Circulating epinephrine is not required for chronic stress to enhance metastasis.

Signaling through ß-adrenergic receptors drives cancer progression and ß-blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that ß-adrenergic signaling induced by chronic stress accelerates metastasis, and that ß2-adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. ß2-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence ß2-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals.

Increased pro-inflammatory cytokines, glial activation and oxidative stress in the hippocampus after short-term bilateral adrenalectomy.

BACKGROUND: Bilateral adrenalectomy has been shown to damage the hippocampal neurons. Although the effects of long-term adrenalectomy have been studied extensively there are few publications on the effects of short-term adrenalectomy. In the present study we aimed to investigate the effects of short-term bilateral adrenalectomy on the levels of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α; the response of microglia and astrocytes to neuronal cell death as well as oxidative stress markers GSH, SOD and MDA over the course of time (4 h, 24 h, 3 days, 1 week and 2 weeks) in the hippocampus of Wistar rats. RESULTS: Our results showed a transient significant elevation of pro-inflammatory cytokines IL-1ß and IL-6 from 4 h to 3 days in the adrenalectomized compared to sham operated rats. After 1 week, the elevation of both cytokines returns to the sham levels. Surprisingly, TNF-α levels were significantly elevated at 4 h only in adrenalectomized compared to sham operated rats. The occurrence of neuronal cell death in the hippocampus following adrenalectomy was confirmed by Fluoro-Jade B staining. Our results showed a time dependent increase in degenerated neurons in the dorsal blade of the dentate gyrus from 3 days to 2 weeks after adrenalectomy. Our results revealed an early activation of microglia on day three whereas activation of astroglia in the hippocampus was observed at 1 week postoperatively. A progression of microglia and astroglia activation all over the dentate gyrus and their appearance for the first time in CA3 of adrenalectomized rats hippocampi compared to sham operated was seen after 2 weeks of surgery. Quantitative analysis revealed a significant increase in the number of microglia (3, 7 and 14 days) and astrocytes (7 and 14 days) of ADX compared to sham operated rats. Our study revealed no major signs of oxidative stress until 2 weeks after adrenalectomy when a significant decrease of GSH levels and SOD activity as well as an increase in MDA levels were found in adrenalectomized compared to sham rats. CONCLUSION: Our study showed an early increase in the pro-inflammatory cytokines followed by neurodegeneration and activation of glial cells as well as oxidative stress. Taking these findings together it could be speculated that the early inflammatory components might contribute to the initiation of the biological cascade responsible for subsequent neuronal death in the current neurodegenerative animal model. These findings suggest that inflammatory mechanisms precede neurodegeneration and glial activation.

Regulation of nonclassical renin-angiotensin system receptor gene expression in the adrenal medulla by acute and repeated immobilization stress.

The involvement of the nonclassical renin-angiotensin system (RAS) in the adrenomedullary response to stress is unclear. Therefore, we examined basal and immobilization stress (IMO)-triggered changes in gene expression of the classical and nonclassical RAS receptors in the rat adrenal medulla, specifically the angiotensin II type 2 (AT2) and type 4 (AT4) receptors, (pro)renin receptor [(P)RR], and Mas receptor (MasR). All RAS receptors were identified, with AT2 receptor mRNA levels being the most abundant, followed by the (P)RR, AT1A receptor, AT4 receptor, and MasR. Following a single IMO, AT2 and AT4 receptor mRNA levels decreased by 90 and 50%, respectively. Their mRNA levels were also transiently decreased by repeated IMO. MasR mRNA levels displayed a 75% transient decrease as well. Conversely, (P)RR mRNA levels were increased by 50% following single or repeated IMO. Because of its abundance, the function of the (P)RR was explored in PC-12 cells. Prorenin activation of the (P)RR increased phosphorylation of extracellular signal-regulated kinase 1/2 and tyrosine hydroxylase at Ser(31), likely increasing its enzymatic activity and catecholamine biosynthesis. Together, the broad and dynamic changes in gene expression of the nonclassical RAS receptors implicate their role in the intricate response of the adrenomedullary catecholaminergic system to stress.

