Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 67
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Ann Oncol ; 29(12): 2363-2370, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30307529

RESUMEN

Background: Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.


Asunto(s)
Linfoma de Células B Grandes Difuso/mortalidad , Transcriptoma/genética , Microambiente Tumoral/genética , Adulto , Anciano , Algoritmos , Biopsia , Análisis por Conglomerados , Estudios de Cohortes , Biología Computacional , Conjuntos de Datos como Asunto , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Adhesión en Parafina , Valor Predictivo de las Pruebas , Pronóstico , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Reproducibilidad de los Resultados , Análisis de Supervivencia , Adulto Joven
5.
J R Army Med Corps ; 161(3): 200-5, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26253125

RESUMEN

Hypertension and hypertension-related diseases are a leading cause of morbidity and mortality worldwide. A diagnosis of hypertension can have serious occupational implications for military personnel. This article examines the diagnosis and management of hypertension in military personnel, in the context of current international standards. We consider the consequences of hypertension in the military environment and potential military-specific issues relating to hypertension.


Asunto(s)
Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Personal Militar , Adulto , Electrocardiografía , Humanos , Hipertensión/etiología , Hipertensión/fisiopatología , Masculino , Guías de Práctica Clínica como Asunto
8.
Exp Physiol ; 96(11): 1118-1128, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21824998

RESUMEN

Regular physical exercise reduces the risk of cardiovascular disease and improves outcome in patients with cardiovascular diseases. The dynamic changes in blood pressure and heart rate with acute exercise are independently predictive of prognosis. Quantification of the haemodynamic response to exercise training in genetically modified mouse models may provide insight into the molecular mechanisms underlying the beneficial effects of exercise. We describe, for the first time, the use of radiotelemetry to provide continuous blood pressure monitoring in C57BL/6J mice during a programme of voluntary wheel exercise with continuous simultaneous recording and analysis of wheel rotations and beat-by-beat haemodynamic parameters. We define distinct haemodynamic profiles at rest, during normal cage activity and during episodes of voluntary wheel running. We show that whilst cage activity is associated with significant rises both in blood pressure and in heart rate, voluntary wheel running leads to a further substantial rise in heart rate with only a small increment in blood pressure. With 5 weeks of chronic exercise training, resting heart rate progressively falls, but heart rate during episodes of wheel running initially increases. In contrast, there are minimal changes in blood pressure in response to chronic exercise training. Finally, we have quantified the acute changes in heart rate at the onset of and recovery from individual episodes of wheel running, revealing that changes in heart rate are extremely rapid and that the peak rate of change of heart rate increases with chronic exercise training. The results of this study have important implications for the use of genetically modified mouse models to investigate the beneficial haemodynamic effects of chronic exercise on blood pressure and cardiovascular diseases.


Asunto(s)
Frecuencia Cardíaca/fisiología , Hemodinámica/fisiología , Condicionamiento Físico Animal/fisiología , Animales , Presión Sanguínea/fisiología , Ratones , Ratones Endogámicos C57BL , Monitoreo Fisiológico , Actividad Motora , Carrera , Telemetría
10.
Am J Physiol Heart Circ Physiol ; 299(4): H1045-63, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20656884

RESUMEN

Mathematical modeling of Ca(2+) dynamics in the heart has the potential to provide an integrated understanding of Ca(2+)-handling mechanisms. However, many previous published models used heterogeneous experimental data sources from a variety of animals and temperatures to characterize model parameters and motivate model equations. This methodology limits the direct comparison of these models with any particular experimental data set. To directly address this issue, in this study, we present a biophysically based model of Ca(2+) dynamics directly fitted to experimental data collected in left ventricular myocytes isolated from the C57BL/6 mouse, the most commonly used genetic background for genetically modified mice in studies of heart diseases. This Ca(2+) dynamics model was then integrated into an existing mouse cardiac electrophysiology model, which was reparameterized using experimental data recorded at consistent and physiological temperatures. The model was validated against the experimentally observed frequency response of Ca(2+) dynamics, action potential shape, dependence of action potential duration on cycle length, and electrical restitution. Using this framework, the implications of cardiac Na(+)/Ca(2+) exchanger (NCX) overexpression in transgenic mice were investigated. These simulations showed that heterozygous overexpression of the canine cardiac NCX increases intracellular Ca(2+) concentration transient magnitude and sarcoplasmic reticulum Ca(2+) loading, in agreement with experimental observations, whereas acute overexpression of the murine cardiac NCX results in a significant loss of Ca(2+) from the cell and, hence, depressed sarcoplasmic reticulum Ca(2+) load and intracellular Ca(2+) concentration transient magnitude. From this analysis, we conclude that these differences are primarily due to the presence of allosteric regulation in the canine cardiac NCX, which has not been observed experimentally in the wild-type mouse heart.


