RESUMEN
The classic renin-angiotensin system is partly responsible for controlling aldosterone secretion from the adrenal cortex via the peptide angiotensin II (ANG II). In addition, there is a local adrenocortical renin-angiotensin system that may be involved in the control of aldosterone synthesis in the zona glomerulosa (ZG). To characterize the long-term control of adrenal steroidogenesis, we utilized adrenal glands from renin knockout (KO) rats and compared steroidogenesis in vitro and steroidogenic enzyme expression to wild-type (WT) controls (Dahl S rat). Adrenal capsules (ZG; aldosterone production) and subcapsules [zona reticularis/fasciculata (ZFR); corticosterone production] were separately dispersed and studied in vitro. Plasma renin activity and ANG II concentrations were extremely low in the KO rats. Basal and cAMP-stimulated aldosterone production was significantly reduced in renin KO ZG cells, whereas corticosterone production was not different between WT and KO ZFR cells. As expected, adrenal renin mRNA expression was lower in the renin KO compared with the WT rat. Real-time PCR and immunohistochemical analysis showed a significant decrease in P450aldo (Cyp11b2) mRNA and protein expression in the ZG from the renin KO rat. The reduction in aldosterone synthesis in the ZG of the renin KO adrenal seems to be accounted for by a specific decrease in P450aldo and may be due to the absence of chronic stimulation of the ZG by circulating ANG II or to a reduction in locally released ANG II within the adrenal gland.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Aldosterona/biosíntesis , Corticosterona/biosíntesis , Técnicas de Inactivación de Genes , Sistema Renina-Angiotensina , Renina/deficiencia , Glándulas Suprarrenales/efectos de los fármacos , Angiotensina II/sangre , Animales , Bucladesina/farmacología , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Relación Dosis-Respuesta a Droga , Retroalimentación Fisiológica , Femenino , Genotipo , Fenotipo , ARN Mensajero/metabolismo , Ratas Endogámicas Dahl , Ratas Transgénicas , Renina/sangre , Renina/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Zona Fascicular/metabolismo , Zona Glomerular/metabolismo , Zona Reticular/metabolismoRESUMEN
Renal denervation has been shown to lower arterial pressure in some hypertensive patients, yet it remains unclear whether this is due to ablation of afferent or efferent renal nerves. To investigate the role of afferent renal nerves in arterial pressure regulation, previous studies have used methods that disrupt both renal and nonrenal afferent signaling. The present study was conducted to develop and validate a technique for selective ablation of afferent renal nerves that does not disrupt other afferent pathways. To do this, we adapted a technique for sensory denervation of the adrenal gland by topical application of capsaicin and tested the hypothesis that exposure of the renal nerves to capsaicin (renal-CAP) causes ablation of afferent but not efferent renal nerves. Renal-CAP had no effect on renal content of the efferent nerve markers tyrosine hydroxylase and norepinephrine; however, the afferent nerve marker, calcitonin gene-related peptide was largely depleted from the kidney 10 days after intervention, but returned to roughly half of control levels by 7 wk postintervention. Moreover, renal-CAP abolished the cardiovascular responses to acute pharmacological stimulation of afferent renal nerves. Renal-CAP rats showed normal weight gain, as well as cardiovascular and fluid balance regulation during dietary sodium loading. To some extent, renal-CAP did blunt the bradycardic response and increase the dipsogenic response to increased salt intake. Lastly, renal-CAP significantly attenuated the development of deoxycorticosterone acetate-salt hypertension. These results demonstrate that renal-CAP effectively causes selective ablation of afferent renal nerves in rats.
Asunto(s)
Capsaicina/farmacología , Desnervación , Riñón/efectos de los fármacos , Riñón/inervación , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Desnervación/métodos , Modelos Animales de Enfermedad , Hipertensión/fisiopatología , Riñón/metabolismo , Masculino , Ratas Sprague-Dawley , Cloruro de Sodio DietéticoRESUMEN
The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoids, yet how the clock is synchronized to the external environment is unknown. Using mPER2::Luciferase (mPER2Luc) knockin mice, in which luciferase is rhythmically expressed under the control of the mouse Per2 clock gene, we hypothesized that ACTH transmits entrainment signals to the adrenal. Adrenal explants were administered ACTH at different phases of the mPER2Luc rhythm. Treatment with ACTH 1-39 produced a phase delay that was phase-dependent, with a maximum at circadian time (CT)18; ACTH did not alter the period or amplitude of the rhythm. Forskolin produced a parallel response, suggesting that the phase delay was cAMP-mediated. The response to ACTH was concentration-dependent and peptide-specific. Pulse administration (60 min) of ACTH 1-39 also produced phase delays restricted to late CTs. In contrast to ACTH 1-39, other ACTH fragments, including α-melanocyte-stimulating hormone, which do not activate the melanocortin 2 (MC2/ACTH) receptor, had no effect. The finding that ACTH in vitro phase delays the adrenal mPER2luc rhythm in a monophasic fashion argues for ACTH as a key resetter, but not the sole entrainer, of the adrenal clock.
