RESUMO
Natural products are ligands and potential inhibitors of Alzheimer's disease (AD) tau. Dihydromyricetin (DHM) is a CNS active natural product. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH allowing formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All salt formulations show better inhibitory activity against AD tau than the non-salt form, with efficacies correlating to enhanced solubilities. These results underscore the role of structural chemistry in guiding selection of solubilizing agents for chemical formulation. We propose DHM salts are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding. Additionally, DHM is a suitable lead for medicinal chemistry and possible development of CNS pharmaceuticals.
RESUMO
BACKGROUND: We have recently reported that oral treatment of adult male C57BL/6J mice with a non-absorbable antibiotic cocktail resulted in an increase in ethanol intake and in significant reductions in butyrate-producing gut microbiota populations. This work led us to hypothesize that reduction in butyrate levels within the gut is linked to antibiotic-induced increases in voluntary ethanol consumption. OBJECTIVE: This study tested whether ad libitum sodium butyrate supplementation can prevent antibiotic-induced ethanol consumption in mice. METHODS: Sodium butyrate was provided to adult male C57BL/6J mice in drinking water alone or in combination with antibiotic cocktail. Effects on ethanol (20%) intake were measured using drinking in the dark and modified 2-bottle choice paradigms. Body parameters, food and liquid intake, cecum, and adipose tissues were measured during and/or at the conclusion of the drinking in the dark study. Cecal 16s rRNA was analyzed for microbiota diversity and changes in specific bacterial phyla/species. RESULTS: In drinking in the dark, sodium butyrate supplementation prevented antibiotic-induced increases in ethanol intake without altering basal ethanol consumption. Furthermore, sodium butyrate supplementation lowered ethanol preference in the 2-bottle choice study. Ethanol intake was correlated to specific bacterial phyla/species. Sodium butyrate did not affect the changes in microbiota diversity and composition induced by antibiotic cocktail. CONCLUSIONS: The findings support a role of gut microbiota-derived butyrate in regulating alcohol-induced behaviors. Additionally, the work contributes to efforts in development of novel microbiome-based strategies as novel preventative and intervention-based therapeutics to address alcohol use disorder.
Assuntos
Antibacterianos , Etanol , Animais , Ácido Butírico/farmacologia , Suplementos Nutricionais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16SRESUMO
The mixed-function oxidase which activates the carcinogen dimethylnitrosamine (DMN) was determined in the rat liver as a function of animal age. DMN-demethylase activity increased considerably at first to reach a maximum on day 29, and then substantially decreased to day 59; thereafter, enzyme activity remained essentially stable up to at least day 110. Pretreatment with 3-methylcholanthrene, which caused a pronounced decrease in this enzyme activity, did not affect the general shape of the age-dependence curve. The results suggest that rats between weaning and sexual maturity are more susceptible to the carcinogenic effects of pulse doses of DMN than are neonates or adult animals.
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Envelhecimento , Dimetilnitrosamina/metabolismo , Fígado/enzimologia , Nitrosaminas/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Animais , Masculino , Metilcolantreno/farmacologia , Microssomos Hepáticos/enzimologia , RatosRESUMO
Goal-attainment scaling, a method for evaluating treatment programs, has been reported to benefit therapeutic encounters. In order to evaluate its effect on staff therapeutic behavior, raters were trained to rate the appropriateness of inpatient behavior and the staffs' responses to it. General distribution of the goal-attainment scale on a psychiatric inpatient unit influenced the delivery of positive social reinforcement for appropriate behavior.
