RESUMEN
In glucocorticoid-remediable aldosteronism (GRA), there is a large interfamily variation of phenotype. We report three subjects with GRA in a single family (parents, two brothers and two sisters), of whom only one (proband) displayed classical features of the mineralocorticoid excess. The proband was a man found to be hypertensive and hypokalaemic at the age of 24 years. Plasma renin activity was suppressed and plasma aldosterone was repeatedly elevated. Blood pressure and aldosterone levels normalized within 5 days of dexamethasone therapy. The presence of a chimaeric CYP11B1/CYP11B2 gene was demonstrated by long-PCR and Southern blotting (crossover site at the end of intron 3) in the proband, in the younger sister (sibling 1) and in the father. In these patients, sequencing of the chimaeric portion of CYP11B1 did not reveal any mutation, while sequencing of the chimaeric portion of CYP11B2 showed a V386A polymorphism in exon 7, known to cause only a minimal impairment of enzymatic activity. Sibling 1 was normotensive, normokalaemic and had normal PRA and aldosterone. The father had normal blood pressure and potassium, low-normal PRA and normal aldosterone. All three subjects had elevated levels of urinary 18-hydroxycortisol and 18-oxocortisol. Baseline 11-deoxycorticosterone (DOC), corticosterone (B) and aldosterone were high in the proband and normal in the father and sibling 1; 11-deoxycortisol (S) and cortisol (F) were normal. ACTH induced a normal increase of B, DOC, S and F, and an excessive aldosterone increase in all three patients. Abnormalities in the chimaeric portions of CYB11B1 or CYP11B2 genes did not account for the phenotypic disparity of the different members in a single GRA family. Altered regulation of the chimaeric gene may be responsible for differences in its activity.
Asunto(s)
Dexametasona/uso terapéutico , Glucocorticoides/uso terapéutico , Hidrocortisona/análogos & derivados , Hiperaldosteronismo/genética , Adulto , Anciano , Aldosterona/sangre , Aldosterona/orina , Cortodoxona/orina , Citocromo P-450 CYP11B2/genética , Femenino , Genotipo , Humanos , Hidrocortisona/orina , Hiperaldosteronismo/tratamiento farmacológico , Hiperaldosteronismo/metabolismo , Hipertensión/genética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Renina/sangre , Renina/orina , Esteroide 11-beta-Hidroxilasa/genéticaRESUMEN
Pheochromocytomas are rare tumours of catecholamine-producing chromaffin cells leading to hypertension and symptoms of catecholamine excess. They can be benign or malignant, sporadic or familial tumours. Genetic syndromes associated with pheochromocytoma are MEN II, VHL disease and neurofibromatosis type 1. Usually, pheochromocytomas occur in the adrenal medulla. Clinical manifestations include hypertension (which can be intermittent, stable or in the form of hypertensive peaks) and symptoms related to catecholamine excess such as headache, palpitations and tachycardia, pallor, anxiety and nervousness, nausea, vomiting, weight loss. This clinical syndrome can be mimicked by various hyperkinetic and hyperadrenergic states. When pheochromocytoma is suspected, the first diagnostic step is represented by the measurement of catecholamines and their metabolites (metanephrines) in urine and plasma. Chro-mogranin A measurement can be useful. The clonidine suppression test may be helpful in ruling out other conditions that may elevate catecholamines and metanephrines. Localiza-tion and staging of pheochromocytoma is based on MRI, which is more sensitive than CT scan, and (131)I-MIBG scintiscan. The best therapeutic option for pheochromocytoma is surgery with a laparoscopic approach. An appropriate pre-, intra- and postoperative medical management of the patient is mandatory. In the absence of optimal medical treatment, intraoperative mortality reaches 50%.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/terapia , Algoritmos , Humanos , Feocromocitoma/complicaciones , Feocromocitoma/terapiaRESUMEN
OBJECTIVE: 11beta-Hydroxylase and aldosterone synthase are two highly homologous genes involved in different forms of human hypertension and in different animal models of hypertension. It has been shown that the conservative substitution D147E in the human CYP11B2 gene results in an increased production of corticosterone and aldosterone in vitro. A gene conversion between the CYP11B1 and CYP11B2 genes could be responsible for such a substitution. METHODS: In this study we investigated the presence of the mutation D147E of CYP11B2 in a group of 128 patients with primary aldosteronism, 68 patients with essential hypertension and increased corticosterone production and in 48 normal volunteers. RESULTS AND CONCLUSIONS: We did not identify any patient carrying this mutation, indicating that if it exists it is very rare and so has no relevance in determining the increased steroid excretion seen in some subtypes of human hypertension.
