Na,K-ATPase in kidneys of rats with hereditary hypertension induced by stress]

It has been found that Na, K-ATP-ase activity in microsomal fraction obtained from the medullar layer of kidneys of stress-sensitive hypertensive rats (SSHR) which were subjected to stress effects is lower by 20-40% than that in the Wistar rats. In hypertensive animals the stress (30-min immobilization) has led to a considerable increase in blood tension. Values I50 for ouabain and dependence of activity on the ratio of Na and K ions in the medium are similar in animals of both lines subjected to the stress. There are also no considerable differences in the protein composition of microsomal fraction from kidneys of rats of both lines. The effects which increase permeability of vesicules (channel-forming agent alamecytin, lubrol WX, freezing-thawing) activate Na,K-ATP-ase in the preparation from the kidneys of rats of the both lines. Under maximum activation there is a removal of differences in activity of the enzyme obtained from the tissues of the SSHR and Wistar animals after the stress action. Blood serum of SSHR rats after the stress inhibits purified Na,K-ATP-ase to the greater extent than the Wistar rat blood serum after the same effect. It is supposed that differences in Na,K-ATP-ase activity in microsomal fraction from the kidneys of rats of the above lines are stipulated by the differences in the "latent" ATP-ase activity.     

Effect of androsole acetate on blood pressure of stress-sensitive hypertensive rats.

The basal and stress-induced blood pressure was found to decrease in rats with inherited stress sensitive hypertension (SSHR) followed by androzole acetate administration orally (30 mg/kg body weight) for eight days. The basal levels of arterial blood pressure was decreased by 17.5% and that of stress-induced animals--by 19%.     

Role of the hypophyseo-adrenal system in regulating the acid-secreting function of the kidneys

The experiments on male albino rats have shown that both stress and hydrocortisone elevate the urinary excretion of hydrogen ions in the form of titrated acids and ammonium ions. Desoxycorticosterone acetate (DOCSA) in intact rats, adrenal- and hypophysectomy lower ammonium ions excretion. Both stress and DOCSA increase the tubular sodium reabsorption, while hydrocortisone, adrenal- and hypophysectomy decrease it. A conclusion is made that both glucocorticoids and mineralocorticoids participate in the renal functional change under stress. It should be underlined that glucocorticoids stimulate the secretion while mineralocorticoids play the leading part in maintenance of sodium homeostasis.     

Effect of the exercise-induced increase in glucocorticoids on endurance in the rat

To investigate the effect of the increase in glucocorticoids during exercise on endurance, rats were either sham operated (SO) or adrenalectomized. All adrenalectomized rats were given a subcutaneously implanted corticosterone pellet at the time of adrenalectomy. Adrenalectomized rats were injected with corticosterone (ADX Cort) or corn oil (ADX) 5 min before exercise. Rats were killed at rest or after running on a treadmill (21 m/min, 15% grade) until exhaustion. SO rats ran 138 +/- 6 min compared with 114 +/- 9 min for ADX Cort and 89 +/- 8 min for ADX. All differences in run times were significant (P less than 0.05). Corticosterone levels were similar in exhausted SO and ADX Cort groups. ADX exhausted rats had corticosterone levels similar to resting values in SO and ADX rats. Inhibition of the rise in glucocorticoids during exercise had no effect on liver glycogen, liver adenosine 3',5'-cyclic monophosphate, plasma insulin, blood glucose, lactate, glycerol, or 3-hydroxybutyrate, plasma norepinephrine, or red quadriceps and soleus glycogen. Plasma free fatty acids were significantly depressed at exhaustion in ADX rats compared with SO. These data show that glucocorticoids exert effects within the time frame of a prolonged exercise bout and play a role in increasing endurance.     

Glucocorticoids and the regulation of phosphoenolpyruvate carboxykinase (guanosine triphosphate) in the rat.

The effect glucocorticoids on the synthesis and degradation of phosphoenolpyruvate carboxykinase (GTP)(EC4.1.1.32) in rat liver and kidney in vivo was studied immunochemically. The glucocorticoid analogue triamcinolone (9alpha-fluoro-11beta, 21-dihydroxy-16alpha,17alpha-isopropylidenedioxypregna-1,4-diene-3,20-dione) increased the synthesis rate of the kidney enzyme in starved animals. Both triamcinolone and cortisol decreased the synthesis rate of hepatic phosphoenolpyruvate carboxykinase (GTP) in fed and starved rats, but were without effect on the degradation rate of the enzyme. This effect of triamcinolone in liver was reversed by injection of dibutyryl cyclic AMP. However, in diabetic animals glucocorticoids increased the synthesis rate of hepatic phosphoenolpyruvate carboxykinase (GTP). Triamcinolone administration to starved rats in vivo is shown to cause an increase in the portal blood concentrations of insulin and glucose. Since the physiological de-inducer of liver phosphoenolpyruvate carboxykinase (GTP) is insulin, this is the probable cause of the decrease in the synthesis rate of the hepatic enzyme noted when glucocorticoids are administered to non-diabetic animals.     

