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We previously demonstrated that in rats gastric acid secretion declines after birth and drops steeply on day 12 of life. In the present study, we investigated the part played in this decline by prostaglandin E2 (PGE2) from maternal milk. PGE2 content was first measured in the milk of untreated dams 0, 1, 5, 10, 12, 15, and 18 days after parturition. PGE2 levels were high during the first 5 days (123.5-200.5 pg/ml), declined significantly between days 10 and 15 (56.6-85.4 pg/ml; P less than 0.05), and dropped to 18.4 pg/ml on day 18. We also found that depleting milk of PGE2 prevented drop of acid secretion in 12-day-old suckling rats. Injecting lactating dams with indomethacin significantly reduced milk PGE2 content by 65% vs. milk of untreated dams. Surprisingly, administration of sesame oil, the indomethacin vehicle to the dams, increased milk PGE2 content by 182%. In the pups of the indomethacin-treated dams, acid secretion did not drop. On the contrary, in vivo basal and histamine-induced acid output rose markedly by 40 and 50%, respectively, and in vitro the net movements of 36Cl and 22Na measured in the isolated stomach indicated that active Cl- secretion had resumed. Mucosal PGE2 did not appear to be significantly involved in early development of acid secretion because administration of indomethacin to pups from untreated dams did not significantly modify the secretion measured on day 12. Data indicate that maternal milk depletion of PGE2 prevents the drop of gastric acid secretion previously observed in 12-day-old pups and suggest that in infant rats maternal PGE2 plays a physiological part in regulating acid secretion.

Several lines of evidence, mostly derived from animal studies, indicate that changes in fetal environment may affect renal development. Besides maternal hyperglycemia or drug exposure, that were recently found to alter nephrogenesis, changes in vitamin A supply to the fetus may prove to be responsible for most of the variations in nephron number found in the population. A low vitamin A status in the fetus may be a major cause of inborn nephron deficit, either as a feature of intrauterine growth retardation or independently of growth retardation. The possibility that vitamin A status may also influence renal vascular development is raised. We suggest that low vitamin A supply to the fetus plays a role in the intrauterine programming of chronic renal disease and hypertension.

In the rat, in utero exposure to gentamicin during early renal differentiation leads to a permanent nephron deficit. The aim of the present study was to analyze, in vitro, the potential direct effect of gentamicin on early nephrogenesis.We used paired rat metanephric organ cultures from 14 (F14) or 15-day-old (F15) fetuses. We measured gentamicin accumulation into explanted metanephroi and then assessed in vitro growth in the absence or presence of the drug. Glomerular labeling and counting were performed on the whole explant to analyze the effect of antibiotics on early nephrogenesis.Growth of F14 metanephric explants in the presence of 50 micrograms of gentamicin/ml was significantly reduced from 4 days onwards as compared to controls, whereas F15 explants grown with gentamicin displayed a normal in vitro development. After 6 days of culture, F14 and F15 explants had the same accumulation of gentamicin (1 microgram/mg protein) but the gentamicin content was 4 times larger in F15 explants. At both ages, gentamicin-exposed metanephric explants exhibited a significant reduction in their number of nephrons. However, the effects of 50 micrograms of gentamicin/ml on nephrogenesis were significantly more drastic on F14 than F15 explants (35% versus 18%). When grown with 0.5 microgram of gentamicin/ml, F14 explants still exhibited a 16% defect in nephrogenesis as compared with controls, and about the same reduction was observed for cultures in the presence of 100 micrograms/ml of streptomycin and 100 IU/ml of penicillin. Incubation of F14 explants with streptomycin alone for 6 days had no effect on nephrogenesis.These results indicate that gentamicin induces a significant reduction in the number of nephrons in metanephric explants and that this effect is more important on less differentiated metanephroi. Metanephric organ culture combined with glomerular labeling represents a useful model to test the effect of various growth factors and other drugs on early nephrogenesis.

Nonpregnant and pregnant guinea pigs in the last third of gestation were injected intramuscularly with 4 mg of gentamicin per kg, and drug concentrations in plasma were determined by radioimmunoassay at several intervals after injection. The maximum gentamicin concentration was lower in pregnant than in nonpregnant animals (14.6 +/- 0.7 micrograms/ml versus 21.6 +/- 0.7 micrograms/ml), and the peak time occurred significantly later (0.57 +/- 0.12 h versus 0.13 +/- 0.02 h). Four hours after gentamicin injection, drug concentrations in plasma were 2.1 +/- 0.8 and 0.3 +/- 0.1 micrograms/ml in pregnant and nonpregnant animals, respectively. Pregnant animals therefore eliminated the drug from their plasma more slowly. These data provide good evidence that the kinetics of plasma gentamicin varies in pregnant females because its volume of distribution was larger in pregnant than in nonpregnant animals. Detectable but small amounts of gentamicin (less than or equal to 0.50 microgram/ml) were found in the plasma of 46 of 57 fetuses. However, no net variations in these concentrations were observed during the period between 15 min and 6 h after injection to the mother. Gentamicin concentrations were also determined in the kidneys, liver, lungs, heart, and brain of fetal guinea pigs after administration to their mothers of one daily injection of 4 mg/kg for 7 days. Gentamicin was present in all these fetal organs; however, as in the adult organs, the kidneys contained far more than any of the others. Gentamicin concentrations were not significantly different in the kidney cortex and medulla (1.79 +/- 0.16 versus 1.48 +/- 0.92 micrograms/g), indicating that, contrary to what is observed for adults, renal accumulation of gentamicin in the fetus does not occur preferentially in the cortex.