Assuntos
Logro , Objetivos , Motivação , Transtornos Psicóticos/reabilitação , Reforço Social , Atitude do Pessoal de Saúde , Estudos de Avaliação como Assunto , Florida , Hospitais Psiquiátricos , Humanos , Comportamento SocialRESUMO
We recently developed ultra-sensitive ethanol receptors (USERs) as a novel tool for investigation of single receptor subunit populations sensitized to extremely low ethanol concentrations that do not affect other receptors in the nervous system. To this end, we found that mutations within the extracellular Loop 2 region of glycine receptors (GlyRs) and γ-aminobutyric acid type A receptors (GABAARs) can significantly increase receptor sensitivity to micro-molar concentrations of ethanol resulting in up to a 100-fold increase in ethanol sensitivity relative to wild-type (WT) receptors. The current study investigated: (1) Whether structural manipulations of Loop 2 in α1 GlyRs could similarly increase receptor sensitivity to other anesthetics; and (2) If mutations exclusive to the C-terminal end of Loop 2 are sufficient to impart these changes. We expressed α1 GlyR USERs in Xenopus oocytes and tested the effects of three classes of anesthetics, isoflurane (volatile), propofol (intravenous), and lidocaine (local), known to enhance glycine-induced chloride currents using two-electrode voltage clamp electrophysiology. Loop 2 mutations produced a significant 10-fold increase in isoflurane and lidocaine sensitivity, but no increase in propofol sensitivity compared to WT α1 GlyRs. Interestingly, we also found that structural manipulations in the C-terminal end of Loop 2 were sufficient and selective for α1 GlyR modulation by ethanol, isoflurane, and lidocaine. These studies are the first to report the extracellular region of α1 GlyRs as a site of lidocaine action. Overall, the findings suggest that Loop 2 of α1 GlyRs is a key region that mediates isoflurane and lidocaine modulation. Moreover, the results identify important amino acids in Loop 2 that regulate isoflurane, lidocaine, and ethanol action. Collectively, these data indicate the commonality of the sites for isoflurane, lidocaine, and ethanol action, and the structural requirements for allosteric modulation on α1 GlyRs within the extracellular Loop 2 region.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Hipnóticos e Sedativos/farmacologia , Receptores de Glicina/química , Receptores de Glicina/metabolismo , Animais , Biofísica , Relação Dose-Resposta a Droga , Estimulação Elétrica , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Isoflurano/farmacologia , Lidocaína/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Mutação/genética , Oócitos , Técnicas de Patch-Clamp , Propofol/farmacologia , Receptores de Glicina/genética , XenopusRESUMO
Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.
Assuntos
Pressão Sanguínea , Taxa de Filtração Glomerular , Hipertensão/etiologia , Renina/metabolismo , Adolescente , Adulto , Feminino , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , MasculinoRESUMO
The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human alpha-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the alpha-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the alpha-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.
Assuntos
Pressão Sanguínea , Proteínas de Ligação a Calmodulina/genética , Proteínas do Citoesqueleto/genética , Sódio/metabolismo , Adolescente , Adulto , Alelos , Análise de Variância , Sequência de Bases , DNA/genética , Eritrócitos/metabolismo , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Oligonucleotídeos Antissenso/genética , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Escócia , Sódio/sangue , Tionucleotídeos/genéticaRESUMO
The case is reported of a young woman with severe hypertension, unilateral renal artery stenosis, variously normal or marginally high plasma concentrations of active renin, angiotensin II, aldosterone, sodium, and potassium; and normal total exchangeable and total body sodium and potassium. Arteriograms and ureter catheterization showed the stenosis to be severe, but the unstimulated renal vein renin and angiotensin II differential to be modest. Captopril caused an initial fall in angiotensin II and arterial pressure. During prolonged captopril treatment, plasma angiotensin II and aldosterone remained depressed; exchangeable and total body sodium and potassium were unaltered. Blood pressure fell further to normal levels during prolonged captopril treatment, while subsequent surgical correction of the renal artery stenosis was curative; absolute values of blood pressure and plasma angiotensin II were similar in both situations. The findings support, without proving, the concept that chronic modest elevation of angiotensin II may be responsible for sustained hypertension in unilateral renal artery stenosis. Patients of this type contrast sharply with those, also with severe renal artery stenosis or occlusion, who have gross elevation of renin, angiotensin II, and aldosterone, with sodium and potassium deficiency. Captopril or surgery are effective in both syndromes, but the manner of response to treatment differs markedly.
Assuntos
Angiotensina II/sangue , Captopril/uso terapêutico , Hipertensão Renal/metabolismo , Hipertensão Renovascular/metabolismo , Prolina/análogos & derivados , Obstrução da Artéria Renal/sangue , Adulto , Aldosterona/sangue , Angiotensina II/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hipertensão Renovascular/sangue , Potássio/metabolismo , Obstrução da Artéria Renal/tratamento farmacológico , Obstrução da Artéria Renal/cirurgia , Renina/sangue , Sódio/metabolismoRESUMO
The beta adrenergic blocking drug, timolol, tended to correct the hypokalemia of short-term bendrofluazide treatment in 6 healthy male subjects and although the effect was small it was significant. Timolol also reduced the rise in plasma aldosterone and urine potassium excretion following bendrofluazide and increased the urine sodium/potassium ratio. There was no evidence of a shift of potassium from the intracellular to the extracellular space.
Assuntos
Bendroflumetiazida/efeitos adversos , Hipopotassemia/tratamento farmacológico , Propanolaminas/uso terapêutico , Timolol/uso terapêutico , Bendroflumetiazida/antagonistas & inibidores , Bendroflumetiazida/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipopotassemia/induzido quimicamente , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Masculino , Potássio/metabolismo , Sódio/metabolismo , Timolol/farmacologiaRESUMO
Treatment of 6 healthy adult men with a beta-blocker, timolol, resulted in a rise in serum phosphate which was maintained for the 5 days of therapy. This rise was accompanied by a transient fall in urine phosphate and a rise in the tubular maximum for phosphate reabsorption per unit glomerular filtration rate (TmPO4/GFR). No change in circulating parathyroid hormone or growth hormone could be demonstrated.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Fosfatos/metabolismo , Adulto , Cálcio/sangue , Cálcio/urina , Creatinina/sangue , Creatinina/urina , Taxa de Filtração Glomerular , Humanos , Masculino , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Fosfatos/urina , Fatores de Tempo , Timolol/farmacologiaRESUMO
The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a long-term reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Hipertensão/tratamento farmacológico , Obstrução da Artéria Renal/tratamento farmacológico , Administração Oral , Adulto , Aldosterona/sangue , Angiotensina I/sangue , Angiotensina II/sangue , Composição Corporal/efeitos dos fármacos , Creatinina/sangue , Avaliação de Medicamentos , Enalapril , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/complicações , Rim/irrigação sanguínea , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Postura , Potássio/metabolismo , Obstrução da Artéria Renal/complicações , Renina/sangue , Sódio/metabolismoRESUMO
The effect of a dietary sodium restriction (15 mmol/day) on the development of adrenocorticotrophic hormone (ACTH) hypertension was examined in six normal male subjects. When ACTH (1 mg/day) was given for 5 days to subjects on a sodium-restricted diet, systolic blood pressure rose (116 +/- 4 to 125 +/- 4 mmHg, P less than 0.001), while diastolic blood pressure was unchanged. There was a modest antinatriuresis (cumulative Na+ balance, 59 +/- 2 mmol) which was reflected in a small rise in exchangeable body sodium (65 +/- 15 mmol); plasma concentrations of active renin and angiotensin II both fell during ACTH treatment. Plasma volume rose (2.8 +/- 0.2 to 3.6 +/- 0.16 l, P less than 0.01) while extracellular fluid volume was unchanged. Plasma concentration of atrial natriuretic peptide (ANP) rose to more than twice basal. Glomerular filtration rate (inulin clearance) increased (111 +/- 9 to 131 +/- 7 ml/min, P less than 0.001), renal plasma flow, measured as the rate of para-aminohippurate (PAH) clearance, was unaltered and calculated filtration fraction rose. Dietary sodium restriction did not, therefore, prevent an ACTH-induced increase in blood pressure. The increase in plasma volume with ACTH is not dependent on renal sodium retention and is associated with increased concentrations of ANP. When these data are compared with findings previously reported in subjects given the same dose of ACTH when on normal or high sodium intakes, it is clear that, although the action of ACTH in raising blood pressure is not dependent on exogenous sodium or extracellular fluid volume expansion, sodium retention can modify the level of blood pressure attained.
