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We performed a preliminary study of neutron resonance absorption imaging to investigate the spatial distribution of constituent elements in borosilicate glasses containing simulated high-level radioactive waste, in which elemental inhomogeneities affect the physical and chemical stabilities of the glass. Dips generated by the resonance absorptions of Rh, Pd, Na, Gd, Cs, and Sm were observed in the neutron transmission spectra of the glass samples. The spatial distributions of these elements were obtained from the neutron transmission images at the resonance energies. The distributions of Rh and Pd visualized the sedimentation of these platinum group elements. In contrast, the lanthanides (Gd and Sm) and Cs were uniformly dispersed. These results show that neutron resonance absorption imaging is a promising tool for characterizing borosilicate glasses and investigating the vitrification mechanism of high-level radioactive waste.
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Differential cross sections and photon-beam asymmetries for the γ[over â]pâπ^{-}Δ^{++}(1232) reaction have been measured for 0.7
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Aims: The intra-articular administration of tranexamic acid (TXA) has been shown to be effective in reducing blood loss in unicompartmental knee arthroplasty and anterior cruciate reconstruction. The effects on human articular cartilage, however, remains unknown. Our aim, in this study, was to investigate any detrimental effect of TXA on chondrocytes, and to establish if there was a safe dose for its use in clinical practice. The hypothesis was that TXA would cause a dose-dependent damage to human articular cartilage. Materials and Methods: The cellular morphology, adhesion, metabolic activity, and viability of human chondrocytes when increasing the concentration (0 mg/ml to 40 mg/ml) and length of exposure to TXA (0 to 12 hours) were analyzed in a 2D model. This was then repeated, excluding cellular adhesion, in a 3D model and confirmed in viable samples of articular cartilage. Results: Increasing concentrations above 20 mg/ml resulted in atypical morphology, reduced cellular adhesion and metabolic activity associated with increased chondrocyte death. However, the cell matrix was not affected by the concentration of TXA or the length of exposure, and offered cellular protection for concentrations below 20 mg/ml. Conclusion: These results show that when in vitro chondrocytes are exposed to higher concentrations of TXA, such as that expected following recommended intra-articular administration, cytotoxicity is observed. This effect is dose-dependent, such that a tissue concentration of 10 mg/ml to 20 mg/ml could be expected to be safe. Cite this article: Bone Joint J 2018;100-B:404-12.
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Antifibrinolíticos/administración & dosificación , Antifibrinolíticos/toxicidad , Cartílago Articular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Ácido Tranexámico/administración & dosificación , Ácido Tranexámico/toxicidad , Administración Tópica , Reconstrucción del Ligamento Cruzado Anterior , Apoptosis/efectos de los fármacos , Artroplastia de Reemplazo de Rodilla , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
The Ï-Λ(1520) interference effect in the γpâK^{+}K^{-}p reaction has been measured for the first time in the energy range from 1.673 to 2.173 GeV. The relative phases between Ï and Λ(1520) production amplitudes were obtained in the kinematic region where the two resonances overlap. The measurement results support strong constructive interference when K^{+}K^{-} pairs are observed at forward angles but destructive interference for proton emission at forward angles. Furthermore, the observed interference effect does not account for the sqrt[s]=2.1 GeV bump structure in forward differential cross sections for Ï photoproduction. This fact suggests possible exotic structures such as a hidden-strangeness pentaquark state, a new Pomeron exchange, or rescattering processes via other hyperon states.
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Root herbivores can affect plant fitness, and roots often contain the same secondary metabolites that act as defenses in shoots, but the ecology and evolution of root chemical defense have been little investigated. Here, we investigated genetic variance, heritability, and correlations among defensive phenolic compounds in shoot vs. root tissues of common evening primrose, Oenothera biennis. Across 20 genotypes, there were roughly similar concentrations of total phenolics in shoots vs. roots, but the allocation of particular phenolics to shoots vs. roots varied along a continuum of genotype growth rate. Slow-growing genotypes allocated 2-fold more of the potential pro-oxidant oenothein B to shoots than roots, whereas fast-growing genotypes had roughly equivalent above and belowground concentrations. Phenolic concentrations in both roots and shoots were strongly heritable, with mostly positive patterns of genetic covariation. Nonetheless, there was genotype-specific variation in the presence/absence of two major ellagitannins (oenothein A and its precursor oenothein B), indicating two different chemotypes based on alterations in this chemical pathway. Overall, the presence of strong genetic variation in root defenses suggests ample scope for the evolution of these compounds as defenses against root herbivores.
