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Biomedical subjects

E O Johnson

Publications and source records attributed to E O Johnson.

11 recordsLinked to original sources
PubMed1992

Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis.

Environmental events, both physical and emotional, can produce stress reactions to widely varying degrees. Stress can affect many aspects of physiology, and levels of stress, emotional status, and means of coping with stress can influence health and disease. The stress system consists of brain elements, of which the main components are the corticotropin-releasing hormone (CRH) and locus ceruleus (LC)-norepinephrine (NE)/autonomic systems, as well as their peripheral effectors, the pituitary-adrenal axis and the autonomic system, which function to coordinate the stress response. Activation of the stress system results in behavioral and physical changes which allow the organism to adapt. This system is closely integrated with other central nervous system elements involved in the regulation of behavior and emotion, in addition to the axes responsible for reproduction, growth and immunity. With current trends in stress research which focus on understanding the mechanisms through which the stress-response is adaptive or becomes maladaptive, there is a growing association of stress system dysfunction, characterized by hyperactivity and/or hypoactivity to various pathophysiological states. The purpose of this review is to 1) define the concepts of stress and the stress response from a historical perspective, 2) present a dynamic overview of the biobehavioral mechanisms that participate in the stress response, and 3) examine the consequences of stress on the physiologic and behavioral well-being of the organism by integrating knowledge from apparently disparate fields of science.

Animals↗
PubMed1992

Cholecystokinin-octapeptide stimulates hypothalamic-pituitary-adrenal function in rats: role of corticotropin-releasing hormone.

Peripherally-administered cholecystokinin (CCK) is a profound suppressor of food intake, can promote anxiety, and causes the acute release of ACTH into plasma. Centrally administered corticotropin-releasing hormone (CRH), on the other hand, not only represents the principal stimulus to the pituitary corticotroph cell, but also has been shown to suppress appetite and to be profoundly anxiogenic. Because of the overlap in the effects of peripherally administered CCK and of centrally administered CRH, we report here a study to determine whether sulphated CCK octapeptide (CCK-8) could induce the release of CRH within the central nervous system. To accomplish this task, we first assessed the dose-related effects of CCK-8 on ACTH release. Graded doses of CCK-8 (0.1-10 micrograms/kg BW) given in an i.v. bolus to freely moving male rats, resulted in a dose-dependent increase of plasma immunoreactive (IR)-ACTH (ED50: 1-10 micrograms/kg BW). The lowest maximal stimulatory dose of CCK-8 (5 micrograms/kg BW) was used in all subsequent experiments. To evaluate whether CCK-induced ACTH secretion was mediated by a peripheral CCK receptor, an i.v. bolus injection of vehicle or L-364,718 (1 mg/kg BW), a specific, highly potent peripheral CCK receptor antagonist, was given before the i.v. administration of CCK-8 or vehicle. Plasma IR-ACTH response to CCK-8 was significantly attenuated by L-364,718. A role for the vagal afferents that contain CCK receptors in peripherally administered CCK-mediated hypothalamic-pituitary-adrenal (HPA) axis activation was examined in animals that had been pretreated with capsaicin, a potent neurotoxin that destroys vagal afferents. Plasma IR-ACTH and IR-corticosterone responses in capsaicin-treated animals were significantly lower than those in vehicle treated rats. In subsequent in vivo experiments, pituitary stalk-transected and sham-operated animals were used to evaluate whether CCK-8 stimulates the HPA axis via a centrally mediated mechanism. IR-ACTH and IR-corticosterone responses to i.v. CCK-8 were significantly reduced in the pituitary stalk-transected compared to sham-operated animals. In further effort to determine whether the central nervous system was involved in the plasma IR-ACTH response to the peripheral administration of i.v. CCK-8, we compared the effects of the i.v. administration of CRH antisera vs. normal rabbit serum on this parameter. IR-ACTH and IR-corticosterone responses to i.v. CCK-8 were significantly reduced in the context of pretreatment with CRH antisera compared to the administration of normal rabbit serum.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1991

Effects of short and long duration hypothyroidism and hyperthyroidism on the plasma adrenocorticotropin and corticosterone responses to ovine corticotropin-releasing hormone in rats.

