Sympathoadrenal Response Research Articles

The Locus for Hypoglycemic Detection Shifts With the Rate of Fall in Glycemia

To ascertain whether portal glucose sensing extends beyond the portal vein to the superior mesenteric vein and then test whether the role of portal-superior mesenteric glucose sensors varies with the rate of fall in glycemia. Chronically cannulated rats underwent afferent ablation of the portal vein (PV) or portal and superior mesenteric veins (PMV) or sham operation (control). One week later, animals underwent hyperinsulinemic-hypoglycemic clamps in which the hypoglycemic nadir, 2.48 +/- 0.06 mmol/l, was reached at a rate of decline in glucose of -0.09 or -0.21 mmol x l(-1) x min(-1) (PMV and control only). Additional PMV and control animals received an intravenous injection of the glucopenic agent 2-deoxyglucose. RESULTS; Inducing hypoglycemia slowly, at a rate of -0.09 mmol x l(-1) x min(-1), resulted in a 26-fold increase in epinephrine (23.39 +/- 0.62 nmol/l) and 12-fold increase in norepinephrine (11.42 +/- 0.92 nmol/l) for controls (P < 0.001). The epinephrine response to hypoglycemia was suppressed by 91% in PMV (2.09 +/- 0.07 nmol/l) vs. 61% in PV (9.05 +/- 1.59 nmol/l) (P < 0.001). The norepinephrine response to hypoglycemia was suppressed by 94 and 80% in PMV and PV, respectively, compared with that in controls. In contrast, when arterial glucose was lowered to 2.49 +/- 0.06 mmol/l within 20 min, no significant differences were observed in the catecholamine responses for PMV and controls over the first 45 min of hypoglycemia (20-65 min). Only at min 105 were catecholamines significantly lower for PMV vs. controls. Injection of 2-deoxyglucose induced a very rapid sympathoadrenal response with no significant differences between PMV and controls. The critical locus for hypoglycemic detection shifts away from the portal-mesenteric vein to some other loci (e.g., the brain) when hypoglycemia develops rapidly.

Responses of the Hypothalamopituitary Adrenal Axis and the Sympathoadrenal System to Isolation/Restraint Stress in Sheep of Different Adiposity

There is evidence that levels of adipose tissue can influence responses of the hypothalamopituitary-adrenal (HPA) axis to stress in humans and rats but this has not been explored in sheep. Also, little is known about the sympathoadrenal responses to stress in individuals with relatively different levels of adipose tissue. We tested the hypothesis that the stress-induced activation of the HPA axis and sympathoadrenal system is lower in ovariectomized ewes with low levels of body fat (lean) than ovariectomized ewes with high levels of body fat (fat). Ewes underwent dietary manipulation for 3 months to yield a group of lean ewes (n = 7) with a mean (±SEM) live weight of 39.1 ± 0.9 kg and body fat of 8.9 ± 0.6% and fat ewes (n = 7) with a mean (±SEM) live weight of 69.0 ± 1.8 kg and body fat of 31.7 ± 3.4%. Fat ewes also had higher circulating concentrations of leptin than lean ewes. Blood samples were collected every 15 min over 8 h when no stress was imposed (control day) and on a separate day when 4 h of isolation/restraint was imposed after 4 h of pretreatment sampling (stress day). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, epinephrine and norepinephrine did not change significantly over the control day and did not differ between lean and fat ewes. Stress did not affect plasma leptin levels. All stress hormones increased significantly during isolation/restraint stress. The ACTH, cortisol and epinephrine responses were greater in fat ewes than lean ewes but norepinephrine responses were similar. Our results suggest that relative levels of adipose tissue influence the stress-induced activity of the hypothalamopituitary-adrenal axis and some aspects of the sympathoadrenal system with fat animals having higher responses than lean animals.