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Oenothera biennis/química , Evolución Molecular , Genotipo , Taninos Hidrolizables/metabolismo , Oenothera biennis/genética , Oenothera biennis/crecimiento & desarrollo , Raíces de Plantas/química , Brotes de la Planta/química , Polifenoles/metabolismoRESUMEN
OBJECTIVE: To determine whether vascular function assessed by low-flow-mediated constriction (L-FMC), a novel non-invasive method, complements the information obtained with "traditional" flow-mediated dilatation (FMD). DESIGN AND PATIENTS: In protocol 1, 12 healthy young volunteers underwent FMD and L-FMC measurements at rest and immediately after isometric exercise of the same hand. In protocol 2, 24 patients with coronary artery disease, 24 with congestive heart failure, 24 hypertensive patients and 64 healthy volunteers were enrolled to undergo L-FMC and FMD measurements. RESULTS: In protocol 1, exercise was associated with mean (SD) increases in radial artery blood flow, diameter and L-FMC (from -5.1 (1.5)% to -7.8 (3.4)%, p<0.05), while FMD was significantly blunted (from 6.0 (2.4)% to 3.0 (3.2)%, p<0.05). In protocol 2, both FMD and L-FMC were blunted in the patient groups. Receiver operating curve analysis showed that, as compared with FMD alone, the combination of L-FMC and FMD significantly improved the sensitivity and specificity in detecting patients diagnosed with cardiovascular disease (p<0.05). CONCLUSION: In the first protocol, FMD and L-FMC were shown to be reciprocally regulated. A blunted FMD may, in certain cases, be an expression of increased resting vascular activation and not only of impaired endothelial function. In the second protocol, a statistical approach showed that implementation of L-FMC provides a better characterisation than FMD of vascular function in cardiovascular disease. Vascular (endothelial) function is a complex phenomenon which requires a multifaceted approach; it is suggested that a combination of L-FMC and FMD will provide additive and complementary information to "traditional" FMD measurements.
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Arteria Radial/fisiología , Vasoconstricción/fisiología , Vasodilatación/fisiología , Adulto , Anciano , Velocidad del Flujo Sanguíneo/fisiología , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/fisiopatología , Ejercicio Físico/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
OBJECTIVE: To determine whether the influence of sleep apnoea (SA) on the risk of death differs in patients with ischaemic and in those with non-ischaemic heart failure (HF). DESIGN: Prospective observational study. PATIENTS: Consecutive patients with HF with left ventricular ejection fraction < or =45% newly referred to the HF clinic between 1 September 1997 and 1 December 2004. MAIN OUTCOME MEASURES: Patients underwent sleep studies and were divided into those with moderate to severe SA (apnoea-hypopnoea index > or =15/h of sleep) and those with mild to no SA (apnoea-hypopnoea index <15/h of sleep). They were followed up for a mean of 32 months to determine all-cause mortality rate. RESULTS: Of 193 patients, 34 (18%) died. In the ischaemic group, mortality risk adjusted for confounding factors was significantly higher in those with SA than in those without it (18.9 vs 4.6 deaths/100 patient-years, hazards ratio (HR) = 3.03, 95% CI 1.04 to 8.84, p = 0.043). In contrast, in the non-ischaemic HF group, there was no difference in adjusted mortality risk between those with, and those without, SA (3.9 vs 4.0 deaths/100 patient-years, p = 0.929). CONCLUSIONS: In patients with HF, the presence of SA is independently associated with an increased risk of death in those with ischaemic, but not in those with non-ischaemic, aetiology. These findings suggest that patients with ischaemic cardiomyopathy are more susceptible to the adverse haemodynamic, autonomic and inflammatory consequences of SA than are those with non-ischaemic cardiomyopathy.
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Insuficiencia Cardíaca/mortalidad , Isquemia Miocárdica/mortalidad , Síndromes de la Apnea del Sueño/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatía Dilatada/mortalidad , Causas de Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Disfunción Ventricular Izquierda/mortalidadRESUMEN
Representatives of three ancient gene families of the antioxidant enzyme superoxide dismutase (SOD) can be found in most metazoans. In mammals and Caenorhabditis elegans, there is at least one gene each of the cytoplasmic, mitochondrial and extracellular lineages of SOD genes. The cytoplasmic SOD was one of the first enzymes to be implicated in ageing due to its protection against damaging oxygen free radicals. In contrast to other metazoans, insects were thought to lack a gene for the extracellular SOD. We have cloned and sequenced an SOD mRNA in the ant Lasius niger that appears to belong to this extracellular family. Subsequent searches and analyses of SOD gene sequences in insect databases revealed that insects do indeed express all three SOD genes including the extracellular form. We conclude that insects as well as other metazoans appear to have the full repertoire of the three families of SOD.
