Prevention and treatment of the complications of diabetes mellitus.
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Aged↗
Biomedical subjects
M Carnes
Publications and source records attributed to M Carnes.
Apparent seasonal rhythms in hypothalamic neuropeptides in rats without photoperiod changes.
An apparent seasonal or circannual rhythm in the hypothalamic content of CRF, TRH, neurotensin, and neuromedin N has been observed in 12 separate monthly coherts (n = 10@ or 130 total) adult, male Sprague-Dawley rats obtained at the same time each month from a single commercial supplier and held under constant (12:12) photoperiod conditions since birth. Both annual and 4-month (terannual) harmonics can be statistically discerned in these apparent rhythms, which exhibit cycles containing concentration changes up to 3-fold the lowest levels across the year (CRF increases 390%, TRH increases 173%, neurotensin increases 136%, and neuromedin N increases 150%). Hypothalamic somatostatin did not exhibit these statistically significant robust rhythms nor did any peptide in regions outside the hypothalamus. These data indicate that a mechanism allowing enhanced or diminished physiological availability of these regulatory neuropeptides at different times of the year may exist and may display distinct cycles even in the absence of normal photoperiod cues. Possible regulatory responses of pituitary receptor populations for these hypothalamic peptides must be considered. As certain of these neuropeptides also appear to be altered in the cerebrospinal fluid of patients with major depression or schizophrenia, similar hypothalamic cyclic changes may underly psychiatric symptoms with seasonal periodicity.
Animals↗
Menopause and the aging female reproductive system.
Only in this century have so many women lived beyond reproductive age. Cultural upheavals in industrial nations have made reproduction an option, a hygienic issue, and the ending of reproductive capacity a crisis of aging. A woman's hormonal milieu changes during her climacteric and beyond with multiple potential symptomatic consequences. Treatment with hormones can ameliorate the symptoms of menopause and potentially decrease the risk for the long-term consequences of the menopause. Objective scientific data for absolutes regarding hormone replacement therapy are lacking, but, increasingly, this epoch in the physical and emotional life of a woman is being defined by new cultural expectations.
Aged↗
Model simulations of ACTH pulsatility.
Using high intensity venous sampling (1-2 min integrated intervals) we have observed rapid (< 10 min) large amplitude (up to 80 pg/ml) fluctuations in plasma ACTH concentrations in addition to variations at longer time scales. We developed a mathematical model to assess whether plausible physiological explanations could account for our observations and compared model simulations with time series from two human subjects. Three key features enabled the model to accurately simulate the observed time series. 1) The pattern of instantaneous secretory events comprising a pulse followed a Poisson process during baseline activity and rapidly shifted to a step function pattern during a pulsatile episode. 2) The fraction of secreted ACTH shunted between a fast and slow clearance mechanism varied biphasically between baseline and pulsatile states. 3) A brief rate-sensitive suppression of secretion was invoked when secretory rates increased above a threshold amount.
Adrenocorticotropic Hormone↗
Screening for depression: single question versus GDS.
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Aged↗
Evidence that ACTH secretion is regulated by serotonin2A/2C (5-HT2A/2C) receptors.
The present study characterized the serotonin (5-HT) receptor subtypes mediating adrenal corticotropic hormone (ACTH) and corticosterone responses to 5-HT agonists in conscious rats. The 5-HT2A/5-HT2C agonist (+/-(-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HC1 (DOI) increased plasma ACTH and corticosterone in a dose-dependent manner. The 5-HT2A/5-HT2C antagonist ritanserin (0.01 and 0.1 mg/kg sc) inhibited the DOI-induced increase in plasma ACTH, but not corticosterone. Low doses of spiperone (0.01 and 0.1 mg/kg sc) significantly reduced the ACTH response to DOI. Because spiperone has a higher affinity for 5-HT2A than 5-HT2C receptors, these data suggest that DOI stimulates ACTH secretion through 5-HT2A receptors. 5-methoxy-3-[1,2,3,4-tetrahydro-4-pyridinyl]-1H-indole (RU 24969) is a potent 5-HT1A/1B and moderate 5-HT2C agonist that also has been suggested to release 5-HT. However, p-chlorophenylalanine (PCPA) did not reduce the effect of RU 24969 on plasma ACTH, suggesting that RU 24969 only acts as a direct agonist. 6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid (LY53857) injected into the lateral cerebral ventricles (i.c.v.) inhibited the ACTH, but not corticosterone response to peripheral injection of RU 24969, suggesting that central 5-HT2A/2C receptors mediate the ACTH response. LY53857 injection (i.c.v.) also inhibited the effect of p-chloroamphetamine (i.c.v.) on plasma ACTH. However, the corticosterone response was not inhibited by LY53857, suggesting a distinct location of 5-HT receptors regulating corticosterone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
The role of serotonergic neurons in intravenous hypertonic saline-induced secretion of vasopressin, oxytocin, and ACTH.
