 7.07 +/- 0.47 ml/h to 3.97 +/- 0.36 ml/h (P less than 0.01) and, over 4 h, decreased the rate of lung liquid secretion from 9.42 +/- 1.76 ml/h to 4.91 +/- 1.54 ml/h (P less than 0.005), whereas it had no significant effect on lung liquid volume. The incidence of fetal breathing movements decreased from 52.9 +/- 2.5% to 22.6 +/- 3.5% during 6-h periods of fetal asphyxia. Thus, although fetal asphyxia decreased the net production of lung liquid, lung liquid volume was maintained probably, because the net efflux of fluid from the lungs via the trachea decreased to a similar extent.     

Increased pulmonary vascular filtration pressure does not alter lung liquid secretion in fetal sheep.

The purpose of this study was to determine whether an increase in pulmonary vascular filtration pressure affects net production of liquid within the lumen of the fetal lung. We studied 14 chronically catheterized fetal lambs [130 +/- 3 (SD) days gestation] before, during, and after a 4-h rapid (500 ml/h) intravenous infusion of isotonic saline. In seven fetuses we measured pulmonary arterial and left atrial pressures, lung lymph flow, and protein osmotic pressures in plasma and lymph. In eight lambs with a chronically implanted tracheal loop cannula, we measured the change in luminal lung liquid volume over time by progressive dilution of tracheally instilled 125I-albumin, which stays within the lung lumen. Saline infusion increased pulmonary vascular pressures by 2-3 mmHg and decreased the plasma-lymph difference in protein osmotic pressure by 1 mmHg. Lung lymph flow increased from 1.9 +/- 0.6 to 3.9 +/- 1.2 (SD) ml/h; net production of luminal lung liquid did not change (12 +/- 5 to 12 +/- 6 ml/h). Thus an increase in net fluid filtration pressure in the pulmonary circulation, which was sufficient to double lung lymph flow, had no significant effect on luminal lung liquid secretion in fetal sheep.     

Alveolar and lung liquid clearance in anesthetized rabbits

Alveolar and lung liquid clearance were studied over 8 h in intact anesthetized ventilated rabbits by instillation of either isosmolar Ringer lactate (2 ml/kg) or autologous plasma (2 or 3 ml/kg) into one lower lobe. The half time for lung liquid clearance of the isosmolar Ringer lactate was 3.3 h and that for plasma clearance was 6 h. In the plasma experiments, the alveolar protein concentration after 1 h was 5.2 +/- 0.8 g/dl, which was significantly greater than the initial instilled protein concentration of 4.3 +/- 0.7 g/dl (P less than 0.05). Thus alveolar protein concentration increased by 21 +/- 12% over 1 h, which matched clearance from the entire lung of 19 +/- 11% of the instilled volume. Overall the rate of alveolar and lung liquid clearance in rabbits was significantly faster than in prior studies in dogs and sheep. The fast alveolar liquid clearance rate in rabbits was not due to higher endogenous catecholamine release, because intravenous and alveolar (5 x 10(-5) M) propranolol did not slow the clearance. Also, beta-adrenergic therapy with alveolar terbutaline (10(-5) or 10(-4) M) did not increase the alveolar or lung liquid clearance rates. Phloridzin (10(-3) M) did not slow alveolar liquid clearance. However, amiloride (10(-4) M) inhibited 75% of the basal alveolar liquid clearance in rabbits, thus providing evidence that alveolar liquid clearance in rabbits depends primarily on sodium-dependent transport. This rabbit study provides further evidence for important species differences in the basal rates of alveolar liquid and solute clearance as well as the response to beta-adrenergic agonists and ion transport inhibitors.     

