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AIM: To evaluate splenic phenotype in autosomal dominant polycystic kidney disease (ADPKD) including presence of cysts and splenomegaly to determine if these are ADPKD related or represent unrelated incidental findings. MATERIALS AND METHODS: The axial/coronal T2-weighted images of ADPKD patients (n=215) and age/gender-matched controls (n=215) were evaluated for the presence of T2-bright splenic lesions by three blinded observers. Spleen volume (SV) was evaluated in the context of clinical and imaging features as well as results of gene testing for PKD1 and PKD2 mutations. RESULTS: T2-bright splenic lesions were found in 16 of 215 (7%) ADPKD patients compared to 11 of 215 (5%) control patients (p=0.32) and their prevalence was similar in patients with either PKD1 or PKD2 mutations. Median SV was significantly higher in ADPKD patients than controls (236 [182; 313 ml] versus 176 [129; 264 ml], p<0.0001). In multivariable analysis, height-adjusted SV (htSV) was not associated with the presence of liver cysts, haemorrhagic cysts, or infections; however, htSV was directly associated with height-adjusted total kidney volume (htTKV), a biomarker for ADPKD disease severity. CONCLUSIONS: The prevalence of T2-bright splenic lesions is similar in ADPKD patients and non-ADPKD controls, suggesting no relation to the diagnosis of ADPKD; however, splenic enlargement in ADPKD compared to controls could not be explained by liver cystic involvement, by infection/inflammatory conditions, or by haemorrhagic renal cysts. This combined with direct correlation of htSV with htTKV, a biomarker of ADPKD severity, suggests splenomegaly may be related to the pathogenesis of ADPKD.
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Riñón Poliquístico Autosómico Dominante/patología , Bazo/patología , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Fenotipo , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Bazo/diagnóstico por imagenRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by loss of function mutations of PKD1 or PKD2 genes. Although PKD1 is highly polymorphic and the new mutation rate is relatively high, the role of mosaicism is incompletely defined. Herein, we describe the molecular analysis of ADPKD in a 19-year-old female proband and her father. The proband had a PKD1 truncation mutation c.10745dupC (p.Val3584ArgfsX43), which was absent in paternal peripheral blood lymphocytes (PBL). However, very low quantities of this mutation were detected in the father's sperm DNA, but not in DNA from his buccal cells or urine sediment. Next generation sequencing (NGS) analysis determined the level of this mutation in the father's PBL, buccal cells and sperm to be â¼3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in â¼10% of her father's sperm indicates that it probably occurred early in embryogenesis. In ADPKD cases where a de novo mutation is suspected because of negative PKD gene testing of PBL, additional evaluation with more sensitive methods (e.g. NGS) of the proband PBL and paternal sperm can enhance detection of mosaicism and facilitate genetic counseling.
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Genes Dominantes/genética , Mosaicismo , Enfermedades Renales Poliquísticas/genética , Canales Catiónicos TRPP/genética , Adulto , Secuencia de Bases , Biología Computacional , Femenino , Mutación de Línea Germinal/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Enfermedades Renales Poliquísticas/diagnóstico por imagen , Radiografía , Adulto JovenRESUMEN
Autosomal-dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder characterized by abnormal proliferation of renal tubular epithelium, leading to massive kidney enlargement and progressive chronic kidney disease. ADPKD is caused by mutations in PKD1 and PKD2 genes. Herein, we describe and characterize a novel missense mutation in the PKD2 gene (c.1320G>T) in a 41-year-old White man with kidney cysts and a family history of ADPKD. This mutation abolishes a conserved acceptor splice site of intron 5, resulting in a premature termination following the addition of three aberrant amino acids (PKD2 p.L441C fsX4). We demonstrate that the aberrantly spliced transcript is found in substantial amounts in the patient's peripheral blood leukocytes (PBL), and show that this alternative splicing of exon 6 occurs, to a lesser magnitude, in other patients with ADPKD and in normal control individuals. The biological and clinical significance of this splice variant in ADPKD is currently unknown.
