Timing the end of nocturnal sleep.
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Adrenocorticotropic Hormone↗
Biomedical subjects
H L Fehm
Publications and source records attributed to H L Fehm.
A determinant factor in the efficacy of GHRH administration in promoting sleep: high peak concentration versus recurrent increasing slopes.
A previous experiment indicated a greater efficacy of episodic than continuous growth hormone (GH)-releasing hormone (GHRH) administration in enhancing sleep. The greater efficacy of episodic administration could principally result from two factors, i.e. the greater peak concentration reached after episodic administration or the recurrence of increasing slopes in GHRH concentration. In order to investigate which factor essentially determines the pharmacodynamics of sleep promotion after GHRH, effects after a transient high peak in GHRH concentration were compared with those of repetitive increases in GHRH concentration. Sleep, plasma concentrations of GH, and GHRH were examined in healthy subjects after evening administration of a 'single' i.v. bolus of 50 micrograms GHRH, after five 'repetitive' boluses of 10 micrograms GHRH, and after placebo. Compared with placebo, single GHRH significantly increased time spent in stage 4 sleep (p < .01) and in stage 2 sleep, reduced time spent in wakefulness and onset latency of stage 4 sleep (p < .05, for each), while repetitive GHRH remained without effects. GH secretory activity also tended to be higher after single than repetitive GHRH. Thus, results suggest the relevance of a transiently high concentration of GHRH in blood as an essential factor in enhancing the central nervous sleep process.
Adult↗
EEG complexity and performance measures of creative thinking.
The electroencephalogram (EEG) was used because of its dimensional complexity to establish a differentiation of divergent versus convergent thought, considered fundamental modes of cortical processing. In 28 men, the EEG was recorded while solving tasks of divergent and convergent thinking and during mental relaxation. The EEG during divergent thought was compared between subjects achieving high versus low performance scores on this type of task. The dimensional complexity of the EEG was greater during divergent thinking than during convergent thinking. While solving tasks of divergent thinking, subjects with high performance scores had a lower EEG dimension than did subjects with low scores, in particular over frontal cortical areas. The changes were not reflected in single frequency bands of conventional EEG analysis. Based on Hebb's view of neuron assemblies as functional processing units, the higher EEG complexity during divergent than convergent thinking could be the result of the concurrent activation of a greater number of independently oscillating processing units.
Adult↗
Central nervous system effects of intranasally administered insulin during euglycemia in men.
Insulin receptors have been detected in several structures of the brain, yet the biological significance of insulin acting on the brain remains rather unclear. In humans, direct central nervous effects of insulin are difficult to distinguish from alterations in neuronal functions because of insulin-induced decrease in blood glucose levels. Since several intranasally administered viruses, peptides, and hormones have been shown to penetrate directly from the nose to the brain, we tested whether insulin after intranasal administration likewise has access to the brain. After a 60-min baseline period, insulin (20 IU H-Insulin 100 Hoechst) or vehicle (2.7 mg/ml m-Cresol) was intranasally administered every 15 min to 18 healthy subjects according to a double-blind within-subject crossover design. Auditory-evoked potentials (AEP) indexing cortical sensory processing were recorded while the subjects performed a vigilance task (oddball paradigm) during the baseline phase and after 60 min of intranasal treatment with insulin or placebo. Blood glucose and serum insulin levels were not affected by intranasal insulin. Compared with placebo, intranasal administration of insulin reduced amplitudes of the N1 (P < 0.005) and P3 (P < 0.02) components of the AEP and increased P3 latency (P < 0.05). The reduction in P3 amplitude was most pronounced over the frontal recording site (2.42 +/- 1.00 vs. 4.92 +/- 0.79 microV, P < 0.0005). At this site, after insulin administration, a broad negative shift developed in the AEP between 280 and 500 ms poststimulus (area under the curve -166.0 +/- 183.8 vs. 270.8 +/- 138.7 microV x ms after placebo, P < 0.01). The results suggest that after intranasal administration, insulin directly enters the brain and exerts distinct influences on central nervous functions in humans.