Asunto(s)
Corteza Suprarrenal/fisiología , Hormona Adrenocorticotrópica/fisiología , Ritmo Circadiano/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Corteza Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Animales , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/genética , Técnicas de Sustitución del Gen , Luciferasas/genética , Masculino , Ratones , Ratones Mutantes , Técnicas de Cultivo de Órganos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Receptor de Melanocortina Tipo 2/metabolismo , alfa-MSH/metabolismoRESUMEN
Circadian rhythms in glucocorticoids are the product of interactions between the hypothalamic-pituitary-adrenal (HPA) axis and the mammalian clock gene system. The adrenal clock can generate the glucocorticoid rhythm that in turn synchronizes other peripheral clocks to maintain homeostasis. Stress acutely activates and chronically upregulates the HPA axis, suggesting that the adrenal clock could be modulated by stress. However, there is no direct evidence that stress affects the adrenal clock rhythm. We tested the hypothesis that a model of chronic subordination stress (CSS) that has a major impact on HPA axis regulation, metabolism, and emotional behavior alters adrenal and pituitary clock gene rhythms. Clock gene rhythms were assessed using mPER2::Luciferase (PER2Luc) knockin mice in which in vitro bioluminescence rhythms reflect the Per2 clock gene expression. PER2Luc mice that experienced CSS for 2 wk showed positive energy balance reflected by increased body weight and food intake. Additionally, CSS phase advanced the adrenal (â¼2 h) and the pituitary (â¼1 h) PER2Luc rhythm compared with control mice. The activity rhythm was not affected. The adrenal clock phase shift was associated with increased feed conversion efficiency, suggesting that the metabolic phenotype in CSS mice may be related to altered adrenal clock rhythmicity. Interestingly, a single subordination experience followed by 8 h sensory housing also phase advanced the adrenal, but not the pituitary, PER2Luc rhythm. Overall, these data demonstrate a stress-induced phase shift in a peripheral clock gene rhythm and differential stress sensitivity of two peripheral clocks within the HPA axis, suggesting a link between clock desynchrony and individual vulnerability to stress.
Asunto(s)
Ritmo Circadiano/genética , Sistema Hipotálamo-Hipofisario/metabolismo , Proteínas Circadianas Period/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Fisiológico/genética , Núcleo Supraquiasmático/metabolismo , Animales , Ritmo Circadiano/fisiología , Corticosterona/metabolismo , Ingestión de Alimentos/fisiología , Glucocorticoides/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Circadianas Period/genética , Factores de TiempoRESUMEN
Forty-eight hours of water deprivation (WD) in conscious rats results in a paradoxical increase in mean arterial pressure (MAP). Previous studies suggest this may be due to increased sympathetic nerve activity (SNA). However, this remains to be investigated in conscious, freely behaving animals. The purpose of this study was to determine, in conscious rats, the role of the sympathetic nervous system (SNS) in mediating WD-induced increases in MAP and to identify which vascular beds are targeted by increased SNA. Each rat was chronically instrumented with a radiotelemetry transmitter to measure MAP and heart rate (HR) and an indwelling venous catheter for plasma sampling and/or drug delivery. MAP and HR were continuously measured during a 2-day baseline period followed by 48 h of WD and then a recovery period. By the end of the WD period, MAP increased by â¼15 mmHg in control groups, whereas HR did not change significantly. Chronic blockade of α(1)/ß(1)-adrenergic receptors significantly attenuated the WD-induced increase in MAP, suggesting a role for global activation of the SNS. However, the MAP response to WD was unaffected by selective denervations of the hindlimb, renal, or splanchnic vascular beds, or by adrenal demedullation. In contrast, complete adrenalectomy (with corticosterone and aldosterone replaced) significantly attenuated the MAP response to WD in the same time frame as α(1)/ß(1)-adrenergic receptor blockade. These results suggest that, in conscious water-deprived rats, the SNS contributes to the MAP response and may be linked to release of adrenocortical hormones. Finally, this sympathetically mediated response is not dependent on increased SNA to one specific vascular bed.
