Effect of atrial natriuretic peptide on adrenal renin and aldosterone

The effect of atrial natriuretic peptide (ANP) on adrenal renin and aldosterone was investigated in anesthetized rats. Under pentobarbital anesthesia 40 mg/kg), intravenous infusion of ANP (0.25 micrograms/kg/min) for 45 min failed to alter the adrenal renin, adrenal aldosterone, and plasma aldosterone (PA). In this condition, intraperitoneal injection of ACTH (10 micrograms/kg) significantly increased the adrenal renin (from 2.4 +/- 0.1 to 5.0 +/- 0.08 ng/mg protein/h, P less than 0.05), adrenal aldosterone (from 13.6 +/- 1.3 to 22.7 +/- 2.3 ng/mg protein, P less than 0.01) and PA (from 59.8 +/- 5.8 to 75.5 +/- 7.4 ng/dl, P less than 0.05), respectively. Under ACTH stimulation, ANP infusion induced significant decreases in adrenal renin (from 5.0 +/- 0.08 to 2.8 +/- 0.2 ng/mg protein/h, P less than 0.05), adrenal aldosterone (from 22.7 +/- 2.3 to 16.2 +/- 1.8 ng/mg protein, P less than 0.05) and PA (from 75.5 +/- 7.4 to 61.6 +/- 4.9 ng/dl). These results suggest a possible role for adrenal renin in the mechanism underlying the inhibitory effect of ANP on aldosterone production in vivo.     

Enkephalin peptides in fetal sheep, changes with gestation, origin and production by the placenta.

Enkephalin-containing peptides have been followed in the circulation of fetal sheep between 118-143 days gestation. Using a combination of radioimmunoassay and hplc met5-enkephalin was found in the concentration range 60-500 pg/ml and proenkephalins containing met5-enkephalin had a concentration of 150-4000 pg/ml. The concentration of both increased towards term. The sources of the enkephalin peptides was investigated by measurement of differences across the umbilical circulation and by studying the effects of fetal adrenal demedullation and chemical sympathectomy. The placenta showed a continuous net output of enkephalin peptides which increased close to term. This placental output was increased sharply by reduction of uterine blood flow either using compression of the uterine artery or through infusion of adrenaline at 35 micrograms/min into the maternal circulation. Maternal hypoxia caused by breathing 9% O2 plus 3% CO2 also increased fetal plasma enkephalin levels, although not output from the placenta. Adrenal demedullation, particularly if accompanied by chemical sympathectomy depressed fetal plasma enkephalin concentrations and sharply suppressed the fetal peptide responses to maternal hypoxia. It is concluded that the placenta and the fetal adrenal are important sources of met5-enkephalin-containing peptides in the fetal circulation. The placental production appears to be closely tied to changes in uterine perfusion and adrenal output changes in response to fetal oxygenation.     

Activation of adrenal function in fetal sheep by the infusion of adrenocorticotropin to the fetus in utero

We determined whether ACTH1-24, infused into fetal lambs at a rate that is known to cause premature labor, elicits changes in the responsiveness of the fetal adrenal glands, and alters the pattern of corticosteroid output. Plasma cortisol (F), corticosterone (B) and progesterone (P4) were measured during 72 h of infusion of saline or ACTH (10 micrograms/h) beginning on Day 127 of pregnancy. Adrenals were then dispersed into isolated cells, and the output of F, B and P4 after exogenous ACTH determined in vitro. Plasma concentrations of F and B were higher in ACTH-treated fetuses. The increment in F (5-to 7-fold) was greater than that in B (2-fold) such that the F:B ratio in plasma of ACTH-treated fetuses on Days 2 and 3 of infusion was 2.5 times higher than in controls. After 72 h of infusion, the adrenal weights in ACTH-treated fetuses (741 +/- 38 mg, +/- SEM; n = 4) were greater than in the control animals (349 +/- 11 mg). There was a significant effect of ACTH pretreatment in vivo on F output by isolated adrenal cells in vitro. Mean increments in F output after addition of ACTH1-24 (5000 pg/ml) in vitro rose from 368 +/- 235 pg/50,000 cells in controls, to 64,639 +/- 19,875 pg/50,000 cells after ACTH in vivo. There was no significant effect of ACTH in vivo on B output in vitro; the ratio of F:B output, either in the absence or presence of ACTH in vitro, was significantly higher in cells from ACTH-pretreated fetuses. There was a significant effect of in vivo ACTH on in vitro P4 output. After ACTH treatment in vivo there was an increase in the vitro output ratio of F:P4, but no change in the output ratio of B:P4. We conclude that ACTH treatment of the fetal lamb in vivo results in activation of fetal adrenal function, increased fetal adrenal responsiveness to ACTH, and directed corticosteroid biosynthesis towards cortisol. Our results are consistent with an increase in fetal adrenal 17 alpha-hydroxylase activity after ACTH treatment.     