Administration, Intranasal↗
Fetal hemoglobin in starvation ketosis of young women.
Ketones can reactivate the production of fetal hemoglobin (HbF) in vitro and in vivo. A reactivation of HbF by ketones, which are generated during starvation, remains largely speculative. Therefore, we investigated HbF in 31 women with anorexia nervosa or bulimia, using both of these as models of intermittent starvation ketosis. For comparison, we also studied 42 female control subjects matched for age. beta-Hydroxybutyrate levels were higher in patients than in controls (460 +/- 90 v 110 +/- 20 mumol/L; P < .0001). We correlated beta-hydroxybutyrate, metabolic, and hematologic parameters with HbF. HbF was measured with high pressure liquid chromatography. The data were analyzed with logistic regression analysis. An elevated HbF fraction (> 0.87%) was observed four times as often in patients than in controls (29% v 7%, P = .01). After adjustment for age, we found HbF elevations associated with beta-hydroxybutyrate levels (P = .005). No other correlations between the various metabolic/ hematologic parameters and HbF were significant. In conclusion, beta-hydroxybutyrate generated in starvation is associated with increased levels of HbF. Thus, unrestrained lipolysis can produce beta-hydroxybutyrate in sufficient quantities to induce a clinically measurable amount of HbF. These findings suggest that intermittent ketosis might also explain some increases of HbF in type 1 diabetes and pregnancy.
Adolescent↗
Neuropsychological effects of vasopressin in healthy humans.
Animal research indicated that vasopressin (VP) exerts its principle behavioral influence, the improvement of memory formation, through an action on septo-hippocampal and connected limbic structures. Here human research is reviewed with the notion of a comparable effect of VP in healthy humans. Although the human studies yielded less consistent results than those in rats, they indicate that VP is able to improve declarative memory formation which is the type of memory essentially relying on hippocampal function. The effect appears to center on the encoding process for memory. In examinations of event-related brain potentials (ERPs) VP was consistently found to increase the 'mismatch negativity' (MMN) and the P3 components which are ERP potentials closely linked to the hippocampal processing of novel, unexpected and salient events. Enhanced processing of these stimulus aspects is considered to precipitate memory encoding. The regulation of voluntary selective attention and arousal do not appear to be primary targets of VP effects in humans. A mediation of effects by peripheral changes can be excluded since the central nervous effects were observed in studies using intranasal VP administration providing a direct access to brain functions.
Animals↗
Intranasal angiotensin II directly influences central nervous regulation of blood pressure.
Intranasal administration of some peptides has been shown to directly influence central nervous functions, thus pointing to a nose-brain pathway for these substances in humans. The present study investigated whether intranasal administration of angiotensin II (ANG II) affects central nervous functions of cardiovascular control in a different way from intravenously administered ANG II. In a balanced cross-over design 12 healthy men were treated with ANG II intravenously (2.5 microg), ANG II intranasally (400 microg), and placebo. Angiotensin II, vasopressin, norepinephrine, and epinephrine plasma levels were assessed every 10 min; blood pressure, heart rate, and systemic vascular resistance were measured by a Dinamap, and by continuous, noninvasive body plethysmography. Also, feelings of activation and mood were measured. Intranasal and intravenous administration invoked equivalent increases in plasma levels of ANG II, and induced an acute rise in blood pressure of comparable size and duration. However, subsequent blood pressure profiles differed dependent on intravenous and intranasal ANG II administration; after intravenous ANG II administration blood pressure remained enhanced at an intermediate level, but it returned to normal or even decreased below normal levels after intranasal ANG II administration. Intranasal ANG II also counteracted the decrease in norepinephrine levels observed after intravenous administration of ANG II. Intranasal but not intravenous ANG II enhanced plasma concentrations of vasopressin. This diverging pattern of effects bears similarities with effects of intracerebroventricular administration of ANG II in animals, suggesting that the effects after intranasal administration reflect a direct central nervous action of ANG II.
Administration, Intranasal↗
Angiotensin converting enzyme inhibition by captopril influences cardiac work in healthy hearts.
