Acute Effect of Cluster and Traditional Set Configurations on Myokines Associated with Hypertrophy.

This study compared the acute cytokine response, and kinetic and kinematic profile following back squat exercise in resistance-trained men. In a randomized, cross-over design, 10 resistance-trained men (27±4 y, 1.80±0.07 m, 82.8±6.7 kg, 16.3±3.5% fat) performed the back squat exercise using traditional and cluster set configurations. Kinetic and kinematic data were sampled throughout each condition. Venous blood was sampled prior, immediately post, 30 min, 60 min, 24 h, and 48 h post-exercise for plasma interleukin-6 (IL-6) and interleukin-15 (IL-15). Cluster sets allowed for greater mean power (mean difference, 110 W; 90% confidence interval, ±63 W; benefit odds, 41 447:1), driven by higher overall mean velocities (0.053 m∙s-1; 0.039 m∙s-1; 3 105:1) as evidenced by the lack of clear contrasts for mean force. IL-15 increased post-exercise in both conditions, but increased at 24 h (0.13 pg·mL-1; ±0.11 pg·mL-1; 486:1) and 48 h (0.12 pg·mL-1; ±0.10 pg·mL-1; 667:1) in traditional sets only. IL-6 increased similarly in both conditions, post-exercise through 60 min post. Cluster set configurations allow for greater mean power, attributed to higher velocities. Despite a similar response of IL-6, traditional set configuration may provide a greater stimulus for hypertrophy as evidenced by a secondary increase in IL-15.

Assessment of power, speed, and agility in athletic, preadolescent youth.

AIM: The aim of this report was to assess power, speed, and agility in athletic, preadolescent youth, and determine how agility related to muscular strength and power. METHODS: Boys (N.=53) and girls (N.=104) completed vertical jump (VJ), standing long jump (SLJ), seated medicine ball throw (SMBT), proagility shuttle run (PRO), partial curl-ups (CURL), and 20 yd sprint (20 SP). One-way analysis of variance for gender comparison and multiple regression analysis for determining association among tests were used. RESULTS: No gender differences (P>0.05) existed for VJ or PRO. However, boys performed better on SLJ (P=0.03; 162.61+24.64 vs.154.51+20.78 cm), 20 SP (P=0.001; 3.70+0.35 vs. 3.96+0.33 s), and CURL (P=0.02; 35.16+9.67 vs. 31.48+8.80) while girls scored higher on SMBT (P=0.001; 340.46+68.58 vs. 287.12+56.39 cm). Among girls, PRO was correlated (P<0.01) with SLJ (r=-0.70) and VJ (r=-0.67). In boys, correlations (P<0.01) existed between VJ and SLJ (r=0.73) and 20 SP and PRO (r=0.72). CONCLUSION: The current study supports previous research that found a correlation between SLJ and VJ. SLJ, VJ and SP were significant predictors of PRO, accounting for 55%, 46%, and 43% of the variation, respectively. The PRO agility test is easy to administer and requires lower body strength and power necessary for the quick changes in direction inherent to ground-based field sports. When designing a performance-related test battery for young athletes, PRO, SLJ, and VJ are effective measures and worthy of inclusion.

Hybrid delivery of cluster-set resistance training for individuals previously treated for lung cancer: the results of a single-arm feasibility trial.

