Exposure to long-term hypoxia (LTH) results in altered cortisol responses in the ovine fetus. The present study was designed to test the hypothesis that LTH alters adrenal responsiveness to fetal hypotension. Pregnant ewes were maintained at high altitude (3,820 meters) from day 30 of gestation. Normoxic control and LTH fetuses were catheterized on day 132 of gestation. In the LTH group, maternal Po(2) was maintained comparable to that observed at altitude ( approximately 60 mmHg) by nitrogen infusion through a tracheal catheter. On day 137, fetuses received a 5-h saline infusion followed by infusion of sodium nitroprusside to reduce fetal arterial pressure by 30-35% for 10 min. The study was repeated on day 139 of gestation with a continuous cortisol infusion (10 microg/min). Hypothalamic and pituitary tissues were collected from additional fetuses for assessment of glucocorticoid receptors. During the saline infusion in response to hypotension, plasma ACTH increased over preinfusion mean values in both groups (P < 0.05). Plasma cortisol concentrations increased in both groups concomitant with increased ACTH secretion. However, peak values in the LTH fetuses were significantly higher compared with controls (P < 0.05). During the cortisol infusion, the ACTH response was eliminated in both groups, with ACTH levels significantly lower in the LTH group (P < 0.05). Glucocorticoid receptor binding was not different between groups. These results demonstrate an enhanced cortisol response to hypotension in LTH fetuses that does not appear to be the result of an increase in negative feedback sensitivity of the hypothalamic-pituitary-adrenal axis.
ABSTRACT-Ebelactone B (EB) (10-'-10-' M) inhibited dose-dependently carboxypeptidase (CP) Y-like exopeptidase, one of the major kininases separated from rat urine, whereas it inhibited neither CPA, CPB or neutral endopeptidase (NEP). Degradation of bradykinin (BK) to BK-(1-8) in rat urine was completely inhibited by EB (10-5 M) with the increased generation of BK-(1-7). Intraduodenal administration of EB (3 mg/kg) to anesthetized rats caused marked diuresis (by 110%) and natriuresis (130%), in parallel with the increase in urinary kinin levels (110%). Intravenous infusion of a BK antagonist, Hoe140 (3 mg/kg/hr), strongly blocked both EB-induced diuresis and natriuresis. EB may be a novel type of diuretic and natriuretic agent that acts by increasing urinary kinin levels. Bradykinin (BK) is very active in renal function because it participates in increasing the renal blood flow and in di uresis and natriuresis (1). We have reported that the degra dation pathway of BK in rat urine is quite different from that in plasma because of the difference in kininases present (2). The major kininases in rat urine were neutral endopeptidase (NEP) and carboxypeptidase (CP) Y-like exopeptidase (3), whereas angiotensin converting enzyme (ACE) and CPN mainly degrade BK in rat plasma (2).Ebelactones, isolated from actinomycetes, were report ed to inhibit some enzymes such as esterase, lipase and N formylmethionine aminopeptidase (4). In the present paper, we report that Ebelactone B (EB) selectively in hibited not only CPY from yeast but also CPY-like exopep tidase in rat urine without inhibition of other kininases in plasma and urine. Furthermore, administration of EB to anesthetized rats caused diuresis and natriuresis via in creased urinary kinin excretion. This suggests that EB is a candidate for a new type of diuretic and natriuretic agent. NEP and CPY-like exopeptidase in rat urine were sepa rated by using a Superdex 200 column as described in the previous paper (3). Plasma samples were prepared from blood collected from the carotid artery under ether anesthesia (2). Enzyme activities of isolated CPA, CPB and CPY were determined with peptide substrates: Z-Gly Phe for CPA (5), Bz-Gly-Arg for CPB (6) and Z-Phe-Leu for CPY (7). Assays of kininase activity and detection of BK fragments were carried out by HPLC (2, 3). The in vivo effects of EB were studied in male Sprague-Dawley strain rats (SPF, 8 to 10-week-old, anesthetized with sodium pentobarbital, 40 mg/kg, i.p.). Urine was collected through a polyethylene cannula inserted into the bladder to estimate the volume of urine and urinary so dium and potassium levels. Physiological saline was in fused (6 ml/kg/hr) via the jugular vein throughout the experimental period. Urine volume was estimated by its weight, and urinary sodium and potassium levels were as sayed by flame photometry (8). For the assay of kinin in the urine, urine was collected directly into plastic tubes containing absolute ethanol through a polyethylene can nula inserted into both ureters under pentobarbital...
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