This study tested the effect of brain serotonin (5-HT) depletion on the secretion of oxytocin (OT), vasopressin (VP), and adrenocorticotropin (ACTH) due to an osmotic load. The 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) was used to deplete brain 5-HT. The OT, VP, and ACTH osmotic sensitivity (slope of delta[OT]/delta[Osm]) and the osmotic threshold (X intercept of delta[OT]/delta[Osm]) were evaluated. Depletion of brain 5-HT decreased the OT osmotic sensitivity by > 80% (p < 0.001) without changing the OT osmotic threshold. Brain 5-HT depletion had no effect on the VP osmotic sensitivity and increased the VP osmotic threshold from 287.8 +/- 1.5 to 293.1 +/- 2.0 mOsm/kg (p < 0.05). The plasma ACTH increase due to infusion of hypertonic saline was not affected by brain 5-HT depletion. Brain 5-HT depletion significantly (p < 0.01) decreased the pituitary content of OT and VP by 38 and 32%, respectively, without changing ACTH content. These results provide evidence for a functional role of serotonergic neurons in osmoregulation of plasma and pituitary concentration of OT and VP, but not ACTH.
5,7-Dihydroxytryptamine↗
High intensity venous sampling reveals subtle alterations in plasma adrenocorticotropin patterns in old rats.
Dysregulation of the hypothalamic-pituitary-adrenocortical axis has been theoretically linked to the processes of aging for decades. To investigate the effects of age on high frequency rhythms of plasma ACTH at the time of circadian activation, integrated 2-min blood samples were collected over 4 h in 10 young and 14 old rats with simultaneous plasma volume replacement. Plasma ACTH time series were analyzed in the time and frequency domains. Relative to young rats, old rats had a significantly later onset of the diurnal surge, more spectral power (R2) at lower frequencies, a lack of correlation between the slope of the spectral background continuum and the R2 at periods less than approximately 11 min, a stretching of the time scale in the composite spectra by 18.5%, and an amplitude reduction of the major composite spectral peak by 31%. These findings support the existence of subtle, but significant, alterations in the pattern of plasma ACTH with age and a delayed response of the hypothalamic-pituitary-adrenocortical axis to circadian activation. The differences in spectra suggest a weaker coupling with age between the high frequency signal input (that may reflect depolarization of groups of corticotrophs) and the system response, which could account for the delay in onset of the diurnal surge seen in the time domain.
Adrenocorticotropic Hormone↗
Effect of cocaine injections on the neuroendocrine response to the serotonin agonist MK-212.
This study was undertaken to examine whether several of the hormones that can be released by activation of serotonin receptors will be affected by long-term cocaine administration. Male rats received cocaine injections (15 mg/kg, IP) twice daily for 7 days. Forty-two hr after the last cocaine injection, the rats were challenged with increasing doses (0, 1, 5, 10 mg/kg, IP) of the 5-HT1/5-HT2 agonist MK-212 (6-chloro-2-[1-piper-azinyl]-pyrazine). The following observations were made: (1) cocaine reduced the rate of body weight gain; (2) cocaine inhibited the stimulatory effect of MK-212 on plasma vasopressin, oxytocin, and prolactin concentrations and on plasma renin activity and concentration; (3) cocaine did not inhibit the stimulatory effect of MK-212 on plasma ACTH or corticosterone concentrations. The data indicate that a wide-spectrum 5-HT (serotonin) agonist such as MK-212 can reveal differential neuroendocrine responses. This effect could be related to cocaine-induced changes in the different 5-HT receptor subtypes that regulate the secretion of these hormones.
Adrenocorticotropic Hormone↗
Comparison of neuroendocrine and behavioral effects of ipsapirone, a 5-HT1A agonist, in three stress paradigms: immobilization, forced swim and conditioned fear.