Pathophysiology and diagnosis of disorders of the adrenal medulla: focus on pheochromocytoma.

The principal function of the adrenal medulla is the production and secretion of catecholamines. During stressful challenging conditions, catecholamines exert a pivotal homeostatic role. Although the main adrenomedullary catecholamine, epinephrine, has a wide array of adrenoreceptor-mediated effects, its absence does not cause life-threatening problems. In contrast, excess production of catecholamines due to an adrenomedullary tumor, specifically pheochromocytoma, results in significant morbidity and mortality. Despite being rare, pheochromocytoma has a notoriously bad reputation because of its potential devastating effects if undetected and untreated. The paroxysmal signs and symptoms and the risks of missing or delaying the diagnosis are well known for most physicians. Nevertheless, even today the diagnosis is still overlooked in a considerable number of patients. Prevention and complete cure are however possible by early diagnosis and appropriate treatment but these patients remain a challenge for physicians. Yet, biochemical proof of presence or absence of catecholamine excess has become more easy and straightforward due to developments in assay methodology. This also applies to radiological and functional imaging techniques for locating the tumor. The importance of genetic testing for underlying germline mutations in susceptibility genes for patients and relatives is increasingly recognized. Yet, the effectiveness of genetic testing, in terms of costs and benefits to health, has not been definitively established. Further improvement in knowledge of genotype-phenotype relationships in pheochromocytoma will open new avenues to a more rationalized and personalized diagnostic approach of affected patients.

[The role of stress axes in cancer incidence and proliferation]. / Die Rolle der Stressachsen in der Entstehung und Proliferation einer Krebserkankung.

Psychosocial stressors can modulate the different stages of neoplastic events. It is established that there is activation of 2 well-known stress axes under stress, the hypothalamic-pituitary-adrenal axis and sympatho-adrenal-medullary axis, where especially the proliferating promoting effects on the malignant tumor events are known to depend on ß-adrenergic receptors. A new model focuses on the positive activating stress, which leads through the activation of the sympathetic hypothalamic-adipocyte axis to inhibition of tumor growth and reduction of obesity. This leads in mice to increased gene expression of the neurotrophin BDNF, which activates the sympathetic fibers of the white adipose tissue. Over consecutive stimulation of the ß-adrenergic receptors and thus the release of leptin, its promotional effect on the tumor growth is inhibited. In the clinical context, these results support the role of complex ß-adrenergic signal transduction pathways.

Role of TrkB expression in rat adrenal gland during acute immobilization stress.

Expression of tyrosine receptor kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), is markedly elevated in the adrenal medulla during immobilization stress. Catecholamine release was confirmed in vitro by stimulating chromaffin cells with recombinant BDNF. We investigated the role of TrkB and the localization of BDNF in the adrenal gland during immobilization stress for 60 min. Blood catecholamine levels increased after stimulation with TrkB expressed in the adrenal medulla during 60-min stress; however, blood catecholamine levels did not increase in adrenalectomized rats. Furthermore, expression of BDNF mRNA and protein was detected in the adrenal medulla during 60-min stress. Similarly, in rats undergoing sympathetic nerve block with propranolol, BDNF mRNA and protein were detected in the adrenal medulla during 60-min stress. These results suggest that signal transduction of TrkB in the adrenal medulla evokes catecholamine release. In addition, catecholamine release was evoked by both the hypothalamic-pituitary-adrenal axis and autocrine signaling by BDNF in the adrenal gland. BDNF-TrkB interaction may play a role in a positive feedback loop in the adrenal medulla during immobilization stress.