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Espacio Extracelular/metabolismo , Insectos/genética , Filogenia , Superóxido Dismutasa/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Teorema de Bayes , Cartilla de ADN , Insectos/metabolismo , Modelos Genéticos , Datos de Secuencia Molecular , Técnicas de Amplificación de Ácido Nucleico , Alineación de Secuencia , Análisis de Secuencia de ADN , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Nitric oxide synthase (NOS) uses arginine for the production of nitric oxide (NO). High intracellular concentrations of arginine suggest that NOS activity should be independent of plasma arginine supply. However, under certain conditions, increased plasma arginine concentrations appear to be associated with increased NOS activity. The purpose of this study was to explore arginine transport within the human coronary and peripheral circulation METHODS AND RESULTS: Mass-labeled 15N2-arginine was infused to steady state before cardiac catheterization in 31 patients. After diagnostic angiography, a catheter was placed in the coronary sinus. The transcardiac concentration gradient (aorta-coronary sinus) of 15N2-arginine was used as a measure of arginine transport at baseline and during infusions of acetylcholine and N(G)-monomethyl-L-arginine (L-NMMA). No gradient was detected at rest. During the infusion of acetylcholine, a significant gradient was detected (2.5+/-1.2 micromol/L, P=0.01) corresponding to a fractional extraction of 11.7+/-7.5%. This is consistent with in vitro studies that suggest that stimulation of NOS induces arginine transport. During the infusion of L-NMMA, the concentration of 15N2-arginine increased in the coronary sinus, producing a gradient of -3.9+/-1.3 micromol/L (P=0.0002), corresponding to a fractional production of 20.5+/-5.0%. This is consistent with in vitro studies that suggest that L-NMMA induces the efflux of arginine from the cell to the extracellular space via transporter-mediated transstimulation. CONCLUSIONS: The use of steady-state 15N2-arginine to examine transorgan L-arginine gradients represents a novel tool for the study of L-arginine transport and the mechanisms of endothelial and NOS dysfunction.
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Arginina/farmacocinética , Vasos Coronarios/metabolismo , Óxido Nítrico Sintasa/metabolismo , Acetilcolina/farmacología , Anciano , Arginina/sangre , Transporte Biológico , Vasos Sanguíneos/metabolismo , Cateterismo Cardíaco , Endotelio Vascular/enzimología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III , Isótopos de Nitrógeno/farmacocinética , Especificidad de Órganos , omega-N-Metilarginina/farmacologíaRESUMEN
A wide variety of functional domains exist within human genes. Since different domains vary in their roles regarding overall gene function, the ability for a mutation in a gene region to produce disease varies among domains. We tested two hypotheses regarding distributions of mutations among functional domains by using (1) sets of single nucleotide disease mutations for six genes (CFTR, TSC2, G6PD, PAX6, RS1, and PAH) and (2) sets of polymorphic replacement and silent mutations found in two genes (CFTR and TSC2). First, we tested the null hypothesis that sets of mutations are uniformly distributed among functional domains within genes. Second, we tested the null hypothesis that disease mutations are distributed among gene regions according to expectations derived from the distribution of evolutionary conserved and variable amino acid sites throughout each gene. In contrast to the mainly uniform distribution of sets of silent and polymorphic mutations, sets of disease mutations generally rejected the null hypotheses of both uniform and evolutionary-influenced distributions. Although the disease mutation data showed a better agreement with the evolutionary-derived expectations, disease mutations were found to be statistically overabundant in conserved domains, and under-represented in variable regions, even after accounting for amino acid site variability of domains over long-term evolutionary history. This finding suggests that there is a non-additive influence of amino acid site conservation on the observed intragenic distribution of disease mutations, and underscores the importance of understanding the patterns of neutral amino acid substitutions permitted in a gene over long-term evolutionary history.