Effects of (D-ala2, met5)-enkephalinamide and naloxone on ACTH and corticosterone secretion

An intravenous administration of (D-ala2, met5)-enkephalinamide (DALA) caused a significant elevation of plasma ACTH and corticosterone at 10 to 20 min after injection in unanesthetized freely moving rats. An intraperitoneal administration of cyproheptadine tended to reduce plasma ACTH and corticosterone levels at 60 min after injection, but it did not attenuate the DALA-induced ACTH and corticosterone elevation. A large dose of naloxone (1-10 mg/kg body weight) caused a significant elevation in plasma corticosterone, but naloxone at 10 mg/kg body weight reduced the basal ACTH level and DALA-induced ACTH elevation. When both DALA and naloxone were injected, the steroidogenic effect was attenuated. Neither DALA nor naloxone affected the basal ACTH release and CRF-induced ACTH stimulation in rat anterior pituitary cell cultures. These results suggest that DALA acts at the extra-hypophyseal level to stimulate ACTH and corticosterone and that the naloxone stimulatory effect on steroidogenesis acts on the adrenal gland or is mediated by stimulating corticosterone stimulating factors other than ACTH.     

The effects of ACTH1-24 or cortisol on pulmonary maturation in the adrenalectomized ovine fetus

Pulmonary maturation in 8 ovine fetuses bilaterally adrenalectomized at 98-101 days and infused at term with either ACTH1-24 or cortisol was compared with that in 4 untreated sham-operated controls. Four of the adrenalectomized fetuses were infused intravascularly with ACTH1-24 5 micrograms/h for 84 h before delivery and the other four were infused with cortisol 1 mg/h for 72 h. The high plasma concentrations of immunoreactive ACTH in the adrenalectomized fetuses (2762 +/- 1339 ng/l, mean +/- SD) were not significantly elevated by infusion of ACTH1-24 but were markedly depressed by infusion of cortisol. Distensibility (V40) of the lungs was less than that of controls in both the ACTH1-24-infused and cortisol-infused fetuses (1.86 +/- 0.31 ml/g vs 0.62 +/- 0.13 ml/g and 1.27 +/- 0.34 ml/g respectively) but it was significantly greater in the cortisol-infused fetuses compared to those infused with ACTH1-24. The volume of air retained at 5 cm H2O pressure (V5) during deflation was markedly reduced in adrenalectomized fetuses (controls 1.14 +/- 0.52 ml/g vs 0.25 +/- 0.25 ml/g and 0.12 +/- 0.6 ml/g). The wet weight of the lungs and the concentrations of saturated phosphatylcholine in lung tissue and lavage fluid were lower in the adrenalectomized fetuses than in controls but the differences were not significant. It is concluded that infusion of ACTH1-24 at term in adrenalectomized fetuses is probably without effect whereas cortisol enhances distensibility.     