BACKGROUND: Individuals with non-small cell lung cancer (NSCLC) are burdened by long-lasting symptoms (e.g., dyspnea and fatigue) post-treatment. These symptoms often reduce physical activity levels and increase the risk of functional decline. Though we have previously proposed cluster-set resistance training to mitigate symptom burden in lung cancer, there is currently no data on the feasibility or acceptability of this mode of exercise in cancer. Therefore, the purpose of this study was to investigate the feasibility and acceptability of a hybrid-delivery home-based cluster-set resistance training program in individuals with NSCLC stages I-III (i.e., early stage). METHODS: This study aimed to recruit individuals with NSCLC stages I-III post-treatment to participate in 8 weeks of home-based resistance training, 3 days per week. The program included supervised sessions in the participants' homes and virtual supervision via videoconferencing. The primary outcome measure of feasibility was evaluated through recruitment, retention, and intervention fidelity (i.e., proportion of exercise completed, relative to what was prescribed). Intervention acceptability (i.e., ease and quality of virtual delivery, level of difficulty, and home-based approach) was assessed using a 4-point Likert-type scale from "strongly disagree" to "strongly agree". RESULTS: Fourteen participants were recruited over a 6-month period, with 11 completing the intervention (2 withdrew due to unrelated illness, 1 withdrew due to requiring active treatment), yielding a retention rate of 79%. Characteristics of the participants who completed the intervention (n = 11) were as follows: mean age: 71 ± 10 years, mean BMI: 29.1 ± 6.5, and average time since diagnosis was 62 ± 51 months. Of completers, 27% were male, and 36% were Black; 10 were stage I (91%), and one was stage II (9%). Mean session attendance was 86.4 ± 9.5%. Mean intervention fidelity was 83.1 ± 13.1%. With regard to acceptability, > 90% of participants positively rated all aspects of the intervention delivery. No adverse events related to exercise were recorded. CONCLUSIONS: The hybrid delivery of a home-based resistance exercise program for individuals previously treated for early-stage NSCLC was found to be safe and feasible. Adaptations to the program for future interventions are required, particularly surrounding resistance exercise programming, and intervention delivery with home visits. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05014035 . Registered January 20, 2021.

Study protocol: investigating the feasibility of a hybrid delivery of home-based cluster set resistance training for individuals previously treated for lung cancer.

BACKGROUND: Symptom burden remains a critical concern for individuals with non-small cell lung cancer (NSCLC) following the completion of treatment. The most common symptom clusters, dyspnea (shortness of breath) and fatigue, can contribute to physical decline, reductions in quality of life, and a higher risk of comorbidities and mortality. Dyspnea is a primary limiter of exercise capacity in individuals with lung cancer, resulting in exercise avoidance and an accelerated physical decline. As such, designing resistance training with cluster sets to mitigate symptoms of dyspnea and fatigue may result in improved exercise tolerance. Thus, maintaining the exercise stimulus via cluster sets, combined with improved tolerance of the exercise, could result in the maintenance of physical function and quality of life. The purpose of this study is to investigate the feasibility and preliminary efficacy of a hybrid-delivery home-based cluster-set resistance training program in individuals with NSCLC. METHODS: Individuals with NSCLC (n = 15), within 12 months of completion of treatment, will be recruited to participate in this single-arm feasibility trial. Participants will complete 8 weeks of home-based resistance training designed to minimize dyspnea and fatigue. The hybrid delivery of the program will include supervised sessions in the participants' home and virtual supervision via video conferencing. The primary outcome of feasibility will be quantified by recruitment rates, retention, acceptability, and intervention fidelity. Exploratory outcomes (dyspnea, fatigue, quality of life, physical function, and body composition) will be assessed pre- and post-intervention. DISCUSSION: This study will provide important data on the feasibility of delivering this intervention and inform procedures for a future randomized controlled trial. TRIAL REGISTRATION: Record not yet public.

Contribution of thickened drinks, food and enteral and parenteral fluids to fluid intake in hospitalised patients with dysphagia.