Although beneficial effects of angiotensin converting enzyme (ACE) inhibition have been demonstrated in ill (ischemic, failing) hearts, it has not been proved that ACE inhibition induces changes in healthy hearts. The question is of clinical relevance, as many hypertensive patients do not display cardiac damage at the onset of treatment with ACE inhibitors, and possible changes in cardiac work might turn out more or less advantageous in the development of hypertensive heart disease. In a refined working heart preparation allowing measurement of cardiac work, including the contribution of atrial work and paracrine cardiac regulation, effects of captopril on cardiac dynamics were assessed. Coronary overflow of bradykinin, norepinephrine, and lactate was measured. Hearts were perfused for 20 min with vehicle or captopril at 3 x 10(-8), 3 x 10(-7), 3 x 10(-6), and 3 x 10(-5) mol/L. At the highest concentration, captopril increased coronary flow. Extending previous studies, the present study demonstrates that, in a concentration-dependent manner, captopril decreased oxygen consumption and maximal left ventricular pressure although the bradykinin outflow was not affected. From these influences of the drug on cardiac work and metabolism in healthy hearts, a protective influence of captopril in acute, critical situations of cardiac malnourishment or cardiac overload may be derived.
Angiotensin-Converting Enzyme Inhibitors↗
Scalp recorded direct current brain potentials during human sleep.
The direct current (DC) potential recorded from the scalp of awake humans has been considered a reflection of general changes in cortical excitability. This study examined DC potential shifts in humans during a night of continuous sleep. Standard polysomnographic recordings and skin temperature were measured simultaneously. Contrary to expectations, average DC potential level indicated higher negativity during nonrapid eye movement (NREM) sleep than REM sleep and wakefulness. Moreover, a dynamic regulation of the DC potential level was revealed in association with the NREM-REM sleep cycle comprising four successive phases: (i) a steep 'NREM-transition-negative shift' during the initial 10-15 min of the NREM sleep period; (ii) a more subtle 'NREM-positive slope' during the subsequent NREM sleep period; (iii) a steep 'REM-transition-positive shift' starting shortly prior to the REM sleep period, and (iv) a 'REM-negative slope', characterizing the remaining greater part of the REM sleep period. DC potential changes were only weakly related to changes in slow-wave activity (r2 < 0.18). The NREM-negative slope and REM-positive slope could reflect, respectively, gradually increasing and decreasing cortical excitability resulting from widespread changes in the depolarization of apical dendrites. In contrast, the NREM-transition-negative shift and the REM-transition-positive shift may reflect the progression and retrogression, respectively, of a long-lasting hyperpolarization in deeply lying neurons.
Adult↗
Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system.
This review focuses on experiments in humans examining the regulation of the hypothalamo-pituitary-adrenal (HPA) system during nocturnal sleep. The HPA system is a most important mediator of the organism's response to stress. The early phase of nocturnal sleep dominated by extended epochs of slow wave sleep (SWS), is the only time of day in which secretory activity of this axis is subject to a pronounced and persistent inhibition resulting in minimum concentrations of ACTH and cortisol. During late sleep predominated by rapid eye movement (REM) sleep. HPA secretory activity reaches a diurnal maximum. Comparison of the response to administration of exogenous secretagogues of ACTH in men during sleep and nocturnal wakefulness indicated that early sleep, and in particular SWS, is associated with an inhibition of pituitary-adrenocortical responsiveness, which is presumably due to hypothalamic secretion of an as yet unknown release inhibiting factor of ACTH. Pituitary-adrenocortical responsiveness during early sleep was disinhibited after canrenoate which is a selective blocker of mineralocorticoid receptors (MR) located primarily in limbic-hippocampal structures. Hippocampal neuronal networks are known to integrate corticosteroid feedback via both, the MR and the classical glucocorticoid receptor (GR). Prevailing MR related activity in this network seems to act as a trigger for the inhibition of the HPA system. During early sleep, the same hippocampal network appears to be concurrently involved in the formation of declarative memory. Activation of GR after administration of dexamethasone completely blocked the formation of declarative memory during early sleep, indicating that the inhibition of HPA secretory activity is a necessary prerequisite for this memory process. Dysfunction of the described neuro-endocrine mode of regulation during early sleep is present in patients with Cushing's disease, in patients with severe depression and in aged humans. All of these groups show insufficient inhibition of HPA secretory activity particular prominent during early sleep, and reduced SWS in concert with impairments of declarative memory function. First clinical trials suggest that this trias of symptoms may benefit from intranasal treatment with neuropeptides like vasopressin and growth hormone releasing hormone.