The role of hormones of hypothalamic-pituitary-adrenocortical system in regulation of pain sensitivity

The review focuses on the role of hypothalamic-pituitary-adrenocortical system (HPAS) in regulation of pain sensitivity and discusses the mechanisms involved in this process. Analgesic effects of exogenous hormones of HPAS (corticotropin-releasing hormone (CRH), ACTH, glucocorticoids) have been shown in rats. It is mediated by both opioid and non-opioid mechanisms. Endogenous glucocorticoids produce development of analgesia mediated by non-opioid mechanisms. Analgesic effect of ACTH is mediated by both non-glucocorticoids mechanisms associated with endogenous glucocorticoids and opioid mechanisms. In contrast to ACTH, analgesic effect of CRH is mediated only by non-opioid mechanisms associated or dissociated with endogenous glucocorticoids. The neurons of midbrain periaqueductal gray matter may be involved in the analgesia induced by glucocorticoids.     

Effect of insulin and hydrocortisone on various indices of energy metabolism in rats irradiated with 6.0 MeV fast neutrons

Neutron irradiation (1 Gy, 0.5 + 0.5 Gy) causes hypersecretion of glucocorticoids. The administration of hydrocortisone imitates, in intact rats, and increases, in irradiated rats, the radiation inhibition of energy metabolism. The increase of radical oxidation in irradiated tissues is a probable cause of radiation hypercorticism; glucocorticoids are the inhibitors of radical oxidation. Insulin injections to irradiated rats normalize the main indices of energy metabolism.     

Glucocorticoid suppression of the sympathetic nervous system and adrenal medulla

Studies were performed to evaluate the effects of glucocorticoids on the activity of the sympathetic nervous system and adrenal medulla. Plasma concentrations of norepinephrine and epinephrine were measured in rats in which endogenous glucocorticoids were removed by bilateral adrenalectomy and in rats to which exogenous glucocorticoids were administered. In intact rats, dexamethasone (2.5, 25 or 250 micrograms) pretreatment suppressed ether vapor-induced elevations of norepinephrine and epinephrine concentrations in plasma. Corticosterone (3 mg/kg), similar to dexamethasone, attenuated the elevation of plasma concentrations of norepinephrine and epinephrine in rats exposed to ether vapor. Glucocorticoids did not alter the elevation of plasma catecholamines stimulated by intracerebroventricular injections of corticotropin-releasing factor or calcitonin gene-related peptide, thus demonstrating functional integrity of the sympathetic nervous system and adrenal medulla. Adrenalectomy resulted in elevation of basal plasma norepinephrine levels and accentuation of ether vapor-induced elevations of plasma norepinephrine concentrations in rats. Dexamethasone (25 ug) administration blunted the effects of adrenalectomy on both basal and ether vapor-stimulated levels of plasma norepinephrine. It is concluded that glucocorticoids acting at as yet undefined sites may be involved in the regulation of sympathetic nervous system and adrenal medullary function.     

Role of glucocorticoids in the stress-induced suppression of testicular steroidogenesis in adult male rats.

We have examined the role of glucocorticoids in the stress-induced inhibition of testicular steroidogenesis. Immobilization (3 hr) reduced plasma testosterone (T) levels to 24% of control values but did not affect plasma LH levels. This reduction was partially reversed by in vivo injections of the antiglucocorticoid, RU486, prior to the stress session at a dose of 10 mg/kg BW, but not at 1.0 or 50 mg/kg BW. Stressed rats that were treated with 10 mg/kg BW RU486 had twofold higher plasma T levels than vehicle-treated stressed animals. Injections of RU486 did not affect plasma LH levels in control or stressed rats and did not affect T levels of unstressed rats. Stressed rats had eightfold higher plasma corticosterone levels than controls, and RU486 had no effect on control or stress levels of corticosterone. The possible role of glucocorticoids in mediating the effect of stress on testicular T production was investigated also in vitro by incubating testicular interstitial cells from unstressed rats for 3 hr with corticosterone (0, 0.01, 0.1, or 1.0 microM) or dexamethasone (0, 0.001, 0.01, or 0.1 microM), followed by an additional 2 hr with hCG (0, 25, 50, or 100 microIU). Both corticosterone and dexamethasone inhibited hCG-stimulated T production in a dose-dependent manner. Cells incubated with the highest concentration of either of the glucocorticoids showed significantly reduced responses to hCG stimulation. In the absence of hCG, in vitro T production was not affected by dexamethasone or 0.01 and 0.1 microM corticosterone. However, the highest dose of corticosterone (1.0 microM) produced a 63% elevation in basal T production. Coincubation of testicular interstitial cells with corticosterone (1.0 microM) or dexamethasone (0.1 microM) and RU486 (0.01, 0.1, and 1.0 microM) reversed the glucocorticoid-induced suppressions of T production in a dose-dependent manner. Our results suggest that during stress increases in plasma levels of glucocorticoids in male rats act via glucocorticoid receptors on testicular interstitial cells to suppress the testicular response to gonadotropins, and that the decline of testosterone production during immobilization stress is in part mediated by a direct action of glucocorticoids on the testis.     