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Evolución Molecular , Enfermedades Genéticas Congénitas/genética , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Estructura Terciaria de Proteína/genética , Secuencia Conservada/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Bases de Datos Genéticas , Proteínas del Ojo/genética , Glucosafosfato Deshidrogenasa/genética , Proteínas de Homeodominio/genética , Humanos , Proteína 1 de Transporte de Anión Orgánico/genética , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , Filogenia , Proteínas Represoras/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorAsunto(s)
Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Factor Natriurético Atrial/sangre , Canadá , Cardiología , Desfibriladores Implantables , Humanos , Péptido Natriurético Encefálico , Sociedades MédicasRESUMEN
Dried whey and whey protein are important food ingredients. Functionality of whey products has been studied extensively. Flavor inconsistency and flavors which may carry through to the finished product can limit whey ingredient applications in dairy and nondairy foods. The goal of this research was to determine the flavor and flavor variability of commercially produced liquid Cheddar cheese whey. Liquid Cheddar cheese whey from five culture blends from two different stirred-curd Cheddar cheese manufacturing facilities was collected. Whey flavor was characterized using instrumental and sensory methods. Wide variation in whey headspace volatiles was observed between different manufacturing facilities (P < 0.05). Hexanal and diacetyl were two key volatiles that varied widely (P < 0.05). FFA profiles determined by solid-phase microextraction and degree of proteolysis of the whey samples were also different (P < 0.05). Differences in whey flavor profiles were also confirmed by descriptive sensory analysis (P < 0.05). Differences in liquid whey flavor were attributed to differences in milk source, processing and handling and starter culture blend. The flavor of liquid Cheddar cheese whey is variable and impacted by milk source and starter culture rotation. Results from this study will aid future studies that address the impact of liquid whey flavor variability on flavor of dried whey ingredients.
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Queso , Proteínas de la Leche , Gusto , Aminoácidos/análisis , Queso/análisis , Ácidos Grasos no Esterificados/análisis , Femenino , Humanos , Hidrólisis , Masculino , Proteínas de la Leche/química , Proteínas de la Leche/metabolismo , Odorantes/análisis , Volatilización , Proteína de Suero de LecheRESUMEN
AIMS: We recently found that resting muscle sympathetic nerve activity is inversely related to peak oxygen uptake (VO(2) peak) in patients with heart failure, suggesting a peripheral neurogenic limit to exercise in heart failure. No such relationship was observed in healthy controls. To determine whether this observation is specific to sympathetic discharge to skeletal muscle, we tested the null hypothesis that VO(2) peak would not relate to resting cardiac noradrenaline spillover, which is also elevated in heart failure. METHODS AND RESULTS: We measured cardiac noradrenaline spillover at rest by a radiotracer technique and VO(2) peak, during cycle ergometry, by open circuit spirometry in 49 heart failure patients (mean age 54.4+/-1.4 (SE)). There was a significant relationship between age and peak VO(2) (P=0.022). There was no significant relationship between cardiac noradrenaline spillover and either absolute or relative VO(2) peak (P=0.136), with age included in a multiple linear regression model, and none between cardiac noradrenaline spillover and the percent predicted VO2) peak achieved (P=0.34). CONCLUSIONS: Reduced exercise capacity in heart failure relates more closely to sympathetic traffic to skeletal muscle than to cardiac sympathetic outflow, as assessed by noradrenaline spillover. This finding lends further support to the concept of a predominantly peripheral neurogenic limit to exercise.
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Agonistas alfa-Adrenérgicos/uso terapéutico , Insuficiencia Cardíaca/sangre , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/fisiología , Norepinefrina/uso terapéutico , Consumo de Oxígeno/efectos de los fármacos , Prueba de Esfuerzo , Femenino , Insuficiencia Cardíaca/tratamiento farmacológico , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Valor Predictivo de las Pruebas , Presión Esfenoidal Pulmonar/fisiología , Resultado del Tratamiento , Función Ventricular Izquierda/fisiologíaRESUMEN
Hypocapnia contributes to the genesis of Cheyne-Stokes respiration and central sleep apnoea in patients with congestive heart failure (CHF) and is associated with increased mortality. However, the cause of hypocapnia in patients with chronic stable CHF is unknown. Since pulmonary congestion can induce hyperventilation via stimulation of pulmonary vagal afferents, the present study tested the hypothesis that in patients with CHF (carbon dioxide tension in arterial blood (Pa,CO2)) is inversely related to pulmonary capillary wedge pressure (PCWP), and that alterations in PCWP would cause inverse changes in Pa,CO2. In 11 CHF patients undergoing diagnostic cardiac catheterization, haemodynamic variables and arterial blood gas tensions were measured simultaneously at baseline. In three patients, these measurements were repeated after coronary angiographic dye infusion and nitroglycerine infusion. At baseline, Pa,CO2 correlated inversely with PCWP (r=-0.80, p=0.003). In the three patients in whom multiple measurements were made, acute alterations in PCWP caused inversely proportional changes in Pa,CO2. The present study concludes that in patients with congestive heart failure, pulmonary capillary wedge pressure is an important determinant of carbon dioxide tension in arterial blood. These findings imply that hypocapnia in patients with chronic stable congestive heart failure is a respiratory manifestation of elevated left ventricular filling pressures.