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Quistes/genética , Fallo Renal Crónico/genética , Riñón/patología , Mutación Missense , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPP/genética , Adulto , Quistes/patología , Análisis Mutacional de ADN , Exones , Humanos , Fallo Renal Crónico/diagnóstico por imagen , Fallo Renal Crónico/etiología , Masculino , Datos de Secuencia Molecular , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Sitios de Empalme de ARN , Empalme del ARN , Canales Catiónicos TRPP/metabolismo , UltrasonografíaRESUMEN
Spatial patterning in the apparent density of subchondral bone can be used to discriminate between species that differ in their joint loading conditions. This study provides an experimental test of two hypotheses that relate aspects of subchondral apparent density patterns to joint loading conditions. First, the region of maximum subchondral apparent density (RMD) will correspond to differences in joint posture at the time of peak locomotor loads; and second, differences in maximum density between individuals will correspond to differences in exercise level. These hypotheses were tested using three age-matched samples of juvenile sheep. Two groups of five sheep were exercised, at moderate walking speeds, twice daily for 45 days on a treadmill with either a 0% or 15% grade. The remaining sheep were not exercised. Sheep walking on the inclined treadmill used more flexed knee postures than those in the level walking group at the time of peak vertical ground reaction forces. Kinematic measurements of knee posture were compared with knee postures estimated from the spatial position of the RMD on the medial femoral condyle. Our results show that the difference in the position of the RMD between the incline and level walking groups corresponded to the difference in knee postures obtained kinematically; however, exercised and nonexercised sheep did not differ in the magnitude of apparent density. These results suggest that patterns of subchondral apparent density are good indicators of the experimental modifications in joint posture during locomotion and may, therefore, be used to investigate differences between species in habitual joint loading.
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Densidad Ósea , Fémur/fisiología , Esfuerzo Físico/fisiología , Postura , Rodilla de Cuadrúpedos/fisiología , Adaptación Fisiológica , Animales , Fémur/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Modelos Biológicos , Rango del Movimiento Articular , Reproducibilidad de los Resultados , Ovinos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Grabación en Video , Caminata , Soporte de PesoRESUMEN
The spectrum of disorders associated with an elevated blood pressure (BP) encompasses chronic uncomplicated hypertension and the hypertensive crises, including hypertensive urgencies and emergencies. Although these syndromes vary widely in their presentations, clinical courses, and outcomes they share pathophysiologic mechanisms and, consequently, therapeutic responses to specifically targeted antihypertensive drug types. Nevertheless, hypertensive crises are often treated with drugs which, in that setting are either unsafe or are of unsubstantiated efficacy. The purpose of this review is to examine the pathophysiology of commonly encountered hypertensive crises, including stroke, hypertensive encephalopathy, aortic dissection, acute pulmonary edema, and preeclampsia-eclampsia and to provide a rational approach to their treatment based upon relevant pathophysiologic and pharmacologic principles. Measurement of plasma renin activity (PRA) level often provides insight regarding pathophysiology and predicts efficacy of antihypertensive treatments in the individual patient. However, in hypertensive crises, drug therapy is initiated before the PRA level is known. Nevertheless, the renin-angiotensin dependence (R-type) or volume dependence (V-type) of hypertension can often be deduced by the BP response to drugs that interrupt the renin system (R-drugs) or that decrease body volume (V-drugs). Based upon these considerations, a treatment algorithm is provided to guide drug selection in patients presenting with a hypertensive crisis.