Expression Levels of mRNAs for Catecholamine Biosynthetic Enzymes as Markers of Acute Response to Contusion Stress during the Early Postmortem Period

Various stresses can be followed by sudden unexpected deaths, and autopsies sometimes fail to identify pathological findings that determine the cause of death. Pathologists occasionally explain such deaths as being due to overstimulation of sympathoadrenal systems, but postmortem assessment of antemortem sympathoadrenal activity has not been established. An animal model of weight injuries was used to quantify sympathoadrenal response to contusion stress, which is common in forensic fields. A weight was dropped from a given height onto the right dorsal limb of each anesthetized rat, with a control group and three stress groups (n = 4, each): 1000 g-80 cm, 1000 g-40 cm, and 500 g-40 cm. To explore the postmortem changes, we also included ten groups comprised of control and 1000 g-80 cm groups, whose tissues were harvested during 12 hours after euthanasia. Real-time quantitative polymerase-chain reaction was performed to quantify relative expression levels of mRNAs for catecholamine biosynthetic enzymes in the adrenals and the anterocervical ganglia: tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). The expression levels of all target mRNAs in the adrenals increased with the intensity of impact (TH, p < 0.0005; DBH and PNMT, p < 0.005), and particularly, TH mRNA level exhibited near-stepwise elevation (p < 0.05). In contrast, no significant differences were detected in the anterocervical ganglia. Moreover, these mRNA levels in the adrenals decreased with increasing postmortem interval length. Thus, TH mRNA level may be a good marker of sympathoadrenal response to contusion stress during the early postmortem period.

Physiological Responses to Exercise at Altitude

Studies performed over the past decade have yielded new information related to the physiological and metabolic adjustments made in response to both short- and long-term high-altitude exposure. These investigations have examined the potential mechanisms responsible for the alterations observed in such key variables as heart rate, stroke volume, cardiac output, muscle blood flow, substrate utilization and mitochondrial function, both at rest and during exercise of varying intensities. Additionally, the occurrence and mechanisms related to the 'lactate paradox' continues to intrigue investigators. It is apparent that exposure to high altitude is an environmental stressor that elicits a robust sympathoadrenal response that contributes to many of the critical adjustments and adaptations mentioned above. Furthermore, as some of these important physiological adaptations are known to enhance performance, it has become popular to incorporate an aspect of altitude living/training into the training regimens of endurance athletes (e.g. 'live high-train low'). Finally, it is important to note that many factors influence the extent to which individuals adjust and adapt to the stress imposed by exposure to high altitude. Included among these are (i) the degree of hypoxia; (ii) the duration of exposure to hypoxic conditions; (iii) the exercise intensity (absolute vs relative workload); and (iv) the inter-individual variability in adapting to hypoxic environments ('responders' vs 'non-responders').

Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia

The posterior paraventricular nucleus of the thalamus (THPVP) has been identified as a forebrain region that modulates the central nervous system (CNS) response to recurrent experiences of stressors. The THPVP is activated in response to a single (SH) or recurrent (RH) experience of the metabolic stress of hypoglycemia. In this study, we evaluated whether temporary experimental inactivation of the THPVP would modify the neuroendocrine response to SH or RH. Infusion of lidocaine (LIDO) or vehicle had no effect on the neuroendocrine response to SH, comparable to findings with other stressors. THPVP vehicle infusion concomitant with RH resulted in a prevention of the expected impairment of neuroendocrine responses, relative to SH. LIDO infusion with RH resulted in significantly decreased glucagon and sympathoadrenal responses, relative to SH. These results suggest that the THPVP may contribute to the sympathoadrenal stimulation induced by hypoglycemia; and emphasizes that the THPVP is a forebrain region that may contribute to the coordinated CNS response to metabolic stressors.

Attenuation of counterregulatory responses to recurrent hypoglycemia by active thalamic inhibition: a mechanism for hypoglycemia-associated autonomic failure.

Hypoglycemia, the limiting factor in the glycemic management of diabetes, is the result of the interplay of therapeutic insulin excess and compromised glycemic defenses. The key feature of the latter is an attenuated sympathoadrenal response to hypoglycemia that typically follows an episode of recent antecedent iatrogenic hypoglycemia, a phenomenon termed hypoglycemia-associated autonomic failure (HAAF) in diabetes. We investigated the role of cerebral mechanisms in HAAF by measuring regional brain activation during recurrent hypoglycemia with attenuated counterregulatory responses and comparing it with initial hypoglycemia in healthy individuals. We used [(15)O]water and positron emission tomography to measure regional cerebral blood flow as a marker of brain synaptic activity during hyperinsulinemic hypoglycemic clamps (55 mg/dl [3.0 mmol/l]) in the naïve condition (day 1) and after approximately 24 h of interval interprandial hypoglycemia (day 2) in nine healthy adults. Interval hypoglycemia produced attenuated sympathoadrenal, symptomatic, and other counterregulatory responses to hypoglycemia on day 2, a model of HAAF. Synaptic activity in the dorsal midline thalamus during hypoglycemia was significantly greater on day 2 than day 1 (P = 0.004). Greater synaptic activity associated with attenuated counterregulatory responses indicates that the dorsal midline thalamus plays an active inhibitory role in reducing sympathoadrenal and symptomatic responses to hypoglycemia when previous hypoglycemia has occurred, the key feature of HAAF in diabetes.