Asunto(s)
Fenómenos Biofísicos/fisiología , Ventrículos Cardíacos/metabolismo , Modelos Teóricos , Miocitos Cardíacos/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Potenciales de Acción/fisiología , Animales , Calcio/metabolismo , Perros , Ventrículos Cardíacos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , Miocitos Cardíacos/citología , Técnicas de Placa-Clamp , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Reproducibilidad de los Resultados , Retículo Sarcoplasmático/metabolismo , Intercambiador de Sodio-Calcio/genética
11.
Eur Respir J ; 32(6): 1488-96, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18653654

RESUMEN

Obstructive sleep apnoea syndrome (OSAS) has been associated with hypertension, stroke and myocardial ischaemia in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on established risk factors for cardiovascular disease remains incompletely understood. A total of 102 males with moderate-to-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 51) CPAP treatment for 4 weeks to investigate the effects of active treatment on 24-h urinary catecholamine excretion, baroreflex sensitivity (BRS), arterial stiffness (augmentation index) and 24-h ambulatory blood pressure (ABP). After 4 weeks of therapeutic CPAP, significant reductions were seen in urine normetanephrine excretion (from mean+/-sd 179.7+/-80.1 to 132.7+/-46.5 micromol x mol(-1) creatinine) and augmentation index (from 14.5+/-11.3 to 9.1+/-13.8%) compared with the subtherapeutic control group. Furthermore, therapeutic CPAP significantly improved BRS (from 7.1+/-3.3 to 8.8+/-4.2 ms x mmHg(-1)) and reduced mean arterial ABP by 2.6+/-5.4 mmHg. In conclusion, treatment of obstructive sleep apnoea with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness and by increasing sensitivity of the arterial baroreflex.


Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Presión de las Vías Aéreas Positiva Contínua/efectos adversos , Apnea Obstructiva del Sueño/fisiopatología , Adulto , Anciano , Barorreflejo , Presión Sanguínea , Enfermedades Cardiovasculares/complicaciones , Catecolaminas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Normetanefrina/metabolismo , Factores de Riesgo , Sueño , Apnea Obstructiva del Sueño/complicaciones , Resultado del Tratamiento
13.
Circ Res ; 92(5): e52-9, 2003 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-12623875

RESUMEN

A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.


Asunto(s)
Calcio/metabolismo , Contracción Miocárdica , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/fisiología , Óxido Nítrico Sintasa/fisiología , Ornitina/análogos & derivados , Animales , Calcio/análisis , Canales de Calcio/fisiología , Conductividad Eléctrica , Inhibidores Enzimáticos/farmacología , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/enzimología , Ratones , Ratones Noqueados , Miocardio/enzimología , Miocardio/metabolismo , Miocitos Cardíacos/citología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo I , Ornitina/farmacología , Técnicas de Placa-Clamp , Retículo Sarcoplasmático/química , Retículo Sarcoplasmático/enzimología , Función Ventricular
14.
Cardiovasc Res ; 67(4): 613-23, 2005 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-15936740