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Dióxido de Carbono/sangre , Insuficiencia Cardíaca/fisiopatología , Presión Esfenoidal Pulmonar/fisiología , Anciano , Arterias , Humanos , Masculino , Persona de Mediana Edad , Presión Parcial , Función Ventricular Izquierda/fisiologíaRESUMEN
OBJECTIVES: The purpose of this study was to determine whether carvedilol's alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF). BACKGROUND: Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain. METHODS: We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation. RESULTS: Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol. CONCLUSIONS: Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.
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Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/uso terapéutico , Antagonistas Adrenérgicos beta/uso terapéutico , Carbazoles/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Metoprolol/uso terapéutico , Propanolaminas/uso terapéutico , Vasodilatadores/uso terapéutico , Fibras Adrenérgicas/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos beta/farmacología , Carbazoles/farmacocinética , Carvedilol , Enfermedad Crónica , Método Doble Ciego , Monitoreo de Drogas , Medicina Basada en la Evidencia , Prueba de Esfuerzo/efectos de los fármacos , Femenino , Análisis de Fourier , Fuerza de la Mano , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Contracción Isométrica/efectos de los fármacos , Cuidados a Largo Plazo , Masculino , Metoprolol/farmacología , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Unión Neuroefectora/efectos de los fármacos , Pronóstico , Propanolaminas/farmacocinética , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasodilatadores/farmacologíaAsunto(s)
Tolerancia a Medicamentos/fisiología , Donantes de Óxido Nítrico/farmacología , Nitrocompuestos/farmacología , Disponibilidad Biológica , Radicales Libres/metabolismo , Humanos , Nitroglicerina/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Hidrolasas Diéster Fosfóricas/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective beta-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional beta(2)-adrenergic receptors. METHODS AND RESULTS: Thirty-six patients with chronic heart failure were randomized to the nonselective beta-blocker carvedilol or the selective beta-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (-1.7+/-0.5 nmol/min, P<0.01) and cardiac norepinephrine spillover (-87+/-29 pmol/min, P<0.01). By contrast, in the metoprolol group (n=14), there were no significant changes in total body or cardiac norepinephrine spillover. Responses in the carvedilol group were significantly different from those observed in the metoprolol group (P<0.05). Both agents caused a reduction in heart rate and increases in pulse pressure, although mean arterial pressure did not change. Importantly, microneurographic measures of sympathetic nerve traffic to skeletal muscle did not change in either group. CONCLUSIONS: Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective beta-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional beta-adrenergic receptors.
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Antagonistas Adrenérgicos beta/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Receptores Adrenérgicos beta/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea/efectos de los fármacos , Carbazoles/administración & dosificación , Carvedilol , Enfermedad Crónica , Método Doble Ciego , Esquema de Medicación , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Metoprolol/administración & dosificación , Persona de Mediana Edad , Músculo Esquelético/inervación , Norepinefrina/metabolismo , Propanolaminas/administración & dosificación , Especificidad por Sustrato , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
OBJECTIVES: We studied the effects of nitroglycerin (GTN) therapy on the response to endothelium-dependent and independent vasoactive agents in the forearm circulation of healthy subjects. BACKGROUND: Recent evidence suggests that therapy with GTN may induce specific changes in endothelial cell function, including increased superoxide anion production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of patients with ischemic heart disease. METHODS: Forearm blood flow was measured with venous occlusion, mercury-in-silastic strain gauge plethysmography. RESULTS: Sixteen male volunteers (26 +/- 6 years) were randomized to no therapy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 microg/min), N-monomethyl-L-arginine (L-NMMA) (1, 2, 4 micromol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 microg/min) were recorded. The vasodilator responses to Ach were blunted in the GTN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ between groups. CONCLUSIONS: The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.