Evidence for direct inhibitory effects of dopamine on zona glomerulosa secretion of 18-hydroxycorticosterone in rhesus monkeys

This study was designed to more selectively investigate the dopaminergic regulation of 18-hydroxycorticosterone (18-OHB) and aldosterone production by the adrenal zona glomerulosa. Mature rhesus monkeys received either an infusion of dopamine (2 micrograms/kg/min) or 5% dextrose (0.2 ml/min) over a 60 min period (N=6). Dopamine had no effect on plasma levels of renin activity, cortisol, corticosterone, aldosterone or blood pressure. However, dopamine suppressed (p less than 0.05) plasma 18-OHB levels from a baseline of 31.6 +/- 3.5 ng/dl to 23.6 +/- 2.1 ng/dl at 60 min after onset of infusion. This observation is in agreement with some studies in humans but differs from others in which no depression in 18-OHB was observed following dopamine infusion. Dopamine infusion markedly (p less than 0.001) suppressed plasma PRL levels by 30 min after onset of infusion. Corticosteroid responses to metoclopramide (200 micrograms/kg) after dexamethasone 1 mg im every 6 h X 5 days or placebo treatment (vehicle im every 6 h X 5 days) was then evaluated. Dexamethasone significantly suppressed basal cortisol, corticosterone, 18-OHB and aldosterone. Although dexamethasone blunted the prolactin response, it did not inhibit the aldosterone response to metoclopramide. The 18-OHB response to metoclopramide was increased (p less than 0.01) following dexamethasone treatment. Following dexamethasone suppression, 18-OHB levels were still lowered (p less than 0.05) by dopamine infusion. These results suggest that dopamine selectively inhibits zona glomerulosa production of 18-OHB and aldosterone in rhesus monkeys.     

Effect of functional adrenalectomy on glucagon secretion and circulating catecholamines during insulin hypoglycemia in the dog

The present study was carried out to determine whether an increase in the pancreatic immunoreactive glucagon (IRG) secretion during the acute phase of insulin-induced hypoglycemia depends on circulating catecholamines of adrenal origin. Hypoglycemia was induced by a bolus insulin injection (0.15 IU/kg, i.v.) in dogs anesthetized with sodium pentobarbital (35 mg/kg, i.v.). Plasma aortic epinephrine (E) and norepinephrine (NE) concentrations increased significantly 30 min after the injection of insulin. At this time point, a functional adrenalectomy (diversion of bilateral adrenal venous blood from the systemic circulation) was performed for 5 min. The increased aortic E and NE concentrations significantly decreased reaching, within 5 min, a level below the corresponding preinjection control value. The basal output of pancreatic IRG (6.58 +/- 1.12 ng/min, n = 6) significantly increased (24.93 +/- 2.77 ng/min, p less than 0.05, n = 6) 30 min after insulin injection. During the functional adrenalectomy, the increased pancreatic IRG output diminished rapidly, within 5 min, to approximately 50% (11.73 +/- 3.19 ng/min, p less than 0.05, n = 6) of the value observed 30 min after insulin administration. In the other group of dogs receiving sham adrenalectomy, the increased aortic E and NE concentrations and pancreatic IRG output following insulin injection remained elevated above the levels observed immediately before the sham adrenalectomy. The net decrease in IRG output during the adrenalectomy was significant (p less than 0.05) compared with the corresponding net IRG output observed in the sham group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenocortical responses to adrenocorticotrophin in the rat

The time course of plasma adrenocorticotrophin (ACTH), adrenal cyclic AMP, adrenal corticosterone, and plasma corticosterone was measured in male Sprague-Dawley rats whose endogenous release of ACTH had been blocked (1) following rapid injections of 100 and 300 ng ACTH/100 g body weight, i.v., (2) during prolonged infusions at rates of 1, 2, and 4 ng ACTH/min per 100 g body weight, and (3) after termination of 30-min infusions at rates extending from 0.06 to 8 ng ACTH/min per 100 g body weight. Following injections, the time course of the variables is similar to the one simulated from our models of adrenal cortical secretion, including the simulation of an intermediate variable of our models of the adrenal cortex cell which was presumed to correspond to cyclic AMP. However, during prolonged infusions there is an unexpected overshoot of adrenal cyclic AMP content whereas adrenal and plasma corticosterone concentrations rise to a steady-state value without overshoot. The total amount of cyclic AMP gradually increases following the three increasing infusion rates of ACTH whereas similar levels of plasma corticosterone concentrations are reached at steady state; therefore the saturation of the adrenal cortical secretion is due to a step ulterior to cyclic AMP formation in the steroidogenesis. After 30-min infusions, plasma corticosterone concentration reaches its maximal value following a rate of ACTH input which evokes only a 4-fold increase in adrenal cyclic AMP content; however, there is a 250-fold increase of adrenal cyclic AMP with respect to control value following the higher rates of infusion of ACTH.     