RESUMEN

OBJECTIVE: Cardiac parasympathetic nerve activity is reduced in most cardiovascular disease states, and this may contribute to enhanced cardiac sympathetic responsiveness. Disruption of inhibitory G-proteins (Gi) ablates the cholinergic pathway and increases cardiac endothelial nitric oxide (NO) synthase (eNOS) expression, suggesting that NO may offset the impaired attenuation of beta-adrenergic regulation of supraventricular excitability. To test this, we investigated the role of endogenous NO production on beta-adrenergic regulation of rate (HR), contraction (CR) and calcium (Ca2+) handling in atria following blockade of Gi-coupled muscarinic receptors. METHODS: Mice were administered pertussis toxin (PTx, n=105) or saline (C, n=100) intraperitoneally. After 3 days, we measured CR, HR, and NOS protein levels in isolated atria. Intracellular calcium (Ca2+) transients and Ca2+ current density (I(Ca)) were also measured in atrial myocytes. RESULTS: PTx treatment increased atrial myocyte eNOS protein levels compared to C (P<0.05). This did not affect basal atrial function but was associated with a significant reduction in the CR and HR response to isoprenaline (ISO) compared with C. NOS inhibition normalized responses in PTx atria with respect to responses in C atria (P<0.05), which were unaffected. Furthermore, PTx did not affect ISO-stimulated HR and CR in eNOS gene knockout mice (n=40). In agreement with these findings, the ISO-mediated increase in Ca2+ transient was suppressed in PTx-treated myocytes (P<0.05), whereas I(Ca) did not differ between groups. CONCLUSION: eNOS-derived NO inhibits beta-adrenergic responses following disruption of Gi signaling. This suggests that increased eNOS expression may be a compensatory mechanism which reduces beta-adrenergic regulation of heart rate when cardiac parasympathetic control is impaired.


Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/antagonistas & inhibidores , Isoproterenol/farmacología , Miocitos Cardíacos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Toxina del Pertussis/farmacología , Animales , Western Blotting/métodos , Calcio/metabolismo , Canales de Calcio/metabolismo , Caveolina 3/metabolismo , Expresión Génica/efectos de los fármacos , Atrios Cardíacos , Inmunohistoquímica/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Óxido Nítrico/metabolismo , Técnicas de Placa-Clamp , Transducción de Señal/efectos de los fármacos
15.
Blood Cancer J ; 6: e425, 2016 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-27176801

RESUMEN

An update at 7 years was conceived for our multicenter phase II study in which 55 elderly high-risk untreated diffuse large B-cell lymphoma patients were treated with (90)Y-ibritumomab tiuxetan after a short course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) as long-term follow-up analyses of this combined therapeutic modality are lacking. The overall response rate to the entire regimen was 80%, including 73% (40/55) of complete response (CR) rate and 7% (4/55) of partial response rate. At the time of writing, 24/55 (43.6%) patients experienced a progression disease and 20 of 40 (50%) patients who obtained a CR are still alive in continuous CR. With a median follow-up of 7 years, the disease-free survival was 43.3% and the progression-free survival was 36.1%. The overall survival at 7.9 years was 38.9% (27 deaths mainly because of lymphoma). Two patients developed secondary hematological malignancies, an acute myeloid leukemia and a myelodysplastic syndrome, at 4 and 3 years from radioimmunotherapy, respectively. Our data confirm the feasibility, efficacy and safety of four cycles of R-CHOP followed by radioimmunotherapy consolidation even in the long term: this combination allows dispensing less chemotherapy in a frail group of patients without invalidating response quality and duration.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/terapia , Radioisótopos de Itrio/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Combinada , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Prednisona/uso terapéutico , Radioinmunoterapia , Rituximab , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéutico , Radioisótopos de Itrio/administración & dosificación
16.
Circulation ; 101(23): 2716-20, 2000 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-10851209

RESUMEN

BACKGROUND: Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis. METHODS AND RESULTS: Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by (31)phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9+/-1.4 to 13.4+/-1.8 minutes (P<0.0001) with the right forearm and from 5.7+/-0.4 to 7.6+/-0.9 minutes (P<0.05) with the left (P<0.05 for the interaction between treatment and side). Right forearm blood flow at rest was 66% higher (P<0.01) after right TST, but this difference decreased as the exercise progressed. After right TST, a significant reduction occurred in muscle acidification and phosphocreatine depletion during ipsilateral forearm exercise. This was associated with a significantly reduced mean arterial pressure response to right handgrip, whereas the pressor response to left handgrip did not change. CONCLUSIONS: Sympathetic denervation of the upper limb significantly improves forearm skeletal muscle bioenergetics and exercise performance in patients with idiopathic palmar hyperhidrosis.