Effects of vasomotor- and mediator-induced hypotension on bronchomotor tone in swine

We studied the sympathetic neural response on airways to hypotensive stimuli in 19 swine in vivo. The effects of pharmacologically induced hypotension with nitroprusside (NTP) and hypotension elicited by intravenous compound 48/80 (48/80), a mast cell degranulating agent, were compared after equivalent reductions in mean arterial blood pressure (MAP). Reduction of the MAP to 60% of base line with NTP in six swine caused an increase in plasma epinephrine (E) from 60 +/- 28 to 705 +/- 276 pg/ml (P = 0.032) and plasma norepinephrine (NE) from 270 +/- 46 to 796 +/- 131 pg/ml (P = 0.032). Comparable reduction in MAP elicited with 48/80 in six other swine caused a substantially greater increase in both plasma E (9,581 +/- 4,147 pg/ml; P = 0.012 vs. NTP group) and plasma NE (2,239 +/- 637 pg/ml; P = 0.041 vs. NTP group). Catecholamine secretion attenuated mediator-induced changes in lung resistance (RL). In animals receiving 48/80, RL increased from 2.97 +/- 0.31 to 7.44 +/- 0.56 cmH2O.l-1.s. In animals having ganglionic blockade with 7.5 mg/kg iv hexamethonium and beta-adrenergic blockade with propranolol (4.0 mg/kg iv followed by 40 micrograms/kg-1.min-1), comparable doses of 48/80 caused an increase in RL to 18.6 +/- 4.55 cmH2O.l-1.s (P less than 0.04 vs. swine receiving neither hexamethonium nor propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Naloxone evokes large-amplitude GnRH pulses in luteal-phase ewes

Ewes were sampled during the mid-late luteal phase of the oestrous cycle. Hypophysial portal and jugular venous blood samples were collected at 5-10 min intervals for a minimum of 3 h, before i.v. infusions of saline (12 ml/h; N = 6) or naloxone (40 mg/h; N = 6) for 2 h. During the 2-h saline infusion 2/6 sheep exhibited a GnRH/LH pulse; 3/6 saline infused ewes did not show a pulse during the 6-8-h portal blood sampling period. In contrast, large amplitude GnRH/LH pulses were observed during naloxone treatment in 5/6 ewes. The mean (+/- s.e.m.) amplitude of the LH secretory episodes during the naloxone infusion (1.07 +/- 0.11 ng/ml) was significantly (P less than 0.05) greater than that before the infusion in the same sheep (0.54 +/- 0.15 ng/ml). Naloxone significantly (P less than 0.005) increased the mean GnRH pulse amplitude in the 5/6 responding ewes from a pre-infusion value of 0.99 +/- 0.22 pg/min to 4.39 +/- 1.10 pg/min during infusion. This episodic GnRH secretory rate during naloxone treatment was also significantly (P less than 0.05) greater than in the saline-infused sheep (1.53 +/- 0.28 pg/min). Plasma FSH and prolactin concentrations did not change in response to the opiate antagonist. Perturbation of the endogenous opioid peptide system in the ewe by naloxone therefore increases the secretion of hypothalamic GnRH into the hypophysial portal vasculature. The response is characterized by a large-amplitude GnRH pulse which, in turn, causes a large-amplitude pulse of LH to be released by the pituitary gland.     

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.     

Cortisol effect on atrial natriuretic factor response to hypertonic saline in fetal sheep.

Atrial natriuretic factor (ANF) is released following a variety of stimuli including hypertonicity in the fetus. To study the effect that cortisol has on fetal ANF release, seven chronically instrumented fetal sheep at gestational ages ranging from 110-132 days were studied in two experiments. In one experiment (CORTISOL), a continuous cortisol (with EtOH vehicle) infusion was maintained. In the other experiment (CONTROL), the vehicle was infused alone. Ninety minutes from the start of this infusion, a hypertonic saline bolus (12 meg/kg) was given. Osmolality, ANF, cortisol, pH, PO2, PCO2, mean arterial pressure (MAP), heart rate (HR), and hematocrit (HCT) were followed over a 120-min period. Following hypertonic saline, serum osmolality increased from 290.6 +/- 2.3 mOsm/kg to 310.4 +/- 2.5 mOsm/kg (P < 0.01). Baseline values for pH, PO2, and HCT were 7.37 +/- 0.01, 22.5 +/- 1.6 mmHg, and 33.9 +/- 1.2 respectively. Each of these variables fell following hypertonic saline infusion. MAP rose from 40.6 +/- 1.7 mmHg to 47.0 +/- 2.4 mmHg (P < 0.01). However, there were no differences between CONTROL and CORTISOL experiments in any of the above changes. Cortisol levels in the CONTROL group did not change during the course of the experiment, but in the CORTISOL group rose from 8.2 +/- 4.4 ng/ml to 33.0 +/- 9.9 ng/ml (P = 0.02). Plasma ANF levels prior to hypertonic saline were similar (124.8 +/- 17.7 pg/ml and 127.6 +/- 26.1 pg/ml) in the CONTROL and CORTISOL groups respectively and rose following hypertonic saline to a maximum of 155.3 +/- 16.6 pg/ml and 189.2 +/- 42.7 pg/ml (P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Homeostatic regulation of airway smooth muscle tone by catecholamine secretion in swine