Asunto(s)
Presión Sanguínea/fisiología , Prazosina/análogos & derivados , Sistema Nervioso Simpático/fisiología , Simpaticolíticos/farmacología , Privación de Agua/fisiología , Corteza Suprarrenal/inervación , Corteza Suprarrenal/fisiología , Corteza Suprarrenal/cirugía , Adrenalectomía , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Conducta Animal/fisiología , Presión Sanguínea/efectos de los fármacos , Estado de Conciencia/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Riñón/inervación , Riñón/fisiología , Masculino , Concentración Osmolar , Prazosina/farmacología , Ratas , Ratas Sprague-Dawley , Simpatectomía , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
DOCA-salt treatment increases mean arterial pressure (MAP), while central infusion of benzamil attenuates this effect. The present study used c-Fos immunoreactivity to assess the role of benzamil-sensitive proteins in the brain on neural activity following chronic DOCA-salt treatment. Uninephrectomized rats were instrumented with telemetry transmitters for measurement of MAP and with an intracerebroventricular (ICV) cannula for benzamil administration. Groups included rats receiving DOCA-salt treatment alone, rats receiving DOCA-salt treatment with ICV benzamil, and appropriate controls. At study completion, MAP in vehicle-treated DOCA-salt rats reached 142 ± 4 mmHg. In contrast DOCA-salt rats receiving ICV benzamil had lower MAP (124 ± 3 mmHg). MAP in normotensive controls was 102 ± 3 mmHg. c-Fos immunoreactivity was quantified in the supraoptic nucleus (SON) and across subnuclei of the hypothalamic paraventricular nucleus (PVN), as well as other cardiovascular regulatory sites. Compared with vehicle-treated normotensive controls, c-Fos expression was increased in the SON and all subnuclei of the PVN, but not in other key autonomic nuclei, such as the rostroventrolateral medulla. Moreover, benzamil treatment decreased c-Fos immunoreactivity in the SON and in medial parvocellular and posterior magnocellular neurons of the PVN in DOCA-salt rats but not areas associated with regulation of sympathetic activity. Our results do not support the hypothesis that DOCA-salt increases neuronal activity (as indicated by c-Fos immunoreactivity) of other key regions that regulate sympathetic activity. These results suggest that ICV benzamil attenuates DOCA-salt hypertension by modulation of neuroendocrine-related PVN nuclei rather than inhibition of PVN sympathetic premotor neurons in the PVN and rostroventrolateral medulla.
Asunto(s)
Amilorida/análogos & derivados , Sistema Nervioso Autónomo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Desoxicorticosterona/farmacología , Neuronas/efectos de los fármacos , Amilorida/farmacología , Análisis de Varianza , Animales , Encéfalo/metabolismo , Recuento de Células , Inmunohistoquímica , Inyecciones Intraventriculares , Masculino , Mineralocorticoides/farmacología , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , TelemetríaRESUMEN
BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by the loss of dystrophin. Severe and ultimately lethal, DMD progresses relatively slowly in that patients become wheelchair bound only around age twelve with a survival expectancy reaching the third decade of life. METHODS: The mildly-affected mdx mouse model of DMD, and transgenic DysΔMTB-mdx and Fiona-mdx mice expressing dystrophin or utrophin, respectively, were exposed to either mild (scruffing) or severe (subordination stress) stress paradigms and profiled for their behavioral and physiological responses. A subgroup of mdx mice exposed to subordination stress were pretreated with the beta-blocker metoprolol. FINDINGS: Subordination stress caused lethality in â¼30% of mdx mice within 24 h and â¼70% lethality within 48 h, which was not rescued by metoprolol. Lethality was associated with heart damage, waddling gait and hypo-locomotion, as well as marked up-regulation of the hypothalamus-pituitary-adrenocortical axis. A novel cardiovascular phenotype emerged in mdx mice, in that scruffing caused a transient drop in arterial pressure, while subordination stress caused severe and sustained hypotension with concurrent tachycardia. Transgenic expression of dystrophin or utrophin in skeletal muscle protected mdx mice from scruffing and social stress-induced responses including mortality. INTERPRETATION: We have identified a robust new stress phenotype in the otherwise mildly affected mdx mouse that suggests relatively benign handling may impact the outcome of behavioural experiments, but which should also expedite the knowledge-based therapy development for DMD. FUNDING: Greg Marzolf Jr. Foundation, Summer's Wish Fund, NIAMS, Muscular Dystrophy Association, University of Minnesota and John and Cheri Gunvalson Trust.
