RESUMO
We employed a novel immunoradiometric assay to measure plasma levels of active renin and prorenin in physiologic and pharmacologic studies designed to characterize renin biosynthesis and processing in response to both chronic and acute stimuli of renin secretion in normal human subjects. Stimulation of renin secretion with prolonged dietary sodium restriction or amiloride resulted in marked increases in the plasma levels of prorenin, active renin, and plasma renin activity (PRA); suppression of renin secretion with indomethacin resulted in parallel decreases in prorenin, active renin, and PRA. In contrast, acute stimulation with upright activity or administration of an angiotensin-converting enzyme inhibitor, which increased active renin and PRA from 2- to 15-fold, had no effect on prorenin levels. Based on studies in cultured human juxtaglomerular tumor cells, it has been proposed that prorenin is secreted constitutively whereas active renin is stored in and released from secretory granules through a regulated pathway. Our studies are consistent with such a model: the parallel changes in active renin and prorenin with experimental maneuvers of long duration suggest that both the constitutive and regulated pathways are altered under these conditions. The increase in active renin levels in the absence of a change in prorenin that occurs in response to acute stimuli presumably represents the release of preformed active enzyme that is stored in secretory granules.
Assuntos
Precursores Enzimáticos/sangue , Renina/sangue , Adulto , Aldosterona/urina , Amilorida/farmacologia , Eletrólitos/sangue , Eletrólitos/urina , Humanos , Indometacina/farmacologia , Masculino , Pessoa de Meia-Idade , Postura , Radioimunoensaio , Sódio na DietaRESUMO
Abnormalities in glomerular function have been observed frequently in the early stages of both clinical and experimental diabetes mellitus. Because prostaglandins (PGs) are present in the glomerulus and have profound effects on glomerular hemodynamics, and because abnormalities of PG metabolism have been noted in other tissues from diabetics, we studied PG biosynthesis in glomeruli obtained from rats in the early stages of experimental diabetes mellitus. Streptozotocin, 60 mg/kg, was administered intravenously to male Sprague-Dawley rats. Control rats received an equal volume of the vehicle. Glomeruli were isolated 9-23 d later. Production of eicosanoids was determined by two methods: by direct radioimmunoassay after incubation of glomeruli under basal conditions and in the presence of arachidonic acid (C20:4), 30 microM, and by radiometric high-performance liquid chromatography (HPLC) after incubation of glomeruli with [14C]C20:4. When assessed by radioimmunoassay, mean basal production of both prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) was twofold greater in the diabetic animals whereas production of thromboxane B2 (TXB2) was not significantly greater than control. In response to C20:4, both PGE2 and PGF2 alpha were also greater in the diabetic animals, but these differences were not statistically significant. The increased rate of basal PG production did not appear to be related directly to the severity of the diabetic state as reflected by the degree of hyperglycemia at the time of sacrifice. In fact, the rates of glomerular PG production in the individual diabetic animals correlated inversely with the plasma glucose concentration. The increased rate of PG synthesis did not appear to be due to a nonspecific effect of streptozotocin inasmuch as glomerular PG production was not increased significantly in streptozotocin-treated rats which were made euglycemic by insulin therapy. Furthermore, addition of streptozotocin, 1-10 mM, to the incubation media had no effect on PGE2 production by normal glomeruli. PGE2 production by normal glomeruli was also not influenced by varying the glucose concentration in the incubation media over a range of 1-40 mM. When metabolism of [14C]C20:4 was evaluated by high-performance liquid chromatography conversion to labeled PGE2, PGF2 alpha, TXB2, and hydroxyheptadecatrienoic acid by diabetic glomeruli was two- to threefold greater compared with that in control glomeruli, whereas no significant difference in conversion to 12- and 15-hydroxyeicosatetraenoic acid occurred. These findings indicate that glomerular cyclooxygenase but not lipoxygenase activity was increased in the diabetic animals. A concomitant increase in glomerular phospholipase activity may also have been present to account for the more pronounced differences in PG production noted in the absence of exogenous unlabeled C20:4. These abnormalities in PG biosynthesis by diabetic glomeruli may contribute to the altered glomerular hemodynamics in this pathophysiologic setting.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Glomérulos Renais/metabolismo , Prostaglandinas/biossíntese , Animais , Dinoprosta , Dinoprostona , Técnicas In Vitro , Glomérulos Renais/efeitos dos fármacos , Masculino , Prostaglandinas E/biossíntese , Prostaglandinas F/biossíntese , Ratos , Ratos Endogâmicos , Estreptozocina/toxicidade , Tromboxano B2/biossínteseRESUMO