We studied the homeostatic secretory response of catecholamine secretion elicited by progressive bronchoconstriction in 18 swine in vivo. The potential reserve of the sympathetic nervous system (SNS) was first assessed by exogenous nicotinic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). A dose of 250 micrograms/kg iv DMPP caused an increase in plasma norepinephrine (NE) concentration from 207 +/- 86 (basal) to 2,625 +/- 448 pg/ml (P less than 0.02) and in plasma epinephrine (EPI) from 10 +/- 5.0 to 1,410 +/- 432 pg/ml (P less than 0.05) in four swine. In four other swine, bronchoconstriction induced by aerosolized prostaglandin F2 alpha caused approximately a fivefold increase in airway resistance without hemodynamic changes. No increase in plasma EPI was observed. However, plasma NE increased from 330 +/- 131 to 1,540 +/- 182 pg/ml (P less than 0.02). In five swine receiving aerosolized acetylcholine (ACh), similar changes in airways resistance were not associated with significant changes in catecholamine concentration when mean arterial blood pressure (MAP) was unchanged. However, inhalation of sufficient ACh to cause a greater than 10% decrease in MAP caused progressive increase in catecholamine secretion. Plasma EPI increased from 32 +/- 16 (MAP = 124 +/- 7 Torr) to 1,165 +/- 522 pg/ml (MAP = 94 +/- Torr). Hypoxemia that occurred with bronchoconstriction (greater than or equal to 50 Torr) did not cause catecholamine secretion. However, severe hypoxemia (PO2 less than 30 Torr) caused large increases in plasma EPI concentrations from 84 +/- 27 to 1,463 +/- 945 pg/ml (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans

The sympathetic nervous system (SNS) plays an important role in the regulation of energy expenditure. However, whether tonic SNS activity contributes to resting metabolic rate (RMR) in healthy adult humans is controversial, with the majority of studies showing no effect. We hypothesized that an intravenous propranolol infusion designed to achieve complete beta-adrenergic blockade would result in a significant acute decrease in RMR in healthy adults. RMR (ventilated hood, indirect calorimetry) was measured in 29 healthy adults (15 males, 14 females) before and during complete beta-adrenergic blockade documented by plasma propranolol concentrations > or =100 ng/ml, lack of heart rate response to isoproterenol, and a plateau in RMR with increased doses of propranolol. Propranolol infusion evoked an acute decrease in RMR (-71 +/- 11 kcal/day; -5 +/- 0.7%, P < 0.0001), whereas RMR was unchanged from baseline levels during a saline control infusion (P > 0.05). The response to propranolol differed from the response to saline control (P < 0.01). The absolute and percent decreases in RMR with propranolol were modestly related to baseline plasma concentration of norepinephrine (r = 0.38, P = 0.05; r = 0.44, P = 0.02, respectively). These findings provide direct evidence for the concept of tonic sympathetic beta-adrenergic support of RMR in healthy nonobese adults.     

Effect of metabolic acidosis on fetal renal haemodynamics

The effects of metabolic acidosis on renal haemodynamics and intrarenal blood flow distribution was studied in two groups of chronically-catheterized fetal sheep between 122 and 130 days of gestation. One group (experimental group) was studied before and during infusion of 1.1 M lactic acid, whereas the second group received on infusion of dextrose 5% (w/v) in water and served as a time-control group. Infusion of lactic acid for 2 h decreased fetal arterial pH from 7.37 +/- 0.01 to 6.95 +/- 0.02, did not change arterial blood pressure, but produced a significant decrease in renal blood flow (41 +/- 3 to 33 +/- 7 ml/min, P less than 0.05) and a significant increase in renal vascular resistance (1.42 +/- 0.13 to 1.86 +/- 0.18 mmHg/ml/min, P less than 0.05). Moreover, a significant decline in cortical blood flow was also observed in the outer portion of the renal cortex during lactic acidosis. Taken together, these results suggest that metabolic acidosis produces significant changes in fetal renal haemodynamics not associated with changes in arterial blood pressure.     