Inhibition of cortisol production in isolated guinea-pig adrenal cells

Cortisol, added to 1 ml incubation medium containing 3-4 X 10(5) isolated guinea-pig adrenal cells, provoked a decrease in basal and ACTH (250 pg)-stimulated cortisol production, in correlation with the amounts used (50 ng-2,000 ng). A decrease in aldosterone production could be seen when cortisol concentrations reached or exceeded 1,000 ng/ml. There were no variations in either androgens (delta 4-androstenedione, dehydropiandrosterone) or 17-hydroxyprogesterone. Only 11-deoxycortisol was slightly increased. Using increasing concentrations of ACTH (50-250 pg), both in the absence and in the presence of 1,000 ng cortisol, it was noted that the inhibition induced by cortisol was of a competitive type and could be overcome by ACTH. This decrease in cortisol was concomitant with an increase in 11-deoxycortisol. Neither corticosterone nor dexamethasone reduced cortisol production. In addition, it was shown that the conversion of tritiated 11-deoxycortisol to radioactive cortisol increased significantly under the influence of 250 pg ACTH (mean relative variation of 21.7% +/- 7.7 (SEM), n = 6, P less than 0.05); but decreased significantly under the combined effect of 1,000 ng exogenous cortisol and the same dose of ACTH: (mean relative variation of 4.3% +/- 1 (SEM), n = 8, P less than 0.005). There is therefore reason to believe that the concentrations of cortisol at the adrenal level modulate the stimulation induced by ACTH and that this self-adjustment forms part of the control mechanisms involved in corticosteroidogenesis.     

Ability of cortisol and progesterone to mediate the stimulatory effect of adrenocorticotropic hormone upon testosterone production by the porcine testis

The influence of corticosteroids and progesterone upon porcine testicular testosterone production was investigated by administration of exogenous adrenocorticotropic hormone (ACTH), cortisol and progesterone, and by applying a specific stressor. Synthetic ACTH (10 micrograms/kg BW) increased (P less than 0.01) peripheral concentrations of testosterone to peak levels of 5.58 +/- 0.74 ng/ml by 90 min but had no effect upon levels of luteinizing hormone (LH). Concentrations of corticosteroids and progesterone also increased (P less than 0.01) to peak levels of 162.26 +/- 25.61 and 8.49 +/- 1.00 ng/ml by 135 and 90 min, respectively. Exogenous cortisol (1.5 mg X three doses every 5 min) had no effect upon circulating levels of either testosterone or LH, although peripheral concentrations of corticosteroids were elevated (P less than 0.01) to peak levels of 263.57 +/- 35.03 ng/ml by 10 min after first injection. Exogenous progesterone (50 micrograms X three doses every 5 min) had no effect upon circulating levels of either testosterone or LH, although concentrations of progesterone were elevated (P less than 0.01) to peak levels of 17.17 +/- 1.5 ng/ml by 15 min after first injection. Application of an acute stressor for 5 min increased (P less than 0.05) concentrations of corticosteroids and progesterone to peak levels of 121.32 +/- 12.63 and 1.87 +/- 0.29 ng/ml by 10 and 15 min, respectively. However, concentrations of testosterone were not significantly affected (P greater than 0.10). These results indicate that the increase in testicular testosterone production which occurs in boars following ACTH administration is not mediated by either cortisol or progesterone.     

