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Progesterone secretion by adrenal glands of hamsters and comparison of ACTH influence in rats and hamsters.

Studies were designed to determine a) if adrenal glands of hamsters secrete progesterone (PROG), b) the effects of adrenocritocotropin (ACTH) administration on adrenocortial function of rats and hamsters under the surgical conditions necessary for collection of adrenal venous blood from the left renal vein, and c) the effects of blood loss during sample collection. PROG was quantitated by the competitive protein-binding method after extraction and separation by sephadex LH-20 column chromatography. The presence of interfering quantities of androstenedione necessitated two column chromatographic steps. Glucocorticoids (11-OHCS) were determined fluorometrically. PROG was detected in adrenal venous plasma of female hamsters. The PROG concentration and secretory rate were 91 +/- 12 ng/ml and 4 +/- 1 ng/min, respectively, while the peripheral plasma level of the same animals was 2 +/- 0.2 ng/ml, indicating that the adrenal glands of female hamsters are capable of secreting PROG. ACTH administration increased PROG secretory rates in both hamsters (3 +/- 1 to 14 +/- 3 ng/min) and rats (62 +/- 9 to 152 +/- 32 ng/min) on estrus, as well as increasing the 11-OHCS secretory rate of hamsters (16 +/- 1 to 33 +/- 4 ng/min), but not of rats. The greater increase in PRCC than in 11-OHCS secretion may be related to excess PROG formation relative to the capacity of the 17alpha- or 21-hydroxylating enzyme systems. The adrenal venous PROG concentration and secretory rate of female hamsters infused with 10% dextran while collecting adrenal venous blood did not differ significantly from those of the non-infused animals, suggesting that this amount of blood loss (1 ml) does not influence PROG secretion.

Adrenal Glands

Oxygenation of frog gastric mucosa in vitro.

We have recently shown that 5% CO2/95% O2 in the serosal bathing solution, with 100% O2 in the mucosal solution, results in CO2-diffusion limitation of acid secretion in bullfrog gastric mucosa. Changing to 10% CO2/90% 02 on both surfaces doubles the acid secretory rate. We calculate that, were the rate of oxygen consumption to increase significantly as a result of secretory stimulation, the tissue would now be oxygen limited. This prediction is tested by raising the P02 by increasing the total pressure in a hyperbaric chamber. Since no change in acid secretory rate or potential difference was observed upon changing from PO2 = 0.9 to PO2 = 1.9 atm, we conclude that the tissue is not O2 limited at normal pressure. Decreasing PO2 below 0.9 atm, by contrast, decreases the acid secretory rate and raises both PD and resistance. We infer that the rate of oxygen consumption did not rise significantly when acid secretion was increased by supplying sufficient CO2.

Animals

A comparative study of adrenal progesterone secretion during the estrous cycles of hamsters and rats.

Adrenal secretory rates and peripheral plasma levels of progesterone (PROG) were determined during the estrous cycles of hamsters and 4-day cyclic rats. In both species, the PROG concentrations in peripheral plasma were never more than 6% of those observed in adrenal venous plasma. In hamsters, adrenal PROG secretory rates varied from 3.8 +/- 0.8 ng/min at 0800 hr on proestrus (P) to 8.5 +/- 1 ng/min at 2000 hr on estrus (E). The rates noted on P were among the lowest observed and were similar to those noted at 0800 hr the following morning. In rats, adrenal PROG secretory rates varied from 57 +/- 9 ng/min at 0800 hr on E to 130 +/- 18 ng/min at 2000 hr on P. A significant decline occurred between 2000 hr on P and 0800 hr the following morning. Rats secreted 3 to 8 times more PROG than did hamsters when the secretory rates are expressed as ng/min/100 mg adrenal. In hamsters, the data suggest a relative lack of influence of female reproductive hormones on adrenal PROG secretion and in turn the latter may not be involved in reproductive hormonal changes leading to ovulation. In rats, the increased adrenal PROG secretion noted on P may be due to the influence of reproductive hormones on adrenocortical function. This elevated rate may in turn influence the hypothalamo-hypophyseal-ovarian axis.