Adrenomedullary function in patients with nonclassic congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is classified into three types based on disease severity: classic salt-wasting, classic simple virilizing, and nonclassic. Adrenomedullary dysplasia and epinephrine deficiency have been described in classic CAH, resulting in glucose dysregulation. Our objective was to investigate adrenomedullary function in nonclassic CAH and to evaluate adrenomedullary function according to disease severity. Adrenomedullary function was evaluated in response to a standardized cycle ergonometer test in 23 CAH patients (14 females, age 9-38 years; 6 salt-wasting, 7 simple virilizing, 5 nonclassic receiving glucocorticoid treatment, 5 nonclassic not receiving glucocorticoid), and 14 controls (7 females, age 12-38 years). Epinephrine, glucose, and cortisol were measured at baseline and peak exercise. CAH patients and controls were similar in age and anthropometric measures. Patients with nonclassic CAH who were not receiving glucocorticoid and controls experienced the expected stress-induced rise in epinephrine, glucose, and cortisol. Compared to controls, patients with all types of CAH receiving glucocorticoid had impaired exercise-induced changes in epinephrine (salt-wasting: p=0.01;simple virilizing: p=0.01; nonclassic: p=0.03), and cortisol (salt-wasting: p=0.004; simple virilizing: p=0.006; nonclassic: p=0.03). Salt-wasting patients displayed the most significant impairment, including impairment in glucose response relative to controls (p=0.03). Hydrocortisone dose was negatively correlated with epinephrine response (r=-0.58; p=0.007) and glucose response (r=-0.60; p=0.002). The present study demonstrates that untreated patients with nonclassic CAH have normal adrenomedullary function. The degree of epinephrine deficiency in patients with CAH is associated with the severity of adrenocortical dysfunction, as well as glucocorticoid therapy.

[Treatment of adult men with congenital adrenal hyperplasia syndrome due to 21-hydroxylase deficiency]. / Behandlung des klassischen adrenogenitalen Syndroms mit 21-Hydroxylase-Defekt bei erwachsenen Männern.

Information about the treatment of males with congenital adrenal hyperplasia (CAH) is scarce and there are no therapeutical guidelines. The aim of this review is to provide a survey of the current data. An extensive literature research was performed in PubMed for relevant articles published in the last ten years. The aim in the treatment of adult male CAH patients is preservation of fertility, prevention of an addisonian crisis, blood pressure management, prevention of testicular adrenal rest tumors (TART), maintaining well-being and good quality of life, satisfactory sexual function and prevention of long-term side effects of gluco- and mineralocorticoid therapy. The change from paediatric to adult medicine should be handled in a transition outpatient clinic organized by paediatric and adult endocrinologists. Most studies have included only small numbers of patients. The steroid therapy is usually orientated on an individual basis; but, general guidelines are lacking. It is reported that fertility is often impaired and related to the occurrence of TART. Some of these tumors are responsive to altered glucocorticoid therapy. However, glucocorticoid-resistant TART have been described, and testis-sparing surgery seems to be a treatment option. A future system of regular follow-up visits and standardized therapy guidelines are essential to provide a better medical care and a higher quality of life for male patients with CAH.

Diagnosis and management of tumors of the adrenal medulla.