Plasma fibronectin therapy and lung protein clearance with bacteremia after surgery

Plasma fibronectin modulates macrophage phagocytic function and can also incorporate into the insoluble tissue pool of fibronectin where it influences endothelial cell adhesion and tissue integrity. We studied the effect of postoperative bacteremia on lung protein clearance in relation to plasma fibronectin levels using the unanesthetized sheep lung lymph fistula model and the effect of infusion of purified human plasma fibronectin on lung protein clearance. Sheep received live Pseudomonas aeruginosa (5 X 10(8) iv) at a time of normal plasma fibronectin (590 +/- 37 micrograms/ml) or 5 days later at a time corresponding to elevation of plasma fibronectin (921 +/- 114 micrograms/ml). After the first bacterial challenge, there was a 22% decrease (P less than 0.05) in plasma fibronectin. Lung lymph flow (QL) initially increased 308% (P less than 0.05) by 2 h (0 h = 4.7 +/- 1.1 ml/h; 2 h = 14.4 +/- 3.5 ml/h), and the total protein lymph-to-plasma concentration ratio (L/P) declined. This was followed by a sustained second phase response over 3-12 h which was characterized by a 202-393% elevation in QL (P less than 0.05), an increase in the L/P ratio, and a 240-480% (P less than 0.05) increase in lung transvascular protein clearance (TVPC = QL X L/P). Sheep with elevated fibronectin levels also manifested the early (2 h) elevation in QL (P less than 0.05) coupled with a decline in L/P ratio after the second bacterial challenge, but the second-phase increase in TVPC was markedly attenuated. Intravenous infusion of 500 mg of human plasma fibronectin into normal sheep to elevate the fibronectin level comparable to that in the hyperfibronectinemic sheep also attenuated (P less than 0.05) the second-phase (3-12 h) increase in lung protein clearance with sepsis. Thus elevation of plasma fibronectin during postoperative Gram-negative bacteremia may protect the lung vascular barrier. This response may be mediated by either fibronectin's opsonic support of phagocytic function or its influence on lung endothelial cell adhesion.     

Decrease in plasma prostaglandin E2 is not essential for the establishment of continuous breathing at birth in sheep

Depression of prostanoid concentrations by indomethacin induces continuous breathing in fetal sheep, but it is not known whether this is associated with changes in fetal behaviour. Furthermore, the relationship between changes in prostaglandin E2 (PGE2) concentration after delivery and the appearance of continuous breathing has not been examined. We hypothesized that the decrease in fetal PGE2 by infusion of indomethacin would induce continuous breathing and a change in behaviour such that the fetus should come to resemble a newborn lamb; and coinciding with the establishment of continuous breathing at birth, PGE2 concentrations would decrease to a critical level below that present in the fetus. We found that continuous breathing in fetal sheep induced by infusion of indomethacin was related to a decrease in PGE2 from 436 +/- 114 to 189 +/- 73 pg/ml (P less than 0.005) but that this was not associated with fetal wakefulness. In addition, measurements of carotid arterial PGE2 concentrations showed that the beginning of continuous breathing after birth occurred at a plasma concentration of PGE2 of 1245 +/- 260 pg/ml, a value about three times higher than the 422 +/- 53 pg/ml measured in the fetus during breathing activity. Together these findings suggest that PGE2 is not primarily involved in the establishment of continuous breathing at birth.     