We report here a study of the plasma ACTH and corticosterone responses to synthetic ovine CRH (oCRH) in hypothyroid and hyperthyroid rats studied 7, 15, and 60 days after either thyroidectomy or the administration of pharmacological doses of T4. The purpose of this study was to further clarify the time-dependent effects of alterations in thyroid status on the functional integrity of the hypothalamic-pituitary-adrenal axis and to aid in the interpretation of the oCRH stimulation test in hypo- and hyperthyroid states. Our data demonstrate that hypothyroid rats have a significant reduction in the cerebrospinal fluid (CSF) levels of corticosterone and a significant decrease in adrenal weight in association with significant increases in the plasma ACTH response to oCRH. On the other hand, the corticosterone response to the ACTH released during the oCRH stimulation test was significantly reduced in hypothyroidism. With increasing duration of thyroidectomy-induced hypothyroidism, there was a progressive fall in CSF corticosterone levels, a progressive increase in the plasma ACTH response to oCRH, and a gradual normalization of the corticosterone responses to the ACTH released during oCRH stimulation. Our findings in hyperthyroid rats were generally the converse of those seen in hypothyroidism. Hence, there was a significant increase in the CSF levels of corticosterone and a significant increase in adrenal weight in association with an initial slight decrease in the ACTH response to oCRH. On the other hand, the corticosterone response to the ACTH released during oCRH stimulation was significantly increased. There was a gradual increase in the magnitude of the rise in CSF corticosterone levels with time, as well as a gradual normalization of adrenocortical responses during oCRH stimulation. The ACTH plasma clearance rates were similar in hypo-, hyper-, and euthyroid rats. Our data do not permit definitive identification of the precise locus in the hypothalamic-pituitary-adrenal axis that is principally affected by experimentally induced alterations in thyroid status. However, these data are most compatible with a subtle hypothyroid-induced centrally mediated adrenal insufficiency and a subtle hyperthyroid-induced centrally mediated hypercortisolism. These data also suggest that alterations in hypothalamic-pituitary-adrenal function in states of disturbed thyroid function become somewhat more pronounced as the duration of thyroid dysfunction increases. The fact that pituitary-adrenal responses to oCRH are consistently altered in states of thyroid dysfunction may be relevant to the clinical interpretation of oCRH stimulation tests.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1990

Glucocorticoids inhibit estradiol-mediated uterine growth: possible role of the uterine estradiol receptor.

Stress-related activation of the hypothalamic-pituitary-adrenal axis (HPA) is associated with suppression of the reproductive axis. This effect has been explained by findings indicating that corticotropin-releasing hormone suppresses hypothalamic gonadotropin-releasing hormone (GnRH) secretion via an opioid peptide-mediated mechanism, and that glucocorticoids suppress both GnRH and gonadotropin secretion and inhibit testosterone and estradiol production by the testis and ovary, respectively. To evaluate whether glucocorticoids suppress the effects of estradiol on its target tissues, we examined the ability of dexamethasone to inhibit estradiol-stimulated uterine and thymic growth in ovariectomized rats. Estradiol alone, given daily for 5 days, caused dose-dependent uterine and thymic growth. Dexamethasone alone, given daily for 5 days, caused a dose-dependent decrease in body weight gain and in thymic growth. When estradiol and dexamethasone were administered simultaneously, however, body weight gain and thymic growth were also inhibited (p less than 0.05). Dexamethasone decreased estradiol-induced uterine cytosolic and nuclear estrogen receptor concentrations (E2 R0, p less than 0.05; E2nR0, respectively), but had no effect on estradiol-induced progesterone receptor concentrations (P4R0, p greater than 0.05). Levels of uterine glucocorticoid receptors were not affected by estrogen and/or dexamethasone treatment. These findings suggest that stress levels of glucocorticoids, administered over a 5-day interval, block the estradiol-stimulated growth of female sex hormone target tissues. This effect may be partially mediated by a glucocorticoid-induced decrease of the estradiol receptor concentration. Thus, another mechanism by which the HPA may influence reproductive function during stress is by a direct effect of glucocorticoids on the target tissues of sex steroids.

Animals↗
PubMed1990

Interactions between tumor necrosis factor-alpha, hypothalamic corticotropin-releasing hormone, and adrenocorticotropin secretion in the rat.