Ipsapirone is an anxiolytic drug and a serotonin1A (5-HT1A) agonist. The aim of the present study was to investigate the effects of low doses of ipsapirone on the hormonal and behavioral response to three stress procedures: immobilization, forced swim and conditioned emotional response (CER). We examined the effect of ipsapirone (0.1, 0.5 or 1.0 mg/kg) on plasma renin concentration (PRC), adrenal corticotropic hormone (ACTH), corticosterone, prolactin and defecation in rats exposed to immobilization, forced swim or CER stress. All three stressors significantly elevated all the hormone levels (P less than 0.01). Immobilization-induced elevations of PRC, and corticosterone were inhibited by the highest doses of ipsapirone (0.5 and 1 mg/kg, i.p.). However, ipsapirone did not modify the immobilization-induced elevations of plasma ACTH, prolactin or defecation. Ipsapirone was relatively ineffective at reducing the endocrine responses to forced swim. Ipsapirone reduced some, but not all of the hormonal responses to CER stress. CER-induced elevations of corticosterone and prolactin were not inhibited by ipsapirone. However, the ACTH response to CER was significantly (P less than 0.01) inhibited by all doses of ipsapirone and the highest dose of ipsapirone attenuated the renin response. In contrast with the hormonal responses, ipsapirone inhibited all of the behavioral responses to CER stress. Ipsapirone inhibited CER-induced freezing behavior and defecation, while dose-dependently reversing the suppressive effect of CER on exploring, grooming and rearing behaviors. In conclusion, there is a dissociation between the influence of ipsapirone on the endocrine and behavioral responses to CER stress. Ipsapirone also has differential effects on the neuroendocrine response to the three stressors studied. Ipsapirone was most effective in attenuating the hormonal responses to CER, followed by immobilization and swim stress. Of the hormones studied, the stimulation of renin secretion after exposure to the three stressors was most sensitive to ipsapirone, while corticosterone and prolactin were the least sensitive to ipsapirone.
Animals↗
Prior chronic exposure to cocaine inhibits the serotonergic stimulation of ACTH and secretion of corticosterone.
The effect of long-term pretreatment with cocaine on serotonergic regulation of ACTH (adrenocorticotropic hormone; corticotropin) and secretion of corticosterone in rats was investigated. The following observations were made: (1) Pretreatment with cocaine had no significant effect on basal levels of ACTH and corticosterone in plasma. However, cocaine caused a reduction in the ability of the 5-HT (5-hydroxytryptamine, serotonin) releaser p-chloroamphetamine (PCA) to increase corticosterone in plasma, 42 hr after the last injection of cocaine. (2) Exposure to cocaine for 7 days was sufficient to produce a maximal inhibition of the PCA-induced increase in ACTH in plasma. (3) The inhibitory effect of cocaine on PCA-induced release of ACTH was more marked than on corticosterone. (4) Conversely, the dose-dependent stimulatory effect of two 5-HT1 agonists, RU 24969 (5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole) and m-CPP (m-chlorophenylpiperazine), on ACTH and corticosterone was not reduced by 7 days of exposure to cocaine. Taken together, these findings indicate that pretreatment with cocaine reduced the function of serotonergic nerve-terminals but not postsynaptic receptors, that stimulate ACTH and secretion of corticosterone.
Adrenocorticotropic Hormone↗
A comparison of a two-wheeled walker and a three-wheeled walker in a geriatric population.
OBJECTIVE: There are few data on the effect of walkers on gait and mobility or on comparisons of different walker types. We compared a commonly used 4-legged, 2-wheeled walker and a newer 3-legged, 3-wheeled walker in measures of gait, mobility, and patient satisfaction. DESIGN: Cross-over controlled trial. SETTING: In the Physical Therapy Department of a Veterans Affairs hospital. PARTICIPANTS: Subjects were 15 male and female frail elderly veterans (mean age, 82 years), both inpatients and outpatients, consecutively enrolled from a sample of 35 patients referred to the Physical Therapy Department for mobility problems. Subjects met the following criteria: age 65 or over, ambulatory, no prior use of a wheeled walker, stable medical condition, and informed consent. INTERVENTION: Subjects were evaluated without either walker and with each of the two walkers on a 15-foot walkway and a 60-foot obstacle course. Subjects were asked which walker they preferred. OUTCOME MEASURE: Outcome measures were stride length on the walkway, time on an obstacle course, and walker preference. RESULTS: Stride length was 1.4 inches (3.6 cm) greater with the 3-wheeled walker than with the 2-wheeled walker (P = 0.016 by Wilcoxon signed-rank test). Time on the obstacle course was 16.0 seconds less with the 3-wheeled walker than the 2-wheeled walker (P = 0.002). The 3-wheeled walker was subjectively preferred. CONCLUSIONS: The 3-wheeled walker appears to have a greater positive impact on gait and mobility than the 2-wheeled walker.