The adrenal medulla consists of chromaffin cells, the site of catecholamine biosynthesis. Pheochromocytomas are chromaffin-cell tumors; 80-85 % arise from the adrenal medulla and 15-20 % arise from extra-adrenal chromaffin tissues (paragangliomas). Neuroblastomas are primitive tumors that derive from the same blastic precursor as in pheochromocytomas, and are distributed along the sympathetic nervous system. Pheochromocytomas account for 6.5 % of incidentally discovered adrenal tumors; they are found in 50 % of patients with multiple endocrine neoplasia 2A (MEN 2A) and 5-25 % of patients with von Hippel-Lindau (VHL) syndrome. Neuroblastomas are the most common solid extra-cranial tumors in children, and account for 7-10 % of all tumors. The diagnosis of pheochromocytoma should first be established biochemically by measuring plasma free metanephrines (the measurement of urinary fractionated metanephrines is the second choice). Measurements of homovanillic acid (HVA), norepinephrine and vanilmandelic acid (VMA) in urine are a necessity in patients with suspected neuroblastoma. Anatomical (radiological) imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is necessary for both pheochromocytomas and neuroblastomas. Functional (nuclear medicine) methods are useful for both tumors. Scintigraphy with [123I]-metaiodobenzylguanidine is the specific functional imaging test of first choice; if this is not available, scintigraphy with [131I]-MIBG is the second choice. Other newer specific modalities that have been used for evaluating pheochromocytomas include positron emission tomography (PET) with [18F]-F-fluorodopamine (F-DA) and [18F]-F-dihydroxyphenylalanine (DOPA). These should be used when MIBG scintigraphy is negative. Primary treatment for both types of tumor is surgical; chemotherapy is used for inoperable disease. After successful surgery, survival of patients with benign, sporadic pheochromocytomas is believed to be equal to that of the general population. Depending on the extent of disease and age, patients with neuroblastomas have cure rates of 15-90 %.

Recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation.

Antecedent hypoglycemia is a primary factor in hypoglycemia-associated autonomic failure, a pathophysiological condition characterized by impaired glucose counterregulatory function. Conventional therapeutic strategies involving administration of intermediate dosage-release formulations of insulin in the management of insulin-dependent diabetes mellitus result in frequent iatrogenic hypoglycemia. This study investigated the neuroanatomical location, direction, and magnitude of CNS neuronal genomic activation by singular versus repeated induction of hypoglycemic bouts of greater than 6 h duration achieved by administration of the intermediate-acting insulin, humulin neutral protamine Hagedorn (NPH). Adult male rats injected subcutaneously with Humulin NPH exhibited robust immunolabeling for the nuclear transcription factor, Fos, in discrete telencephalic, diencephalic, midbrain, and caudal hindbrain loci in a pattern that was not identical to that described for regular insulin. Administration of four doses of insulin on as many days significantly diminished or extinguished Fos immunostaining within the parvocellular hypothalamic paraventricular nucleus, lateral hypothalamic area, dorsomedial hypothalamic nucleus, thalamic paraventricular nucleus, nucleus tractus solitarius, and area postrema, but did not modify labeling of other metabolic loci. However, numbers of Fos-immunoreactivity-positive magnocellular neurons in the hypothalamic paraventricular and supraoptic nuclei were significantly increased after the second and fourth insulin doses, relative to the single-dose group. Concurrent observations of exacerbated hypoglycemia and modified patterns of glucoregulatory hormone secretion after serial injections of intermediate-acting insulin suggest that central mechanisms governing compensatory endocrine responses, specifically glucagon, become habituated to repetitive hypoglycemia of extended duration. Resultant alterations in CNS-islet and -adrenomedullary output and hypothalamic-pituitary-adrenal activity may reflect diminished neuronal activation within one or more of the brain loci characterized here by nonuniform transcriptional activation. The current studies provide a neuroanatomical foundation for further investigation of the neurochemical phenotypes and interconnectivity of functionally adaptive neurons, underlying cellular and molecular mechanisms of diminished or enhanced activation, as well as the impact of these modified cellular responses on glucose counterregulation during administration of intermediate-acting insulin.

Adrenal medullary function and expression of catecholamine-synthesizing enzymes in mice with hypothalamic obesity.