BACKGROUND: Studies amongst older people with acute dysphagic stroke requiring thickened fluids have assessed fluid intakes from combinations of beverage, food, enteral and parenteral sources, but not all sources simultaneously. The present study aimed to comprehensively assess total water intake from food, beverages, enteral and parenteral sources amongst dysphagic adult in-patients receiving thickened fluids. METHODS: Patients requiring thickened fluid following dysphagia diagnosis were recruited consecutively from a tertiary teaching hospital's medical and neurosurgical wards. Fluid intake from food and beverages was assessed by wastage, direct observation and quantified from enteral and parenteral sources through clinical medical records. RESULTS: No patients achieved their calculated fluid requirements unless enteral or parenteral fluids were received. The mean daily fluid intake from food was greater than from beverages whether receiving diet alone (food: 807 +/- 363 mL, food and beverages: 370 +/- 179 mL; P < 0.001) or diet with enteral or parenteral fluid support (food: 455 +/- 408 mL, food and beverages: 263 +/- 232 mL; P < 0.001). Greater daily fluid intakes occurred when receiving enteral and parenteral fluid in addition to oral dietary intake, irrespective of age group, whether assistance was required, diagnosis and whether stage 3 or stage 2 thickened fluids were required (P < 0.05). After enteral and parenteral sources, food provided the most important contribution to daily fluid intakes. CONCLUSIONS: The greatest contribution to oral fluid intake was from food, not beverages. Designing menus and food services that promote and encourage the enjoyment of fluid dense foods, in contrast to thickened beverages, may present an important way to improve fluid intakes of those with dysphagia. Supplemental enteral or parenteral fluid may be necessary to achieve minimum calculated fluid requirements.

cis-dichlorodiammineplatinum(II) chemotherapy in experimental murine myeloma MOPC 104E.

Data are presented indicating marked antineoplastic activity for cis-dichlorodiammineplatinum(II) in MOPC 104E myeloma. One-eighteenth of the dose that produced 100% cures can be combined with noncurative, low doses of cyclophosphamide and 1,3-bis(2-chloroethyl)-1-nitrosourea to produce antineoplastic activity of the same degree as that produced by much higher dose regimens which regularly produce cures. Since, in the past, results of therapeutic trials in plasma cell tumors in humans have paralleled results in this animal model, clinical trials of cis-dichlorodiammineplatinum in multiple myeloma appear warranted.

Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition.

Plasma CRH was measured in maternal plasma throughout the third trimester of pregnancy, during labor, and postpartum. CRH levels were also measured in arterial and venous umbilical cord plasma samples. In normal pregnant women, plasma CRH increased from 50 +/- 15 (+/- SEM) pg/mL at 28 weeks gestation (n = 41) to 1462 +/- 182 pg/mL at 40 weeks (n = 55) and 1680 +/- 101 pg/mL (n = 65) in labor. Women with pregnancy-induced hypertension (n = 49) had plasma CRH levels significantly elevated above this normal range. Similarly, women who subsequently went into premature labor had raised levels several weeks before the onset of labor. After delivery, plasma CRH returned to normal within 15 h. Total plasma cortisol levels varied little throughout the third trimester, but increased during labor and remained elevated 2-3 days postpartum. There was, therefore, no correlation between plasma cortisol and CRH, implying that this placental CRH is not primarily involved in the control of the maternal hypothalamo-pituitary adrenal axis during pregnancy. The concentrations of CRH in umbilical cord plasma samples were considerably lower than those in the maternal circulation and were close to those in normal nonpregnant adults.

The evaluation of sodium valproate in the treatment of Nelson's syndrome.

It has previously been reported that sodium valproate (Epilim) lowers plasma ACTH levels in Nelson's syndrome. This report describes further experience with its use. Ten patients with Nelson's syndrome were treated with sodium valproate (600-1200 mg/day) for 5-32 weeks. Plasma ACTH was measured by cytochemical methods and RIA. Initial treatment for 5-12 weeks significantly (P less than 0.005) lowered plasma ACTH from a pretreatment mean of 2460 +/- 1870 ng/liter to 480 +/- 330 ng/liter, and the ACTH circadian rhythm was restored in two patients. On discontinuing treatment, plasma ACTH levels remained suppressed for 3 weeks and rose to pretreatment values in 5-12 weeks. Two patients' plasma ACTH levels failed to show a second response to treatment, while a third patient had a favorable second response to treatment over 32 weeks. In six patients, skin pigmentation lightened with treatment, and in one patient, a reduction in size of a pituitary microadenoma, demonstrated radiographically, occurred with treatment. gamma-Aminobutyric acid and sodium valproate were shown to be ineffective in inhibiting ACTH secretion from cultured pituitary tumor cells from a patient with Nelson's syndrome. The results show that sodium valproate is effective in some cases of Nelson's syndrome. We suggest that it reduces the hypersecretion of ACTH by enhancing gamma-aminobutyric acid function in the hypothalamus, thereby inhibiting the release of corticotropin-releasing factor.