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Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Administración Oral , Algoritmos , Antihipertensivos/administración & dosificación , Aneurisma de la Aorta/complicaciones , Eclampsia/complicaciones , Femenino , Insuficiencia Cardíaca/complicaciones , Humanos , Hipertensión Maligna/complicaciones , Encefalopatía Hipertensiva/complicaciones , Inyecciones Intravenosas , Hemorragia Intracraneal Hipertensiva/complicaciones , Masculino , Embarazo , Edema Pulmonar/complicaciones , Accidente Cerebrovascular/complicaciones , Resultado del TratamientoRESUMEN
Delayed graft function (DGF), defined as persistent renal failure that requires dialysis within the first week after kidney transplantation, occurs commonly after cadaveric renal transplantation (CRT). This has important implications for long-term outcome because the 1-year allograft survival rate is significantly reduced when DGF occurs. The mechanisms contributing to the development of DGF are not well established. However, several lines of evidence indicate that excess renin system activity, in both the cadaver kidney donor and recipient, contributes importantly to the pathogenesis of DGF. If this hypothesis can be verified in clinical studies, then pharmacologic agents that interrupt the renin-angiotensin system (eg, type 1 angiotensin II receptor blockade, angiotensin converting enzyme inhibition, and beta-adrenergic blockade) in the donor and recipient might significantly improve the outcome of cadaveric renal transplants.
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Trasplante de Riñón/fisiología , Riñón/fisiología , Renina/fisiología , Supervivencia de Injerto/fisiología , HumanosRESUMEN
Elevated plasma renin activity (PRA) is associated with increased risk of future myocardial infarction (MI) in ambulatory hypertensive patients. The present study evaluated the relationship of PRA to the diagnosis of acute MI in patients presenting to an emergency department with suspected acute MI. PRA was measured upon entry to the emergency department, before any acute treatment, as part of the standard evaluation of 349 consecutive patients who were hospitalized for suspected MI. Diagnosis of acute MI was confirmed in 73 patients, and ruled out in 276. They did not differ in age (65.9 +/- 2 v 66.1 +/- 1 years), systolic (143 +/- 4 v 140 +/- 2 mm Hg), or diastolic (81 +/- 2 v 81 +/- 1 mm Hg) pressures. Median PRA was 2.7-fold higher in acute MI (0.89 v 0.33 ng/L/s; P < .001). In a multivariate analysis controlling for other cardiac risk factors and prior drug therapy, PRA as a continuous variable was the predominant independent factor associated with acute MI (P < .0001), followed by white race (P = .002) and history of hypertension (P = .047). The height of the PRA level upon entry to the emergency department was directly and independently associated with the diagnosis of acute MI. These new findings extend earlier reports because they encompass acute MI patients, include both hypertensive and normotensive patients, and control for potentially confounding variables. Based on these observations, a randomized clinical trial is warranted to determine whether measurement of PRA in acute MI could refine the process by which treatments are applied.
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Infarto del Miocardio/sangre , Infarto del Miocardio/diagnóstico , Renina/sangre , Anciano , Servicio de Urgencia en Hospital , Femenino , Humanos , Masculino , Análisis MultivarianteRESUMEN
Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during beta-blockade have not been defined. This study quantifies the effects of beta-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of beta-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. Beta-blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. Beta-blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that beta-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during angiotensin converting enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, beta-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of beta-blockers has important implications for the treatment of cardiovascular disease.
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Antagonistas Adrenérgicos beta/uso terapéutico , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Adulto , Anciano , Aldosterona/orina , Angiotensina II/antagonistas & inhibidores , Angiotensina II/sangre , Angiotensina II/genética , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Precursores Enzimáticos/sangre , Precursores Enzimáticos/genética , Femenino , Estudios de Seguimiento , Expresión Génica , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/sangre , Hipertensión/orina , Masculino , Persona de Mediana Edad , Peptidil-Dipeptidasa A/sangre , Peptidil-Dipeptidasa A/efectos de los fármacos , Renina/antagonistas & inhibidores , Renina/sangre , Renina/genética , Sistema Renina-Angiotensina/genética , Resultado del TratamientoRESUMEN
Disorders of the adrenal cortex and medulla are often associated with hypertension, which can be cured surgically in many cases or may require specific and timely medical treatments. Therefore, knowledge of adrenal physiology, biochemistry, and molecular biology is essential such that an appropriate diagnostic evaluation can be conducted efficiently. The most common hypertensive disorder of the adrenal cortex is primary aldosteronism. Aldosterone-producing adenoma is the most common form of primary aldosteronism and is most likely to be cured by unilateral adrenalectomy when aldosterone production is highly autonomous from renin-angiotensin, lateralizes to one adrenal gland, and is associated with overproduction of 18-hydroxycortiocosterone and C18-methyloxygenated metabolites of cortisol. Variants of adrenal hyperplasia that share these characteristics can also be cured by unilateral adrenalectomy.