We studied the effects of tumor necrosis factor-alpha (TNF alpha), a macrophage-derived pleiotropic cytokine produced during the inflammatory/immune response, on the function of the hypothalamic-pituitary-adrenal (HPA) axis of the rat. Intravenous injections of TNF alpha stimulated plasma ACTH and corticosterone secretion in a dose-dependent fashion. This effect was inhibited by a rat CRH antiserum that was administered to the rats 1 h before the TNF alpha injections. This suggested that CRH is a major mediator of the HPA axis response to TNF alpha. We subsequently evaluated the ability of TNF alpha to influence CRH and ACTH secretion in vitro by explanted rat hypothalami in organ culture and by dispersed rat anterior pituicytes in primary culture respectively. Hypothalami were incubated for 40 min with graded concentrations of TNF alpha (10 pM to 1 microM). This cytokine stimulated CRH secretion in a dose-dependent fashion, with an EC50 of 6.7 x 10 pM (P less than 0.05). Preincubation of hypothalamic explants with dexamethasone, indomethacin (1 microM), eicosatetraynoic acid (10 microM), or nordihydroguaiaretic acid (30 microM) resulted in inhibition of TNF alpha-stimulated CRH secretion (P less than 0.05). Interestingly, 4-h incubation with TNF alpha had no effect on ACTH secretion from rat anterior pituicytes at a concentration of 10 nM. Higher concentrations of TNF alpha (100 nM and 1 microM), however, elicited a dose-dependent increase in the ACTH concentration in the medium. Our results suggest that TNF alpha represents one of the immune response mediators that directly or via stimulation of other cytokines act as activators of the HPA axis during immune/inflammatory reactions. This effect appears to be glucocorticoid suppressible and eicosanoid mediated. The primary site of action of TNF alpha appears to by the hypothalamic CRH-secreting neuron. Some pituitary and adrenal effects of TNF alpha, however, cannot be excluded.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1990

Recovery of the rat hypothalamic-pituitary-adrenal axis after discontinuation of prolonged treatment with the synthetic glucocorticoid agonist dexamethasone.

To evaluate the recovery of the hypothalamic-pituitary-adrenal (HPA) axis after discontinuation of prolonged exposure to glucocorticoids, we employed adult male Sprague-Dawley rats which were implanted sc with osmotic minipumps filled with saline (vehicle) or dexamethasone (DEX), 100 micrograms/day, for 7 days. At the end of the glucocorticoid treatment period, the minipumps were removed and both saline- and DEX-treated rats were randomly assigned to five different groups tested at 1, 3, 7, 14, and 21 days after removal of the minipumps. Each group was divided into two subgroups receiving either arecoline (ARE), or ovine CRH (oCRH) stimulation tests. ARE was chosen because it has been shown to selectively stimulate the hypothalamic CRH neuron, whereas oCRH was selected as a probe of the pituitary component of the HPA axis. ARE (0.2 mg/kg) and oCRH (10 micrograms/kg) were injected iv to catheterized, freely moving rats and serial blood samples for plasma ACTH and corticosterone determinations were drawn from the catheter before, and 5, 15, 30, and 60 min after the injection. The day after the tests were performed, the rats were killed by decapitation, and body, adrenal and thymus weights, as well as hypothalamic CRH and pituitary ACTH content were determined. On the day of the stimulation tests, basal plasma levels of ACTH and corticosterone were not different between saline- and DEX-treated rats at any time-point after discontinuation of treatment. The ACTH response to ARE, on the other hand, was suppressed one day after, but became normal 3 days after discontinuation of DEX treatment. ACTH response to oCRH normalized later, after 7 days. Interestingly, corticosterone responses to both ARE and oCRH normalized 7 days after discontinuation of glucocorticoid administration. Body, adrenal and thymus weights were significantly reduced by DEX treatment. They recovered slowly and only after 22 days there was no difference between DEX- and saline-treated rats in body and adrenal weight. In contrast, thymus weight was still low on day 8, began to increase after 15 days, and by day 22 did not reach the values recorded in saline-treated rats. Hypothalamic immunoreactive CRH content was not different between DEX- and saline-treated rats, whereas the content of ACTH in the pituitary gland was lower in the DEX-treated rats the second day after discontinuation of GC treatment, normalized after 4 days and increased significantly after 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMed1990

Effects of peripheral benzodiazepine receptor ligands on hypothalamic-pituitary-adrenal axis function in the rat.