Angiotensin II is known primarily for its effects on blood pressure and electrolyte homeostasis, but recent studies suggest that angiotensin II may play a role in the regulation of cellular growth. This study was undertaken to identify the angiotensin II receptor subtypes expressed during fetal and neonatal development and to characterize their cellular localization. Using an in situ receptor binding assay on sagittal frozen sections of fetal and neonatal rats, bound 125I-[Sar1,Ile8]-angiotensin II was visualized by film and emulsion autoradiography. Bound radioligand was detected by E11 (embryonic day 11) and maximal binding occurred by E19-21. Radioligand binding remained unaltered 30 min after birth, whereas a noticeable and stable decrease was observed 12 h postparturition. The highly abundant angiotensin II receptors were shown to be AT2 by the marked reduction in radioligand binding achieved with PD123177 (10(-7)M), a specific AT2 receptor antagonist, whereas DuP 753 (10(-5)M), an AT1 receptor antagonist, had little effect. Emulsion autoradiography showed radioligand binding in the undifferentiated mesenchyme of the submucosal layers of the intestine and stomach, connective tissue and choroid surrounding the retina, subdermal mesenchyme adjacent to developing cartilage, diaphragm, and tongue. Residual AT2 receptors were found on the dorsal subdermal region of the tongue 72 h after birth. AT1 receptors were detected in the placenta at E13 and in the aorta, kidney, lung, liver, and adrenal gland at E19-21, consistent with an adult distribution. The transient expression of AT2 receptors in the mesenchyme of the fetus suggests a role of angiotensin II in fetal development.
Assuntos
Angiotensina II/metabolismo , Feto/metabolismo , Receptores de Angiotensina/análise , Animais , Autorradiografia , Desenvolvimento Embrionário e Fetal , Feminino , Gravidez , Ratos , Ratos Endogâmicos , Fator de Crescimento Transformador beta/análiseRESUMO
To determine whether decreased renal responsiveness to atrial natriuretic peptide (ANP) in diabetes is mediated by alterations in the renal ANP receptor, ANP receptor density and affinity were measured 17-20 d after streptozotocin injection and compared with values in vehicle-treated controls and streptozotocin-treated rats made euglycemic with insulin. Plasma ANP concentration was significantly greater in hyperglycemic diabetic rats than in control or euglycemic diabetic rats. Both in glomeruli and inner medulla, ANP receptor dissociation constant did not differ among the three study groups, whereas the maximum binding capacity was decreased significantly in hyperglycemic diabetics in comparison with controls and euglycemic diabetics. Glomerular clearance receptors were also decreased significantly in hyperglycemic diabetic rats in comparison with control and euglycemic diabetic rats. To determine whether the decreased number of renal ANP receptors in diabetic rats was associated with a decreased biological response, we measured ANP-dependent cyclic GMP (cGMP) accumulation by isolated glomeruli and inner medullary collecting duct cells in vitro. cGMP accumulation was significantly less in hyperglycemic diabetic rats than in controls or euglycemic diabetic rats both in the presence or absence of the phosphodiesterase inhibitor zaprinast. cGMP phosphodiesterase activity in inner medullary collecting duct cells obtained from control and hyperglycemic diabetic rats did not differ. Thus, the decreased number of biologically active ANP receptors in the kidneys of diabetic rats is accompanied by decreased biological responsiveness in vitro and provides a potential explanation for the reduction in renal sensitivity to ANP in this condition.
Assuntos
Fator Natriurético Atrial/metabolismo , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Animais , Autorradiografia , Peso Corporal , Membrana Celular/metabolismo , GMP Cíclico/metabolismo , Citosol/metabolismo , Guanilato Ciclase/metabolismo , Glomérulos Renais/metabolismo , Masculino , Diester Fosfórico Hidrolases/metabolismo , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Aldosterone receptors from rat kidney slices were utilized in a competitive binding technique to analyze the contribution of various steroids to plasma "mineralocorticoid" activity and to assess their possible role in hypertension. To consider simultaneously the plasma binding, steroids were incubated with slices in undiluted plasma; competitor activities for [3H]aldosterone binding were aldosterone, 100%; deoxycorticosterone, 16.2%; cortisol, 0.4%; and 18-hydroxy-deoxy-corticosterone and d18-hydroxy-corticosterone, 0.1%. These steroids were more active in buffer than plasma, suggesting that they bind to plasma and that this reduces their receptor binding. Analysis of the competition data suggests that at normal plasma concentrations, aldosterone occupies the receptors to a major extent, cortisol occupies some of the receptors, and deoxycorticosterone and 8-hydroxydeoxycorticosterone contribute little to receptor occupancy. Two steroids implicated in low-renin essential hypertension, 16beta-hydroxy-dehydro-epiandrosterone and 16-oxoandrostenediol, did not have significant competitor activity. Competitor activity in plasmas from normal subjects taken at 12 noon (upright) was greater than that in those taken at 8 a.m. (supine). Since the 12 noon samples had higher aldosterone and lower cortisol levels than the 8 a.m. samples, the competitor activity under these physiological circumstances reflects aldosterone more than cortisol. The competitor activities of plasmas from patients relative to normal subjects (100+/-12.1%; mean+/-SEM) were: normal renin "essential" hypertension, 117+/-14%; low-renin essential hypertension, 101+/-6.6%; and primary aldosteronism, 176+/-14.3%. Thus a significant increase in activity of steroids that interact with mineralocorticoid receptors was detected in primary aldosteronism (P LESS THAN 0.01) BUT WAS NOT DETECTED IN LOW-RENIN OR NORMAL-RENIN ESSENTIAL HYPERTENSION.