Attenuated adrenergic responses to exercise in women with fibromyalgia – A controlled study

The pathogenesis of widespread pain and fibromyalgia (FM) is unknown. Altered responses from the hypothalamus–pituitary–adrenal axis, sympathetic nervous system and muscular system have been suggested as being of importance. The present study was undertaken to determine: (i) whether the sympathoadrenal response to repetitive isometric contractions until exhaustion is altered in patients with FM, and (ii) whether sympathoadrenal responses are associated with muscle fatigue and pain during exercise. Nineteen women with FM, and 19 healthy women matched for age, smoking and self-reported physical activity, participated. Maximal voluntary contraction (MVC), repetitive isometric contractions (6 s contraction and 4 s resting phases) were performed with both quadriceps muscles at 30% of MVC until exhaustion. Muscle activity was recorded from the quadriceps muscles by surface electromyography (EMG). Plasma adrenalin (Adr), noradrenalin (NAdr) and cortisol were measured and perceived exertion and pain reported during exercise. Attenuated Adr responses ( p < 0.001) with normal plasma NAdr and cortisol ( p > 0.19) responses were found during exercise in the FM group compared with the control group. Significantly higher EMG amplitude (%EMG max) during the contraction phases ( p = 0.001) was found in the FM than in the control group. Perceived exertion and pain responses to exercise were higher in the FM group than in the controls ( p < 0.001), without relationship to the sympathoadrenal responses. In conclusion; the exercise was perceived as being more painful and strenuous in the FM group. Muscle performance was altered with increased muscle activity during the exercise. Women with FM showed an attenuated Adr response to repetitive isometric exercise.

Electrocardiographic alterations during hyperinsulinemic hypoglycemia in healthy subjects

We evaluated the arrhythmogenic potential of hypoglycemia by studying electrocardiographic (ECG) changes in response to hyperinsulinemic hypoglycemia and associated sympathoadrenal counterregulatory responses in healthy subjects.

Hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons

To elucidate the type of spinal afferent involved in hypoglycemic detection at the portal vein, we considered the potential role of capsaicin-sensitive primary sensory neurons. Specifically, we examined the effect of capsaicin-induced ablation of portal vein afferents on the sympathoadrenal response to hypoglycemia. Under anesthesia, the portal vein was isolated in rats and either capsaicin (CAP) or the vehicle (CON) solution applied topically. During the same surgery, the carotid artery (sampling) and jugular vein (infusion) were cannulated. One week later, all animals underwent a hyperinsulinemic hypoglycemic clamp, with glucose (variable) and insulin (25 mU x kg(-1) x min(-1)) infused via the jugular vein. Systemic hypoglycemia (2.76 +/- 0.05 mM) was induced by minute 75 and sustained until minute 105. By design, no significant differences were observed in arterial glucose or insulin concentrations between groups. When hypoglycemia was induced in CON, the plasma epinephrine concentration increased from 0.67 +/- 0.05 nM at basal to 36.15 +/- 2.32 nM by minute 105. Compared with CON, CAP animals demonstrated an 80% suppression in epinephrine levels by minute 105, 7.11 +/- 0.55 nM (P < 0.001). A similar response to hypoglycemia was observed for norepinephrine, with CAP values suppressed by 48% compared with CON. Immunohistochemical analysis of the portal vein revealed an 85% decrease in the number of calcitonin gene-related peptide-reactive nerve fibers following capsaicin-induced ablation. That the suppression in the sympathoadrenal response was comparable to our previous findings for total denervation of the portal vein indicates that hypoglycemic detection at the portal vein is mediated by capsaicin-sensitive primary sensory neurons.

Angiotensin II AT 1 receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress

Sustained pretreatment with angiotensin II AT 1 receptor antagonists prevents the sympathoadrenal and hormonal responses to 24 h isolation stress. To elucidate the mechanism of the anti-stress effects of AT 1 receptor antagonism, we examined the effect of subcutaneous infusion of candesartan, a non-competitive AT 1 receptor antagonist, 0.5 mg/kg/day for 14 days, to Wistar rats on the hypothalamic pituitary adrenal (HPA) axis after 24 h isolation stress. In the morning of day 15, we measured AT 1 receptors corticotropin-releasing factor (CRF) mRNA and immunoreactive CRF in the paraventricular nucleus (PVN), the pituitary adrenocorticotropin hormone (ACTH) and adrenal corticosterone content, and the urinary corticosterone excretion. In rats not treated with candesartan, 24 h isolation stress increased pituitary ACTH, adrenal corticosterone content and AT 1 receptor binding in the PVN but decreased CRF mRNA and CRF content in the PVN. This indicates enhanced CRF utilization not compensated by CRF gene transcription and effective glucocorticoid feedback inhibition in spite of the increase in AT 1 receptor expression. The effects of stress on HPA axis activation and CRF mRNA and content in the PVN were prevented by candesartan pretreatment, suggesting that activation of AT 1 receptors is required for the HPA axis response to isolation. Our results support the hypothesis that the activity of PVN AT 1 receptors is part of the mechanism necessary for development of a full stress-induced HPA axis activation. Inhibition of central AT 1 receptors limits the CRF response to stress and should be considered as a therapeutic tool to preserve homeostasis under chronic stress conditions.

Pain and Sympathoadrenal Responses to Dynamic Exercise in Women with the Fibromyalgia Syndrome

Objectives: To determine whether sympathoadrenal responses during exhaustive bicycling is attenuated in fibromyalgia syndrome [FMS] patients compared to demographically matched healthy normal control [HNC] subjects, and whether pain during exercise is related to sympathoadrenal responses. Another objective was to determine whether exercise exacerbates pain and fatigue in the subsequent days.Methods: Thirty women [15 FMS, 15 HNC] women matched for age, exercise frequency, and smoking habits bicycled with a stepwise increment in workload until exhaustion. Heart rate, oxygen uptake, and plasma catecholamine concentrations were determined before, during, and after exercise. Pain and perceived exertion were recorded during exercise. Average pain, sleep disturbance, and fatigue were recorded for the seven days preceding the exercise and for Day 1 and Day 7 after the exercise.Results: Plasma catecholamine concentrations, heart-rate, and oxygen uptake increased similarly during exercise in FMS patients and contro...

Brain and peripheral angiotensin II play a major role in stress

Angiotensin II (Ang II), the active principle of the renin-angiotensin system (RAS), was discovered as a vasoconstrictive, fluid retentive circulating hormone. It was revealed later that there are local RAS in many organs, including the brain. The physiological receptor for Ang II, the AT1 receptor type, was found to be highly expressed in many tissues and brain areas involved in the hypothalamic-pituitary-adrenal axis response to stress and in the sympathoadrenal system. The production of circulating and local Ang II, and the expression of AT1 receptors increase during stress. Blockade of peripheral and brain AT1 receptors with receptor antagonists administered peripherally prevented the hormonal and sympathoadrenal response to isolation stress, the stress-related alterations in cortical CRF1 and benzodiazepine receptors, part of the GABAA complex, and reduced anxiety in rodents. AT1 receptor blockade prevented the ulcerations of the gastric mucosa produced by cold-restraint stress, by preservation of the gastric blood flow, prevention of the stress-induced inflammatory response of the gastric mucosa, and partial blockade of the sympathoadrenal response to the stress. Our observations demonstrate that Ang II is an important stress hormone, and that blockade of AT1 receptors could be proposed as a potentially useful therapy for stress-induced disorders.