Asunto(s)
Aldosterona/biosíntesis , Corticosterona/biosíntesis , Citocromo P-450 CYP11B2/genética , Hipertensión/sangre , Hipertensión/genética , Mutación/genética , Anciano , Aldosterona/sangre , Corticosterona/sangre , Exones/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Renina/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Hypertension is a condition where adrenergic responsiveness, sympathetic activity and adrenoceptors are somewhat altered. Many techniques are available to assess human sympathetic nervous system activity. They each present limitations and disadvantages. Characterization and subdivision of the alpha and beta-adrenoceptors, according to their localization and answer to different agonists, was facilitated in recent years by the extensive use of pharmacological and molecular biology techniques. Some adrenoceptor studies were conducted on animal models, human tissues and peripheral blood cells to assess their changes in various forms and stages of hypertension. Our group has pointed out that alpha1-adrenergic receptors expressed by human peripheral blood lymphocytes underwent changes of density in essential hypertensives, compared to normotensive control subjects. The importance of these findings could provide an assessment of alpha1-peripheral receptors with possible future clinical implications in the pathophysiology and treatment of hypertension.
Asunto(s)
Hipertensión/fisiopatología , Receptores Adrenérgicos/fisiología , Animales , Humanos , Linfocitos/fisiología , Músculo Liso Vascular/fisiopatología , Nervios Periféricos/fisiopatología , Receptores Adrenérgicos alfa/clasificación , Receptores Adrenérgicos alfa/fisiología , Receptores Adrenérgicos beta/clasificación , Receptores Adrenérgicos beta/fisiología , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
The relationships between heart rate variability (HRV), left ventricular mass and diastolic function in borderline hypertensive patients (BHT) were evaluated. 24 h Holter electrocardiogram (ECG) and blood pressure (BP) monitoring, M and 2 D echocardiogram and Doppler analysis in 42 BHT with and without left ventricular hypertrophy (LVH) and in 20 normotensive controls were assessed. From 24-h ECG, time domain indexes of HRV were calculated. Standard Deviation of all Cycles (SDNN) and Standard Deviation of the means of heart periods over five-minute intervals (SDANN) were significantly reduced in BHT with LVH but not in BHT without LVH. No significant differences of short-term variability measures were detectable, although a progressive decrease among control subjects and BHT with and without LVH was observed. Diastolic left ventricular compliance evaluated by early to late transmitral flow velocity ratio (E/A ratio) significantly declined from normotensive subjects to BHT with LVH. There was a significant positive correlation between E/A and SDNN and SDANN throughout all studied groups. This indicates that BHT with LVH has a reduced HRV compared to other groups. This impairment is probably related to left ventricular mass and left ventricular filling abnormalities.
Asunto(s)
Frecuencia Cardíaca/fisiología , Hipertensión/complicaciones , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda , Adulto , Estudios de Casos y Controles , Diástole , Ecocardiografía , Femenino , Humanos , Hipertensión/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
1 alpha1-Adrenoceptor subtypes were investigated in cytospin centrifuged preparations of human peripheral blood lymphocytes by in situ hybridization and immunocytochemistry. 2 In situ hybridization cytochemistry revealed alpha1A-, alpha1B-, and alpha1D-receptor mRNA in human peripheral blood lymphocytes. Lymphocytes hybridized for alpha1A receptor subtype represented approximately 30% of total lymphocytes, those hybridized for alpha1Beta- and alpha1D-receptor subtypes averaged 42 and 25% of total lymphocytes, respectively. 3 Cytospin centrifuged lymphocytes exposed to anti-alpha1A-, alpha1Beta- or alpha1D-receptor protein antibodies, developed specific immunostaining. Approximately 27% of total lymphocytes were immunoreactive for alpha1A-receptor protein, 40% displayed alpha1B-receptor protein immunoreactivity and 22% alpha1D-receptor protein immunoreactivity. Analysis of percentages as well as of lymphocyte morphology of in situ hybridized and immunolabelled lymphocytes suggests the co-expression of mRNA receptor signal and protein receptor immunostaining in the same lymphocyte. 4 The demonstration of both alpha1-adrenoceptor mRNA and receptor protein subtypes suggests that alpha1-adrenoceptors may have a role in regulating lymphocyte function. 5 The possibility of demonstrating receptor protein immunoreactivity in a small amount of blood, such as that required for preparing cytospin-centrifuged lymphocytes, may stimulate research to evaluate the role of these receptors in lymphocytes and to establish if assessment of lymphocyte alpha1-adrenoceptors may represent a marker of their status in health and disease.