Asunto(s)
Distrofina/genética , Trastornos Neurológicos de la Marcha/mortalidad , Insuficiencia Cardíaca/mortalidad , Distrofia Muscular de Duchenne/mortalidad , Estrés Psicológico/mortalidad , Utrofina/genética , Antagonistas Adrenérgicos beta/farmacología , Animales , Presión Arterial/efectos de los fármacos , Modelos Animales de Enfermedad , Distrofina/metabolismo , Trastornos Neurológicos de la Marcha/complicaciones , Trastornos Neurológicos de la Marcha/genética , Trastornos Neurológicos de la Marcha/fisiopatología , Expresión Génica , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipotensión/complicaciones , Hipotensión/genética , Hipotensión/mortalidad , Hipotensión/fisiopatología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Masculino , Metoprolol/farmacología , Ratones , Ratones Endogámicos mdx , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatología , Estrés Psicológico/complicaciones , Estrés Psicológico/genética , Estrés Psicológico/fisiopatología , Análisis de Supervivencia , Taquicardia/complicaciones , Taquicardia/genética , Taquicardia/mortalidad , Taquicardia/fisiopatología , Transgenes , Utrofina/metabolismoRESUMEN
It is increasingly clear that significant differential regulation of pituitary and adrenal gland activation exists, leading to a dissociation of plasma adrenocorticotropic hormone and corticosteroid secretion during fetal, postnatal and adult life. An increasing number of preclinical and clinical studies report dissociation of adrenocorticotropic hormone and cortisol levels in critical illness, inflammation and mental disorders. Mechanisms involve an altered adrenal sensitivity, aberrant receptor expression or modulation of adrenal function by cytokines, vasoactive factors or neuropeptides. The degree of dissociation has been associated with the level of complications of sepsis, surgery, malignant disease and depression. The separation of adrenocorticotropic hormone and corticosteroid secretion is of clinical relevance and should be incorporated into our view on endocrine stress regulation.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Hormona Adrenocorticotrópica/sangre , Animales , Humanos , Hidrocortisona/sangreRESUMEN
The circadian glucocorticoid (GC) rhythm is dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and an adrenal clock that is synchronized by the SCN. To determine whether the adrenal clock modulates GC responses to stress, experiments used female and male Cyp11A1Cre/+::Bmal1Fl/Fl knockout [side-chain cleavage (SCC)-KO] mice, in which the core clock gene, Bmal1, is deleted in all steroidogenic tissues, including the adrenal cortex. Following restraint stress, female and male SCC-KO mice demonstrate augmented plasma corticosterone but not plasma ACTH. In contrast, following submaximal scruff stress, plasma corticosterone was elevated only in female SCC-KO mice. Adrenal sensitivity to ACTH was measured in vitro using acutely dispersed adrenocortical cells. Maximal corticosterone responses to ACTH were elevated in cells from female KO mice without affecting the EC50 response. Neither the maximum nor the EC50 response to ACTH was affected in male cells, indicating that female SCC-KO mice show a stronger adrenal phenotype. Parallel experiments were conducted using female Cyp11B2 (Aldosterone Synthase)Cre/+::Bmal1Fl/Fl mice and adrenal cortex-specific Bmal1-null (Ad-KO) mice. Plasma corticosterone was increased in Ad-KO mice following restraint or scruff stress, and in vitro responses to ACTH were elevated in adrenal cells from Ad-KO mice, replicating data from female SCC-KO mice. Gene analysis showed increased expression of adrenal genes in female SCC-KO mice involved in cell cycle control, cell adhesion-extracellular matrix interaction, and ligand receptor activity that could promote steroid production. These observations underscore a role for adrenal Bmal1 as an attenuator of steroid secretion that is most prominent in female mice.
Asunto(s)
Factores de Transcripción ARNTL/metabolismo , Corteza Suprarrenal/metabolismo , Corticosterona/sangre , Glucocorticoides/metabolismo , Factores de Transcripción ARNTL/genética , Hormona Adrenocorticotrópica , Animales , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Femenino , Genotipo , Masculino , Ratones , Ratones Noqueados , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Factores Sexuales , Estrés FisiológicoRESUMEN
The glucocorticoid (GC) rhythm is entrained to light-dark (LD) cycles via a molecular clock in the suprachiasmatic nucleus (SCN) and is maintained by an adrenal clock synchronized by SCN-dependent signals. Targeted deletion of the core clock gene Bmal1 can disrupt adrenal clock function. The requirement of the adrenal clock to stabilize the circadian GC rhythm during exposure to aberrant LD cycles was determined using novel aldosterone synthase (AS)Cre/+::Bmal1Fl/Fl mice in which Bmal1 deletion occurred during postnatal adrenal transdifferentiation. To examine whether adrenal Bmal1 deletion results in loss of the adrenal clock, mice were crossed with mPER2::Luciferase (mPER2Luc/+) mice. Adrenals from ASCre/+::Bmal1+/+::PER2Luc/+ [control (CTRL)] mice show mPER2Luc rhythms ex vivo, whereas slices from ASCre/+::Bmal1Fl/Fl::PER2Luc/+ [knockout (KO)] mice show dampened rhythms. To monitor corticosterone rhythmicity, mice were implanted with subcutaneous microdialysis probes and sampled at 60-minute intervals for up to 3 days under 12:12-hour [τ (T) 24] LD or 3.5:3.5-hour (T7) LD cycles. Corticosterone rhythms were entrained to T24 LD in CTRL and KO mice. Under T7 LD, circadian corticosterone rhythms persisted in most CTRL mice but not KO mice. Hyperadrenocorticism also was observed in KO mice under T7 LD, reflected by increased corticosterone peak amplitude, total daily corticosterone, and responses to ACTH. Analysis of dysregulated adrenal genes in KO mice exposed to aberrant light identified candidates involved in cholesterol metabolism and trafficking, including steroidogenic acute regulatory protein, which could increase steroidogenesis. Our results show that the adrenal clock functions to buffer steroidogenic responses to aberrant light and stabilize circadian GC rhythmicity.