Corelease of neuropeptide Y like immunoreactivity with catecholamines from the adrenal gland during splanchnic nerve stimulation in anesthetized dogs

The release of neuropeptide Y like immunoreactivity (NPY-li) from the adrenal gland was studied in relation to the secretion of catecholamines (CA: NE, norepinephrine; E, epinephrine) during the left splanchnic nerve stimulation in thiopental-chloralose anesthetized dogs (n = 16). Plasma concentrations of NE, E, and NPY-li were determined in the left adrenal venous and aortic blood. Adrenal outputs of NPY-li, NE, and E were 2.4 +/- 0.4, 1.4 +/- 0.2, and 7.3 +/- 1.7 ng/min, under basal conditions, respectively. These values increased significantly (p less than 0.05; n = 8) in response to a continuous stepwise stimulation at frequencies of 1, 3, and 10 Hz given at 3-min intervals during 9 min, reaching a maximum output of 4.6 +/- 0.9 (NPY-li), 240.2 +/- 50.2 (NE), and 1412.5 +/- 309.7 ng/min (E) at a frequency of 10 Hz. Burst electrical stimulation at 40 Hz for 1 s at 10-s intervals for a period of 10 min produced similar increases (p less than 0.05) in the release of NPY-li (4.8 +/- 1.0 ng/min, n = 8), NE (283.5 +/- 144.3 ng/min, n = 8), and E (1133.5 +/- 430.6 ng/min, n = 8). Adrenal NPY-li output was significantly correlated with adrenal NE output (r = 0.606; n = 24; p less than 0.05) and adrenal E output (r = 0.640; n = 24; p less than 0.05) in dogs receiving the burst stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Structural and functional characteristics of primary cell cultures derived from the adrenal gland tissue of neonatal mallard ducklings (Anas platyrhynchos)

Summary Primary cell cultures were prepared from the adrenal glands of one-day-old mallard ducklings (Anas platyrhynchos). The cells attached equally well to uncoated plastic and glass surfaces and on surfaces that had been coated with collagen. The phase of logarithmic growth occurred between the second and the fourth day, and the cells became confluent between the fifth and the sixth day. Staining with Sudan black B and toluidine blue and viewing fixed preparations by transmission electron microscopy indicated that the cultures consisted mostly of steroidogenic cells. A smaller population of chromaffin cells was also present. Scanning electron microscopy showed that most of the cells had long filopodia, and some cells had numerous surface blebs that were interpreted as exocytotic vesicles. When incubated in Krebs-Henseleit buffer containing 1–24 ACTH the cultured cells released three corticosteroids, namely, corticosterone, aldosterone and deoxycorticosterone. These responses occurred within 15 min of exposure to medium containing 1–24 ACTH and continued throughout a 60-min period of continuous stimulation. The minimally effective concentration of 1–24 ACTH was 0.078 ng per ml (0.0234 nM) and, as the concentration was increased up to 10 ng per ml (2.99 nM), the total output of each hormone during the 60-min incubation period increased significantly according to the following semi-logarithmic relationship: Y=a+b log X, where Y=the total output of hormone, X=the concentration of 1–24 ACTH in the medium, and a=the total output of hormone when the medium contained 1.0 ng of 1–24 ACTH per ml. The total outputs of each hormone in the presence of a maximally effective concentration of 1–24 ACTH, however, were low compared to the responses of similarly stimulated tissue slices taken from the neonatal duckling. It is concluded that most of the cells comprising the confluent cultures were derived from steroidogenic cells in the neonatal adrenal. These cells appeared to retain corticotropin receptors during the course of developing into confluent monolayers, but their diminished steroidogenic capacity to respond when stimulated maximally suggests that some generational changes may have occurred.This work was supported by grants to James Cronshaw and W.N. Holmes from the University of California Committee on Research and the National Science Foundation (DIR-8820923), Washington, DC, USA     

Effect of dexamethasone on steroidogenesis and on adrenocortical cyclic AMP and cyclic GMP responses to ACTH

The inhibitory action of dexamethasone on the adrenal steroidogenic response to ACTH was confirmed by im administration of graded doses (5, 10 and 30 ng) of synthetic beta 1-24 ACTH to young adult male rats which had received dexamethasone (0.1 mg/100 g bw) 4 hr prior to sacrifice. Following this, kinetic studies were performed by measuring plasma corticosterone, adrenocortical cyclic AMP and cyclic GMP before and 4, 12 and 30 min after administration of either 10 or 30 ng of ACTH. These doses were selected because their effects could be either completely or partially inhibited by dexamethasone. In rats without dexamethasone all the doses of ACTH which were checked induced an increase in both corticosterone and cyclic AMP and a decrease in cyclic GMP. With the smallest dose of ACTH the earlier administration of dexamethasone resulted in complete suppression of both the steroidogenic response and the cyclic AMP response. With the largest dose of ACTH both responses were diminished. In dexamethasone-treated rats the decrease in cyclic GMP was significantly less pronounced 4 min after ACTH than it was in non-treated rats. These results support the view that cyclic AMP and cyclic GMP might both be concerned with the mechanism of acute adrenal steroidogenesis.     