Mechanisms of effect of adrenocorticotropic hormone on the rat pain sensitivity

The mechanisms of effect of adrenocortricotropic hormone on pain sensitivity were studied in anaesthetized Sprague-Dawley male rats. Systemic ACTH administration increased the pain thresholds (from 3 min up to the 30 min after injection) in rats with normal production of hormones. The initial stage of ACTH analgesic effect was fully eliminated by blockade of opiate receptors, ACTH-induced reaction was observed only from 15 up to 30 min after injection. In rats with deficiency of glucocorticoids production, the duration of ACTH-induced analgesic effect decreased to 15 min. The analgesic effect was completely prevented by combination of blockade of glucocorticoids production and blockade of opiate receptors. Thus the ACTH-induced analgesic effect is provided at least by two mechanisms: 1) appearing during the first minutes after injection (from 3 min up to 15 min) and mediated by opiate receptors rather than glucocorticoids, and 2) appearing from 15 min up to 30 min after injection and mediated by glucocorticoids but not opiate receptors.     

Maintenance of the spinal nucleus of the bulbocavernosus neuromuscular system is not influenced by physiological levels of glucocorticoids

The spinal nucleus of the bulbocavernosus (SNB) neuromuscular system mediates sexual reflexes, and is highly sexually dimorphic in rats. While maintenance of this system in adulthood is mainly dependent on androgens, there is also evidence to suggest that glucocorticoids may have a catabolic effect. We conducted a series of studies to fully examine the influence of basal glucocorticoids on the size of the SNB motoneurons and the associated bulbocavernosus (BC) and levator ani (LA) muscles. Specifically, we examined whether the muscles and motoneurons of the SNB neuromuscular system are affected by: (1) blockade of endogenous glucocorticoids via delivery of the antagonist RU-486 at doses ranging from low to high, (2) removal of endogenous glucocorticoids via adrenalectomy, or (3) restoration of physiological corticosterone levels via implants following adrenalectomy. In each study, we found that muscle and motoneuron size were unaffected by glucocorticoid manipulation. In contrast to previous results with supraphysiological levels of glucocorticoids, our results indicate that basal, nonstress levels of glucocorticoids do not influence the size of the BC/LA muscles or their associated SNB motoneurons.     

Differential effect of adrenalectomy on rat liver metallothionein mRNA levels in basal and stress conditions.

Liver metallothionein (MT) mRNA and serum MT levels of adrenalectomized (ADX) and sham-ADX rats in basal and stress (1, 3 or 6 h of restraint) conditions have been measured. Serum MT levels were overall lower in ADX than in sham-ADX rats. Basal liver MT mRNA levels were increased in ADX rats, suggesting that glucocorticoids have an inhibitory role on the regulation of liver MT synthesis. In contrast, liver MT mRNA levels were increased by stress in sham-ADX but not in ADX rats, suggesting a stimulatory role for glucocorticoids. These results suggest that glucocorticoids have a different role in liver MT regulation depending on the physiological situation.     

Glucocorticoids stimulate the accumulation of lipids in the rat corpus luteum.

We investigated the physiological basis for the trophic effect of glucocorticoids in rat corpora lutea in the absence of pituitary gonadotropins. Immature (Day 29) Sprague-Dawley rats were given eCG and hCG to induce the development of corpora lutea and were hypophysectomized on Day 32. Beginning on Day 40, rats received twice-daily s.c. injections of either dexamethasone (dex; 200 microg/rat/day) or vehicle (controls) and then were killed on Day 44. Plasma 20alpha-dihydroprogesterone, a major steroid produced by the corpora lutea, was higher (p 2-fold of plasma 20alpha-dihydroprogesterone concentration compared to controls. Glucocorticoid receptor protein (about 92 kDa) was detected in both luteal and nonluteal ovarian tissues in this animal model. These effects of glucocorticoids and the presence of the glucocorticoid receptor raise the possibility of a physiological role for glucocorticoids in the rat corpus luteum.     

The interrelation of the levels of glucocorticoids and insulin in the blood of irradiated animals

Similar changes in blood levels of immunoreactive insulin (IRI) and glucocorticoids (GC) were observed in rats, mice and dogs after X-irradiation with lethal doses. The use of the blood GC/IRI ratio indices in estimating the functional status of the exposed organism is discussed.     

Intestinal maturation: The effect of glucocorticoids on in vivo net magnesium and calcium transport in the rat

We investigated with an $\text{in vivo}$ single pass perfusion technique, the effect of glucocorticoids on net magnesium and calcium absorption from the small and large intestine of suckling and adolescent rats. In control rats, rates of net magnesium and calcium absorption were several fold greater in both small and large intestinal segments of suckling rats compared to corresponding rates in segments of adolescent rats. Methylprednisolone 30 mg/kg body weight daily for three days, suppressed significantly net magnesium and calcium absorption from the small and large intestinal segments of suckling rats only. Methylprednisolone had no effect on either net magnesium or calcium absorption in adolescent rats. The mechanism(s) responsible for the observed decrease in net magnesium and calcium absorption in the suckling period by glucocorticoids are discussed.     

Role of glucocorticoids and catecholamines on hepatic thiobarbituric acid reactants in basal and stress conditions in the rat.

Thiobarbituric acid-reactants (TBARs) are considered to be an index of lipid peroxidation. In the present experiments, the effect of stress and hormones on hepatic TBARs levels was studied in Sprague-Dawley rats. In unstressed conditions adrenalectomized rats showed higher TBARs levels than sham-adrenalectomized rats. The effect of adrenalectomy was reverted by the administration of corticosterone but not by that of aldosterone, indicating that glucocorticoids exert a negative role on the regulation of liver TBARs. The effect of these hormones appears to be a permissive one, since the administration of a long lasting ACTH preparation did not reduce liver TBARs. In contrast to that observed in unstressed rats, glucocorticoids appeared to increase liver TBARs in stressed rats. Nevertheless, other alternative explanations are possible. Finally, no evidence for a role of catecholamines in the regulation of hepatic TBARs was found.     

Effects of corticosterone on muscle mitochondria identifying different sensitivity to glucocorticoids in Lewis and Fischer rats

Previous studies in rat have demonstrated decreased number of mitochondria and uncoupling of oxidative phosphorylation after administration of glucocorticoids but at supraphysiological doses and using synthetic glucocorticoids. To analyze the relationships between corticosterone levels (the natural glucocorticoid in rat) and muscle mitochondrial metabolism, Lewis and Fischer 344 rats were bilaterally adrenalectomized and implanted with different corticosterone pellets (0, 12, 50, 100, and 200 mg of corticosterone). Rats bearing a corticosterone pellet delivering corticosterone at concentrations in the range of chronic stress-induced levels presented a lower amount of functional muscle mitochondria with a decrease in cytochrome c oxidase and citrate synthase activities and a depletion of mitochondrial DNA. Moreover, a strain difference in tissue sensitivity to corticosterone was depicted both in end-organ sensitive to glucocorticoids (body, thymus, and adrenal weights) and in muscle mitochondrial metabolism (Lewis > Fischer). Interestingly, this strain difference was also observed in the absence of corticosterone, with a deleterious effect on muscle mitochondrial metabolism in Fischer rats, whereas no effects were observed in Lewis rats. We therefore postulate that corticosterone is necessary for muscle mitochondrial metabolism exerting its effects in Fischer rats with an inverted U curve, whereby too little (only Fischer) or too much (Fischer and Lewis) corticosterone is deleterious to muscle mitochondrial metabolism. In conclusion, we propose a general model of coordinate regulation of mitochondrial energetic metabolism by glucocorticoids.     

Interaction of the circadian rhythms of the functional activity of the hypophyseal-adrenal system and of the mitotic activity in the esophageal epithelium of rats with experimental hypo- and hypercorticism

In experimental hypercorticism the average daily concentration of glucocorticoids in blood plasma is 4 times higher than in control one, the amplitude of the circadian rhythm increases almost 3 times, the time of maximum concentration does not change. The adrenocorticotrophic hormone (ACTH) average circadian concentration decreases twofold. The adrenalectomy results in abrupt smoothing down of the circadian rhythm of glucocorticoids concentration and in increasing (in 2,4 times) of the average circadian concentration of ACTH. The pattern of circadian rhythm remains, however the acrophase of hormone secretion is shifted. The circadian rhythm of cells devision in esophagus epithelium changes. The maximum of mitotic index is absent in adrenalectomized rats and the amplitude of its circadian variations decreases. In experimental hypercorticism the biphase rhythm of mitoses in induced.