Asunto(s)
Factores de Transcripción ARNTL/genética , Glándulas Suprarrenales/fisiología , Ritmo Circadiano/fisiología , Citocromo P-450 CYP11B2/genética , Glucocorticoides/metabolismo , Luz/efectos adversos , Proteínas Circadianas Period/genética , Glándulas Suprarrenales/crecimiento & desarrollo , Hormona Adrenocorticotrópica/sangre , Animales , Animales Recién Nacidos , Transdiferenciación Celular/genética , Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/metabolismo , Corticosterona/sangre , Citocromo P-450 CYP11B2/metabolismo , Femenino , Masculino , Ratones , Ratones Noqueados , Proteínas Circadianas Period/metabolismo , Fotoperiodo , Núcleo Supraquiasmático/metabolismoRESUMEN
Sodium appetite can be enhanced by the adrenal steroid aldosterone via an unknown brain mechanism. A novel group of neurons in the nucleus tractus solitarius expresses the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, which makes them selectively responsive to aldosterone. Their activation parallels sodium appetite in different paradigms of salt loss even in the absence of aldosterone. These unique aldosterone target neurons may represent a previously unrecognized central convergence point at which hormonal and neural signals can be integrated to drive sodium appetite.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/análisis , Aldosterona/fisiología , Apetito/fisiología , Hiponatremia/fisiopatología , Neuronas/fisiología , Receptores de Mineralocorticoides/análisis , Sodio en la Dieta , Sodio/deficiencia , Núcleo Solitario/fisiología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/fisiología , Adrenalectomía , Aldosterona/administración & dosificación , Aldosterona/farmacología , Animales , Corticosterona/administración & dosificación , Corticosterona/farmacología , Desoxicorticosterona/farmacología , Dieta Hiposódica/efectos adversos , Diuresis/efectos de los fármacos , Furosemida/farmacología , Furosemida/toxicidad , Genes fos , Hiperaldosteronismo/fisiopatología , Hiponatremia/etiología , Bombas de Infusión Implantables , Masculino , Natriuresis/efectos de los fármacos , Neuronas/clasificación , Neuronas/enzimología , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/fisiología , Sodio en la Dieta/administración & dosificaciónRESUMEN
BACKGROUND: Music is considered an ideal therapy for reducing stress in patients receiving mechanical ventilation. Previous studies of the effect of music on stress in such patients have focused solely on indirect markers of the stress response rather than on serum biomarkers. OBJECTIVE: To explore the influence of music on serum biomarkers of the stress response in patients receiving ventilatory support. METHODS: A convenience sample of 10 patients receiving mechanical ventilation was recruited from an 11-bed medical intensive care unit. Patients were randomly assigned to listen to music or to rest quietly for 60 minutes. Levels of corticotropin, cortisol, epinephrine, and norepinephrine were measured 4 times during the 60 minutes. RESULTS: The levels of the 4 biomarkers of the stress response did not differ significantly between patients who listened to music and patients who rested quietly, though the levels of corticotropin and cortisol showed interesting trends. CONCLUSIONS: Additional research is needed with a larger sample size to evaluate further the influence of music on biochemical markers of the stress response in patients receiving mechanical ventilatory support. In future studies, confounding factors such as endotracheal suctioning and administration of medications that influence the stress response should be controlled for.