Influence of prolonged glucocorticoid treatment on intracellular mechanisms involved in ACTH secretion in the rat.

Two chemically characterized peptides, arginine vasopressin (AVP) and corticotrophin-releasing factor-41 (CRF-41), known to stimulate ACTH secretion by interaction with their respective specific receptors on the corticotroph, were shown to cause the accumulation of phosphate esters of inositol (IP) and adenosine 3',5'-monophosphate (cAMP) respectively when added to rat anterior pituitary fragments incubated in vitro. The former 'second messenger' response (IP production) was unaffected in tissues removed from animals treated with prednisolone in the drinking water (1035 mumol/1) for 14 days. On the other hand, the cAMP response, whilst still present, was inhibited by some 50% in tissues taken from such animals. In contrast, pituitary glands from steroid-treated rats failed to respond to challenge with a variety of substances expected to cause the release of ACTH by mimicking or provoking the production of IP or cAMP. Indeed, of the wide range of ACTH secretagogues tested, only the phospholipase A2 activator melittin was able to cause attenuated ACTH release from tissues removed from treated rats. The failure to provoke ACTH release from tissues removed from steroid-treated animals was also seen when submaximal concentrations of CRF-41 or AVP, or hypothalamic extract or 48 mmol K+/1 were used as the stimuli. The staged recovery of the ACTH secretory response and IP and cAMP accumulation in vitro following the withdrawal of prednisolone treatment was also investigated. A cAMP response that did not differ significantly from that of control tissue and a normal ACTH response to K+ and to melittin were all recovered by 3 days after withdrawal, and the response to cholera toxin showed a partial recovery. Responses to all stimuli of ACTH secretion which cause their effect by entering the corticotrophs were normal by 5 days after withdrawal, when the response to CRF-41 was still significantly, and that to AVP still slightly, reduced compared with controls. Surprisingly, restoration of the ACTH response was most delayed when the expectedly most potent extracellular stimulus (hypothalamic extract) was used. In this case, release was still significantly impaired 7 days after steroid withdrawal. The results show that the glucocorticoid acts to compromise several distinct steps in the process whereby extracellular signals such as CRF-41 and AVP cause the secretion of ACTH. The only step that appears to be spared is the generation of IP by AVP.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypertonic citrate solution as an alternative to modified Euro-Collins' solution for lung preservation.

In a canine model of acute ischemic lung injury, a hypertonic citrate solution (HTC) widely used for renal preservation in the United Kingdom, was compared with modified Euro-Collins' solution (ECS) currently the most widely clinically used pulmonary perfusate. Ten beagle dogs underwent left thoracotomy and exclusion of the left lung in situ. The lung was flushed with 30 ml/kg of either HTC or ECS and subjected to 60 min of warm ischemia. The circulation to the lung was then restored, the contralateral lung excluded, and the animal ventilated at a fixed FiO2 of 0.4 for 4 hr. Lung function was assessed by arterial oxygenation and hemodynamic measurements and, following sacrifice, by lung weight gain, bronchoalveolar lavage, and ultrastructural studies. Flush perfusion with HTC was associated with significantly less severe reperfusion injury, as determined by superior arterial oxygenation (PaO2 at 1 hr: HTC--152 mmHg [(95% confidence interval) CI] [122-182], ECS--59 [47-70]; PaO2 at 4 hr: HTC--124 [100-149], ECS--51 [42-61]), lower pulmonary vascular resistance index (PVRI at 4 hrs: HTC--838 dynes sec cm-5m-2 [651-1075], ECS--1233 [963-1588]); and lower lung weight (HTC--85 g [66-107], ECS--146 [114-184]). Bronchoalveolar lavage studies demonstrated an influx of neutrophils following reperfusion that was significantly less marked in the HTC group (increase in % neutrophils: HTC 24 [19-29], ECS 77 [72-82]). Lung injury assessed by electron microscopy tended to be less severe in the HTC animals. We conclude that HTC may offer an alternative superior to ECS for lung preservation.

Amelioration of lung ischemic injury with prostacyclin.

The single-flush technique of lung preservation is thought to be enhanced by prostaglandin treatment. In order to test this hypothesis, ten beagle dogs underwent thoracotomy and in situ flush perfusion of the excluded left lung with 30 ml/kg of cold, modified Euro-Collins' solution. Group 1 (n = 5) received pretreatment with 30 ng/kg/min of PGI2 by infusion and as an additive to the flush (20 micrograms/L). Group 2 (n = 5) received no PGI2 and served as controls. Following 60 min of warm ischemia, the left lung was reperfused, the contralateral lung excluded, and the animal ventilated at a fixed FiO2 of 0.4 for 4 hr. The severity of reperfusion injury was assessed by arterial oxygenation and hemodynamic measurements and, following sacrifice, by lung weight gain and bronchoalveolar lavage and ultrastructural studies. PGI2 therapy resulted in significant amelioration of reperfusion injury, with superior oxygenation at both 1 and 4 hr (PaO2 at 1 and 4 hr, respectively; PGI2: 145 mmHg +/- 17.0 and 114 +/- 11.2; no PGI2: 59 mmHg +/- 5.8 and 51 +/- 4.5; P less than 0.01 at both times), lower pulmonary vascular resistance index at 4 hr (PVRI; PGI2: 913 dynes sec cm-5m-2 +/- 91; no PGI2: 1239 +/- 68; P less than 0.05) and lower lung weight (PGI2: 76 g +/- 4; no PGI2: 146 +/- 10; P less than 0.001). Bronchoalveolar lavage studies revealed an influx of neutrophils following reperfusion that was less marked in the PGI2 group (increase in % neutrophils; PGI2: 50.4 +/- 6.7; no PGI2: 76.9 +/- 6.0; P less than 0.05). Lung injury score assessed by electron microscopy was lower in the PGI2 group (PGI2: 5.2 +/- 1.1; no PGI2; 8.1 +/- 0.5; P less than 0.05). It is concluded that PGI2 treatment is protective against ischemic lung injury in this model.

Structure-activity relationship of various corticosteroids on the feedback control of corticotrophin secretion.

Several steroids occurring in the pathway of corticosteroid biosynthesis were investigated for their ability to exert a fast or delayed feedback inhibition of stress-induced release of corticotrophin. Rats were injected subcutaneously with vehicle or a steroid either 10 min (fast feedback) or 4 h (delayed feedback) before they were subjected to stress which consisted of a 2 min exposure to ether vapour. 2 Changes in plasma corticosterone concentration and in vitro corticosterone production by excised adrenal glands were used as indices of corticotrophin release. 3 Among the steroids tested only 11beta, 21-dihydroxypregn-4-ene-3, 20-dione (corticosterone) and 11beta, 17alpha, 21-trihydroxypregn-4-ene-3, 20-dione (cortisol) inhibited the stress response 10 min after their administration. Therefore, it appears that the fast feedback mechanism is limited to steroids with a 21-hydroxyl and a 11beta-hydroxyl group. 4 In contrast, many steroids caused inhibition of the stress response 4 h after their administration. These steroids were corticosterone, cortisol, 21-hydroxypregn-4-ene-3, 20-dione (11-deoxycorticosterone), 17alpha, 21-dihydroxypregn-4-ene-3, 20-dione (11-deoxycortisol), 11beta-hydroxypregn-4-ene-3, 20-dione (11beta-hydroxyprogesterone) and 11beta, 17alpha-dihydroxypregn-4-ene-3, 20-dione (11beta, 17alpha-dihydroxyprogesterone). Thus, either the 21-hydroxyl group (e.g. 11-deoxycorticosterone) or the 11beta-hydroxyl group (e.g. 11beta-hydroxyprogesterone) is sufficient for delayed feedback activity. The 11alpha-hydroxyl group, e.g. 11alpha, 17alpha, 21-trihydroxypregn-4-ene-3, 20-dione (11-epicortisol) renders the steroid inactive on both feedback mechanisms. 5 18,21-Dihydroxypregn-4-ene-3, 20-dione (18-hydroxydeoxycorticosterone) was found to be the only steroid that is secreted by the adrenal gland of the rat in quantities sufficient to cause exaggeration of the stress-induced release of corticotrophin. This steroid has been implicated as a possible hypertensive agent, and its role in the control of corticotrophin secretion is discussed here.