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Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , Diagnóstico Diferencial , HumanosRESUMEN
BACKGROUND: Angiotensin II (Ang II) levels are normally very low in human plasma, approximately 5 pg/ml. They are usually measured by radioimmunoassay after extraction and concentration. An additional high-performance liquid chromatography (HPLC) step is reportedly necessary for accurate measurement but it is laborious and time-consuming, severely limiting the number of samples that can be assayed. OBJECTIVE: To investigate whether the HPLC step was necessary for measuring Ang II in human plasma samples in our laboratory using our own Ang II antiserum. DESIGN: Human plasma Ang II levels, measured with and without the HPLC step, were compared in two different studies. Since the action of renin is the rate-limiting step in the production of Ang II in plasma, the relationships of plasma renin activity (PRA) to Ang II levels measured with and without HPLC were also evaluated. In the first study, 108 blood samples were collected from 29 hypertensive patients during placebo or treatment with the Ang II antagonist BMS-186295. In the second study blood samples were collected from 12 normal subjects before and during beta-adrenergic blockade. RESULTS: In samples collected during angiotensin II antagonism, which predictably increased plasma Ang II levels, a highly significant relationship between the Ang II measurements with and without HPLC was found (y = 0.99x + 1.7; r = 0.97, P < 0.001). The y intercept of 1.7 pg/ml suggested that the nonspecific immunoreactivity was close to 2 pg/ml in samples assayed without the HPLC step. During beta-adrenergic blockade, which predictably suppressed plasma renin levels, highly significantly linear relationships between HPLC and non-HPLC Ang II measurements (y = 1.3x + 1.6; r = 0.93. P < 0.001, n = 16) and between non HPLC Ang II and PRA (y = 1.9x + 1.7; r = 0.73, P < 0.001, n = 108) were again found. The relationship between PRA and HPLC Ang II was also highly significant (y = 1.4x + 0.04; r = 0.92, P < 0.001, n = 16), but the y intercept was significantly lower (P < 0.001), approaching zero, indicating the removal of nonspecific immunoreactivity during the HPLC step. CONCLUSIONS: These results demonstrate once more that, when using polyclonal antibody 182, the accuracy of the Ang II measurement in human plasma is improved by the inclusion of a HPLC step, especially for samples with Ang II levels in the normal-to-low range. They also show that plasma Ang II and PRA increase or decrease proportionally during treatment with Ang II antagonists or beta-adrenergic blockade, respectively.