Angiotensin-(1--7) in the ovine fetus

In the adult animal, ANG-(1-7) may counterbalance some effects of ANG II. Its effects in the fetus are unknown. Basal ANG-(1-7), ANG I, ANG II, and renin concentrations were measured in plasma from ovine fetuses and their mothers (n = 10) at 111 days of gestation. In the fetus, concentrations of ANG I, ANG-(1-7), and ANG II were 86 +/- 21, 13 +/- 2, and 14 +/- 2 fmol/ml, respectively. In the ewe, concentrations of ANG I were significantly lower (20 +/- 4 fmol/ml, P < 0.05) as were concentrations of ANG-(1-7) (2.9 +/- 0.6 fmol/ml), whereas ANG II concentrations were not different (10 +/- 1 fmol/ml). Plasma renin concentrations were higher in the fetus (4.8 +/- 1.1 pmol ANG I x ml(-1) x h(-1)) than in the ewe (0.9 +/- 0.2 pmol x ml(-1) x h(-1), P < 0.05). Infusion of ANG-(1-7) (approximately 9 microg/h) for a 3-day period caused a significant increase in plasma concentrations of ANG-(1-7) reaching a maximum of 448 +/- 146 fmol/ml on day 3 of infusion. Plasma levels of ANG I and II as well as renin were unchanged by the infusion. Urine flow rate, glomerular filtration rate, and fetal arterial blood pressure did not change and were not different than values in fetuses receiving a saline infusion for 3 days (n = 5). However, the osmolality of amniotic and allantoic fluid was significantly higher in fetuses that received ANG-(1-7). Also, compared with the saline-infused animals, mRNA expression levels of renin, the AT(1) receptor, and AT(2) receptor were elevated in kidneys of fetuses that received infusions of ANG-(1-7). Infusion of an ANG-(1-7) antagonist ([D-Ala(7)]-ANG-(1-7), 20 microg/h) for 3 days had no effect on fetal blood pressure or renal function. In conclusion, although infusion of ANG-(1-7) did not affect fetal urine flow rate, glomerular filtration rate, or blood pressure, changes in fetal fluids and gene expression indicate that ANG-(1-7) may play a role in the fetal kidney.     

Changes in somatostatin-like immunoreactivity in lungs from perinatal guinea pigs and the effects of somatostatin-14 on lung liquid production.

Somatostatin-like immunoreactivity was measured by radioimmunoassay with a monoclonal antibody in lungs from perinatal guinea pigs (62 +/- 2 days of gestation). Fetuses delivered by Caesarean section and dissected before breathing showed 4748 +/- 758 pg/lung (n = 25). Fetuses allowed to breathe (neonates) showed marked increases in activity: 7629 +/- 1355 pg/lung (n = 12) after breathing 30 seconds, and 10729 +/- 1064 pg/lung (n = 6) after breathing 3 minutes (2.3-fold increase, P < 0.005). Values then declined (5203 +/- 1050 pg/lung (n = 9) at 30 minutes; 1458 +/- 105 pg/lung (n = 4) at 60 minutes). Changes were similar in pg/g wet tissue. HPLC characterized the immunoreactive peptides as somatostatin-14 (SS-14) and somatostatin-28 (SS-28) in both fetuses and neonates (n = 11). SS-28 made up only 13.7 +/- 1.7% of the activity; this percentage did not change with breathing. The effects of synthetic SS-14 on lung liquid production were investigated in in vitro lungs from 42 fetal guinea pigs. All 21 preparations immersed in 10(-5)-10(-7) M SS-14 during the middle hour of 3 h incubations reduced production, often approaching zero after treatment (rates, ml/kg body weight per h, succeeding hours: 10(-5) M (n = 9), 3.09 +/- 0.68, 0.93 +/- 0.39, -0.05 +/- 0.60 (fall significant during and after treatment, P < 0.025-0.005); 10(-6) M (n = 6), 3.06 +/- 0.68, 1.29 +/- 0.58, 0.36 +/- 0.38 (P < 0.05-0.005); 10(-7) M (n = 6), 1.96 +/- 0.66, 1.11 +/- 0.34, 0.64 +/- 0.28 (P < 0.05-0.025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscarinic influences on growth hormone secretion in the fetal and neonatal sheep: pharmacological studies and in vitro binding studies