Antecedent Hindbrain Glucoprivation Does Not Impair the Counterregulatory Response to Hypoglycemia

Recurrent hypoglycemia impairs hormonal counterregulatory responses (CRRs) to further bouts of hypoglycemia. The hypothalamus and hindbrain are both critical for sensing hypoglycemia and triggering CRRs. Hypothalamic glucose sensing sites are implicated in the pathogenesis of defective CRRs; however, the contribution of hindbrain glucose sensing has not been elucidated. Using a rat model, we compared the effect of antecedent glucoprivation targeting hindbrain or hypothalamic glucose sensing sites with the effect of antecedent recurrent hypoglycemia on CRR to hypoglycemia induced 24 h later. Recurrent hypoglycemia decreased sympathoadrenal (1,470 +/- 325 vs. 3,811 +/- 540 pg/ml in controls [t = 60 min], P = 0.001) and glucagon secretion (222 +/- 43 vs. 494 +/- 56 pg/ml in controls [t = 60]), P = 0.003) in response to hypoglycemia. Antecedent 5-thio-glucose (5TG) injected into the hindbrain did not impair sympathoadrenal (3,806 +/- 344 pg/ml [t = 60]) or glucagon (513 +/- 56 pg/ml [t = 60]) responses to subsequent hypoglycemia. However, antecedent 5TG delivered into the third ventricle was sufficient to blunt CRRs to hypoglycemia. These results show that hindbrain glucose sensing is not involved in the development of defective CRRs. However, neural substrates surrounding the third ventricle are particularly sensitive to glucoprivic stimulation and may contribute importantly to the development of defective CRRs.

Birth Weight, Stress, and the Metabolic Syndrome in Adult Life

There is now widespread agreement that small size at birth is associated with an increased risk of the metabolic syndrome (glucose intolerance, high blood pressure, and dyslipidemia) and related pathologies, including cardiovascular disease in later life. Evidence is emerging that suggests that programming of hormonal systems in response to an adverse fetal environment may be one of the mechanisms underlying these long-term consequences of growth restriction in early life. In particular, alterations in neuroendocrine responses to stress may be important. Recent research suggests that increased adrenocortical and sympathoadrenal responses are associated with small size at birth. Epidemiological studies show that such physiological alterations in these neuroendocrine systems may have potent effects on risk of cardiovascular disease through their influence on risk factors, such as plasma glucose and lipid concentrations and blood pressure.

Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia- induced hormonal counterregulation

Recurrent episodes of hypoglycemia impair sympathoadrenal counterregulatory responses (CRRs) to a subsequent episode of hypoglycemia. For individuals with type 1 diabetes, this markedly increases (by 25-fold) the risk of severe hypoglycemia and is a major limitation to optimal insulin therapy. The mechanisms through which this maladaptive response occurs remain unknown. The corticotrophin-releasing factor (CRF) family of neuropeptides and their receptors (CRFR1 and CRFR2) play a critical role in regulating the neuroendocrine stress response. Here we show in the Sprague-Dawley rat that direct in vivo application to the ventromedial hypothalamus (VMH), a key glucose-sensing region, of urocortin I (UCN I), an endogenous CRFR2 agonist, suppressed (approximately 55-60%), whereas CRF, a predominantly CRFR1 agonist, amplified (approximately 50-70%) CRR to hypoglycemia. UCN I was shown to directly alter the glucose sensitivity of VMH glucose-sensing neurons in whole-cell current clamp recordings in brain slices. Interestingly, the suppressive effect of UCN I-mediated CRFR2 activation persisted for at least 24 hours after in vivo VMH microinjection. Our data suggest that regulation of the CRR is largely determined by the interaction between CRFR2-mediated suppression and CRFR1-mediated activation in the VMH.

Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes

A reduced sympathoadrenal response, induced by recent antecedent hypoglycemia, is the key feature of hypoglycemia-associated autonomic failure (HAAF) and, thus, the pathogenesis of iatrogenic hypoglycemia in diabetes. Understanding of the mechanism(s) of that reduced response awaits new insight into its basic molecular, cellular, organ, and whole-body physiology and pathophysiology in experimental models. In this issue of the JCI, McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor-2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats (see the related article beginning on page 1723). Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF.