Hippocampus↗
Enhanced selective attention after low-dose administration of the benzodiazepine antagonist flumazenil.
Although recognized for their sedative properties, benzodiazepines are also known to impair sustained and selective attention. Flumazenil at low doses may act to antagonize benzodiazepine-induced effects. This study examined whether low doses of flumazenil would improve event-related brain potential (ERP) indicators of selective attention and induce feelings of activation and anxiety in healthy men. Data from 11 men (24-30 years) who received intravenous flumazenil (0.2 mg, plus 0.3 mg 30 minutes later) and placebo were analyzed according to a double-blind crossover design. ERPs were recorded while subjects performed an auditory selective attention task. Mismatch negativity (MMN), processing negativity (PN), and the P3 component were extracted from the ERP as markers of preattentive mismatch processing, selective attention, and stimulus processing within working memory, respectively. Counting accuracy and performance on a letter cancellation test were used as behavioral indicators of attention. Mood was assessed by an adjective checklist and the State-Trait Anxiety Inventory. Flumazenil significantly increased PN over frontocortical areas, indicating improved selective attention (p < 0.05). Increases in the P3 amplitude and MMN after drug treatment remained nonsignificant. Subjects felt more activated and extraverted after flumazenil treatment than after placebo (p < 0.05). Anxiety was not increased. The findings of this study confirm the concept that flumazenil administered at a low dose in humans exerts effects opposite to those of benzodiazepines.
Adrenocorticotropic Hormone↗
The stress hormone adrenocorticotropin enhances sympathetic outflow to the muscle vascular bed in humans.
OBJECTIVE: To examine the role of adrenocorticotropin in the regulation of the sympathetic outflow to the muscle vascular bed in healthy female humans. DESIGN: Eight healthy, nonsmoking female subjects (aged 18-33 years) were examined before and after injection of 0.25 mg adrenocorticotropin 1-24 or placebo according to a balanced, double-blind cross-over protocol. METHODS: Muscle sympathetic nerve activity, arterial pressure, and heart rate were continuously recorded both under basal conditions and during a 50 min period after injection of each substance. Furthermore, sympathoexcitatory capacities of inspiratory apneas and cold pressure tests performed before and after injection of adrenocorticotropin were determined. RESULTS: The injection of adrenocorticotropin rapidly increased burst frequency of muscle sympathetic nerve activity (P < 0.01). The maximal effect of adrenocorticotropin, with an increase in burst frequency of 63%, occurred during the third minute after injection and waned subsequently, but muscle sympathetic nerve activity remained significantly increased during the first 10 min after injection. The stimulatory effect of adrenocorticotropin had disappeared 40 min after injection. The sympathoexcitatory capacity of a maximal inspiratory apnea and a cold pressure test, respectively, remained unchanged 10 and 45 min after the administration of adrenocorticotropin compared with control. Neither blood pressure nor heart rate was significantly affected by administration of the peptide. CONCLUSIONS: The data establish that the stress hormone adrenocorticotropin acutely increases sympathetic outflow to the muscle vascular bed in female humans. This effect is most likely mediated via central nervous system autonomic centers. The influence of adrenocorticotropin on the sympathetic nervous system might contribute to the alteration of response to stress in the course of the development of hypertension and could also add to the hypertensiogenic effects of corticosteroids and mineralocorticoids in states with excess adrenocorticotropin.
Adolescent↗
Familial coexistence of primary antiphospholipid syndrome and factor VLeiden.
The antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder in which thromboembolism and thrombocytopenia occur. The antiphospholipid antibodies in these patients may cause acquired activated protein C resistance, whereas hereditary activated protein C resistance results from a common single point mutation in coagulation factor V (factor VLeiden). In a family of 11 members with 4 normal subjects, autoimmune thrombocytopenia was documented in 6 patients. Three out of these were found to have thrombocytopenia associated with primary APS. In addition, these 3 subjects were also heterozygous for the factor VLeiden. Only in this group of individuals did life threatening thromboembolic complications occur, while other thrombocytopenic family members showed no thrombotic manifestations. Genetic studies revealed no linkage between APS and HLA class II alleles. Taken together, we present a family with autoimmune thrombocytopenia, which is associated with primary APS in at least 50% of thrombocytopenic individuals. The coexistence of both APS and factor VLeiden in thrombocytopenic subjects, led to an increased number of thrombotic events, suggesting a critical role of combined acquired and hereditary activated protein C resistance in the development of thrombosis in this family. Since no association between APS and specific HLA groups was found, other underlying risk factors for the development of APS must be considered.
Adolescent↗
Influence of exogenous atrial natriuretic peptide on the pituitary-adrenal response to corticotropin-releasing hormone and vasopressin in healthy men.
Atrial natriuretic peptide (ANP) has been considered a potential candidate participating in the inhibitory control of pituitary-adrenal secretory activity. Here, we investigated the influence of ANP, infused at two different doses and over infusion intervals of two different durations, on the release of ACTH and cortisol after stimulation with CRH and with combined administration of CRH and vasopressin (VP). In young healthy men, three experiments were conducted. In Exp I, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 45-min period of ANP infusion at a rate of 4.4 microg/min (starting 15 min before CRH injection). In Exp II, ACTH/cortisol secretory responses to CRH (50 microg) were examined during and after a 90-min infusion period of ANP administered at rates of 4.4 and 8.8 microg/min. In Exp III, ANP was infused at a rate of 4.4 microg/min over 90 min, but instead of CRH, a combined administration of CRH (50 microg) and VP (0.5 IU infused within 5 min) was employed to stimulate ACTH/cortisol release. ANP diminished pituitary-adrenal secretory responses within the first hour after stimulation with exogenous secretagogues. Thereafter, the effect of ANP turned in the opposite direction, with distinctly enhanced concentrations of ACTH and cortisol during the third hour after stimulation. The inhibitory effect of ANP during the first hour of the pituitary-adrenal response was more pronounced on concentrations of cortisol than ACTH and was also more pronounced after combined administration of CRH/VP than after stimulation with CRH alone. Increasing the dose of ANP enhanced the late stimulatory effect on ACTH/cortisol release, thereby terminating the early period of inhibited ACTH/cortisol release more abruptly. The late stimulatory effect was enhanced with prolonged infusion of ANP. In addition, it was associated with reduced hematocrit, increased urine volumes collected, increased heart rate, and enhanced plasma VP concentrations. Together, these changes suggest that the late stimulatory effect of ANP on ACTH/cortisol release reflects an effect secondary to its hypovolemic actions. This stimulatory effect originating from peripheral systemic actions of ANP after exogenous administration appears to override a more direct inhibitory action of the peptide on pituitary-adrenal secretory activity. Therefore, we would expect that with localized release into portal hypophyseal blood the inhibitory component of the action of ANP on pituitary-adrenal secretory activity prevails.
Adrenocorticotropic Hormone↗
Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men.
