RESUMEN
BACKGROUND: The pathophysiology of vasovagal syncope is poorly understood, and the treatment usually ineffective. Our clinical experience is that patients with vasovagal syncope fall into 2 groups, based on their supine systolic blood pressure, which is either normal (>100 mm Hg) or low (70-100 mm Hg). We investigated neural circulatory control in these 2 phenotypes. METHODS AND RESULTS: Sympathetic nervous testing was at 3 levels: electric, measuring sympathetic nerve firing (microneurography); neurochemical, quantifying norepinephrine spillover to plasma; and cellular, with Western blot analysis of sympathetic nerve proteins. Testing was done during head-up tilt (HUT), simulating the gravitational stress of standing, in 18 healthy control subjects and 36 patients with vasovagal syncope, 15 with the low blood pressure phenotype and 21 with normal blood pressure. Microneurography and norepinephrine spillover increased significantly during HUT in healthy subjects. The microneurography response during HUT was normal in normal blood pressure and accentuated in low blood pressure phenotype (P=0.05). Norepinephrine spillover response was paradoxically subnormal during HUT in both patient groups (P=0.001), who thus exhibited disjunction between nerve firing and neurotransmitter release; this lowered norepinephrine availability, impairing the neural circulatory response. Subnormal norepinephrine spillover in low blood pressure phenotype was linked to low tyrosine hydroxylase (43.7% normal, P=0.001), rate-limiting in norepinephrine synthesis, and in normal blood pressure to increased levels of the norepinephrine transporter (135% normal, P=0.019), augmenting transmitter reuptake. CONCLUSIONS: Patients with recurrent vasovagal syncope, when phenotyped into 2 clinical groups based on their supine blood pressure, show unique sympathetic nervous system abnormalities. It is predicted that future therapy targeting the specific mechanisms identified in the present report should translate into more effective treatment.
Asunto(s)
Fenotipo , Sistema Nervioso Simpático/fisiopatología , Síncope Vasovagal/fisiopatología , Adulto , Presión Sanguínea/fisiología , Estudios de Casos y Controles , Dinamina I/metabolismo , Femenino , Humanos , Masculino , Norepinefrina/sangre , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Recurrencia , Sistema Nervioso Simpático/metabolismo , Síncope Vasovagal/sangre , Síncope Vasovagal/epidemiología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
OBJECTIVE: Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function. RESEARCH DESIGN AND METHODS: Untreated men and women (mean age 55 +/- 1 year; BMI 32.3 +/- 0.5 kg/m(2)) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks. RESULTS: Body weight decreased by -7.1 +/- 0.6 and -8.4 +/- 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 +/- 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by -96 +/- 30 and -101 +/- 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by -12 +/- 6 and -19 +/- 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups. CONCLUSIONS: The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.
Asunto(s)
Aclimatación/fisiología , Dieta Reductora , Ejercicio Físico , Estilo de Vida , Síndrome Metabólico/complicaciones , Obesidad/rehabilitación , Sistema Nervioso Simpático/fisiopatología , Aerobiosis , Presión Sanguínea , Tamaño Corporal , Peso Corporal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Norepinefrina/metabolismo , Obesidad/complicaciones , Obesidad/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: The purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted. RESEARCH DESIGN AND METHODS: Thirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 +/- 1 years (mean +/- SE) with BMI 31.6 +/- 0.6 kg/m2, who fulfilled the Adult Treatment Panel III criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program. RESULTS: Body weight decreased by 8.1 +/- 0.9 and 8.4 +/- 1.1 kg and resting norepinephrine spillover by 94 +/- 31 and 166 +/- 58 ng/min (all P < or = 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged -3 +/- 25 versus 73 +/- 24 ng/min at 30 min (P = 0.039), 36 +/- 21 versus 115 +/- 28 ng/min at 60 min (P = 0.045), 9 +/- 21 versus 179 +/- 50 ng/min at 90 min (P < 0.001), and 40 +/- 48 versus 106 +/- 39 ng/min at 120 min (P = 0.24). CONCLUSIONS: Weight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis.
Asunto(s)
Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Síndrome Metabólico/prevención & control , Síndrome Metabólico/fisiopatología , Obesidad/prevención & control , Obesidad/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Pérdida de Peso/fisiología , Glucemia/metabolismo , Presión Sanguínea , Ingestión de Energía , Epinefrina/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Hemodinámica/fisiología , Humanos , Pierna/irrigación sanguínea , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Obesidad/complicaciones , Posmenopausia , Flujo Sanguíneo RegionalRESUMEN
BACKGROUND: Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese. OBJECTIVE: The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose. DESIGN: Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load. RESULTS: IR subjects had a higher insulin area under the curve from 0 to 120 min (AUC(0-120): 13,468 +/- 677 compared with 6399 +/- 612 mU/L . min; P < 0.001), glucose AUC(0-120) (P < 0.05), and resting MSNA (41 +/- 3 compared with 31 +/- 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 +/- 7% and 40 +/- 13%, respectively; P < or = 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC(0-120) were independent (inverse) predictors of the SNS response. CONCLUSIONS: IR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.
Asunto(s)
Glucemia/metabolismo , Glucosa/farmacología , Síndrome Metabólico/fisiopatología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/inervación , Obesidad/fisiopatología , Sistema Nervioso Simpático/fisiología , Área Bajo la Curva , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Estudios de Casos y Controles , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Infusiones Intravenosas , Insulina/sangre , Resistencia a la Insulina , Pierna/irrigación sanguínea , Pierna/inervación , Masculino , Tasa de Depuración Metabólica , Síndrome Metabólico/sangre , Persona de Mediana Edad , Norepinefrina/metabolismo , Norepinefrina/farmacocinética , Obesidad/sangre , Flujo Sanguíneo Regional/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Leptin plays a key role in the regulation of body weight through the sympathetic nervous system; however, the contributions of leptin-receptor polymorphisms to obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between leptin-receptor polymorphisms, plasma leptin and whole-body norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.4-39.5 kg/m(2)), we measured leptin-receptor polymorphisms (Gln223Arg, Lys656Asn, and Lys109Arg), plasma leptin levels, whole-body NE spillover, whole-body NE clearance, BMI and blood pressure (BP) levels in the supine position after overnight fasting. Overweight-obese (BMI>or=25 kg/m(2)) subjects had significantly greater BMI, BP levels, plasma leptin and whole-body NE spillover compared to lean (BMI<25 kg/m(2)) subjects, but the NE clearance was similar. Overweight-obese subjects had significantly higher frequencies of the Arg223 allele and the Arg223 homozygous allele of Gln223Arg and the Asn656 allele of Lys656Asn compared to lean subjects. Subjects carrying the Arg223 homozygous or the Asn656 allele had higher levels of plasma leptin, BMI, waist circumference, and waist-to-hip ratio, but significantly less whole-body NE spillover, especially when they were also overweight-obese. BP levels and whole-body NE clearance were similar between subjects with and without the Arg223 homozygous or Asn656 allele. No differences were found in the distributions of the Arg109 allele of Lys109Arg polymorphism between nonobese and overweight-obese subjects. In addition, BMI, BP, plasma leptin levels, whole-body NE spillover and whole-body NE clearance were similar between those with and without the Arg109 allele. Together, these findings demonstrate that leptin-receptor polymorphisms were related to the incidence of obesity in a Caucasian male population. These polymorphisms were accompanied by high plasma leptin levels (leptin resistance) and lower whole-body plasma NE spillover (blunted sympathetic nerve activity). We therefore hypothesize that leptin-receptor play a role in the development of obesity through leptin resistance and blunted leptin-mediated sympathetic nerve activity.
Asunto(s)
Leptina/fisiología , Obesidad/fisiopatología , Polimorfismo Genético , Receptores de Leptina/genética , Sistema Nervioso Simpático/fisiopatología , Adulto , Alelos , Presión Sanguínea , Índice de Masa Corporal , Humanos , Masculino , Persona de Mediana Edad , Obesidad/genética , Población BlancaRESUMEN
CONTEXT: The biological basis for the development of major depressive disorder (MDD) remains incompletely understood. OBJECTIVE: To quantify brain serotonin (5-hydroxytryptamine [5-HT]) turnover in patients with MDD. DESIGN: Patients with depression were studied both untreated and during administration of a selective serotonin reuptake inhibitor (SSRI) in an unblinded study of sequential design. Healthy volunteers were examined on only 1 occasion. Direct internal jugular venous blood sampling was used to directly quantify brain serotonin turnover. The effect of serotonin transporter (5-HTT) genotype on brain serotonin turnover was evaluated and the influence of SSRI therapy on serotonin turnover was investigated. SETTING: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the research catheterization laboratory of a major training hospital and medical research institute. PARTICIPANTS: Studies were performed in 21 patients fulfilling the DSM-IV and International Statistical Classification of Diseases, 10th Revision diagnostic criteria for MDD and in 40 healthy volunteers. INTERVENTIONS: Treatment for patients consisted of SSRI administration for approximately 12 weeks. MAIN OUTCOME MEASURES: Brain serotonin turnover before and after SSRI therapy. RESULTS: Brain serotonin turnover was significantly elevated in unmedicated patients with MDD compared with healthy subjects (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 4.4 [4.3] vs 1.6 [2.4] nmol/L, respectively; P = .003). Analysis of the influence of the 5-HTT genotype in MDD indicated that carriage of the s allele compared with the l allele was associated with greater than a 2-fold increase in brain serotonin turnover (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.5 [4.7] vs 2.7 [2.9] nmol/L, respectively; P = .04). Following SSRI therapy, brain serotonin turnover was substantially reduced (mean [SD] internal jugular venoarterial 5-hydroxyindoleacetic acid plasma concentration difference, 6.0 [4.0] nmol/L prior to treatment vs 2.0 [3.3] nmol/L following therapy; P = .008). CONCLUSIONS: Brain serotonin turnover is elevated in unmedicated patients with MDD and is influenced by the 5-HTT genotype. The marked reduction in serotonin turnover following SSRI treatment and the accompanying improvement in symptoms suggest that high brain serotonin turnover may be a biological substrate of MDD.