The mechanisms underlying the onset of obesity are complex and not completely understood. An imbalance of autonomic nervous system has been proposed to be a major cause of great fat deposits accumulation in hypothalamic obesity models. In this work we therefore investigated the adrenal chromaffin cells in monosodium glutamate (MSG)-treated obese female mice. Newborn mice were injected daily with MSG (4 mg/g body weight) or saline (controls) during the first five days of life and studied at 90 days of age. The adrenal catecholamine content was 56.0% lower in the obese group when compared to lean controls (P < 0.0001). Using isolated adrenal medulla we observed no difference in basal catecholamine secretion percentile between obese and lean animals. However, the percentile of catecholamine secretion stimulated by high K+ concentration was lower in the obese group. There was a decrease in the tyrosine hydroxylase enzyme expression (57.3%, P < 0.004) in adrenal glands of obese mice. Interestingly, the expression of dopamine beta-hydroxylase was also reduced (47.0%, P < 0.005). Phenylethanolamine N-methyltransferase expression was not affected. Our results show that in the MSG model, obesity status is associated with a defective adrenal chromaffin cell function. We conclude that in MSG obesity the low total catecholamine content is directly related to a decrease of key catecholamine-synthesizing enzymes, which by its turn may lead to a defective catecholamine secretion.

Hypertension and adrenal disorders.

Adrenal disorders causing hypertension can be related to the dysfunction of either the adrenal cortex or the adrenal medulla. These disorders, including congenital adrenal hyperplasia (CAH), owing to 11B-hydroxylase deficiency and to 17alpha-hydroxylase deficiency; apparent mineralocorticoid excess; familial hyperaldosteronism type I; primary aldosteronism; Cushing's syndrome; and familial glucocorticoid resistance, primarily affect the adrenal cortex and cause low-renin hypertension. The classic disorder of the adrenal medulla resulting in hypertension is pheochromocytoma, although hypertension in obesity might also be associated with catecholamine secretion. In this review, we discuss these etiologies and the most recent advances in our knowledge of their pathophysiology, diagnosis, and treatment.

Pathophysiological function of adrenomedullin and proadrenomedullin N-terminal peptides in adrenal chromaffin cells.

Adrenomedullin (AM) and peptides of the proadrenomedullin N-terminal 20 peptide (PAMP20) family are multifunctional peptides abundantly expressed in the adrenal medulla. These peptides are released by regulated exocytosis along with catecholamines upon stimulation of adrenal chromaffin cells. They are also released gradually during culture, and this release is stimulated by a 3',5'-cyclic adenosine monophosphate (cAMP)-dependent pathway. The expression and release of AM increase under hypoxia in chromaffin cells. The expression of AM in pheochromocytoma PC12 cells is reduced during neuronal differentiation with nerve growth factor. On the other hand, PAMP20 and PAMP12 suppress catecholamine release and synthesis by interfering with nicotinic cholinergic receptors. AM increases blood flow in the adrenal gland, and causes a gradual release of catecholamine, but does not modify regulated exocytosis upon the stimulation of cells. Current data indicate that the expression of these peptides is regulated by intracellular signaling pathways, and changes under various physiological and pathological conditions. AM and PAMP20 family peptides have distinct physiological functions. PAMP20 and PAMP12 are endogenous peptides that modulate chromaffin cell function in an autocrine manner, whereas AM may mainly regulate vascular cell function in a paracrine manner.

Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia.

We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of alpha-(1-24)-ACTH (100 microg/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to approximately 45 microg/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P = 0.004, final plasma epinephrine levels of 489 +/-64 vs. 816 +/-113 pg/ml), sympathetic neural (P = 0.0022, final plasma norepinephrine levels of 244 +/-15 vs. 342 +/-22 pg/ml), parasympathetic neural (P = 0.0434, final plasma pancreatic polypeptide levels of 312 +/- 37 vs. 424 +/- 56 pg/ml), and neurogenic (autonomic) symptom (P = 0.0097, final symptom score of 7.1 +/-1.5 vs. 10.6 +/- 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus.

Humoral mechanisms in the pathogenesis of postprandial hypotension in patients with essential hypertension.