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Angiotensina II/sangre , Análisis Químico de la Sangre/métodos , Cromatografía Líquida de Alta Presión/métodos , Hipertensión/sangre , Radioinmunoensayo/métodos , Antagonistas Adrenérgicos beta/uso terapéutico , Angiotensina II/antagonistas & inhibidores , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Análisis Químico de la Sangre/estadística & datos numéricos , Presión Sanguínea , Cromatografía Líquida de Alta Presión/estadística & datos numéricos , Estudios de Evaluación como Asunto , Humanos , Hipertensión/tratamiento farmacológico , Irbesartán , Radioinmunoensayo/estadística & datos numéricos , Renina/sangre , Sensibilidad y Especificidad , Tetrazoles/uso terapéuticoRESUMEN
UNLABELLED: Exercise induced renal dysfunction is reported to occur in treated hypertensive patients but not seen normotensive subjects. It is unclear if this phenomenon is related to the disease or to treatment. METHODS: Four normal volunteers and 15 hypertensive subjects (antihypertensive medications were discontinued for more than 4 wk) were studied with upright radionuclide renography at rest and during bicycle exercise. The amount of exercise was sufficient to increase the heart rate at least 20 bpm above the resting value. All subjects were healthy, without evidence of left ventricular hypertrophy renal disease or hypertensive retinal disease. BUN, serum creatinine concentration and urinalysis were normal in all subjects. Renograms were performed for 12-15 min after injection of either 1 mCi[123]orthoidohippurate (OIH) or 2-7 mCi 99mTc-mercaptoacetyltriglycine (MAG3). Visual analysis and mean transit time calculation were performed on the rest and exercise studies. RESULTS: Seven of 14 hypertensive subjects and none of the normal volunteers demonstrated abnormal prolongation in renal transit during exercise which was not seen on the resting renogram. Four of these seven subjects had a history of hypertension for 2 yr or less. CONCLUSION: About 50% of individuals with mild-to-moderate hypertension and normal renal function may have abnormal renal transit of renal excretion agents during exercise, although their baseline studies are normal. This finding is unassociated with therapy and appears to be related directly to the pathophysiology of essential hypertension.
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Hipertensión/diagnóstico por imagen , Riñón/fisiopatología , Renografía por Radioisótopo , Adulto , Estudios de Casos y Controles , Prueba de Esfuerzo , Humanos , Hipertensión/fisiopatología , Radioisótopos de Yodo , Ácido Yodohipúrico , Persona de Mediana Edad , Circulación Renal/fisiología , Tecnecio Tc 99m MertiatidaRESUMEN
OBJECTIVE: To characterize the clinical and laboratory features of primary aldosteronism and to evaluate which diagnostic tests can discriminate surgically curable forms of this syndrome. DESIGN: Retrospective analysis of the following data from 82 patients with primary aldosteronism: blood pressure, serum electrolytes, urinary aldosterone and electrolytes, computed tomographic scans, plasma renin and aldosterone before and during upright posture, atrial natriuretic peptide, and adrenal vein aldosterone and cortisol. Clinical outcomes assessed after treatment included blood pressure, serum electrolytes, and plasma renin activity. RESULTS: Drug therapy was discontinued before diagnostic tests were done in 56 of 82 patients (34 with adenomas and 22 with hyperplasia). Compared with patients with hyperplasia, those with adenomas had higher systolic (184 mm Hg and 161 mm Hg, respectively; P < 0.001) and diastolic blood pressures (112 mm Hg and 105 mm Hg; P = 0.03), lower serum potassium levels (3.0 mmol/L and 3.5 mmol/L; P < 0.001), and higher serum CO2 (P = 0.001), atrial natriuretic peptide (P = 0.008), and urinary 18-methyl oxygenated cortisol metabolite levels (P = 0.02). In patients with adenomas, aldosterone secretion lateralized to one adrenal gland and did not increase during the postural stimulation test; preoperative urinary aldosterone levels were correlated with diastolic pressures (r = 0.58; P = 0.001). Hypertension was "cured" postoperatively in approximately 35% of patients with adenomas and those with hyperplasia (P > 0.2) but was "improved" more frequently in those with adenomas (P = 0.002). Cured patients from both groups were younger than those not cured (mean ages, 43 years and 54 years, respectively; P = 0.002) and had lower preoperative mean plasma renin activity (0.17 ng/mL per hour and 0.50 ng/mL per hour; P < 0.001). All patients with adenomas in whom aldosterone secretion lateralized were either cured or improved. CONCLUSION: Of the 51 patients with primary aldosteronism who had adrenalectomy (43 patients with adenomas and 8 with hyperplasia), those most likely to be cured were younger and had lower plasma renin activity. In patients with adenomas who were cured or improved, aldosterone secretion was more likely to lateralize. Tests that distinguished adenomas from adrenal hyperplasia included the postural stimulation test, urinary excretion rates of 18-oxocortisol and 18-hydroxycortisol, and adrenal vein sampling.