Clearance experiments were performed with young pups born of guinea pigs given a daily injection of 4 mg of gentamicin per kg (body weight) from days 48 to 54 of gestation (term, 68 days). For 3-day-old animals, the glomerular filtration rate was similar to that measured in control guinea pigs of the same age whose mothers were given saline during the same period of gestation. The same applied to fractional excretion of water, urea, total solutes, Na, K, Ca, and Mg but not to fractional phosphate excretion, which increased significantly in the gentamicin group when compared with the controls (mean +/- standard error, 21.7 +/- 4.9 versus 7.3 +/- 1.8%; P less than 0.05; n = 6 for both). The glomerular volume of the juxtamedullary nephrons diminished by about 40%, and their proximal tubule length decreased by about 20%. The glomerular volume of the superficial nephrons also diminished, by about 30%, but their proximal tubule length did not change. The gentamicin concentration was higher in the renal cortex than in the medulla (13.1 +/- 2.6 versus 5.7 +/- 2.2 micrograms/g [dry wt]; P less than 0.01; n = 6 for each). It decreased significantly from days 3 to 20 in both tissues. No functional impairment of the kidney was found in 10-day-old animals, and normal or even supranormal morphometry of the nephrons was observed in the 20-day-old animals. It is concluded that fetal exposure to gentamicin impairs proximal tubular function in the developing animal and might also adversely affect glomerular and tubular growth. However, both the functional and morphometric impairments of nephrons are transitory.

Clearance experiments were carried out in fetal, young, and adult pigs undergoing salt loading. Kidney sections were histologically examined and the proximal tubular length, glomerular volume, and number of glomeruli were estimated. Between days 48 and 55 of gestation, the significant increase in glomerular filtration rate was proportionately higher than the concentration increase in water, total solutes, and sodium reabsorption. During this period, neither the proximal tubular length nor the glomerular volume of the juxtamedullary nephrons changed significantly. The main morphologic change took place in the superficial cortex, where new glomeruli attached to very short tubules differentiated. From day 55 to birth, the increase in water, total solutes, and sodium filtered loads was proportionately smaller than the concomitant increase in tubular reabsorption. During this phase, the major morphologic change was the significant lengthening of the proximal tubules of the juxtamedullary and superficial nephrons. These findings suggest that for water, sodium, and total solutes the maturation of superficial nephrons is accompanied by a phase of functional glomerular preponderance. Despite the differentiation of the superficial nephrons, renal handling of normally filtered glucose did not change significantly. Functional glomerulotubular coupling for water, sodium, and total solutes took place soon after birth.

Kidneys of newborn rats, whose mothers were given 75 mg/kg of gentamicin daily from the tenth day of gestation to its term, were examined by light and electron microscopy, as were kidneys of control rats whose mothers were given saline during the same period. In the gentamicin-treated group, the numbers of differentiated glomeruli and of S-shaped bodies counted in a median cross-section of the kidney were reduced, compared with those in the control group, but the glomerular volume was the same. In newborn rats issued from gentamicin-treated mothers, the proximal tubular lumen of the mature nephron lying in the deepest cortex was dilated, and their proximal tubular cells exhibited extensive damage, resembling that described in tubular cells of adult rats exposed to gentamicin. The subcapsular nephrogenic zone exhibited focal alterations of cytoplasmic organelle membranes, as well as nuclear lesions of several types, in cells of the nephron anlagen of the undifferentiated metanephric blastema, which were otherwise of normal appearance.

The maturation of renal function was investigated by clearance studies in 11 fetal, 9 young, and 4 adult guinea pigs undergoing salt loading (NaCl 1.5%, 75 mul min-1 100 g-1) and in 10 young and 4 adult animals under nondiuretic conditions. The fetal preparation described makes it possible to obtain two to four steady clearance periods for each animal. In the fetus, GFR increased significantly with age, but less than in the newborn. Fractional water and sodium reabsorption was generally low, and net renal secretion of potassium was observed in some cases. Fetal urine was sometimes slightly hypertonic. The effectiveness of the diuretic and natriuretic response following saline expansion was smaller in young than adult animals. The fractional excretion rate of solutes and water increased as a function of age in the young animal and the urinary Na/K concentration ratio showed a marked drop around birth. This latter observation suggests that during the first days of life the effect of saline expansion on the proximal tubule is partially blunted by enhanced sodium reabsorption from the distal nephron due to the high concentration of circulating aldosterone.

In the mammalian foetus, the blood oxygen tension is low (PaO2 congruent to 25 Torr). The factors limiting the oxygen transfer from maternal into foetal blood are mainly the vascular arrangement and the distribution of blood flow within the placenta. The oxygen diffusion across the placenta in facilitated by a higher oxygen affinity in foetal than in maternal blood. During placental gas exchange the Bohr Effect acts in both the maternal and foetal blood to shift their oxyhaemoglobin dissociation curve so that the mean oxygen pressure gradient across the placental membrane is increased. The two main characteristics of foetal blood, a high oxygen capacity and a high oxygen affinity are well adapted to hypoxaemia since, together with a high cardiac output, they ensure an adequate oxygen supply to the foetal tissues. These characteristics of foetal blood disappear during the postnatal period in all the species thus far investigated. The change in the blood oxygen affinity which occurs in the foetus and the newborn have been attributed in some species to the presence of a foetal haemoglobin (HbF) which differs from the adult haemoglobin (HbA) either by an intrinsically higher oxygen affinity, independant of any intracellular cofactor, or by an impaired reactivity towards cofactors which alter haemoglobin oxygen affinity by directly interacting with the haemoglobin molecule (2,3 DPG, CO2). In those species in which HbF has not been shown to be structurally and functionally different from HbA, change in 2,3 DPG concentration can explain change in oxygen affinity.