Asunto(s)
Musicoterapia , Respiración Artificial/psicología , Estrés Psicológico/terapia , Hormona Adrenocorticotrópica/sangre , Anciano , Biomarcadores/sangre , Epinefrina/sangre , Femenino , Humanos , Hidrocortisona/sangre , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Proyectos Piloto , Estrés Psicológico/sangreRESUMEN
The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoid production, yet it is unclear how the clock responds to acute stress. We hypothesized that stress-induced ACTH provides a signal that phase shifts the adrenal clock. To assess whether acute stress phase shifts the adrenal clock in vivo in a phase-dependent manner, mPER2:LUC mice on a 12:12-h light:dark cycle underwent restraint stress for 15 min or no stress at zeitgeber time (ZT) 2 (early subjective day) or at ZT16 (early subjective night). Adrenal explants from mice stressed at ZT2 showed mPER2:LUC rhythms that were phase-advanced by ~2 h, whereas adrenals from mice stressed at ZT16 showed rhythms that were phase-delayed by ~2 h. The biphasic response was also observed in mice injected subcutaneously either with saline or with ACTH at ZT2 or ZT16. Blockade of the ACTH response with the glucocorticoid, dexamethasone, prevented restraint stress-induced phase shifts in the mPER2:LUC rhythm both at ZT2 and at ZT16. The finding that acute stress results in a phase-dependent shift in the adrenal mPER2:LUC rhythm that can be blocked by dexamethasone indicates that stress-induced effectors, including ACTH, act to phase shift the adrenal clock rhythm.
RESUMEN
Light is a powerful entrainer of circadian clocks in almost all eukaryotic organisms promoting synchronization of internal circadian rhythms with external environmental light-dark (LD) cycles. In mammals, the circadian system is organized in a hierarchical manner, in which a central pacemaker in the suprachiasmatic nucleus (SCN) synchronizes oscillators in peripheral tissues. Recent evidence demonstrates that photoentrainment of the SCN proceeds via signaling from a subpopulation of retinal ganglion cells (RGCs) which are melanopsin-expressing and intrinsically photosensitive (ipRGCs). However, it is still unclear whether photoentrainment of peripheral clocks is mediated exclusively by the ipRGC system or if signaling from RGCs that do not express melanopsin also plays a role. Here we have used genetic "silencing" of ipRGC neurotransmission in mice to investigate whether this photoreceptive system is obligatory for the photoentrainment of peripheral circadian clocks. Genetic silencing of ipRGC neurotransmission in mice was achieved by expression of tetanus toxin light chain in melanopsin-expressing cells (Opn4::TeNT mouse line). Rhythms of the clock gene Period 2 in various peripheral tissues were measured by crossbreeding Opn4::TeNT mice with PER2 luciferase knock-in mice (mPER2Luc). We found that in Opn4::TeNT mice the pupillary light reflex, light modulation of activity, and circadian photoentrainment of locomotor activity were severely impaired. Furthermore, ex vivo cultures from Opn4::TeNT, mPER2Luc mice of the adrenal gland, cornea, lung, liver, pituitary and spleen exhibited robust circadian rhythms of PER2::LUC bioluminescence. However, their peak bioluminescence rhythms were not aligned to the projected LD cycles indicating their lack of photic entrainment in vivo. Finally, we found that the circadian rhythm in adrenal corticosterone in Opn4::TeNT mice, as monitored by in vivo subcutaneous microdialysis, was desynchronized from environmental LD cycles. Our findings reveal a non-redundant role of ipRGCs for photic entrainment of peripheral tissues, highlighting the importance of this photoreceptive system for the organismal adaptation to daily environmental LD cycles.
Asunto(s)
Relojes Circadianos , Células Ganglionares de la Retina/fisiología , Opsinas de Bastones/genética , Toxina Tetánica/metabolismo , Animales , Ritmo Circadiano , Corticosterona/metabolismo , Ratones , Proteínas Circadianas Period/metabolismo , Opsinas de Bastones/metabolismo , Núcleo Supraquiasmático/metabolismoRESUMEN
Genetic predisposition and environmental challenges interact to determine individual vulnerability to obesity and type 2 diabetes. We previously established a mouse model of chronic subordination stress-induced hyperphagia, obesity, metabolic like-syndrome and insulin resistance in the presence of a high-fat diet. However, it remains to be established if social stress could also aggravate glucose intolerance in subjects genetically predisposed to develop obesity and type 2 diabetes. To answer this question, we subjected genetically obese mice due to deficiency of the leptin receptor (db/db strain) to chronic subordination stress. Over five weeks, subordination stress in db/db mice led to persistent hyperphagia, hyperglycemia and exacerbated glucose intolerance altogether suggestive of an aggravated disorder when compared to controls. On the contrary, body weight and fat mass were similarly affected in stressed and control mice likely due to the hyperactivity shown by subordinate mice. Stressed db/db mice also showed increased plasma inflammatory markers. Altogether our results suggest that chronic stress can aggravate glucose intolerance but not obesity in genetically predisposed subjects on the basis of a disrupted leptin circuitry.