Asunto(s)
Encéfalo/metabolismo , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Serotonina/metabolismo , Adulto , Estudios de Casos y Controles , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Serotonina/genética , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
BACKGROUND: Evidence exists linking major depressive disorder (MDD) with clinical cardiovascular events. The importance of the sympathetic nervous system in the generation of cardiac risk in other contexts is established. OBJECTIVE: To examine the importance of the sympathetic nervous system in the generation of cardiac risk in patients with major depressive disorder (MDD). METHODS: Studies were performed in 39 patients meeting the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for MDD and in 76 healthy subjects. Treatment for patients consisted of selective serotonin reuptake inhibition (SSRI) for 12 weeks. Whole body and cardiac sympathetic activity were examined using noradrenaline isotope dilution methodology and sympathetic nerve recording techniques. Measurement of the extraction of infused tritiated noradrenaline by the heart, and estimation of cardiac dihydroxyphenylglycol production provided direct quantification of neuronal noradrenaline reuptake. RESULTS: Sympathetic activity, particularly in the heart and for the whole body, in patients with MDD followed a bimodal distribution. Elevated values were observed in patients with co-morbid panic disorder (P = 0.006). Consistent with a defect in noradrenaline reuptake, the cardiac extraction of tritiated noradrenaline (0.80 +/- 0.01 versus 0.56 +/- 0.04%, P < 0.001) and cardiac dihydroxyphenylglycol overflow (109 +/- 8 versus 73 +/- 11, P = 0.01) were reduced in patients with MDD. SSRI therapy abolished the excessive sympathetic activation, with whole body noradrenaline spillover falling from 518 +/- 83 to 290 +/- 41 ng/min (P = 0.008). CONCLUSIONS: We have identified a subset of patients with MDD in whom sympathetic nervous activity is extraordinarily high, including in the sympathetic outflow to the heart. Treatment with an SSRI may reduce sympathetic activity in a manner likely to reduce cardiac risk.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Trastorno Depresivo Mayor/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Adulto , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Estudios de Casos y Controles , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Femenino , Corazón/inervación , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Trastorno de Pánico/complicaciones , Trastorno de Pánico/fisiopatología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.
Asunto(s)
Encéfalo/efectos de los fármacos , Citalopram/uso terapéutico , Ácido Hidroxiindolacético/metabolismo , Trastorno de Pánico/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Serotonina/metabolismo , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Casos y Controles , Cateterismo Venoso Central , Cateterismo Periférico , Circulación Cerebrovascular , Citalopram/farmacología , Genotipo , Humanos , Ácido Hidroxiindolacético/sangre , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/metabolismo , Persona de Mediana Edad , Norepinefrina/metabolismo , Trastorno de Pánico/sangre , Trastorno de Pánico/diagnóstico por imagen , Trastorno de Pánico/metabolismo , Trastorno de Pánico/fisiopatología , Proyectos de Investigación , Serotonina/sangre , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Índice de Severidad de la Enfermedad , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
The link between the human sympathoadrenalmedullary system and the adipocyte hormone leptin is controversial. We measured total and regional norepinephrine spillover, epinephrine secretion rate, and extra-adipocyte leptin release in 22 lean [body mass index (BMI) < 26] and 20 obese (BMI > 28) normotensive men who underwent arterial and central venous catheterization. Because plasma clearance of leptin is primarily by renal removal, for men at steady state we could estimate whole body leptin release to plasma from renal plasma leptin extraction. Whole body leptin release was 1,950 +/- 643 (means +/- SE) ng/min in obese men and 382 +/- 124 ng/min in lean men (P < 0.05). Total and renal norepinephrine spillover rates correlated directly with whole body leptin secretion rate. Leptin is released from multiple nonadipocyte sites, which we tested by use of simultaneous arteriovenous blood sampling. We found a surprisingly large contribution of brain leptin release to the plasma leptin pool, 529 +/- 175 ng/min (> 40% whole body leptin release), with greater leptin release in obese than in lean men, 935 +/- 321 vs. 160 +/- 59 ng/min (P = 0.045). In parallel with leptin measurements, we also quantified brain serotonin turnover and jugular overflow of neuropeptide Y (NPY). Brain serotonin turnover was higher in obese than in lean men, 227 +/- 112 vs. 21 +/- 14 ng/min (P = 0.019), as was overflow of NPY from the brain, 12.9 +/- 1.4 vs. 5.3 +/- 2.2 ng/min (P = 0.042). These results suggest that leptin is released within the brain and at an increased rate in obese humans, in whom activation of brain serotonergic and NPY mechanisms also exists.