Effect of bilateral adrenalectomy and corticosteroid therapy on the secretion of corticotrophin-releasing factor activity from the hypothalamus of the rat in vitro.

The rat hypothalamus in vitro preparation was used to investigate the effect of bilateral adrenalectomy, with and without replacement therapy, on the release of corticotrophin-releasing factor(CRF). Corticotrophin-releasing factor was estimated using 48 h basal hypothalamic lesioned assay rats and corticosterone production of excised adrenals was used as the end point. Bilateral adrenalectomy resulted in depletion of hypothalamic CRF content within the first 2 h after the operation but this effect was prevented by replacement therapy with corticosterone. Thereafter, the hypothalamic CRF content returned to values not significantly different from the intact control level. Bilateral adrenalectomy caused an increase in both basal and acetylcholine-induced release of CRF and it is suggested that corticosteroids exert a negative feedback effect on the hypothalamus.

Effect on various putative neurotransmitters on the secretion of corticotrophin-releasing hormone from the rat hypothalamus in vitro-a model of the neurotransmitters involved.

The effect of incubating the hypothalamus of adult male rats with various neurotransmitters upon the release of corticotrophin-releasing hormone (CRH) was studied. The CRH activity in the incubation medium was assayed in 48 h median eminence-lesioned rats and the corticosteroidogenesis of excised adrenals in vitro was used as the end-point. 5-Hydroxytryptamine (100 pg/ml-10ng/ml) caused a dose-dependent release of CRH which was antagonized by methysergide (30-100 ng/ml). The response to 5-hydroxytryptamine was also inhibited by hexamethonium and atropine which indicated that it was acting through a cholinergic interneurone. Melatonin (10 ng) did not alter the basal release of CRH but inhibited the action of both 5-hydroxytryptamine (10 ng) and acetylcholine (3 pg). Thus it appears that both 5-hydroxytryptamine and melatonin play a role in the control of CRH release. Noradrenaline blocked the release of CRH induced by both acetylcholine and 5-hydroxytryptamine and presumably this inhibition was caused by direct action on the CRH neurone. gamma-Aminobutyric acid (GABA) also inhibited the release of CRH and may also be involved in the regulation of CRH secretion. The inhibitory neurotransmitters, noradrenaline, GABA and melatonin, act via independent receptor mechanisms. A model based on the above data is presented.

Dynamics and mechanics of corticosteroid feedback at the hypothalamus and anterior pituitary gland.