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Dieta Hipossódica , Hipertensão/etiologia , Adulto , Fator Natriurético Atrial/sangue , Volume Sanguíneo/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hormônios/sangue , Humanos , Hipertensão/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , MasculinoRESUMO
Exchangeable and plasma electrolytes, blood pressure and aldosterone were measured in groups of patients with idiopathic hyperaldosteronism, primary hyperaldosteronism and essential hypertension and in normal subjects. In idiopathic hyperaldosteronism exchangeable sodium was higher than in both essential hypertensive and normal groups but lower than in primary hyperaldosteronism. Plasma sodium results were similar except that no difference existed between the two forms of hyperaldosteronism. Plasma potassium concentration was lower in idiopathic hyperaldosteronism than in either essential hypertensive or in normal groups, but higher than in primary hyperaldosteronism. Blood pressure correlated with age in all groups and with exchangeable sodium in hypertensive patients. This was also the case with exchangeable sodium:exchangeable potassium ratio, but blood pressure did not correlate with aldosterone in any group. In idiopathic hyperaldosteronism, as in essential hypertension, sodium and blood pressure correlated strongly in male and weakly in female patients. The analysis reveals important differences between idiopathic and primary hyperaldosteronism and also between idiopathic hyperaldosteronism and essential hypertension.
Assuntos
Pressão Sanguínea , Hiperaldosteronismo/fisiopatologia , Hipertensão/fisiopatologia , Potássio/sangue , Sódio/metabolismo , Adulto , Idoso , Feminino , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/metabolismo , Hipertensão/sangue , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Sódio/sangueRESUMO
OBJECTIVE: To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. DESIGN: Double-blind, placebo-controlled, parallel-group study of 28 days' duration. SETTING: Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). PATIENTS: Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period. INTERVENTIONS: Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. MAIN OUTCOME MEASURES: Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. RESULTS: When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. CONCLUSIONS: Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Indanos/uso terapêutico , Neprilisina/antagonistas & inibidores , Propionatos/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Fator Natriurético Atrial/sangue , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Indanos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Propionatos/administração & dosagemRESUMO
Both Adrenocorticotrophin (ACTH) and glucocorticoids raise blood pressure in man and animals, but the relationship of this and altered renal function to other cardiovascular variables, and the differences and similarities of the effects of the two agonists have not been fully explained. The present study compares the effects of ACTH (0.5 mg i.m; every 12 h) and cortisol (50 mg orally, every 6 h) in six normal men over a period of 5 days, preceded and followed by control periods of 3 and 2 days, respectively. Plasma cortisol levels were higher during ACTH treatment than during cortisol treatment. Both treatments raised blood pressure significantly and caused a marked antinatriuresis and expansion of extracellular fluid and plasma volume. ACTH also enhanced potassium excretion but this was less obvious for cortisol. Plasma concentrations of atrial natriuretic peptide rose to more than twice the basal level with both treatments. Both treatments markedly altered renal function. They raised glomerular filtration rate (GFR), i.e. inulin clearance (141% with ACTH; 113% with cortisol) although creatinine clearance was not changed, showing this to be an unreliable index during steroid administration. Filtration fraction (FF) also increased during both treatments, and renal blood flow (RBF) fell, although this achieved statistical significance only during cortisol treatment. Effective renal plasma flow [para-amino hippurate (PAH) clearance] remained unchanged while calculated renal vascular resistance increased. Fractional sodium reabsorption also rose but achieved statistical significance only during ACTH treatment. The similarity of response to treatment suggests that cortisol is largely responsible for the effects of ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Fator Natriurético Atrial/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Eletrólitos/metabolismo , Hidrocortisona/farmacologia , Rim/efeitos dos fármacos , Adulto , Espaço Extracelular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