Adrenal Glands

The turnover and distribution of labelled corticosterone during post-natal development of the duckling (Anas platyrhynchos).

During 6 months of post-natal development in the laboratory, the weight of the adrenal gland relative to body weight decreases exponentially. In the 3 day-old duckling a single intravenous dose of labelled corticosterone becomes distributed in a very large apparent volume and an "extracellular" pool that is greater than the extracellular fluid volume and the pattern of disappearance of labelled hormone from plasma is biphasic. Later during development the volumes of distribution decrease and the biphasic pattern of disappearance becomes less distinct until at 6 months only one phase of disappearance can be detected with confidence. No significant change in plasma corticosterone concentration occurs during this period of development in the laboratory. Estimations of the corticosterone secretory rates, however, indicate that whereas the adrenal weight-specific rate os secretion increases during the first 3 weeks and declines therafter, the bodyf weight-specific secretory rate continues to decline throughtout the period of increasing body weight.

Adrenal Glands

Role of aldosterone in the antihypertensive effect of spironolactone in essential hypertension.

In order to evaluate the relationship between aldosterone status and the blood pressure-lowering effect of spironolactone, 38 patients with essential hypertension were treated with spironolactone (400 mg/day) during one week in hospital on a rigidly sodium-restricted diet. The degree of hyperaldosteronism was assessed by the aldosterone secretory rate after 5 days of salt loading (315 mmol Na+/day). The mean arterial pressure decreased 5.6% (range, -21 to +8%). When the patients were divided into subgroups with low and normal renin activity, there was no difference in the change in mean arterial pressure (-5.0% and -6.1%). When the patients were divided into three groups with low, normal, and supranormal aldosterone secretory rates, the last group had a significantly greater fall in blood pressure after the spironolactone than the other groups (-1.0, -7.1, -11.1%). Thus there was a correlation between the aldosterone secretory rate after sodium loading and the blood pressure-lowering effect of spironolactone (r = -0.53, p less than 0.01). The blood pressure-lowering effect was not related to changes in body weight, kidney function, or plasma electrolytes. Our findings do not provide solid arguments for the view that the blood pressure-lowering effect of high dose spironolactone is due to its antimineralocorticoid activity, but the correlation between the degree of hyperaldosteronism and the blood pressure-lowering effect strongly suggests that aldosterone does play a role in the genesis or maintenance of the hypertension in these patients.

Adult

Differential effects of somatostatin and prostaglandins on gastric histamine release to pentagastrin.

The effects of gastric acid antisecretory agents prostaglandins E2, I2 (PGE2, PGI2) and somatostatin on pentagastrin-stimulated gastric histamine and N tau-methyl histamine secretory rates were examined in anesthetized mixed breed dogs. We infused two gastric acid antisecretory doses of PGE2 and PGI2 to test the effect of prostaglandins on pentagastrin-stimulated gastric histamine release. Neither dose of PGE2 and PGI2 had an effect on pentagastrin-stimulated histamine and N tau-methyl histamine release, even though the prostaglandins caused marked gastric vasodilation. In addition, the infusion of the higher dose of PGE2 and PGI2 alone had no effect on histamine secretory rates. In contrast, somatostatin inhibited both pentagastrin-stimulated gastric histamine release by approximately 95% as well as basal histamine release by approximately 60%. Somatostatin also inhibited the pentagastrin-stimulated N tau-methyl histamine secretory rates. The results indicate that neither PGE2 nor PGI2 at antisecretory doses affect pentagastrin-stimulated gastric histamine release, but somatostatin has a very potent inhibitory effect in that regard. Our data suggest that the mechanisms by which prostaglandins and somatostatin affect gastric acid secretion may be diverse.