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Adrenalectomía , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirugía , Adenoma/complicaciones , Neoplasias de las Glándulas Suprarrenales/complicaciones , Glándulas Suprarrenales/patología , Algoritmos , Enfermedades Cardiovasculares/etiología , Femenino , Humanos , Hiperaldosteronismo/etiología , Hiperaldosteronismo/metabolismo , Hiperplasia/complicaciones , Hipertensión/etiología , Hipertensión/cirugía , Enfermedades Renales/complicaciones , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The use of hypotensive anesthesia is contraindicated in patients with ventricular dysfunction, even though afterload reduction often improves ventricular performance. The purpose of this study was to prospectively assess systemic hemodynamic responses to deliberate hypotension with epidural anesthesia in patients with chronic left ventricular dysfunction. Hemodynamic measurements were performed in 29 patients undergoing total hip arthroplasty under deliberate hypotensive epidural anesthesia using low-dose intravenous epinephrine infusion to maintain mean arterial pressure (MAP) at 50-60 mm Hg. Intraoperative MAP decreased from 100 +/- 16 to 56 +/- 9 mm Hg by 30 min after epidural injection (P < 0.0005). Concurrently, cardiac index (CI) increased from a preanesthetic baseline value of 2.9 +/- 0.5 to 3.3 +/- 0.9 L.min-1.m-2 at 30 min (P < 0.005) after epidural injection and stroke volume index (SVI) increased from 41 +/- 8 to 50 +/- 14 mL.beat-1.m-2 30 min after epidural injection (P < 0.005). Heart rate and central venous and pulmonary artery diastolic pressures were maintained under hypotension with epidural anesthesia in all patients. During deliberate hypotension with epidural anesthesia, patients with a history of congestive heart failure or low preanesthetic CI (< or = 2.5 L.kg-1.m-2) increased their CI and SVI into the normal range. There were no significant perioperative complications in either of these groups. Hypotensive epidural anesthesia can be used successfully in patients with low cardiac output from ventricular dysfunction undergoing total hip arthroplasty.
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Anestesia Epidural , Gasto Cardíaco Bajo/fisiopatología , Hipotensión Controlada , Disfunción Ventricular Izquierda/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Prótesis de Cadera , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Volumen SistólicoAsunto(s)
Cardiopatías/etiología , Hipertensión/complicaciones , Enfermedades Renales/etiología , Cardiopatías/fisiopatología , Cardiopatías/terapia , Hemodinámica , Humanos , Hipertensión/fisiopatología , Enfermedades Renales/fisiopatología , Enfermedades Renales/terapia , Sistema Renina-Angiotensina , Factores de RiesgoRESUMEN
To assess the relative contributions of neural and nonneural stimuli of renin secretion, the effects of an alpha 1-agonist, phenylephrine (Phe), or a beta-agonist, epinephrine (Epi), on plasma renin activity (PRA), renal blood flow (RBF), and glomerular filtration rate (GFR) were compared during sympathetic blockade with epidural hypotensive anesthesia [mean arterial blood pressure (MAP) = 60 and 50 mmHg]. Controls (NaCl) received saline alone to maintain MAP at 50 mmHg. Epi increased PRA (ng.ml-1.h-1) from 0.9 +/- 0.6 to 3.0 +/- 1.5 at 60 mmHg MAP and 4.7 +/- 1.8 at 50 mmHg MAP, with associated decreases in RBF (-33 and -60%, respectively) and GFR (-27 and -53%, respectively). During hypotension with Phe and NaCl, PRA and RBF were unchanged from baseline but GFR decreased. Urinary Na secretion decreased comparably in all three groups. In conclusion, during sympathetic blockade with epidural anesthesia, marked reductions in both renal perfusion pressure and distal nephron Na delivery were insufficient to increase renin secretion. beta-Adrenergic stimulation (e.g., Epi) was required to increase PRA. Epi decreased RBF suggesting an angiotensin II-mediated effect.