Modulation of the responses of fetal sheep to adrenergic stimulation by adrenal demedullation and chemical sympathectomy

The responses to sympathetic stimulation of fetal sheep adrenal-demedullated or sympathectomised by infusion of guanethidine sulphate have been studied. Sympathetic responses in such denervated or sympathectomised fetuses was studied by intravenous infusion of adrenaline or noradrenaline at about 0.4 micrograms/min per kg. This infusion increased plasma concentration 100-200 fold and there was no significant difference between the control fetuses and those in the vasrious treatment groups. Catecholamine infusions at these rates normally have little effect upon fetal blood gas and pH values, but in adrenal-demedullated fetuses adrenaline infusion drepressed fetal arterial PO2 by 4-6 mmHg (P less than 0.05). The heart rate and blood pressure responses to catecholamine infusion in sympathectomised fetuses was, as expected, much increased. Similar observations were made on adrenal-demedullated fetuses, an unexpected finding, and this is taken to illustrate loss of the adrenal medulla is associated with enhanced responsiveness to adrenergic stimulation in peripheral tissues. The majority of the endocrine and metabolic responses, as reflected in fetal plasma concentrations of ACTH, cortisol, insulin, glucose, lactate and fatty acids, to catecholamine infusion were similarly much enhanced by adrenal-demedullation and chemical sympathectomy. Of particular note was a substantial increase in the responsiveness of the fetal adrenal, as reflected in plasma cortisol, to stimulation by ACTH, a change that usually induces labour, but not so in the present sheep. The results on increased sensitivity in adrenal-demedullated fetuses are discussed in relation to likely tissue mechanisms mediating the changes.     

Feedback inhibition of adrenocorticotropin release by corticosterone infusions in the adrenalectomized rat.

Advantage was taken of a specific and sensitive bioassay for rat plasma adrenocorticotropin (ACTH) based on the dispersion of rat adrenal cells with trysin, to investigate the relationship between plasma corticosterone concentration and inhibition of ACTH release under steady-state conditions achieved by graded rates (0-5.12 mug/min per 100 g body weight) of intravenous infusion of the steroid for 45 min in 28-day adrenalectomized rats. In contrast to prior reports involving suppression of stress-induced ACTH release, the inhibitory effect of corticosterone was shown, under our experimental conditions, to be exerted also on the basal rate of ACTH secretion. Indeed, a slight though not significant decrease of plasma ACTH concentration was observed with the corticosterone infusion rate of 0.64 mg/min per 100 g body weight, and further progressive and highly significant drops in concentration were recorded for infusion rates of 2.56 and 5.12 mg/min per 100 g body weight. An increase of the metabolic clearance rate of corticosterone, observed as a function of the infusion rate, was ascribed to saturation by the steroid of the plasma transcortin binding sites.     

The influence of plasma lipoproteins on steroidogenesis of cultured ovine fetal and neonatal adrenal cells