To investigate the ontogenesis of potential cholinergic influences on growth hormone secretion we administered the cholinesterase inhibitor neostigimine, (120 micrograms/kg) to fetal sheep (n = 16) between 77 and 143 days of gestation and to infant lambs (n = 5). Neostigmine administration was associated with a marked rise in fetal growth hormone concentrations. The integrated release of growth hormone in the hour following fetal neostigmine administration was 2880 +/- 425 ng.min/ml compared to -618 +/- 206 ng . min/ml (P less than 0.001) following saline administration (n = 19). There was no relationship between gestational age and the response to neostigmine. In the infant lamb, neostigmine was associated with a lesser (P less than 0.001) but significant (P less than 0.02) growth hormone response. The integrated release was 704 +/- 410 ng . min/ml (n = 5) compared to -44 +/- 40 ng . min/ml following saline (n = 11). The fetal response to neostigmine was abolished by the administration of atropine (200 micrograms/kg bolus followed by 400 micrograms/kg per h infusion) 5 min prior to neostigmine (n = 4). This demonstrates that the effect of neostigmine was mediated by muscarinic receptors. Atropine itself had no effect on fetal growth hormone release (n = 6). In vitro binding studies with the muscarinic ligand, 1-quinuclidinyl [phenyl-4 (n) -3H] benzilate) were performed on homogenates of fetal (n = 3) and adult (n = 3) pituitaries. Scatchard analysis demonstrated both a high affinity and low affinity binding site. The concentration per mg. of original tissue of each of these binding sites was higher (P less than 0.05) in fetal than adult homogenates.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of bumetanide and furosemide on lung liquid secretion in fetal sheep

Thirty-four experiments were carried out on the effects of loop diuretics on lung liquid secretion in 20 fetal sheep (128-145 days gestation) with indwelling catheters. Bumetanide placed in the lung liquid at 2.19 +/- 0.52 X 10(-4) M produced immediate reabsorption of fluid, and effects lasted 3 hr (n = 6). Bumetanide at 1.1 +/- 0.17 X 10(-5) M reduced secretion significantly for 2 hr (n = 4), but at 1.07 +/- 0.06 X 10(-6) M there was no clear effect (n = 6). Controls showed no significant change (n = 6). Furosemide was less effective. At 3.1 +/- 0.07 X 10(-3) M it produced an immediate reabsorption, which lasted 3 hr, but at 1.0 +/- 0.04 X 10(-4) M it increased secretion slightly (n = 4); controls showed no significant change (n = 6). The results are consistent with the presence of a chloride transport system, perhaps with sodium cotransport, as the major factor in fetal lung liquid secretion.     

Perinatal onset of hepatic gluconeogenesis in the lamb

Hepatic gluconeogenesis does not occur in the unstressed fetal sheep. After birth, in addition to glycogenolysis, the newborn lamb must eventually initiate gluconeogenesis to maintain glucose homeostasis. The regulation and time course of this transition have not been defined. We studied six animals in an acute preparation before and after delivery to determine hepatic lactate and glucose uptake, hepatic gluconeogenesis from lactate, and plasma catecholamine and cortisol concentrations. After a priming dose, continuous infusion of [14C]lactate provided tracer substrate for calculations of gluconeogenesis in the fetus and then for ten hours after delivery in the newborn lamb. The radionuclide-labelled microsphere method was used to measure hepatic blood flow. Appreciable gluconeogenesis was not present during the fetal period. Following delivery, the newborn lambs began to produce significant quantities of glucose from lactate at 6 h of age (1.37 +/- 0.84 mg.min-1.100 g-1 min-1 x 100 g-1 liver), when gluconeogenesis from lactate accounted for 22% of hepatic glucose output. Despite the onset of gluconeogenesis, postnatal lambs had blood glucose concentrations that remained less than fetal levels of 23.4 +/- 12.1 mg/dl for the duration of the 10-h study. Plasma norepinephrine concentration was 1380 +/- 1145 pg/ml in the fetus and fell by 2 h after birth. Plasma epinephrine concentrations were highest at 15 min after birth (205 +/- 262 pg/ml), but remained quite low for the remainder of the study. Plasma cortisol concentrations did not vary over the course of study, ranging from 40 to 50 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of platelet-activating factor antagonist SRI 63-441 on endotoxemia in sheep