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Epinefrina/farmacología , Hemodinámica/efectos de los fármacos , Hipotensión/fisiopatología , Riñón/fisiología , Fenilefrina/farmacología , Circulación Renal/efectos de los fármacos , Renina/metabolismo , Anestesia Epidural , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Diástole/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Prótesis de Cadera , Humanos , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Receptores Adrenérgicos/efectos de los fármacos , Receptores Adrenérgicos/fisiología , Circulación Renal/fisiología , Renina/sangre , Sodio/orina , Sístole/efectos de los fármacosRESUMEN
The solid-state structures of (+/-)-(1R,3S,5S)/(1S,3R,5R)- and (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-methylnefopam hydrochloride, epimeric 3-methyl derivatives of the non-narcotic analgesic drug, were determined by single-crystal X-ray diffraction analyses. (+/-)-(1R,3S,5S)/(1S,3R,5S)-3-Methylnefopam hydrochloride gave crystals belonging to the monoclinic space group P2(1)/c, and at ambient temperature, a = 7.993(2), b = 34.376(4), c = 11.785(2) A, beta = 93.06 degrees, V = 3234(2) A3, Z = 8, R(F = 0.070, and Rw(F) = 0.053. (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-3-Methylnefopam hydrochloride gave chiral crystals belonging to the orthorhombic space group P2(1)2(1)2(1), and at 92 K, a = 9.261(2), b = 10.280(2), c = 16.668(4) A, V = 1587(1) A3, Z = 4, R(F) = 0.034, and Rw(F) = 0.035. The two molecules in the asymmetric unit of the (1R,3S,5S)/(1S,3R,5R)-racemic modification had twist-chair-(flattened chair) [TCfC] conformational geometries for the eight-membered ring. Both molecules are virtually identical as shown by a root mean squares fit of 0.077 A in the superimposition of all nonhydrogen atoms in both molecules. The (+)/(-)-(1R,3R,5R)/(1S,3S,5S)-epimers were found in the same boat-(flattened chair) [BfC] conformation previously noted for crystalline nefopam hydrochloride. The TCfC and BfC eight-membered ring conformations of the two 3-methylnefopam diastereomers differ in the -N+H(CH3)CH2CH-fragment chair or boat arrangement vis-a-vis the adjacent flattened region. In both 3-methyl diastereomers, the C(3)-methyl group was disposed in an equatorial orientation, the phenyl group resided in an exo-position, and the -OCH(Ph)-o-C6H4- fragment occupied the flattened region of the eight-membered ring.(ABSTRACT TRUNCATED AT 250 WORDS)
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Analgésicos/farmacología , Nefopam/farmacología , Analgésicos/química , Animales , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Ratones , Conformación Molecular , Nefopam/análogos & derivados , Nefopam/química , Dimensión del Dolor/efectos de los fármacos , EstereoisomerismoRESUMEN
Glomus jugulare tumors have been reported to secrete norepinephrine and cause severe hypertension with features similar to pheochromocytoma. In contrast, epinephrine secretion has not been observed in these neoplasms. This has been attributed to the absence of the norepinephrine-methylating enzyme, phenylethanolamine-N-methyltransferase (PNMT), required for epinephrine synthesis. We report a patient with severe hypertension caused by a glomus tumor that secreted norepinephrine and epinephrine. Following selective venous sampling, catecholamines were quantified by radioenzymatic assay. Marked elevations in norepinephrine and epinephrine release were localized to the glomus tumor. The enzymes involved in catecholamine biosynthesis, including PNMT and tyrosine hydroxylase, were identified immunocytochemically in the tumor. The glomus tumor had staining patterns identical to those observed within normal rat glomus cell. Hypertension resolved with resection of the functioning tumor. This is the first report of PNMT in a functioning paraganglioma of the glomus jugulare region. The factors that determine why functional activity is expressed only rarely by paraganglioma remain undefined.