Asunto(s)
Metabolismo Energético , Contracción Muscular/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/metabolismo , Simpatectomía , Adulto , Femenino , Antebrazo/irrigación sanguínea , Antebrazo/fisiología , Fuerza de la Mano/fisiología , Insuficiencia Cardíaca/metabolismo , Humanos , Hiperhidrosis/cirugía , Espectroscopía de Resonancia Magnética , Masculino , Músculo Esquelético/irrigación sanguínea , Isótopos de Fósforo , Esfuerzo Físico/fisiología , Flujo Sanguíneo Regional , Descanso/fisiología , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/cirugía
17.
Cardiovasc Res ; 43(3): 712-20, 1999 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-10690342

RESUMEN

UNLABELLED: We have recently shown that exogenous nitric oxide (NO) elicits a positive chronotropic response by stimulating the hyperpolarization activated current, I(f). OBJECTIVE: To examine whether L-arginine (L-Arg) can mimic the chronotropic effect of NO by enhancing its endogenous production. METHODS: In spontaneously beating guinea pig atria we evaluated the heart rate (HR) response to increasing concentrations of L-Arg (1 mumol/l to 10 mmol/l), and compared it with that for D-Arg or L-lysine (L-Lys) (all in free base (FB) or hydrochloride (HCl) formulation). RESULTS: L-ArgFB > 100 mumol/l caused a reversible dose-dependent increase in HR (peak effect +64 +/- 7 bpm at 10 mmol/l, P < 0.05, n = 8). However, a similar HR response occurred with D-ArgFB (n = 7) or L-LysFB (n = 6). All FB formulations increased the perfusate pH (peak [pH]o = 8.61 +/- 0.03). Although alkalinization can stimulate NO release from the endothelium, this is unlikely to have contributed to HR changes in our preparation, since neither NG-methyl-L-arginine, (100-500 mumol/l, which per se reduced HR by 8 +/- 1%, P < 0.05, n = 9) nor NO scavenging (fresh 5% red blood cells, n = 9) caused a rightward shift of the concentration-response curve to L-ArgFB. Furthermore, as opposed to FB formulations, L-ArgHCl, D-ArgHCl or L-LysHCl > 1 mmol/l significantly decreased HR and [pH]o (n = 17). The chronotropic effects of L-ArFB or L-ArgHCl were reproduced by changing [pH]o with NaOH (n = 8) or HCl (n = 7), whereas the HR increase with L-ArgFB was prevented by clamping [pH]o at 7.42 +/- 0.07 (n = 10). CONCLUSIONS: In vitro, L-Arg can markedly affect HR through a pH-mediated, NO-independent mechanism. Our data show that the opposing changes in [pH]o induced by different formulations of L-Arg can importantly confound the assessment of the biological effects of this amino acid.


Asunto(s)
Arginina/farmacología , Espacio Extracelular/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos , Eritrocitos/metabolismo , Cobayas , Concentración de Iones de Hidrógeno , Isomerismo , Lisina/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Perfusión , Estimulación Química , omega-N-Metilarginina/farmacología
18.
Cardiovasc Res ; 47(1): 90-8, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10869534