OBJECTIVE: To examine the role of catecholamines and insulin in the development of postprandial hypotension (PPH) in hypertensive patients. PATIENTS: Forty patients with essential hypertension (25 men, 15 women, mean age 68 +/- 2 years). METHOD: Blood pressure and heart rate were recorded in all subjects immediately after a 1903 kJ test meal and at 15-minute intervals for up to 1 hour after the meal. At these time points, circulating levels of norepinephrine, epinephrine, dopamine and C-peptide were measured. RESULTS: Twenty-three patients (58%) had PPH. By 15 minutes norepinephrine had significantly increased in PPH-negative subjects while it rose more slowly in PPH-positive patients and peaked by 45 minutes after the meal. Norepinephrine levels in 15 minutes were lower in PPH-positive than in PPH-negative ones (159.8 +/- 9.7 vs. 212.3 +/- 21.1 pg/ml, p = 0.01). Epinephrine levels rose only in PPH-negative subjects and did not differ significantly at the different time points. However, the area under curve analysis showed significantly lower epinephrine values in PPH-positive subjects (2903 + 247 pg.min.ml-1 vs. 3710 + 284 pg.min.ml-1, p = 0.03). Dopamine increased in both groups, although it was lower in subjects with PPH during the entire study (15 minutes: 68.6 +/- 3.7 vs. 93.7 +/- 11.7 pg/ml, p = 0.02; 30 minutes: 68.8 +/- 3.7 vs. 86.1 +/- 7.7 pg/ml, p = 0.03; 45 minutes: 60.5 +/- 4.2 vs. 79.7 +/- 5.2 pg/ml, p = 0.006). The postprandial C-peptide response did not differ between patients with PPH and those without PPH. CONCLUSIONS: In patients with essential hypertension, a marked decline in postprandial systolic blood pressure is associated with lower postprandial levels of norepinephrine, epinephrine and dopamine as compared to subjects without postprandial hypotension. This indicates that impaired sympatho-adrenal activation after ingestion of a meal may contribute to the development of PPH. Insulin appears not to be involved in the pathogenesis of postprandial hypotension.

Basic and clinical aspects of intraadrenal regulation of steroidogenesis.

The adrenal gland combines essential components of the autonomic nervous system and the HPA axis in close contact. From morphological analyses employing immunohistochemistry, in situ hybridization, the novel technique of laser capture microdissection, and electron microscopy, it has been has shown that the chromaffin cells of the adrenal medulla and the steroid-producing cells of the adrenal cortex are extensively intermingled and functionally interrelated. In in vitro studies, a variety of regulatory factors produced and released by the adrenal medulla were identified as playing an important role in modulating adrenocortical function. An isolated adrenocortical cell deprived of its tissue integrity, input from the nervous system, or intercellular communication with chromaffin, vascular, and immune cells of the adrenal gland, loses its normal capacity to produce glucocorticoids and to adequately respond to the homeostatic challenges of stress. Adrenocortical cells in co-culture with chromaffin cells produced ten times more glucocorticoids than the same number of pure adrenocortical cells and demonstrated marked up-regulation in the mRNA expression of cytochrome p450 enzymes and STAR in the co-culture, while this expression was down-regulated in isolated cells. Transgenic animal models of over-expression or deletion of enzymes involved in catecholamine synthesis, as well as of altered function of components of the HPA axis, provide evidence that the mutual interdependence of the sympatho-adrenal system and the HPA axis at the level of the adrenal gland is of physiologic relevance in vivo. Alterations in intercellular communications, local production of neuropeptides, growth factors and cytokines, and aberrant expression of ectopic receptors on adrenal cells have been implicated in adrenal cell growth, development, hyperplasia, tumor formation, autonomous hormone production, and autoimmune disease. Moreover, we described a direct cellular interaction of lymphocytes with adrenal cells as a novel non-cytokine mediated mechanism of immune endocrine interactions. Highlighting the importance of the extra-pituitary mechanisms of adrenocortical regulation, be them neural or immune, is a worthwhile starting point for a more complete analysis of the human stress system in vivo.

Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice.