Activities of Daily Living↗
Pulsatile ACTH and cortisol in goats: effects of insulin-induced hypoglycemia and dexamethasone.
Insulin-induced hypoglycemia is a metabolic stress that stimulates secretion of adrenocorticotropic hormone (ACTH) and cortisol in a number of animal species. Dexamethasone is a potent synthetic glucocorticoid that suppresses the secretion of ACTH and cortisol. Both ACTH and cortisol exhibit complex secretory patterns demonstrating ultradian and circadian rhythms. This work investigated the pattern of ACTH and cortisol response to hypoglycemia in goats and the effect of dexamethasone on this response. Five goats were pretreated with dexamethasone (0.1 mg/kg) and 5 with saline. Blood samples were taken every 2 min for 60 min before and 60 min after administration of insulin (2.5 IU/kg, i.v.). Immunoreactive ACTH and cortisol were measured in all samples and glucose in selected samples. Data sets were analyzed for significant pulses with the Cluster Analysis program. Complete data sets were compared as well as those for each 30-min interval. Plasma glucose was lower than preinsulin levels at 10 min, declined rapidly between 10 and 30 min, and remained low 30-60 min after insulin injection in both treatment groups. Controls showed a rapid rise in ACTH and cortisol beginning 30 +/- 10 min postinsulin. The increase in mean plasma hormone levels during hypoglycemia was predominantly due to an increase in amplitude of secretory pulses for ACTH and cortisol compared with the 30 min before insulin. Dexamethasone significantly lowered mean ACTH and cortisol levels and prevented alteration in plasma ACTH and cortisol secretion during hypoglycemia but did not totally ablate pulsatile activity of either hormone. The amplitude of ACTH and cortisol pulses was significantly decreased by dexamethasone treatment. The frequency of cortisol but not ACTH pulses was also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
High resolution spectral analysis of plasma adrenocorticotropin reveals a multifactorial frequency structure.
Time series of plasma ACTH concentrations were analyzed with a high resolution spectral analysis program based on digital Fourier transforms. Both coherent signal and stochastic aspects of the time series were analyzed. Samples were collected at 2- and 15-min intervals in control rats and rats immunoneutralized against CRH. The individual and composite spectral distributions revealed significant structure at both the higher and lower ranges of frequencies studied, with multiple periodicities between 4-220 min in both groups. CRH immunoneutralization consistently reduced the amplitude by 82% and compressed the frequency distribution for waveforms with periods longer than 15 min by 23%. A systematic break in the slopes of the background continua occurred between 10 and 15 min in the 2-min time series. This break was unaffected by CRH immunoneutralization. Digital Fourier transform analysis of our ACTH time series suggests a system with a more complex high frequency structure than has previously been appreciated. Our analyses suggest a biological system with the following characteristics: 1) both a fast and a slow response to a fairly constant unspecified fast forcing; 2) the slow response is initiated by the fast response and represents an imperfect integration due to feedback processes; 3) CRH alters the ability of the fast forcing to elicit a slow response without altering the fast response or ACTH clearance; and 4) this alteration consists of both amplitude and frequency modulation in the signal output. This view of ACTH secretion suggests an adaptive and energy-efficient system.
Adrenocorticotropic Hormone↗
The effects of stress on plasma ACTH and corticosterone in young and aging pregnant rats and their fetuses.
Compared to younger rats, old rats exhibit prolonged elevations of plasma ACTH and corticosterone (CORT) in response to stress. In addition, CORT crosses the placenta. To investigate whether fetuses of older rats may be exposed to higher concentrations of CORT during development than fetuses of young rats, we compared the effects of stress on hypothalamic-pituitary-adrenal (HPA) axis function in young and aging pregnant rats and their 19-day-old fetuses. The plasma of the mothers and fetuses was assayed for ACTH and CORT by radioimmunoassay. Both young and aging pregnant rats showed a significant increase in plasma ACTH and CORT immediately after exposure to stress. However, aging rats had more prolonged elevations of ACTH and CORT than young rats. This suggests that, like old male rats, aging pregnant rats have an alteration in feedback inhibition of the HPA axis. Prolonged elevation of CORT was also seen in fetuses of aging mothers. These results have important implications concerning the effects of stress during pregnancy at different maternal ages, and for the potential deleterious consequences of prolonged prenatal elevation in stress hormones on the offspring of aging females.