Corticosteroid feedback mechanisms were investigated at the hypothalamic level using the rat hypothalamus in vitro and the pituitary level using basal hypthalamic-lesioned rats. Both fast and delayed corticosteroid feedback effects were demonstrated at the level of the hypothalamus and pituitary gland with doses of corticosteroids within or near the physiological range. These two phases of feedback were separated temporally by a 'silent period' during which no feedback was apparent. Studies on the mechanism of action of corticosteroids at the hypothalamic level showed that the fast feedback mechanism acts by inhibition of release whilst the delayed feedback mechanism acts by inhibition of both synthesis and release. The fast feedback action of corticosterone does not appear to act by excitation of neuroinhibitory pathways since neither picrotoxin nor phentolamine prevented the feedback action of corticosteroids in vitro. Corticosterone inhibition of corticotrophin releasing factor release was overcome by depolarization of the membrane with K+ suggesting that the mechanism of action of the fast feedback of corticosteroids is by membrane stabilization.

Recovery of the components of the hypothalamo-pituitary-adrenocortical axis in the rat after chronic treatment with prednisolone.

Male Wistar-derived rats (200-250 g) were treated for 14 days with prednisolone 21-sodium succinate at a concentration of 1035 mumol/l in their drinking water. The drug was then replaced with normal tap water and groups of animals were killed at various times during recovery, trunk blood being collected after decapitation. At the same time, hypothalamic slices, anterior pituitary gland fragments and adrenals were removed and their responsiveness assessed by exposure to appropriate stimuli in vitro. Tissues were also extracted to measure changes in content of hormones during recovery. Treatment with prednisolone produced marked reductions in body weight gain, adrenal weight and pituitary ACTH content, but no significant change in hypothalamic corticotrophin-releasing factor (CRF) bio- or immunoreactivity. The ACTH content was restored by 5 days after withdrawal but adrenal weight remained significantly reduced after 9 days of recovery. The responsiveness of the hypothalamus to acetylcholine in vitro was markedly inhibited and was still significantly reduced 7 days after withdrawal. The responsiveness of the anterior pituitary gland to synthetic CRF or arginine vasopressin and that of the adrenal gland to ACTH added in vitro were restored simultaneously after 7 days of withdrawal. In vivo, recovery was assessed by measurement of the response to laparotomy stress. Treatment with prednisolone prevented the increase in the plasma concentrations of ACTH and corticosterone produced by stress, and these responses recovered by 5 days (corticosterone) and 7 days (ACTH) after withdrawal. The abolition of the circadian rhythms of ACTH and corticosterone by treatment was also reversed by 5 days after withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Biphasic inhibition of bioactive hypothalamic corticotrophin releasing factor secretion in vitro by corticosterone and prevention of the second phase by various steroids.

The effect of various steroids on the functional activity of the rat hypothalamus in vitro was investigated. The addition of corticosterone (10(-7) mol/l) for 30 min to the incubation medium inhibited immediately the release of bioactive corticotrophin releasing factor (CRF) by tissue induced by serotonin (2.6 X 10(-8) mol/l). This was followed by a period lasting from 30 min (coincident with removal of the steroid from the medium) to 60 min when no inhibition was seen. Finally a second period of suppression of hypothalamic CRF activity in vitro was shown to be fully established 120 min after addition of the steroid. In more detailed investigations the latter inhibition was shown to occur when the tissue was exposed to the steroid (3 X 10(-7) mol/l) for 5 or 30 min, but not for 1 min, and it was dose-related. Of other steroids investigated, progesterone in high concentrations (3 X 10(-6 mol/l) suppressed to a small extent the functional activity of the hypothalamus in vitro but 17 alpha-hydroxyprogesterone, 11 alpha-hydroxyprogesterone, 11 alpha, 17 alpha-dihydroxyprogesterone and 11-epicortisol had no effect on the delayed inhibition. Progesterone (10(-7) mol/l) potentiated the ability of corticosterone (10(-8) mol/l) to induce the delayed suppression of hypothalamic CRF activity in vitro. In contrast, 17 alpha-hydroxyprogesterone, 11 alpha-hydroxyprogesterone, 11 alpha, 17 alpha-dihydroxyprogesterone and 11-epicortisol competitively antagonized this inhibitory action of corticosterone (3 X 10(-7) mol/l) in a dose-related manner (1.5 X 10(-8)-3 X 10(-8) mol/l). The action of the antagonist 11-epicortisol was similar whether it was added to the tissue in vitro before corticosterone or antagonist and agonist were added together. The functional characterization of steroid action on the hypothalamus may lead to a clearer understanding of the mechanism by which the compounds influence hormone release.