High concentrations of the "peripheral" benzodiazepine (pBZD) binding site ("receptor") have been described in the hypothalamus, the pituitary and the adrenal glands. This study was undertaken to examine the effects of ligands of this binding site on the hypothalamic-pituitary-adrenal axis (HPA). To accomplish this we administered graded doses of the pBZD receptor agonist 4-chloro-diazepam (Ro5-4864) i.v. to catheterized, freely moving adult male Sprague-Dawley rats. Serial blood samples for plasma adrenocorticotropin hormone (ACTH) and corticosterone determinations were drawn from the catheter before and after the injection of the drug. Ro5-4864 significantly stimulated ACTH and corticosterone secretion in a dose-dependent fashion. To examine whether this effect could be antagonized by the pBZD binding site antagonist PK 11195, we treated rats with PK 11195 at doses 10- and 50-times higher than Ro5-4864 before administration of a maximally effective dose of Ro5-4864. Neither dose of PK 11195 antagonized Ro5-4864-induced plasma ACTH or corticosterone elevations. However, this agent, given alone, stimulated ACTH and corticosterone release. Similarly, carbamazepine (CBZ), which binds to the pBZD binding site with low affinity, stimulated weakly the HPA in vivo, reaching statistical significance only at the highest dose tested. To examine the site(s) of action of these compounds on the HPA, we evaluated their effects on hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH secretion in vitro. Ro5-4864 stimulated hypothalamic CRH, but not pituitary ACTH secretion. Neither PK 11195 nor CBZ had any agonist effect on hypothalamic CRH secretion in vitro, whereas both antagonized Ro5-4864-induced CRH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1989

The muscarinic cholinergic agonist arecoline stimulates the rat hypothalamic-pituitary-adrenal axis through a centrally-mediated corticotropin-releasing hormone-dependent mechanism.

Several lines of experimental evidence suggest that acetylcholine and other cholinergic agonists are excitatory to the hypothalamic-pituitary-adrenal (HPA) axis. To examine the site on the HPA axis that is stimulated by cholinergic agents, we evaluated the in vivo and in vitro effects of the muscarinic cholinergic agonist arecoline in intact and pituitary stalk-transected rats as well as on isolated rat hypothalami, dispersed anterior pituicytes, and adrenocortical cells in culture. Arecoline, injected iv to catheterized, freely moving male Sprague-Dawley rats, stimulated plasma ACTH and corticosterone release in a dose-dependent fashion. The muscarinic cholinergic antagonist atropine significantly blunted the ACTH response to arecoline. Pituitary stalk transection led to diminished plasma ACTH and corticosterone responses to arecoline. Similarly, previous administration of anti-CRH serum significantly blunted these responses. These findings suggest that arecoline stimulates the HPA axis centrally, mainly via secretion of CRH. This hypothesis was confirmed by the dose-dependent ability of arecoline to cause hypothalamic CRH secretion in vitro, an effect antagonized by atropine, and its failure to elicit ACTH and corticosterone secretion by dispersed anterior pituicytes and adrenocortical cells in culture, respectively. These data suggest that the muscarinic cholinergic agonist arecoline stimulates the HPA axis in the rat and that this effect is mediated mainly by the release of endogenous CRH. Arecoline, therefore, appears to be a compound suitable to selectively evaluate the responsiveness of the central component of the HPA axis.

Adrenal Cortex↗
PubMed1983

Primary cortisol resistance: a familial syndrome and an animal model.

Primary cortisol resistance in man is a familial disease. It is characterized by increased plasma cortisol concentrations, high urinary free cortisol excretion, a normal circadian pattern of cortisol secretion, resistance to adrenal suppression by dexamethasone and absence of clinical stigmata of Cushing's syndrome. In its severe form, hypertension and hypokalemic alkalosis are present, owing to increased secretion of the sodium-retaining corticoids, corticosterone and deoxycorticosterone. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the disease is revealed only by detailed examination of several parameters of cortisol metabolism. In the whole-cell assay (peripheral mononuclear leukocytes or fibroblasts) the glucocorticoid receptor shows a low affinity for dexamethasone. The receptor may be unsaturable as suggested by decreased receptor concentrations in broken-cell systems. Thus, generalized target-tissue resistance to cortisol, including the pituitary gland and the hypothalamus, is accompanied by a decreased negative feedback of the cortisol-ACTH feedback system resulting in increased ACTH secretion. This causes higher plasma cortisol to compensate for the end-organ resistance and also increases the production of adrenal mineralocorticoids, as by-products. Thus hypertension and hypokalemic alkalosis depends on the degree of the resistance. Cortisol resistance in many New World primate species is characterized by greatly increased plasma cortisol concentrations, decreased cortisol binding globulin capacity and affinity, high levels of plasma and urinary free cortisol, marked resistance of ACTH suppression by dexamethasone, and no physiologic evidence of glucocorticoid hormone excess. Target tissues have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone. The New World primates, unlike man, have compensated for this cortisol resistance with intra-adrenal adaptations over the 50 million years of their evolutionary development. These primates also have abnormalities of other steroid hormone-receptor systems such as progesterone, estrogen, androgen and mineralocorticoid. In contrast, the human syndrome appears to be a recent mutation with pathophysiologic consequences.

Adrenal Gland Diseases↗