We investigated whether platelet-activating factor (PAF) mediates endotoxin-induced systemic and pulmonary vascular derangements by studying the effects of a selective PAF receptor antagonist, SRI 63-441, during endotoxemia in sheep. Endotoxin infusion (1.3 micrograms/kg over 0.5 h) caused a rapid, transient rise in pulmonary arterial pressure (Ppa) from 16 +/- 3 to 36 +/- 10 mmHg (P less than 0.001) and pulmonary vascular resistance (PVR) from 187 +/- 84 to 682 +/- 340 dyn.s.cm-5 (P less than 0.05) at 0.5 h, followed by a persistent elevation in Ppa to 22 +/- 3 mmHg and in PVR to 522 +/- 285 dyn.s.cm-5 at 5 h in anesthetized sheep. Arterial PO2 (PaO2) decreased from 341 +/- 79 to 198 +/- 97 (P less than 0.01) and 202 +/- 161 Torr at 0.5 and 5 h, respectively (inspired O2 fraction = 1.0). SRI 63-441, 20 mg.kg-1.h-1 infused for 5 h, blocked the early rise in Ppa and PVR and fall in PaO2, but had no effect on the late phase pulmonary hypertension or hypoxemia. Endotoxin caused a gradual decrease in mean aortic pressure, which was unaffected by SRI 63-441. Infusion of SRI 63-441 alone caused no hemodynamic alterations. In follow-up studies, endotoxin caused an increase in lung lymph flow (QL) from 3.8 +/- 1.1 to 14.1 +/- 8.0 (P less than 0.05) and 12.7 +/- 8.6 ml/h at 1 and 4 h, respectively. SRI 63-441 abolished the early and attenuated the late increase in QL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fluctuation in responsiveness of LH and lack of responsiveness of FSH to prolonged infusion of morphine and naloxone in the ewe

In ewes in the mid-luteal phase, LH pulse frequency (P less than 0.01) and amplitude (P less than 0.05) increased during a 24 h infusion of naloxone (0.5 mg/kg/h) compared to a 24 h infusion of vehicle (mean +/- s.e.m.; 0.25 +/- 0.03 vs 0.14 +/- 0.01 pulses/h and 0.84 +/- 0.08 vs 0.55 +/- 0.08 ng/ml serum, respectively). The increase in pulse amplitude was immediate, but was less (P less than 0.05) during the second 12 h, compared to the first 12 h, of naloxone infusion (0.52 +/- 0.14 vs 0.98 +/- 0.08 ng/ml serum). Oestradiol concentrations were higher (P less than 0.01) during naloxone than during control infusion (5.63 +/- 0.26 vs 4.13 +/- 0.15 pg/ml serum). In ovariectomized ewes in the breeding season, LH pulse frequency was lower (P less than 0.01) during a 24 h infusion of morphine (0.5 mg/kg/h) than during a 24 h infusion of vehicle (mean +/- s.e.m.; 1.17 +/- 0.08 vs 1.71 +/- 0.06 pulses/h). We conclude that long-term infusion of naloxone results in a sustained increase in LH pulse frequency but only a transient elevation in pulse amplitude. No effects on FSH secretion were noted. LH secretion was sensitive to morphine in the absence of ovarian steroids, suggesting that ovarian steroids are not required for the presence of functional opioid receptors capable of modulating LH release.     

The development of beta-adrenergic mediated inhibition of growth hormone secretion in the ovine fetus

The ontogeny of the suppressive effect of the beta-adrenergic agonist, isoprenaline, on fetal growth hormone (GH) release was examined in 14 chronically-catheterized ovine fetuses. Isoprenaline was administered as an intravenous infusion over 1 h (200 micrograms/kg). In seven fetuses between 72 and 99 days of gestation, isoprenaline had no effect on fetal plasma GH concentrations. In seven older fetuses between 114 and 140 days of gestation, isoprenaline infusion suppressed (P less than 0.02) fetal GH release. No effect was observed in five saline-treated control fetuses (119-131 days). Propranolol (250 micrograms/kg i.v.) administered 5 min prior to the isoprenaline infusion to four fetuses (117-136 days) delayed (P less than 0.05) the onset of the suppressive effect of isoprenaline demonstrating that the action of isoprenaline was mediated by the beta-adrenergic receptor. Propranolol alone (n = 6) had no effect. These observations demonstrate that the potential for beta-adrenergic inhibition of fetal GH release differentiates after 100 days of gestation. Comparison with previous studies of the ontogenesis of the control of GH secretion suggests that the hypothalamic beta-adrenergic control of GH release differentiates with an intermediate time course compared to other potential neuroendocrine controls.