The present study examined the effects of serum and lipoproteins on the function of cultured adrenal cells from 115-127-day-old ovine fetuses and from newborn lambs. On day 1 of culture, corticosteroid output was similar in medium containing 2% horse serum or in serum-free medium, both for fetal and neonatal cells. However, on day 5, cells cultured in the absence of serum produced smaller amounts of these steroids than cells maintained in medium containing serum; the difference was more marked under ACTH1-24 stimulation. Conversely, cAMP production was never lower in the absence than in the presence of serum. When stimulated by ACTH1-24 on day 2 of culture, fetal or neonatal adrenal cells incubated in the presence of a saturating concentration of ovine LDL produced more corticosteroids than cells incubated in serum-free medium; HDL also enhanced ACTH1-24-induced steroidogenesis, but to a lesser extent. VLDL was effective only with neonatal cells. In fetal and neonatal cells cultured for 6 days in ACTH-free medium, VLDL and LDL increased ACTH-induced steroidogenesis, but HDL did not. On the other hand, when cells were cultured in the presence of ACTH1-24, LDL and HDL were equipotent in supporting ACTH1-24-induced steroid output. Three major lipoprotein fractions were observed in serum of fetal and newborn lambs. The concentration of cholesterol was very low in the VLDL fraction of fetuses, but it was similar to that of newborns in LDL. Conversely, 4 times more cholesterol was present in HDL of newborns than in HDL of fetuses. These results suggest that: (i) after several days of cell culture, cholesterol availability is an important limiting factor for the steroidogenesis of cells maintained under serum-free conditions; (ii) both an "LDL pathway" and an "HDL pathway" are operating in adrenal cells from fetal as well as newborn sheep; (iii) LDL and HDL are important physiological sources of cholesterol to support steroidogenesis by fetal and neonatal adrenal cells.     

Effects of ACTH on plasma levels of adrenal steroids in essential hypertension.

Plasma concentrations of progesterone (P), deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OH P), corticosterone (B), deoxycortisol (S), cortisol (F) and aldosterone (A) in 8 control subjects (mean age: 40.5 years) and 10 patients with essential hypertension (EH) (mean age: 48.5 years) were determined before, 4 and 8 hours after an infusion of ACTH at a rate of 25 units per 8 hours. Secretion rates (SR) of 18-hydroxy-11-deoxycorticosterone (18-OH DOC) were measured 24 hours before and again on the day of ACTH infusion. All subjects were studied on the fourth day of a diet containing 135 mEq of sodium and 90 mEq of potassium. There was no statistically significant difference between 8 control subjects and 10 patients with EH in the 7 plasma steroid levels and the SR of 18-OH DOC before ACTH infusion. The mean plasma P response to ACTH was slightly lower in controls than in patients with EH, while that of 17-OH P (in male subjects) was slightly higher. The mean plasma B response was significantly lower after 4 hours of ACTH infusion (p less than 0.01), while that of DOC was significantly higher after 8 hours of ACTH infusion (p less than 0.05) in patients with EH. The mean plasma S rose significantly more in patients with EH (p less than 0.025) at 4 and 8 hours after ACTH infusion. The mean plasma F response to ACTH infusion was slightly lower in patients with EH than in controls. The mean response of 18-OH DOC SR to ACTH infusion was slightly higher in patients with EH than in controls. The mean plasma A response was significantly higher in patients with EH than in controls 4 (p less than 0.05) and 8 hour (p less than 0.001) after an ACTH infusion. These results could be explained in part by abnormalities in the 17- and 11-hydroxylase systems, and that the abnormality in 11-hydroxylation was more pronounced than that in the 17-position. Furthermore, we suspect that the sensitivity of adrenal aldosterone to ACTH might be increased or another accelerated pathway to aldosterone biosynthesis might exist in patients with EH.     

Plasma progesterone response following ACTH administration during mid-gestation in the pregnant Brahman heifer