Animals

Secretion of electrolytes by the pancreas of the anaestetized rat.

1. HCO-3, Na+ and K+ concentrations were measured in bile-free pancreatic juice collected from fasted and fed anaesthetized rats. 2. Resting flow rates averaged 0.62 mul. g-1 .min-1 (fasted) and 2.8 mul. g-1. min-1 (fed) and the mean HCO-3 concentrations, respectively, were 25.8 and 33.3 mM. 3. In fasted rats, instillation of HCl into the duodenum caused flow rate to increase threefold and HCO-3 concentrations to double (66 mM). Intravenous infusion of pure natural (GIH) secretin caused a fivefold increase in flow rate; HCO-3 concentrations, again, doubled (67.5 mM). Infusion of synthetic secretin produced effects essentially the same as those produced by GIH secretin. 4. Infusion of Boots secretin caused a thirteenfold increase in flow rate (8.32 mul.g-1. min-1) but HCO-3 concentrations rose only slightly (43.3 mM). However, following cessation of infusion, when flow rate approximated the maximum obtained with pure secretin, the HCO-3 concentration was much higher (57.2 mM at 3.19 uml.g-1.min-1). In fed animals the responses were similar but maximum flow rates were greater (12 mul. g-1. min-1). 5. Infusion of caerulein produced a secretory rate slightly less than with Boots secretin (5.06 mul. g-1.min-1) and HCO-3 concentrations were plasmalike (30.2 mM); infusion of the synthetic octapeptide of cholecystokinin (OP-CCK) gave similar flow rates and HCO-3 concentrations. 6. Infusion of a mixture of caerulein and GIH secretin mimicked closely the effect of Boots secretin. At maximum flow rates (7.6 mul. g-1. min-1) the HCO-3 concentration was 43.7 mM and at lower flow rates (3.90 mul.g-1. min-1) it rose to 54.2mM. 7. It is concluded that the response of the rat pancreas to secretin is qualitatively similar to that of all other vertebrates so far studied, but, relative to other animals, the response is sluggish. In contrast, the rat pancreas responds well to cholecystokinin (CCK) stimulation, yielding a juice with plasma-like HCO-3 concentration. Boots secretin, which is heavily contaminated with CCK, causes a mixed response resembling that of CCK at high secretory rates and that of pure secretin at lower rates. 8. An unexplained feature of rat pancreatic juice was that K+ concentrations, although plasma-like in unstimulated samples, rose to about 8mM when flow rate increases as a result of secretin, but not CCK, stimulation. In all other animals so far studied, the K+ concentration has been found to be independent of flow rate.

Animals

[Production and metabolism of corticosteroids in the marsh frog, Rana ridibunda Pallas (author's transl)].

Aspects of corticosterone and aldosterone metabolism have been studied in the marsh frog Rana ridibunda Pallas, kept in breeding conditions at a temperature of 16 degrees C. The effects of hypophysectomy on corticosteroid dynamics were also assessed. Two methods, single injection and continuous infusion, were adapted to measure the Metabolic Clearance Rate (MCR), the Secretion Rate (SR) and the half-time (T1/2) of these two hormones, using 3H-corticosterone and 3H-aldosterone as tracers. 10 The two methods provided similar values for the metabolic clearance rate (MCR) when, after the single injection, the MCR was estimated by integrating the area under each disappearance curve of radioactive corticoid. Estimates of MCR by compartmental analysis were not satisfactory. 20 The method of continuous infusion, although carried out in anesthetized animals, is more satisfactory than the single injection in unanesthetized frogs, as the plasma corticosterone in the latter increases significantly during the measurements time. On the contrary, the corticosterone concentration is constant during the infusion, at a little higher than basal level. 30 When measured at the temperature of 20 degrees C, the metabolic clearance rate for corticosterone was higher than that for aldosterone (8.08 +/- 0.29 ml/min/kg versus 5.32 +/- 0.20 ml/min/kg). These values are higher than in fish and lower than in homeothermic vertebrates. 40 The confusion between the adrenal secretory rate and the total production rate, possible for aldosterone, is somewhat hazardous for corticosterone, but production of this steroid from peripheral precursors has not been proved. 50 Adenohypophysectomy reduces the metabolic clearance rate and the secretory rate for corticosterone as well as for aldosterone.