RESUMEN
We previously demonstrated that 7-d-old rat pups exposed to hypoxia from birth exhibit ACTH-independent increases in corticosterone associated with an increase in steroidogenic acute regulatory (StAR) and peripheral-type benzodiazepine receptor (PBR) proteins. The purpose of the present study was to determine whether this increase in corticosterone could be attenuated by chemical sympathectomy induced with guanethidine treatment. Rat pups were exposed to normoxia or hypoxia from birth and treated with vehicle or guanethidine and studied at 7 d of age. Hypoxia per se resulted in an increase in plasma corticosterone without a change in plasma ACTH. Guanethidine treatment attenuated the increase in basal corticosterone in hypoxic pups but did not attenuate ACTH-stimulated corticosterone production. This effect was specific as basal and ACTH-stimulated aldosterone was not affected. Guanethidine also attenuated the increase in StAR protein induced by hypoxia. Neither the effect of hypoxia nor that of guanethidine could be explained by changes in the levels of adrenal tyrosine hydroxylase, StAR, or P450scc mRNA, adrenal tyrosine hydroxylase immunohistochemistry, or adrenal catecholamine content. We conclude that chemical sympathectomy normalizes basal corticosterone levels but has no effect on ACTH-stimulated corticosterone levels in 7-d-old rats exposed to hypoxia from birth. The mechanism of the effect of guanethidine to normalize hypoxia-stimulated basal corticosterone remains to be identified, although StAR protein may be an important mediator. This ACTH-independent increase in corticosterone may be a mechanism by which the neonate can increase circulating glucocorticoids necessary for survival while bypassing the hyporesponsiveness of the neonatal hypothalamic-pituitary-adrenal axis.
Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Corticosterona/sangre , Hipoxia/metabolismo , Receptores de GABA-A , Simpatectomía Química , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/sangre , Aldosterona/sangre , Animales , Animales Recién Nacidos , Peso Corporal , Proteínas Portadoras/metabolismo , Catecolaminas/metabolismo , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Femenino , Guanetidina , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de GABA/metabolismo , Renina/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Simpaticolíticos , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
While the orphan nuclear receptor steroidogenic factor-1 (SF-1) has been shown to function as an induction factor to define adrenocortical cell lineage, it remains unclear whether SF-1 plays an additional role as a growth promoting agent in the adult adrenal cortex. The proliferative potential of the adrenal cortex in adult SF-1(+/-) mice was examined using the model of compensatory adrenal growth following unilateral adrenalectomy (uADX). While the right adrenal gland of wild-type (wt) mice grew significantly after uADX, the adrenal of SF-1(+/-) mice exhibited a blunted, statistically nonsignificant weight increase. Accordingly, a profound increase in the proliferation marker proliferating cell nuclear antigen could be detected only in wt mice after uADX but not in the SF-1(+/-) mice. The proposed key regulator in adrenal compensatory growth, the recently cloned adrenal secretory serine protease was up-regulated in the remaining adrenal of wt mice, whereas this increase was blunted in SF-1(+/-) mice. While no differences in preadipocyte factor-1, the presumed marker of primitive adrenocortical cells, were detectable in the adrenals of wt and SF-1(+/-) mice, an increase in the ACTH receptor as well as agouti-related protein was observed only in wt animals but not in the SF-1(+/-) mice following uADX. Taken together, these results reflect a primary inability of adrenal cortical cells of SF-1(+/-) mice to undergo compensatory adrenal growth in response to uADX.
