To determine whether adrenocorticotropic hormone (ACTH) at plasma concentrations measured during mild hypoxemia and at term affects adrenal blood flow, we measured regional blood flows in five unanesthetized normoxemic fetuses (125-130 days gestation) during a 24-h intravenous infusion of ACTH-(1-24) in isotonic saline solution. Another five fetuses received an infusion of vehicle. Blood flows were determined before the infusion, at 2 and 24 h from its onset, and 24 h afterward using radionuclide-labeled microspheres. Blood flow to the adrenal medulla was fivefold greater than that to the adrenal cortex. Adrenal blood flow rose 99% at 24 h of the ACTH infusion. There was a large increase in adrenal cortical blood flow of 272% at this time but medullary blood flow did not change significantly during ACTH infusion. The rise in cortical blood flow was attributable to decreased vascular resistance. No significant alterations occurred in fetal arterial blood pressure and heart rate, or in blood flow to other lower body organs of the fetus or to the placental cotyledons. These findings are consistent with the hypothesis that the increase in adrenal blood flow observed during fetal hypoxia is associated with changes in plasma ACTH concentration. They are also indicative of selective regulation of cortical and medullary blood flows in the sheep fetus at this stage of gestation.

In the present study, it was hypothesized that the adrenocorticotrophin hormone receptor (ACTH-R) would be up-regulated in the adrenal gland of the sheep fetus following infusion of physiological amounts of ACTH, as shown for adrenal cortical cells in culture. In chronically catheterized sheep, an intravenous infusion of ACTH(1-24) was given to 6 fetuses for 24 h at a rate of 0.5 microg h(-1), starting on Day 126 or 127 of gestation (term approximately 147 days). Four control fetuses received an infusion of vehicle (saline). Total RNA was extracted from the fetal adrenal glands by the guanidinium thiocyanate method. Expression of specific mRNAs was determined by ribonuclease protection assay using cRNA probes directed against: ACTH-R; the steroid enzymes side-chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17apha-hydroxylase (P450c17) and 21beta-hydroxylase (P450c21); and beta-actin. Ratios of mRNA expression to beta-actin mRNA expression (arbitrary units) were calculated to correct for differences in RNA quality between samples. The concentration (mean +/- SEM) of immunoreactive cortisol in fetal plasma was greater after ACTH infusion than after vehicle infusion (47 +/- 3 v. 13 +/- 2 ng mL(-1) respectively; P<0.001). Adrenal expression of P450scc and P450c21 mRNA increased after ACTH infusion (P<0.05), whereas expression of P450c17 and 3beta-HSD mRNA was unchanged. There was no difference in ACTH-R mRNA expression between ACTH- and vehicle-infused fetuses (254 +/- 48 v. 305 +/- 76 arbitrary units respectively). It was concluded that ACTH is able to increase plasma cortisol concentrations in the sheep fetus by up-regulating cortisol synthesis in the adrenal gland, but that in vivo this does not require up-regulation of ACTH-R mRNA.

ABSTRACT. The ontogenetic renal responsiveness to exogenous cortisol was examined in the chronically cannulated ovine fetus. The contribution of effects a t proximal and distal tubule of the kidney were studied also. Cortisol (81.5 pg/h) was infused into immature ovine fetuses (mean gestational age -113.9 days) on five occasions and increased blood cortisol from 0.8 f 0.5 to 21.3 + 6.2 nmol/ liter. This dose of cortisol produced a highly significant diuresis and natriuresis, in part due to an increase in GFR and in part due to a significant decrease in proximal tubular reabsorption of sodium. Cortisol (107.2 + 4.7 &h) was infused into mature fetuses (mean gestational age 133.4 days) and produced an increase in blood cortisol concentration from 11.4 + 5.6 to 33.7 2 6.8 nmol/liter. No natriuresis or diuresis was seen in the mature fetuses. Cortisol caused a significant depression of proximal tubular sodium reabsorption in mature fetuses, but this extra load was reabsorbed in the distal tubule in these fetuses. The inability of the premature or very low birth wt baby to maintain normal sodium balance on a standard salt intake may be due, at least in part, to a "fetal" renal response to the high plasma cortisol concentrations found in such babies. As the kidney matures it becomes capable of increasing distal tubular sodium reabsorption to compensate for any increased distal tubular fluid delivery. (Pediatr Res 26: 6-10, 1989) Abbreviations FRN,, fractional reabsorption of sodium FR,,i, fractional reabsorption of lithium uN,,v, uKV, UclV, Uc.V, renal excretion rate of sodium/ potassium/chloride/calcium may be responsible for neonatal hyponatremia. However, subsequent investigations have shown that a characteristic of this defect is decreased proximal tubule reabsorption of sodium (2) implying that renal insensitivity to aldosterone may be only partially responsible. The relative immaturity of renal function in very low birth wt and premature neonates seems to be important in the pathogenesis of hyponatremia. Premature neonates exhibit a greater natriuresis and a lower GFR in response to oral salt loading when compared to full-term neonates (5, 6). This is consistent with histopathologic studies that show that glomerular formation in the human infant is not complete until late in gestation (7), whereas tubular development is not complete until 1 y after birth (8).In mature mammals the presence of adrenal steroids is essential for normal renal function. A characteristic of adrenalectomized or hypophysectomized animals and patients with adrenal or pituitary insufficiency is a delayed diuresis following oral or parenteral water loading, accompanied by impaired sodium conservation and reduced GFR and renal blood flow. Administration of deoxycortisone acetate or aldosterone in the presence of normal sodium balance and extra-cellular volume has no effect on the delayed diuresis, whereas cortisol-like steroids correct this diuresis (9-1 1).Clinical investigations have reported that premature neonates have higher plasma co...

ABSTRACT. This study examines the effects of infused human atrial natriuretic peptide 1-28 (hANP) on ovine fetal renal function. hANP was infused into chronically cannulated ovine fetuses of 103-128 days gestation (term 142-152 days) at 1.1 (4), 2.2 (5), and 4.4 (5) ~g / h for 2 h. Isotonic saline was infused in 10 control experiments. The fractional reabsorption of infused lithium was used as a marker of proximal tubular sodium reabsorption. Glomerular filtration rate and urinary water and electrolyte excretion were assessed. The blood pressure and heart rate were unaltered by any dose of hANP. The lowest dose (1.1 pg/h) did not produce any significant changes in glomerular filtration rate, urinary electrolyte or water excretion, or fractional reabsorption of lithium. hANP, at 4.4 pg/h, caused a significant ( p < 0.001) 5-fold increase in the excretion of Na, Cl, and Ca, doubled the excretion rate of K and free water clearance, and significantly increased glomerular filtration rate. Fractional sodium reabsorption and fractional reabsorption of lithium were significantly decreased ( p < 0.001, < 0.01, respectively). The results show that the fetal kidney, at this stage, is as responsive to hANP as is the adult kidney. The natriuretic action of hANP is related to increases in glomerular filtration rate and proximal tubular rejection of sodium (as assessed by fractional reabsorption of lithium). The excessive salt loss of the premature or low birth weight neonate, which also involves increased delivery of filtrate to the distal tubule, may be due to endogenous hANP, circulating at high concentrations. (Pediatr Res 22: 11-15, 1987) Abbreviations hANP, human atrial natriuretic peptide 1-28 GFR, glomerular filtration rate FRN,, fractional reabsorption of sodium FRj,j, fractional reabsorption of lithium UN., K , c,, ca V, renal excretion rate of sodium/potassium/ chloride/calcium CIIzo, free water clearance AVP, arginine vasopressin C,.i, clearance of lithium MAP, mean arterial pressure HR, heart rate