Aldosterone

Human tracheobronchial secretions: development of mucous glycoprotein and lysozyme-secreting systems.

Baseline rates for secretion of mucous glycoprotein were similar similar (680--830 microgram/g tissue/24 hour) for cultured tracheal epithelium from newborns of 26--32 weeks' gestation, full term newborns, and older children. Addition of methacholine to culture medium augmented secretory rates of glycoprotein from all tissue sources 3--5 fold. The overall composition of secreted mucous glycoproteins changed little with increasing age. A trend toward less sulfation and toward increased sialic acid and fucose content was noted in secreted glycoproteins from explants of older subjects. Histochemical observations of stored glycoprotein in tracheal tissue, which was subsequently used for organ culture experiments, confirmed that a modest, but consistent sulfate to sialic acid shift occurs during early life. In contrast, baseline secretory rates for lysozyme from tracheal epithelium of preterm infants were one-half as large as rates from epithelium of full term babies and were refractory to cholinergic stimulation. Stimulation of lysozyme secretion by a cholinergic agonist was achieved in all cases by 40 weeks' gestation. We conclude that basal glycoprotein secretion and the mechanism for glycoprotein response to cholinergic stimulation have developed by the earliest age of viability, but that lysozyme secretion is deficient and is unresponsive to cholinergic stimulation in tracheal tissue from preterm newborns.

Age Factors

The intracellular pathway for parathormone biosynthesis and secretion.

The initial translation product of parathormone messenger RNA--preproparathormone--is larger than parathormone. Two amino terminal peptide segments of the peptide chain are removed sequentially to form the 84-amino acid hormone. The first cleavage, the removal of a 25-amino acid extension from preproparathormone, occurs in the rough endoplasmic reticulum, and results in the formation of proparathormone. This peptide moves via an energy-dependent mechanism to the Golgi region of the cell where a specific converting enzyme cleaves a basic hexapeptide segment yielding parathormone itself. A part of the newly formed hormone then is enclosed within prosecretory vesicles, transported to the cellular membrane and secreted. Another portion is stored in mature secretory vesicles and is subject to subsequent secretion. The moment to moment control of parathormone secretion by calcium resides at the plasma membrane, but a tightly coupled response at the level of intracellular hormone degradation is also necessary in order to control intracellular hormone levels in the face of rapid changes in secretory rate. Three major secretory products are released from the parathyroid under the control of extracellular calcium: (1) parathormone, (2) a large protein--"parathyroid secretory protein"--whose function is unknown, and (3) peptide fragments of parathormone. Secretion of hormonal fragments adds to the population of parathormone immunoreactivity in the blood. These fragments appear to be similar if not identical to those formed by peripheral metabolism of parathormone in the liver and kidney.

Calcium

Studies of renin-aldosterone axis in stable normotensive and hypertensive renal allograft recipients.

Functional aspects of the renin-aldosterone axis were investigated in long-term normotensive and hypertensive renal allograft recipients. Unstimulated plasma renin and aldosterone levels were within control range in all patients and rose significantly in response to sodium depletion. However, no difference in the stimulated renin and aldosterone values between normotensive and hypertensive patients was noted. Baseline aldosterone secretory rates were elevated in all patients, but were higher in hypertensive patients than in normotensive patients. In both groups sodium depletion failed to augment this already elevated aldosterone secretion rate. Possibly, changes in the body pool and/or metabolic clearance rate of aldosterone account for elevations in plasma levels despite a relatively fixed secretory rate, though the role played by the lack of normal innervation of the kidneys cannot be ignored. It is unknown whether these observations may be causal or affected by other presently unknown or unmonitored factors. This in part may reflect unfolding problems in the understanding of nonrenal transplant hypertension.