Structure-activity relationships of corticosteroid feedback at the hypothalamic level.

Structure-activity studies on the corticosteroid fast and delayed feedback receptor mechanisms controlling the secretion of corticotrophin releasing factor (CRF) were carried out with the rat hypothalamus in vitro. The secretion of CRF was induced by acetylcholine (3 pg/ml). The fast feedback receptor appears highly specific, and the structure essential for efficacy involves an 11beta-hydroxyl group and an unblocked 21-hydroxyl group. Several steroids showed antagonism and so the binding site is not very specific. 18-hydroxy, 11-deoxycorticosterone, progesterone, 17alpha-hydroxyprogesterone and 11-deoxycorticosterone were antagonists of fast feedback. The delayed feedback receptor required either an 11beta-or a 21-hydroxyl group for efficacy. The binding site required a 17-hydroxyl group when the 11beta- or 21-hydroxyl groups were absent. Binding also involved the 3-oxo,4,5-ene structure since steroids in which these are absent were inactive.

Effect of difluoromethylornithine on the LH surge and subsequent ovulation in the rat.

Female Wistar-derived rats with regular oestrous cycles were injected s.c. at 15.00 h on pro-oestrus with difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase. The drug (10-100 mg/rat) caused a dose-related reduction in the concentration of LH in plasma taken at 19.00 h (the time of the peak of the LH surge in this colony). There was also a dose-related reduction in the pituitary content of total polyamines. The reduction in the plasma concentration of LH was not due to the shifting of the time of the peak of the surge, as concentrations were significantly lower than control from 17.00 to 21.00 h, the overall reduction in total LH release being approximately 50%. The number of ova in the oviducts at 06.00 h next morning was significantly reduced by treatment with 50 mg DFMO/rat, by an average of 70%. Injection of DFMO enhanced the fall in plasma oestradiol concentrations seen between 15.00 and 19.00 h, in a dose-related manner. It also prevented the rise in progesterone concentrations seen in control animals during this period. The ability of DFMO to prevent the rise in plasma concentrations of LH was not secondary to the effects of the drug on ovarian steroid production because DFMO also significantly reduced the LH surge in animals ovariectomized on dioestrus and given appropriate replacement injections of oestradiol and progesterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro.

The effect of six hypothalamic peptides on the basal release of ACTH and that induced by arginine vasopressin (AVP) or by ovine corticotrophin releasing factor (oCRF) from fragments of the rat anterior pituitary gland incubated in vitro was investigated. Dose-response curves to AVP and to oCRF were obtained, and the response to a low dose of oCRF was potentiated by a low dose of AVP. Basal release of ACTH was not affected by any of the peptides in concentrations in the range 10(-12) to 10(-6) mol/l, and only substance P (SP) and somatostatin (SRIF) inhibited significantly the response to oCRF in a dose-related manner. The responses to a range of doses of oCRF or AVP were reduced by 10(-8) and 10(-6) mol SP or SRIF/l, and to a greater extent by the higher dose. Except in the case of 10(-6) mol SRIF/l on the response to AVP, the response was not further diminished by preincubation of the tissue with the peptide before the stimulating agent was added. The inhibition of the responses to AVP or oCRF by 10(-9) mol SP/l was not potentiated by its combination with either 5 X 10(-10) or 10(-8) mol SRIF/l; the inhibitory effects were merely additive. The results suggest that although SRIF and SP are able to modulate the release of ACTH from the anterior pituitary gland, they do so only at a high concentration.(ABSTRACT TRUNCATED AT 250 WORDS)