Adrenocorticotropic Hormone↗
Effects of immunoneutralization of corticotropin-releasing hormone on ultradian rhythms of plasma adrenocorticotropin.
ACTH, like other anterior pituitary peptide hormones, is secreted episodically and demonstrates both circadian and ultradian rhythms. CRH is the major regulator of ACTH release from the pituitary corticotroph. To determine the dependence of ACTH ultradian rhythms on CRH, passive immunoneutralization was used to block the activity of endogenous CRH in rats with indwelling venous catheters. Blood was sampled at 2- and 15-min intervals while blood volume was replaced. Plasma ACTH was measured by RIA. Time-series analysis of plasma ACTH concentrations was performed with PULSAR and Cluster Analysis. The 2 min data demonstrated secretory bursts approximately every 20 min. CRH immunoneutralization had no effect on the frequency of these pulses, but significantly reduced their amplitude. This was the case for raw data as well as data in which lower frequency variation had been filtered out. The 15 min data demonstrated pulsatile secretion, with a secretory episode approximately every 100 min. This lower frequency rhythm was also observed when high frequency components were filtered out of the 2 min data series. Analysis of the 15 min and the filtered 2 min time series showed this rhythm to be almost totally ablated by CRH immunoneutralization. These results suggest that CRH is responsible for amplitude modulation of an underlying CRH-independent rhythm and that through intermittent amplitude modulation of this rhythm a lower frequency rhythm is generated. Comparison between treatment groups of pulses identified by PULSAR or Cluster Analysis yielded similar results, but the programs were discordant with each other. This is the first in vivo evidence of pulsatile ACTH secretion independent of CRH, the first report demonstrating that different ultradian rhythms of ACTH may be regulated by different mechanisms, and the first comparison of PULSAR and Cluster Analysis on plasma ACTH time series.
Activity Cycles↗
Immunoneutralization of corticotropin-releasing hormone prevents the diurnal surge of ACTH.
To determine whether CRH is required for the evening rise in plasma ACTH, rats were injected at 0800 hr with CRH antiserum (anti-CRH) or normal rabbit serum (NRS). Blood samples were taken through venous catheters at 0800 hr before treatment and at 1300, 1700, and 2100 hr. Plasma was assayed for immunoreactive ACTH and corticosterone. There was no significant difference in pretreatment values between the two groups. Immunoneutralization of CRH abolished the rise in plasma ACTH seen at 1700 hr in the NRS group but had little effect on earlier levels. The diurnal elevation in plasma corticosterone continued after anti-CRH treatment, but peak levels occurred earlier. Plasma ACTH and corticosterone were significantly correlated at the time of the diurnal surge, but not at 0800 hr or 1300 hr in the NRS controls or at any time point in the anti-CRH group. These results suggest that CRH is required for the diurnal surge of plasma ACTH. They also confirm previous observations by others that the adrenal cortex does not require active CRH or a diurnal surge of ACTH in order to exhibit a significant diurnal increase in secretion of corticosterone, and that factors other than CRH may be relatively more active than CRH in regulation of ACTH secretion during the time of circadian inactivity.
Adrenocorticotropic Hormone↗
Isolation of a complementary DNA encoding a chitinase with structural homology to a bifunctional lysozyme/chitinase.
An extracellular, acidic chitinase was purified to homogeneity from tobacco necrosis virus-infected leaves of Cucumis sativis. The amino acid sequences of the intact protein and of peptides isolated following endoproteinase Lys-C digestion, cyanogen bromide cleavage, and trypsin digestion were determined. Oligonucleotide probes derived from this sequence were used to isolate a cDNA clone encoding this protein. No significant homology was found between this chitinase and either the basic chitinase isolated from bean or tobacco or the chitinase isolated from Serratia marcescens; however, strong homology was found between the cucumber chitinase and a lysozyme/chitinase from Parthenocissus quinquifolia. The induction of the protein by tobacco necrosis virus infection or salicylate was found to be at the level of RNA accumulation. Genomic Southern analysis indicates that a single gene in the cucumber genome encodes this protein.
Amino Acid Sequence↗