Adult

Inhibition of adrenal function in man by heparin or heparinoid Ro 1-8307.

Heparin and the heparinoid Ro 1-8307 inhibited the secretory rate of aldosterone in physiological or pathological aldosteronism to the level found in normal subjects on liberal sodium intake. In addition, these compounds inhibited corticosterone biosynthesis, although less markedly than that of aldosterone. Indications of interference with cortisol production have not been found. During drug treatment angiotensin, in doses of 5-10 ng/kg b.wt./min, did not stimulate aldosterone secretion. ACTH responsiveness of the adrenals--indicated by the fractional increases of both aldosterone and corticosterone secretory rates--remained unchanged. In two studies heparin had no consistent effect on plasma renin activity.

11-Hydroxycorticosteroids

Pancreatitis as a complication of anticholinesterase insecticide intoxication.

Severe pancreatitis and a pseudocyst occurred in a patient following accidental ingestion of an anticholinesterase insecticide, a substance not previously known to produce pancreatitis. Experiments were done to elucidate the mechanism. In one group of dogs the pancreatic duct was perfused and intraductal pressures were measured. The cholinesterase inhibitor 0,0-diethyl-0-(2-isopropyl-6-methyl-4-pyrimidinyl)phosphorothioate (25 mg/kg) caused a significant increase in the mean intraductal pressure from 12 +/- 2.4 to 27.8 +/- 5.9 cm saline. In a second group of dogs pancreatic secretory rates were measured. Anticholinesterase (75 mg/kg) in combination with secretin infusion (1 U/kg/hr) caused a significant increase in the secretin stimulated flow rate from 0.13 to 0.56 cc/min. Atropine (75 microgram/kg) abolished the anticholinesterase induced pressure and secretory rate increases. In a third group of dogs administration of cholinesterase inhibitor 75 mg/kg and secretin infusion 2 U/kg/hr resulted in acute pancreatic interstitial edema, acinar cell vacuolization, hyperamylasemia and hyperlipasemia. These results suggest that occurrence of pancreatitis as a complication of anticholinesterase insecticide intoxication is the result of hypersecretion and pharmacologic ductal obstruction.

Adult

Quantification of carcinoembryonic antigen-like activities in normal, human gastrointestinal secretions.

The secretion of carcinoembryonic antigen-like (CEA-like) material into the gastrointestinal tract of 28 fasting normal men was quantified by using intestinal perfusion techniques. CEA-like material was recovered from all levels of the gastrointestinal tract. The highest secretory rate was in the colon (mean +/- SE, 2.41 +/- 2.0 mug/minute per colon), followed by pancreatobiliary secretion and pancreatic secretion. The secretory rate from the stomach, duodenum, jejunum, and ileum was less than 20 ng/minute. After perchloric acid extraction, the CEA-like material from the colon had the same chromatographic and radioimmunologic properties as [125I] CEA. These data suggest that the CEA-like material is normally secreted into the gastrointestinal tract and particularly into the colon.

Adult

Pyrogenic renal hyperemia: the role of prostaglandins.

The intravenous administration of triple typhoid vaccine to anesthetized dogs resulted in a significant increase in renal blood flow accompanied by a modest decline in systemic blood pressure. This renal hyperemia was associated with elevated renal secretory rates of renin and prostaglandin E and F. Measurements of the intracortical distribution of radiolabeled microspheres revealed a progressive decrease in outer cortical blood flow rates and a progressive increase in inner cortical flow rates. When meclofenamate, an inhibitor of prostaglandin synthetase, was administered concomitantly with triple typhoid vaccine renal hyperemia did not develop. The renal renin secretory rate increased modestly and intracortical renal blood flow was not redistributed. The increased renal blood flow after triple typhoid vaccine administration to unanesthetized dogs was also reversed by meclofenamate. The marked increase in prostaglandin secretion by the kidney during renal hyperemia following triple typhoid vaccine administration (pyrogen), and the effect of meclofenamate, is consonant with a role for increased renal synthesis and release of prostaglandins.