Previous reports of adrenal progesterone (P4) contributions during late gestation in cattle, and ACTH-induced P4 responses in the non-pregnant heifer, prompted a retrospective investigation to evaluate the plasma P4 response and the relative ratio of plasma cortisol (CT) to P4 following ACTH administration during mid-gestation in pregnant Brahman heifers. Twenty-three pregnant (139.0 +/- 5.0 days of gestation) Brahman heifers received one of the following treatments: 0 (saline; n = 5), 0.125 (n = 4), 0.25 (n = 5), 0.5 (n = 4), or 1.0 (n = 5)IU of ACTH per kg BW. Blood samples were collected at -15 and -0.5 (time 0), 15, 30, 45, 60, 75, 105, 135, 165, 195, and 255-min post-ACTH challenge. Plasma P4 and CT were quantified by RIA. Pre-ACTH P4 did not differ (P > 0.10) among ACTH treatment groups (pooled, 12.1 +/- 0.6 ng/mL). Among peak P4 values at 15-min post-ACTH infusion, control P4 (9.6 +/- 1.2 ng/mL) tended to be lower (P < 0.07) than 0.5 IU ACTH-treated heifers (13.3 +/- 1.1 ng/mL); and were lower (P < 0.02) than 0.25 and 1.0 IU ACTH-treated heifers (14.7 +/- 1.1 and 22.2 +/- 3.7 ng/mL, respectively). During the primary P4 response period (0 to 75-min post-ACTH), the area under the curve (AUC) was greater (P < 0.05) for 1.0 IU ACTH-treated heifers than all other groups. The CT:P4 ratios were lower (time x treatment, P < 0.01) for control heifers than all ACTH-treated heifers. Among ACTH-treated heifers, CT:P4 ratio response and CT:P4 ratio AUC were similar (P > 0.10) following ACTH challenge. In conclusion, acute increases in ACTH elevated plasma P4, likely of adrenal origin, in mid-gestation pregnant heifers, while the CT:P4 ratio (relative output) remained constant irrespective of ACTH dose (0.125-1.0 IU). Whether ACTH-induced increases in P4 in pregnant animals are of physiological significance (e.g., an accessory role in the maintenance of pregnancy during periods of acute stress) remains to be determined.     

The effect of labour on uterine blood flow in the pregnant ewe.

The effect of labour on cardiac output and uterine blood flow was measured in pregnant ewes at a mean gestation of 124 days using radioactive microspheres labelled with 169Yb and 85Sr. Labour was induced by a continuous infusion of ACTH into the foetal circulation. Cardiac ouput measured before ACTH infusion in seven ewes was 5234 +/- 175-9 ml./min (mean +/- S.E.) and total uterine blood flow was 732 +/- 57-9 ml./min (mean +/- S.E.). Measurements during labour in six ewes showed a significant increase in cardiac output to 6175 +/- 149-6 ml./min (P less than 0-005) but no significant change in uterine blood flow. However, the partition of blood flow was altered; thus myometrial flow increased by 67% from 114 +/- 15-4 ml./min to 190 +/- 13-2 ml./min (P less than 0-005) while placental blood flow decreased, although not significantly, from 618 +/- 55-9 ml./min to 575 +/- 40-7 ml./min. Similar changes were observed in one ewe in spontaneous labour at term and in another ewe receiving an infusion of 4 mg oestradiol 17beta over a 24 hr period. It is concluded that labour is not associated with any major alternation in total uterine blood flow although myometrial blood flow is increased. It is not known whether this is due to the rise in circulating oestrogens which occurs prior to parturition in the ewe, or to other factors such as the work of uterine muscle during labour.     

Physiological responses to low dose infusions of atrial peptide in conscious dogs

Mongrel dogs prepared with chronic catheters in their femoral artery and vein and urinary bladder received 60 minute infusions of atrial peptide ranging from 5 to 100 ng/kg/min. Infusion of atrial peptides caused dose dependent increases in plasma atrial peptide concentration with doses of 25 ng/kg/min or less increasing plasma concentrations to levels observed in normal animals during stimulation of endogenous atrial peptide secretion. Atrial peptide infusion at doses of 10 ng/kg/min and above caused significant decreases in mean arterial pressure which were not accompanied by statistically significant changes in heart rate. Atrial peptide infusion at doses of 25 ng/kg/min and above increased urinary sodium excretion and urine flow rate. Atrial peptide infusion was without effect on plasma vasopressin, ACTH and corticosterone concentrations. However, atrial peptide infusion resulted in dose dependent decreases in plasma aldosterone concentration and plasma renin activity, but the decreases were only significant with the high physiologic (25 ng/kg/min) and pharmacologic doses (50 & 100 ng/kg/min). These data show that atrial peptide infusions in conscious dogs have minimal effects when infused in small doses that mimic endogenous atrial peptide release. At higher doses, significant effects on the cardiovascular, renal and endocrine systems can be observed but their physiological significance is unclear.