Interleukin-6 (IL-6) is a proinflammatory cytokine that has been shown to mediate, in addition to immune reactions, various endocrine and central nervous components of the acute phase response. In this context, the present study aimed to specify the contributions of IL-6 to the regulation of pituitary-adrenal secretory activity and GH and TSH secretion, as well as to the regulation of central nervous sleep and mood in healthy men. Effects of a low dose of IL-6 (0.5 microgram/kg body weight) were assessed, inducing plasma IL-6 concentrations closely comparable with those typically observed after infectious challenge. Each of the 16 male subjects participated in two 14-h sessions (between 1800 and 0800 h), receiving either placebo or human recombinant IL-6 sc at 1900 h. Blood was collected repeatedly to determine plasma hormone levels, serum concentrations of cytokines, and C-reactive protein. Moreover, mood was assessed, and sleep recordings were obtained between 2300 and 0700 h. The cytokine induced a prolonged increased in plasma concentrations of ACTH and cortisol (P < 0.001), but led to a decrease in TSH concentrations (P < 0.01). In response to IL-6, subjects reported fatigue and felt more inactive and less capable of concentrating than after placebo. Sleep architecture was altered significantly by the cytokine. Slow-wave sleep was decreased during the first half and increased during the second half of sleep. Rapid eye movement sleep during the entire nocturnal sleep time was significantly decreased. After IL-6, body temperature rose slightly. C-reactive protein concentrations were dramatically increased 12.5 h after substance administration (P < 0.001). IL-6 did not affect serum concentrations of IL-2, IL-8, interferon-alpha, and interferon-gamma. The results underscore the importance of IL-6 in the cascade of cytokines for the neuroendocrine response during the acute phase reaction. In addition, IL-6 appears to be involved in changes of sleep and behavior accompanying infection and inflammatory disorders.
Adrenal Glands↗
Regulation of gonadotrophin secretion by inhibin, testosterone and gonadotrophin-releasing hormone in pituitary cell cultures of male monkeys.
The effects of bovine inhibin, testosterone and GnRH on gonadotrophin secretion by primate pituitary cells were characterized in vitro using pituitaries from six male rhesus monkeys and one male cynomolgus monkey. The effect of inhibin on basal secretion of FSH and LH was investigated. Dose-response curves in monkeys and rats were compared. GnRH dose-response curves in the presence and absence of testosterone were also examined in monkeys. In monkey pituitary cells, testosterone at a concentration of 10(-7) M had no effect on LH or FSH secretion. Inhibin suppressed FSH secretion to 50.8% of that of controls with no effect on LH. In rats, FSH secretion was suppressed to 45.0% of that of controls with a median effective dose (ED50, 95% range) of 1.298 (1.064-1.584) U/ml, compared with 1.024 (0.7204-1.455) U/ml in monkeys. In monkey pituitary cells, LH release was stimulated 9.9-fold and FSH 3.3-fold by GnRH. Testosterone had no effect on basal or GnRH-stimulated gonadotrophin release. These results support the view that the pituitary is not the target organ for the negative feedback action of testosterone in the male. In vitro, inhibin is the major regulator of FSH secretion at the pituitary level.
Analysis of Variance↗
A single administration of dehydroepiandrosterone does not enhance memory performance in young healthy adults, but immediately reduces cortisol levels.
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Administration, Oral↗
Regulation of human thought by neuropeptide ACTH 4-10: an analysis of the EEG's dimensional complexity.
The neuroactive 4-10 fragment of adrenocorticotropin (ACTH 4-10) has been found to impair electroencephalographic (EEG) signs of selective attention in previous studies. It was hypothesized that this effect reflects a more general influence of the peptide weakening the mutual inhibition among frontocortical neuronal networks. Therefore, ACTH 4-10 was expected to loosen attentional control not only over external input but also over internal thoughts. This study examined the effects of ACTH 4-10 on the dimensional complexity of the EEG recorded while subjects solved tasks of convergent analytical thinking and of divergent creative thinking and during mental relaxation. Subjects were tested 30 min after i.v. administration of placebo or ACTH 4-10 (2 mg). ACTH 4-10 enhanced dimensional complexity of the EEG. The effect primarily concerned frontocortical recordings during convergent thinking, which, following placebo, was associated with the lowest EEG dimension. ACTH 4-10 also impaired behavioral performance on tasks of convergent thought, when presented verbally. Results suggest that ACTH 4-10 counteracts the inhibitory control among cortical neuronal networks necessary for orderly analytical thinking.
Adrenocorticotropic Hormone↗