Measurements of exchangeable sodium, arterial pressure and plasma concentrations of active renin, angiotensin II, aldosterone, sodium and potassium were made in 35 hypertensive patients with renal artery stenosis, 30 having unilateral renal arterial lesions. Plasma urea was below 7 mmol/l in 24 of the patients with unilateral lesions. In these and in the whole group of 35 patients there were significant inverse correlations between exchangeable sodium and diastolic blood pressure and between plasma sodium concentration and diastolic pressure. Six patients had hyponatraemia with a plasma sodium concentration less than 135 mmol/l. All were sodium-deplete with secondary hyperaldosteronism, three also having malignant-phase hypertension. Twelve of the patients with unilateral renal artery stenosis underwent bilateral ureteric catheterization. Sodium excretion was greater from the contralateral kidney than from the affected kidney and the rate of sodium excretion from the former, but not from the latter, was significantly related to arterial pressure. The relation of diastolic blood pressure and exchangeable sodium is the opposite of the positive correlation found in essential hypertension and Conn's syndrome. In renal artery stenosis the inverse correlation could result from a natriuretic effect of increased arterial pressure occurring mainly in the contralateral kidney.
Assuntos
Hipertensão Renovascular/sangue , Obstrução da Artéria Renal/sangue , Sódio/sangue , Adulto , Aldosterona/sangue , Angiotensina II/sangue , Pressão Sanguínea , Creatinina/urina , Feminino , Humanos , Hipertensão Renovascular/complicações , Hiponatremia/etiologia , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Obstrução da Artéria Renal/complicações , Renina/sangue , Sódio/urina , Ácido p-Aminoipúrico/urinaRESUMO
Thirty-four patients with untreated Conn's syndrome were studied in a metabolic ward. The final diagnosis in each case was based on the finding and removal of an adrenal cortical adenoma with histological features typical of the disorder. Compared with 34 age and sex-matched normal controls the untreated patients had increased plasma aldosterone concentration, increased blood pressure (183/112 mmHg), increased exchangeable sodium (116.7% of normal), hypokalaemia and increased plasma sodium concentration. Exchangeable potassium was lower than normal and plasma concentrations of active renin, total renin and angiotensin II were lower than normal mean values. Arterial pressure correlated significantly and positively with plasma and exchangeable sodium and there was a significant negative correlation with plasma potassium concentration. Partial regression analysis showed that the relation of exchangeable sodium with blood pressure did not depend on age or renal function but that the relation of blood pressure and plasma potassium could be attributed to the correlation of exchangeable sodium and blood pressure. Multiple regression analysis suggested that exchangeable and plasma sodium were the most important determinants of blood pressure in untreated patients. Spironolactone, amiloride and surgical removal of the adenoma corrected the electrolyte abnormality and usually lowered blood pressure. The fall in exchangeable sodium was related to the fall in blood pressure. The pattern of correlation found by multiple regression analysis in postoperative patients was similar to that in normal subjects. The findings are relevant to some of the mechanisms proposed for the hypertension of mineralocorticoid excess.
Assuntos
Pressão Sanguínea , Eletrólitos/metabolismo , Hiperaldosteronismo/fisiopatologia , Adulto , Aldosterona/sangue , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hiperaldosteronismo/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Mineralocorticoides/farmacologia , Análise de Regressão , Sódio/metabolismo , Vasoconstrição , Vasopressinas/fisiologiaRESUMO
The whole body content of sodium, potassium, chlorine, calcium, phosphorus and nitrogen was measured by neutron activation analysis in 13 patients with untreated primary hyperaldosteronism (Conn's syndrome; aldosterone-secreting adenoma). Concurrently, exchangeable sodium and potassium were estimated by isotope dilution. Results were compared with values in the same patients during treatment with potassium-conserving diuretics and again after removal of the adenoma; and also with those in a series of 30 patients having untreated essential hypertension. Both total body and exchangeable sodium were high in Conn's syndrome before treatment and were reduced by spironolactone or amiloride and by subsequent surgery. There was no evidence of alteration in the proportion of non-exchangeable sodium in this disease, in contrast to earlier reports. Total body and exchangeable potassium were low in untreated Conn's syndrome and increased to normal after therapy: the proportion of non-exchangeable potassium was similar before and after treatment, and also similar to that in essential hypertension. Total body chlorine was increased before treatment in Conn's syndrome and returned to normal with therapy; body calcium, phosphorus and nitrogen were normal throughout.