RESUMEN

OBJECTIVES: We tested the hypothesis that the attenuated heart rate (HR) response to sympathetic activation following swim training in the guinea pig (Cavia porcellus) results from a peripheral modulation of pacemaking by nitric oxide (NO). METHODS: Nitric oxide synthase (NOS) inhibition on the increase in heart rate with sympathetic nerve stimulation (SNS) was investigated in the isolated guinea pig double atrial/right stellate ganglion preparation from exercise trained (6-weeks swimming, n=20) and sedentary animals (n=20). Western blot analysis for neuronal nitric oxide synthase (nNOS) was performed on the stellate ganglion from both groups. RESULTS: Relative to the control group, the exercise group demonstrated typical exercise adaptations of increased ventricular weight/body weight ratio, enhanced skeletal muscle citrate synthase activity and higher concentrations of [3H]ouabain binding sites in both skeletal and cardiac tissue (P<0.05). The increase in heart rate (bpm) with SNS significantly decreased in the exercise group (n=16) compared to the sedentary group (n=16) from 30+/-5 to 17+/-3 bpm at 1 Hz; 67+/-7 to 47+/-4 bpm at 3 Hz; 85+/-9 to 63+/-4 bpm at 5 Hz and 101+/-9 to 78+/-5 bpm at 7 Hz stimulation (P<0.05). The increase in heart rate with cumulative doses (0.1-10 microM) or a single dose (0.1 microM) of bath-applied norepinephrine expressed as the effective doses at which the HR response was 50% of the maximum response (EC50) were similar in both exercise (EC50 -6.08+/-0.16 M, n=8) and sedentary groups (EC50 -6.18+/-0.07 M, n=7). Trained animals had significantly more nNOS protein in left stellate ganglion compared to the sedentary group. In the exercise group, the non-isoform selective NOS inhibitor, N-omega nitro-L-arginine (L-NA, 100 microM) caused a small but significant increase in the heart rate response to SNS. However, the positive chronotropic response to sympathetic nerve stimulation remained significantly attenuated in the exercise group compared to the sedentary group during NOS inhibition (P<0.05). CONCLUSIONS: Our results indicate that there is a significant peripheral pre-synaptic component reducing the HR response to sympathetic activation following training, although NO does not play a dominant role in this response.


Asunto(s)
Frecuencia Cardíaca/fisiología , Óxido Nítrico/fisiología , Esfuerzo Físico/fisiología , Terminales Presinápticos/fisiología , Sistema Nervioso Simpático/fisiología , Animales , Peso Corporal , Estimulación Eléctrica , Cobayas , Atrios Cardíacos , Técnicas In Vitro , Masculino , Norepinefrina/farmacología , Tamaño de los Órganos , Condicionamiento Físico Animal/métodos , Ganglio Estrellado
19.
Cardiovasc Res ; 51(1): 51-8, 2001 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-11399247

RESUMEN

OBJECTIVE: : In sinoatrial (SA) node cells, nitric oxide (NO) exerts a dual effect on the hyperpolarization-activated current, I(f), i.e. in basal conditions NO enhances I(f) whereas in the presence of beta-adrenergic stimulation it decreases it. Recent studies have shown that I(f) is present in ventricular myocytes from hypertrophied or failing hearts where it may promote abnormal automaticity. Since these pathological conditions are associated with increased sympathetic tone and upregulation of myocardial NO production, we set out to investigate whether I(f) is similarly modulated by NO in hypertrophied ventricular myocytes. METHODS: Left ventricular myocytes were isolated from 18-20-month-old spontaneously hypertensive rats (SHRs). Membrane current was measured under whole-cell or amphotericin-perforated patch-clamp conditions, at 35 degrees C. RESULTS: Application of diethylamine-NO (DEA-NO, 1-100 microM) did not alter the amplitude or voltage dependence of activation of I(f) under basal conditions (half-activation voltage, V(h): control -82.9+/-2.6, DEA-NO -84.0+/-2.6 mV). Similarly, I(f) was not affected by the inhibition of endogenous NO production (L-NMMA, 500 microM) or guanylate cyclase (ODQ, 10 microM). Forskolin (10 microM) or isoprenaline (100 nM) elicited a positive shift in V(h) but subsequent application of DEA-NO did not further affect the properties of I(f). CONCLUSIONS: Our results show that, unlike in SA node cells, in SHR ventricular myocytes basal and adrenergically stimulated I(f) is not modulated by exogenous NO or by constitutive NO or cGMP production.


Asunto(s)
Arritmias Cardíacas/fisiopatología , Cardiomegalia/fisiopatología , Hidrazinas/farmacología , Donantes de Óxido Nítrico/farmacología , Nodo Sinoatrial/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Agonistas Adrenérgicos beta/farmacología , Anfotericina B/farmacología , Análisis de Varianza , Animales , Colforsina/farmacología , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Guanilato Ciclasa/farmacología , Isoproterenol/farmacología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxidos de Nitrógeno , Oxadiazoles/farmacología , Técnicas de Placa-Clamp , Penicilamina/análogos & derivados , Penicilamina/farmacología , Piridinas/farmacología , Ratas , Ratas Endogámicas SHR , omega-N-Metilarginina/farmacología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA