Christoph Dodt

Plasma Epinephrine and Norepinephrine Concentrations of Healthy Humans Associated With Nighttime Sleep and Morning Arousal

We assessed the activity of the sympathetic nervous system during undisturbed nocturnal sleep and periods of wakefulness directly before and after sleep in healthy young men. Changes induced by periods of rapid eye movement and by morning awakening, both periods reported to demonstrate an enhanced risk for the onset of cardiovascular diseases, were of particular interest. In 13 healthy men (age, 18 to 35 years), blood for determination of epinephrine and norepinephrine was drawn every 7 minutes between 9:30 PM and 8:30 AM with the subjects resting in a strictly horizontal position. Lights were switched off at 11 PM until awakening at 7 AM. At 8:30 AM, subjects stood up and a final blood sample was drawn. Sleep was monitored somnopolygraphically, and heart rate and blood pressure were continuously measured. Average epinephrine but not norepinephrine concentrations were significantly lower during nocturnal sleep than during wakefulness before and after sleep. In parallel, heart rate and blood pressure declined significantly during sleep. During rapid eye movement sleep, both epinephrine and norepinephrine concentrations were significantly lower than during sleep stages 1 and 2 and slow-wave sleep. Whereas epinephrine concentrations gradually began to increase after morning awakening, norepinephrine levels were not significantly enhanced. However, standing up at the end of the experiment sharply increased norepinephrine concentrations by 180%, whereas epinephrine levels were less enhanced (46%) by the change of body position. This study suggests that the decrease in the activity of the sympathoadrenal branch of the sympathetic nervous system is probably due to an entrainment to the sleep-wake cycle, whereas the low activity of the noradrenergic branches depends mainly on horizontal body position during nocturnal sleep. The activities of the sympathoadrenal and noradrenergic branches of the sympathetic nervous system seem to be downregulated during rapid eye movement sleep. Awakening itself selectively enhances epinephrine levels. Subsequent orthostasis activates both the sympathoadrenal and, most prominently, the noradrenergic branches of the sympathetic nervous system.

Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep.

The view of a general impairment of immune functions associated with aging has been challenged by recent studies including a more detailed evaluation of various cytokines and lymphocyte subsets. In the present human study, effects of age on the production of cytokines by T cells and monocytes were assessed, together with age-dependent changes in subset populations of mononuclear cells (MNC). Blood was collected every 30 min during nocturnal sleep in 16 aged (mean: 79.6 +/- 7.5 years) and in 16 young controls (mean: 24.6 +/- 3.1 years). Nocturnal sleep was chosen as a well-defined period within the 24-h cycle with minimal exogenous influences. The in vitro production of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) was measured after mitogen stimulation with lipopolisaccharide from E. coli (LPS). Production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) was measured after stimulation with phytohemagglutinin (PHA). Regarding MNC subsets, monocytes, lymphocytes, CD3+, CD4+, CD8+, HLA-DR, CD16+, CD25+, and CD19+ were determined. Advanced age was associated with a decreased number of T cells (CD3+) and decreases in the major T cell subsets (CD4+, CD8+, P < 0.001). Production of IL-2 was not affected. However, production of IFN-gamma tended to be enhanced, and numbers of activated T cells (HLA-DR/CD3+), natural killer cells (CD16+), and T cells expressing IL-2 receptors (CD25+/CD3+) were markedly increased in the aged. While monocyte counts were unchanged in the elderly production of IL-1 beta and TNF-alpha mainly derived from these cells, was enhanced (p < 0.05). Results indicate a state of enhanced responsiveness of the T cell compartment and of monocytes in aged which may compensate for the substantial decrease in T cells.

Effects of selective angiotensin II receptor blockade on sympathetic nerve activity in primary hypertensive subjects.

Objective The role of the renin–angiotensin system in the regulation of sympathetic nervous activity in human hypertension was evaluated in patients with moderate primary hypertension. For that purpose, the effects of selective angiotensin II (ANG II) receptor blockade by valsartan on sympathetic outflow to the muscle vascular bed and hemodynamic parameters were examined. Results were compared with the effects of the peripherally acting calcium antagonist amlodipine. Design Eighteen hypertensive but otherwise healthy subjects were examined in a double-blind, placebo-controlled, cross-over protocol receiving either valsartan or amlodipine or placebo for 7 days in a randomized sequence. Treatment periods were separated by washout periods of 2 weeks. Methods At the seventh day of treatment, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA), norepinephrine, renin and angiotensin were measured during resting conditions. Additionally, parameters were measured after administration of negative pressure of −15 mmHg to the lower part of the body and after a cold pressor test. Results Both antihypertensive drugs significantly decreased oscillometrically measured systolic blood pressure and diastolic blood pressure without any difference in effect. While valsartan did not affect the heart rate at rest, amlodipine increased it significantly. Likewise, MSNA was significantly enhanced by amlodipine but not by valsartan. Only ANG II receptor blockade increased renin and angiotensin levels. Conclusions Selective ANG II receptor blockade not only decreases blood pressure, but also shifts the baroreflex set-point for the initiation of counter-regulatory reflex responses of heart rate and blood pressure towards normal blood pressure levels. Thus, data suggest that ANG II plays a pathogenetic role in the elevation of the baroreflex set point in primary hypertensive subjects.

Antimineralocorticoid Canrenoate Enhances Secretory Activity of the Hypothalamus-Pituitary-Adrenocortical (HPA) Axis in Humans

In rats, both hippocampal glucocorticoid and mineralocorticoid receptors (MR) have been shown to participate in the regulation of basal hypothalamus-pituitary-adrenocortical (HPA) secretory activity. Inhibition of hippocampal MRs enhanced the activity of the HPA axis in these animals. We tested the influence of potassium cancrenoate, a selective MR antagonist, on basal cortisol secretion in 10 healthy young men during sleep. Cortisol, ACTH, vasopressin and growth hormone (GH) were determined at 22.00, 23.00, 01.00, 04.00 and 07.00 h. Sleep was monitored by somnopolygraphy. Potassium canrenoate (200 mg) was administered intravenously at 08.00 and 17.00 h the preceding day. Compared with a placebo condition, potassium canrenoate elevated cortisol levels throughout the night, with significant (p < 0.05) increases at 22.00, 23.00, 01.00 and 07.00 h. Effects of canrenoate on ACTH levels were not significant, and there was also no effect on plasma vasopressin levels. GH concentrations at 04.00 and 07.00 h were higher after canrenoate than placebo (p < 0.05). Changes induced by canrenoate paralleling those in animals after intracerebroventricular administration of MR antagonists suggest that central nervous MRs are involved in the regulation of HPA secretory activity also in humans.

To Dip or Not to Dip: On the Physiology of Blood Pressure Decrease During Nocturnal Sleep in Healthy Humans

That sleep is accompanied by a blood pressure decrease is well known; however, the underlying physiology deserves further investigation. The present study examines in healthy subjects 2 main questions: is this dipping actively evoked? and what are the consequences of nondipping for daytime blood pressure? Nocturnal blood pressure was extrinsically elevated in 12 sleeping subjects to mean daytime values by continuously infused phenylephrine. This nondipping significantly lowered morning blood pressure during rest and 3 hours after resuming physical activity compared with a control condition (isotonic saline). Neither muscle sympathetic nerve activity nor sensitivity of &agr;-adrenoceptors was reduced. However, the set point for initiation of regulatory responses through the baroreflex was clearly shifted toward lower blood pressure levels. Our results support the hypothesis of an actively regulated central mechanism for blood pressure resetting and set point consolidation of the baroreflex during nighttime sleep. This is suggested by the fact that extrinsically induced nondipping induces sustained decrease in blood pressure during the following morning through an actively lowered baroreflex set point.

Sympathetic Function in Human Carriers of Melanocortin-4 Receptor Gene Mutations

CONTEXT Melanocortinergic pathways clearly appear to be involved in obesity-associated sympathetic overactivity and its hemodynamic and thermoregulatory consequences. Individuals with dysfunctional mutations in the melanocortin-4 receptor gene (MC4R) are subject to obesity without developing hypertension. OBJECTIVE This study aimed at characterizing the impact of the MC4R on sympathetic nerve traffic relevant to the cardiovascular system in humans. PARTICIPANTS Participants included eight heterozygous carriers of MC4R mutations leading to a reduced function and control subjects matched for gender, age, and body mass index. MEASUREMENTS We investigated vasoconstrictive muscle sympathetic nerve activity (MSNA), a direct measure of central sympathetic nervous outflow. MSNA was recorded microneurographically from the peroneal nerve at supine rest and during apnea-induced sympathoexcitation. Sympathetic activity was correlated with serum leptin levels and hemodynamic and anthropometric data. RESULTS Individuals with MC4R impairment due to functional MC4R mutations were characterized by an inverse correlation between MSNA with body mass index and leptin levels, with the most obese subjects having the lowest MSNA. Resting MSNA, diastolic blood pressure, and heart rate tended to be lower in MC4R mutation carriers, and stimulated MSNA during apnea was significantly lower as compared with control subjects. CONCLUSION The fact that obese subjects with MC4R mutations show an inverse relationship between obesity and MSNA suggests that central sympathetic outflow to the vasculature might depend on functional melanocortinergic pathways. Their dysfunction could explain reduced sympathoexcitability, lower sympathetic nerve-induced lipolysis, and the fact that blood pressure is rarely elevated in this type of obesity.

Endotoxemia causes central downregulation of sympathetic vasomotor tone in healthy humans

Experimental endotoxemia as a model of the initial septic response affects the autonomic nervous system with profound cardiovascular sequelae. Whether the postsynaptic sympathoneural activity to the muscle vascular bed is altered in the early septic phase remains to be determined. The present study aimed to elucidate the early effects of LPS on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation in healthy humans. Young, healthy volunteers randomly received either an LPS bolus (4 ng/kg body wt, n = 11) or placebo (saline; n = 7). Experimental baroreflex assessment (baseline measurements followed by infusion of vasoactive drugs nitroprusside/phenylephrine) was done prior to and 90 min following LPS or placebo challenge. MSNA, heart rate, blood pressure, and blood levels of catecholamines, TNF-alpha and IL-6 were measured sequentially. Endotoxin but not placebo-induced flu-like symptoms and elevated cytokine levels. In contrast to placebo, LPS significantly suppressed MSNA burst frequency 90 min after injection [mean +/- SE: 12.1 +/- 2.9 vs. 27.5 +/- 3.3 burst/min (post- vs. pre-LPS); P < 0.005] but increased heart rate [78.4 +/- 3.1 vs. 60.6 +/- 2.0 beats/min (post- vs. pre-LPS); P < 0.001]. Baseline blood pressure was not altered, but baroreflex testing demonstrated a blunted MSNA response and uncoupling of heart rate modulation to blood pressure changes in the endotoxin group. We conclude that endotoxin challenge in healthy humans has rapid suppressive effects on postsynaptic sympathetic nerve activity to the muscle vascular bed and alters baroreflex function which may contribute to the untoward cardiovascular effects of sepsis.

Effect of facial cooling and cold air inhalation on sympathetic nerve activity in men

In nine healthy subjects, cold stimuli were administered to the forehead and hand, to the oral and nasal cavities via ice cubes and to the bronchial system via inhalation of cold air (-25 degrees C). Blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) from the peroneal nerve were recorded. MSNA expressed as total activity increased during cold air inhalation, cooling of the forehead (P < 0.001, ANOVA), hand and mouth (P < or = 0.05), paralleled by a rise in blood pressure during cold air inhalation and cooling of the forehead and hand (P < 0.01). Cooling of the forehead provoked a faster increase of MSNA expressed as total activity (P < 0.05) and higher levels of diastolic blood pressure (P = 0.05) compared with cooling of the hand. Bradycardia was observed only during cooling of the nasal cavity (P < 0.001) and the forehead (P < 0.05). It is concluded that cooling of the skin and mucous membranes of the tracheobronchial tract elicits sympathetically mediated hemodynamic adaptations, probably via stimulation of cold-sensitive afferents.

Intraneural stimulation elicits an increase in subcutaneous interstitial glycerol levels in humans.

1 The effect of intraneural electrical stimulation of the lateral femoral cutaneous nerve on lipolysis in the innervation territory of the stimulated nerve fascicle was studied in seven healthy women. Lipolysis was evaluated by microdialytic measurement of the interstitial glycerol concentration in subcutaneous adipose tissue. 2 Ten minutes of unilateral intraneural stimulation elicited a 22 ± 8 % (mean ±s.e.m.s) increase in glycerol levels in the stimulated region (P < 0.05), whereas no change was registered in the corresponding area of the contralateral unstimulated leg. 3 Significantly higher glycerol levels in the stimulated vs. contralateral unstimulated region (47 ± 13 %, P < 0.05) were already observed at baseline (30 min resting period preceding the 10 min stimulation), in all probability as a consequence of the nerve searching procedure and trial stimulations. After the 10 min stimulation, the overall glycerol increase was 72 ± 17 % compared with the contralateral leg, illustrating the degree of lipolysis induced by the whole experimental procedure. 4 The sympathetic discharge in the lateral femoral nerve (6 recordings) showed typical characteristics of skin sympathetic activity, and the firing pattern was strikingly similar to simultaneously recorded sympathetic discharge in cutaneous nerve fascicles innervating regions without prominent subcutaneous fat stores (2 double nerve recordings). Thus, no component of cutaneous sympathetic outflow specific for the nerve innervating prominent subcutaneous fat stores could be identified. 5 Our findings suggest that sympathetic nerve fibres travelling in cutaneous nerve fascicles exert a regulatory influence on subcutaneous fat tissue in humans. The combination of intraneural recording/stimulation and subcutaneous microdialysis provides a model for evaluating neural control of human fat metabolism.

Acute Influences of Estrogen and Testosterone on Divergent and Convergent Thinking in Postmenopausal Women

Previous studies indicated an enhanced capability of divergent creative thinking in young women during the ovulatory phase, which expressed itself also by an increased dimensional complexity of ongoing electroencephalographic (EEG) activity. Considering the enhanced plasma levels of estrogen and testosterone characterizing the ovulatory phase, we tested whether short-term administration of estrogen or testosterone in postmenopausal women with constantly low levels of gonadal steroids induces similar changes in divergent thinking. In two placebo-controlled cross-over studies, healthy postmenopausal women (n=12, in each study, mean age 58 years, range 47–65 years) were treated transdermally over 3 days with estrogen and testosterone, respectively, at doses inducing plasma hormone concentrations comparable with those observed in young women around ovulation. Capabilities of divergent thought and convergent analytical thought, performance on motor perseveration, and verbal memory were examined. EEG activity was recorded while subjects performed on tasks of thinking and during mental relaxation. Estrogen impaired divergent thinking (p<0.01) and enhanced convergent thinking, motor perseveration, and memory for the initial word list (p<0.05 for all tests). In parallel, EEG dimensional complexity was reduced (p<0.05). Overall, these changes indicate an estrogen-induced shift from a ‘divergent’ towards a more ‘convergent’ mode of processing. However, overall less consistent, effects of testosterone were opposite to those of estrogen. It increased performance on some of the divergent thinking tasks (p<0.05), and tended to increase EEG dimensional complexity during divergent thinking. Data indicate a differential sensitivity of modes of thinking to short-term treatment with estrogen and testosterone in postmenopausal women.