Adrenergic Influence on the Hormonal Response to Exercise in Endurance Trained Men

Exercise and competitive situations can provoke tremendous adrenergic responses. How these responses influence and impact upon on the endocrine system is poorly understood. PURPOSE: This study evaluated the influence of adrenergic factors on the hormonal responses to maximal exercise in endurance trained men. This was achieved by testing young healthy men during exercise in conditions of β-adrenergic blockade and in well-controlled simulated competition situations which stimulated sympatho-adrenal activity. METHODS: Subjects (n=7) performed maximal exercise to exhaustion on a treadmill during four conditions administered in random order: (1) control-placebo, (2) after administration of 80 mg propranolol, (3) in a simulated competition after a placebo intake, and (4) in a simulated competition after propranolol intake. Blood samples were obtained before (pre-) and three min post-exercise and assayed for select hormones (cortisol [C], growth hormone [GH], testosterone [T]). The data were analyzed with a multi-factorial repeated measures ANOVA procedure. RESULTS: All β-adrenergic blockade and competition situations caused augmented post-exercise C responses (25–45%) as compared to control-placebo condition (p < 0.01). Interestingly, the competition resulted in the greater post-exercise C responses than control-placebo or even in the ?-blockage conditions (p < 0.05); perhaps, due to enhanced subject motivation. GH and T post-exercise responses were slightly, but significantly, higher in the β-adrenergic blockade conditions than either placebo conditions (p < 0.05). CONCLUSION: These results suggest that central adrenergic influences perhaps restrict the C, GH and T responses to maximal exercise. However, with respect to C, the heightened stress of competition results in an enhanced activation of the sympatho-adrenal system responses which overrides the potential adrenergic inhibition.

Metabolic Sensors Mediate Hypoglycemic Detection at the Portal Vein

The current study sought to ascertain whether portal vein glucose sensing is mediated by a metabolic fuel sensor analogous to other metabolic sensors presumed to mediate hypoglycemic detection (e.g., hypothalamic metabosensors). We examined the impact of selectively elevating portal vein concentrations of lactate, pyruvate, or beta-hydroxybutyrate (BHB) on the sympathoadrenal response to insulin-induced hypoglycemia. Male Wistar rats (n = 36), chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion), underwent hyperinsulinemic-hypoglycemic ( approximately 2.5 mmol/l) clamps with either portal or jugular vein infusions of lactate, pyruvate, or BHB. By design, arterial concentrations of glucose and the selected metabolite were matched between portal and jugular (NS). Portal vein concentrations were significantly elevated in portal versus jugular (P < 0.0001) for lactate (5.03 +/- 0.2 vs. 0.84 +/- 0.08 mmol/l), pyruvate (1.81 +/- 0.21 vs. 0.42 +/- 0.03 mmol/l), or BHB (2.02 +/- 0.1 vs. 0.16 +/- 0.03 mmol/l). Elevating portal lactate or pyruvate suppressed both the epinephrine (64% decrease; P < 0.01) and norepinephrine (75% decrease; P < 0.05) responses to hypoglycemia. In contrast, elevating portal BHB levels failed to impact epinephrine (P = 0.51) or norepinephrine (P = 0.47) levels during hypoglycemia. These findings indicate that hypoglycemic detection at the portal vein is mediated by a sensor responding to some metabolic event(s) subsequent to the uptake and oxidation of glucose.

Anesthetic Requirements and Stress Hormone Responses in Spinal Cord-Injured Patients Undergoing Surgery Below the Level of Injury

Neuraxial anesthesia decreases the minimum alveolar concentration. We determined the effects of spinal cord injury (SCI) on sevoflurane requirements and stress hormone response. Twenty-two chronic SCI patients undergoing surgery below the level of the injury were enrolled in the study, and 15 patients without cord injury served as control patients. Bispectral index score was maintained at 40-50. Measurements included end-tidal sevoflurane concentrations, systolic arterial blood pressure, heart rate, and plasma catecholamine and cortisol concentrations. During surgery, systolic arterial blood pressure, heart rate, and Bispectral index were comparable between SCI and control groups. However, end-tidal sevoflurane concentration was significantly smaller in the SCI (0.81%-1.06%) versus control (1.28%-1.31%) patients. In the control group, plasma norepinephrine and cortisol concentrations were significantly increased during and 1 h after surgery compared with awake baseline values. In the SCI group, the sympathoadrenal and cortisol responses were virtually abolished. We conclude that SCI reduces the anesthetic requirement by 20%-39% during surgery below the level of injury, in association with blunted sympathoadrenal and cortisol responses.

Antecedent Hypercortisolemia Is Not Primarily Responsible for Generating Hypoglycemia-Associated Autonomic Failure

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 +/- 53 vs. 337 +/- 57 pg/ml, P = 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 +/- 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 +/- 28 vs. 192 +/- 28 pg/ml, P = NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemia-induced hypercortisolemia is not primarily responsible for the generation of HAAF.