Deficiency of 21-hydroxylase (21-OH), one of the most common genetic defects in humans, causes low glucocorticoid and mineralocorticoid production by the adrenal cortex, but the effect of this disorder on the adrenomedullary system is unknown. Therefore, we analyzed the development, structure, and function of the adrenal medulla in 21-OH-deficient mice, an animal model resembling human congenital adrenal hyperplasia. Chromaffin cells of 21-OH-deficient mice exhibited ultrastructural features of neuronal transdifferentiation with reduced granules, increased rough endoplasmic reticulum and small neurite outgrowth. Migration of chromaffin cells in the adrenal to form a central medulla was impaired. Expression of phenylethanolamine-N-methyltransferase (PNMT) was reduced to 27 +/- 9% (P<0.05), as determined by quantitative TaqMan polymerase chain reaction, and there was a significant reduction of cells staining positive for PNMT in the adrenal medulla of the 21-OH-deficient mice. Adrenal contents of epinephrine were decreased to 30 +/- 2% (P<0. 01) whereas norepinephrine and dopamine levels were reduced to 57 +/- 4% (P<0.01) and 50 +/- 9% (P<0.05), respectively. 21-OH-deficient mice demonstrate severe adrenomedullary dysfunction, with alterations in chromaffin cell migration, development, structure, and catecholamine synthesis. This hitherto unrecognized mechanism may contribute to the frequent clinical, mental, and therapeutic problems encountered in humans with this genetic disease.

Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome.

OBJECTIVE: The author's goal was to develop a pathophysiological model for neuroleptic malignant syndrome with greater explanatory power than the alternative hypotheses of hypothalamic dopamine antagonism (elevated set point) and direct myotoxicity (malignant hyperthermia variant). METHOD: Published clinical findings on neuroleptic malignant syndrome were integrated with data from human and animal studies of muscle physiology, thermoregulation, and autonomic nervous system function. RESULTS: The data show that the sympathetic nervous system's latent capacity for autonomous activity is expressed when tonic inhibitory inputs from higher central nervous system centers are disrupted. These tonic inhibitory inputs are relayed to preganglionic sympathetic neurons by way of dopaminergic hypothalamospinal tracts. The sympathetic nervous system mediates hypothalamic coordination of thermoregulatory activity and is a primary regulator of muscle tone and thermogenesis, augmenting both of these when stimulated. In addition, the sympathetic nervous system modulates all of the other end-organs that function abnormally in neuroleptic malignant syndrome. CONCLUSIONS: There is substantial evidence to support the hypothesis that dysregulated sympathetic nervous system hyperactivity is responsible for most, if not all, features of neuroleptic malignant syndrome. A predisposition to more extreme sympathetic nervous system activation and/or dysfunction in response to emotional or psychological stress may constitute a trait vulnerability for neuroleptic malignant syndrome, which, when coupled with state variables such as acute psychic distress or dopamine receptor antagonism, produces the clinical syndrome of neuroleptic malignant syndrome. This hypothesis provides a more comprehensive explanation for existing clinical data than do the current alternatives.

[The changes of calcitonin gene-related peptide (CGRP)-containing nerve fibers in adrenal gland of burned rats].

OBJECTIVE: To investigate the changes in calcitonin gene-related peptide(CGRP) within the adrenal glands medulla and cortex of the rat during early post burn period and the effect of CGRP on function of adrenal gland of burned rats. METHODS: The rats were randomly divided into two groups: control and burned. The distribution density of CGRP containing nerve fibers and cells in medulla of adrenal gland were determined at different timepoints post burn. RESULTS: 1. The CGRP-containing nerve fibers were distributed in capsule, cortex and medulla. CGRP-containing nerve fibers were associated with CGRP immunoreactive cell in medulla of adrenal glands. 2. Distribution density of CGRP-containing nerve fiber was decreased, but distribution density of CGRP-containing cells in medulla increased. CONCLUSION: CGRP may affect function of the adrenal gland of burned rats.