Asunto(s)
Glándulas Suprarrenales/crecimiento & desarrollo , Adrenalectomía , Proteínas de Unión al ADN/fisiología , Proteínas , Factores de Transcripción/fisiología , Glándulas Suprarrenales/inervación , Hormona Adrenocorticotrópica/sangre , Proteína Relacionada con Agouti , Animales , Proteínas de Unión al Calcio , Corticosterona/sangre , Proteínas de Unión al ADN/análisis , Factores de Transcripción Fushi Tarazu , Proteínas de Homeodominio , Péptidos y Proteínas de Señalización Intercelular , Masculino , Proteínas de la Membrana/análisis , Ratones , Ratones Endogámicos DBA , Antígeno Nuclear de Célula en Proliferación/análisis , Biosíntesis de Proteínas , ARN Mensajero/análisis , Receptores de Corticotropina/biosíntesis , Receptores Citoplasmáticos y Nucleares , Proteínas Represoras/análisis , Serina Endopeptidasas/genética , Factor Esteroidogénico 1 , Factores de Transcripción/análisis , Núcleo Hipotalámico Ventromedial/fisiologíaRESUMEN
Pituitary-derived factors, including ACTH, have been widely implicated in initiating adrenal regeneration. However, recent work has demonstrated that adrenal regeneration is also modulated by adrenal nerves that extensively reinnervate the regenerating adrenal. Moreover, transection of the splanchnic nerve removes sensory calcitonin gene-related peptide (CGRP) and preganglionic sympathetic vesicular acetylcholine transporter (VAChT)-positive fibers from the regenerating gland and delays regeneration. However, it is not known whether the splanchnic nerve effects on adrenal regeneration are mediated by the CGRP-positive or VAChT-positive innervation. The present studies use the drug capsaicin, a neurotoxin selective for a subset of primary afferent neurons, to specifically remove CGRP-positive fibers from the adrenal gland and assess subsequent effects on the recovery of adrenal mass and function after surgical enucleation. Male, Sprague-Dawley rats were anesthetized and treated with capsaicin (vs. vehicle) periaxonally to the thoracic splanchnic nerve (33 mM, 15 minutes) or systemically (30-100 mg/kg for 4 days, s.c.). After 7-12 days of recovery, rats received right adrenalectomy and left adrenal enucleation. At 14 and 21 days postenucleation, prestress and poststress plasma and adrenals glands were collected; adrenals were weighed and fixed for immunolabeling of CGRP-positive nerve fibers. Periaxonal capsaicin treatment decreased adrenal CGRP content prior to surgical enucleation; however, reinnervation by CGRP-positive fibers was not prevented and regeneration was not affected. Systemic capsaicin treatment attenuated the reinnervation by CGRP-positive fibers and increased the rate, but not extent, of adrenal regeneration. These results support the hypothesis that adrenal innervation represents an extra-ACTH mechanism to modulate the rate of adrenal regeneration.
Asunto(s)
Glándulas Suprarrenales/inervación , Glándulas Suprarrenales/fisiología , Hormona Adrenocorticotrópica/fisiología , Capsaicina/farmacología , Proteínas de Transporte de Membrana , Neuronas Aferentes/fisiología , Regeneración , Proteínas de Transporte Vesicular , Animales , Péptido Relacionado con Gen de Calcitonina/análisis , Proteínas Portadoras/análisis , Masculino , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte Vesicular de AcetilcolinaRESUMEN
Several aspects of behavior and physiology, such as sleep and wakefulness, blood pressure, body temperature, and hormone secretion exhibit daily oscillations known as circadian rhythms. These circadian rhythms are orchestrated by an intrinsic biological clock in the suprachiasmatic nuclei (SCN) of the hypothalamus which is adjusted to the daily environmental cycles of day and night by the process of photoentrainment. In mammals, the neuronal signal for photoentrainment arises from a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that send a direct projection to the SCN. ipRGCs also mediate other non-image-forming (NIF) visual responses such as negative masking of locomotor activity by light, and the pupillary light reflex (PLR) via co-release of neurotransmitters glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from their synaptic terminals. The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved. We investigated the role of glutamatergic neurotransmission for circadian photoentrainment and NIF behaviors by selective ablation of ipRGC glutamatergic synaptic transmission in mice. Mutant mice displayed delayed re-entrainment to a 6 h phase shift (advance or delay) in the light cycle and incomplete photoentrainment in a symmetrical skeleton photoperiod regimen (1 h light pulses between 11 h dark periods). Circadian rhythmicity in constant darkness also was reduced in some mutant mice. Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated. Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.
Asunto(s)
Ritmo Circadiano/efectos de la radiación , Ácido Glutámico/metabolismo , Fototransducción/efectos de la radiación , Luz , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/efectos de la radiación , Animales , Técnicas de Inactivación de Genes , Ratones Noqueados , Enmascaramiento Perceptual/fisiología , Fotoperiodo , Reflejo Pupilar/efectos de la radiación , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Hormone secretion from endocrine glands constitutes a primary component of homeostatic control systems that defend whole body tissue viability and function. Endocrine organ secretion is controlled by efferent mechanisms that consist of both hormonal and neural elements. Anatomical evidence for dual control has led to increased understanding of how autonomic neural activity modulates functional sensitivity to hormonal input. The clinical relevance of autonomic-endocrine interactions is illustrated by examining functional control of the adrenal cortex and the ovary, two tissues that require tropic support from the anterior pituitary and receive sympathetic neural input. Extrapituitary mechanisms of adrenal cortical control including sympathetic neural activity have been implicated in controlling the amplitude of the cortisol awakening response (CAR), a diagnostic index of hypothalamic-pituitary-adrenal activity in humans. In addition, increases in sympathetic neural tone have been implicated in polycystic ovary syndrome (PCOS), a leading cause of female infertility. These examples offer strong evidence for the capability of autonomic neural activity to alter the functional sensitivity of endocrine glands. This interaction has significant clinical relevance and needs to be incorporated into our view in assessing endocrine organ function and dysfunction.