Assuntos
Composição Corporal/efeitos dos fármacos , Cloro/metabolismo , Hiperaldosteronismo/metabolismo , Potássio/metabolismo , Sódio/metabolismo , Adulto , Idoso , Cálcio/metabolismo , Feminino , Humanos , Hiperaldosteronismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Análise de Ativação de Nêutrons , Nitrogênio/metabolismo , Fósforo/metabolismoRESUMO
Fifteen patients with hypertension and unilateral renal artery disease were treated with captopril alone; 10 came to operation and were later assessed postoperatively with no drug treatment. Captopril caused both immediate and sustained decreases in plasma angiotensin II and aldosterone, with increases in plasma active renin and blood angiotensin I concentrations. Decrements in systolic and diastolic pressure 2 hours after the first dose of captopril were closely correlated with the initial decreases in plasma angiotensin II. Blood pressure was decreased by long-term captopril therapy irrespective of whether plasma angiotensin II was abnormally high before treatment. The long-term response of both systolic and diastolic pressure correlated well with the response to surgery. By contrast, the blood pressure decrease 2 hours after the initial dose of captopril variously underestimated and overestimated the decrease during prolonged use of the drug and did not relate to surgical outcome. In patients who, before treatment, had secondary aldosteronism, hyponatremia, hypokalemia and sodium and potassium deficiency, captopril corrected these abnormalities. In the remaining patients, long-term captopril therapy did not alter exchangeable sodium, plasma sodium or total body potassium, although plasma potassium levels increased.
Assuntos
Captopril/uso terapêutico , Hipertensão Renal/tratamento farmacológico , Hipertensão Renovascular/tratamento farmacológico , Prolina/análogos & derivados , Obstrução da Artéria Renal/complicações , Adolescente , Adulto , Aldosterona/sangue , Angiotensina II/sangue , Pressão Sanguínea/efeitos dos fármacos , Captopril/efeitos adversos , Feminino , Humanos , Hipertensão Renovascular/sangue , Hipertensão Renovascular/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Avaliação de Processos e Resultados em Cuidados de Saúde , Potássio/sangue , Obstrução da Artéria Renal/cirurgia , Renina/sangueRESUMO
The effect of dopamine (1 microgram/kg per min) on corticosteroid response to ACTH (0.1, 1 and 10 ng/kg per min) was compared with that of a placebo in sodium-replete (150 mmol/day) and -deplete (10 mmol/day) normal man. Dopamine had no effect on aldosterone, cortisol or corticosterone responses in either dietary phase, but increased deoxycorticosterone (897.0 +/- 126.4 (S.E.M.) vs 590.0 +/- 84.3 pmol/l, normal Na+; 1264.2 +/- 84.3 vs 764.5 +/- 84.3 pmol/l, low Na+) and deoxycortisol (6.033 +/- 0.583 vs 5.048 +/- 0.680 nmol/l, normal Na+; 5.112 +/- 0.600 vs 4.130 +/- 0.367 nmol/l, low Na+) levels during ACTH administration (all P less than 0.01). Deoxycorticosterone and corticosterone responses to ACTH were greater during sodium depletion than repletion (both P less than 0.01). Dopamine therefore increased 11-deoxycorticosteroid concentrations during ACTH-stimulated steroidogenesis. This may reflect action of dopamine to increase extra-adrenal formation of 11-deoxycorticosteroids.