Animals

Regulation of the secretory cycles of mucous and serous cells in the human bronchial gland.

Studies of the human bronchial gland in organ culture have allowed us to elucidate some of the factors controlling the synthesis and secretion of bronchial mucus. The secretory cycles of mucous and serous cells appear to differ, the former alternately accumulating and discharging secretory material, while in the latter synthesis and discharge occur simultaneously. Parasympathomimetic agents increase the secretory rate of mucous and serous cells by stimulating discharge, but have no effect on the rate of precursor incorporation into intracellular glycoproteins. Glycoprotein synthesis inhibitors reduce the incorporation of precursors into intracellular macromolecules but do not reduce the rate of discharge of preformed glycoproteins. The rate of glycoprotein synthesis appears to be greater in mucus-secreting cells of hypertrophied glands than of normals. Ouabain reduces the incorporation of glucose and threonine, but not glucosamine, into mucous and serous cells but has no effect on the rate of discharge. In hypertrophied glands, ouabain--sensitive threonine, but not glucose, transport appears to be increased. Exposure of rats to tobacco smoke causes an increase in the size of tracheal and laryngeal glands and in the secretory rate of mucous cells. The anti-inflammatory agent, phenylmethyloxadiazole, prevents both tobacco smoke-induced effects, presumably by reducing the secretory activity of mucous cells.

Animals

Regulation of avian insulin secretion by isolated perfused chicken pancreas.

Chicken insulin secretory responses to glucose, glucagon, tolbutamide, and lack of Mg2+ were measured using isolated perfused in situ chicken pancreata. Although elevating perfusate glucose concentration from 100 to 250 mg/100 ml failed to increase insulin release, 500 mg glucose/100 ml provoked a transient 5-min insulin response. Additionally, 700 mg glucose/100 ml resulted in both a transient response and subsequent elevation in secretory rate that continued throughout the following 50-min stimulatory period. Glucagon (500 microgram/ml) and omission of perfusate Mg2+ potentiated glucose-stimulated insulin output by 6 and 25%, respectively. A faster release of insulin (less than 1 min) occurred during tolbutamide infusion (0.13 mg/ml) than with either 500 or 700 mg glucose per 100 ml (2-3 min); however, secretory rates declined to near basal levels within 5 min. Mammalian-like insulin responses to glucose, glucagon, Mg2+ lack, and tolbutamide suggest similarities between avian and mammalian beta-cell insulin secretory mechanisms. Nevertheless, the relatively high chicken insulin release threshold and low insulin output to glucose indicate that chicken pancreata are relatively glucose insensitive.

Animals

Quantitative aspects of secretion and hepatic removal of glucagon in sheep.

The secretion of immunoreactive glucagon (IRG) into the portal blood and its removal by the liver were determined in conscious-fed sheep by simultaneous measurement of venoarterial plasma concentration differences and portal and hepatic plasma flows. IRG was determined using Manns' antiserum and Unger's 30K antiserum, the latter being highly specific for pancreatic glucagon. In 21 experiments in which Manns' antiserum was used the IRG secretory rate was 7.1 +/- u.4 mug/h. The value using 30K antiserum was lower (5.5 +/- 1.3, n=6), but not significantly different. Although the hepatic extraction ratio (hepatic removal - total IRG presented to the liver) was only 7%, the hepatic removal of 2.4 +/- 0.5 mug/h was equivalent to 31-35% of the portal IRG secretory rate. Since during steady-state conditions, glucagon secretion equals glucagon removal, the liver must account for approximately one-third of the glucagon degraded by the entire body.

Animals