Assuntos
Aldosterona/metabolismo , Hipertensão/sangue , Mineralocorticoides/sangue , Receptores de Superfície Celular , Androstenodióis/sangue , Androstenodióis/farmacologia , Animais , Ligação Competitiva , Corticosterona/análogos & derivados , Corticosterona/sangue , Corticosterona/farmacologia , Depressão Química , Desoxicorticosterona/sangue , Desoxicorticosterona/farmacologia , Hidrocortisona/sangue , Hidrocortisona/farmacologia , Postura , Ratos , Fatores de TempoRESUMO
To determine the effect of diabetes on the cardiac renin-angiotensin system, we compared angiotensin II binding density and renin, angiotensinogen, and type 1 angiotensin II (AT1) receptor mRNA levels in hearts of Sprague-Dawley rats 14 days after the administration of streptozotocin (STZ), in vehicle-treated control rats, and in STZ-administered rats made euglycemic with insulin. Myocardial angiotensin II receptor density, determined using an in situ autoradiographic technique, was increased significantly in hyperglycemic diabetic rats in comparison with control rats and euglycemic diabetic rats (P < 0.01) as a result of an increase in both AT1 and AT2 (type 2 angiotensin II) subtypes. The myocardial AT1 receptor mRNA level, determined by slot blot hybridization, was also significantly greater in the hyperglycemic diabetic rats (P < 0.005). Neither plasma renin concentration nor cardiac renin or angiotensinogen mRNA levels differed among the three study groups. In an additional experiment, control and diabetic rats were infused with angiotensin II (200 ng.kg-1.min-1 i.p. for 7 days) or vehicle. Plasma renin concentration decreased significantly, whereas no significant changes occurred in cardiac renin or angiotensinogen steady-state mRNA levels. As in the first experiment, levels of AT1 receptor mRNA were significantly greater in the diabetic rats. Thus, myocardial angiotensin II receptor density is increased in diabetic rats in association with an increase in steady-state AT1 receptor mRNA levels, an abnormality that appears to be independent of changes in the circulating renin-angiotensin system.
Assuntos
Angiotensina II/metabolismo , Diabetes Mellitus Experimental/metabolismo , Miocárdio/metabolismo , Receptores de Angiotensina/metabolismo , Sistema Renina-Angiotensina , Análise de Variância , Antagonistas de Receptores de Angiotensina , Animais , Compostos de Bifenilo/farmacologia , Expressão Gênica , Hiperglicemia/metabolismo , Imidazóis/farmacologia , Insulina/farmacologia , Cinética , Losartan , Masculino , Piridinas/farmacologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/efeitos dos fármacos , Valores de Referência , Tetrazóis/farmacologiaRESUMO
In rats with STZ-induced diabetes mellitus, a reduction in insulin secretion is associated with increased insulin binding in the liver, muscle, fat, and kidney, but not in the brain. To test the hypothesis that tissue-specific modulation of insulin receptors (IRs) in STZ-induced diabetes occurs at the level of mRNA, IR mRNA levels were measured in the liver, kidney, and brain of Sprague-Dawley rats 15 days after intravenous administration of STZ (60 mg/kg body weight) and compared with those of control rats. Diabetic rats were either left untreated or given differing insulin regimens that were designed to achieve varying degrees of metabolic control. IR mRNA levels were measured by slot blot hybridization with a 32P-labeled rIR probe and standardized by 28S ribosomal RNA determination. Hepatic IR mRNA levels were increased significantly in both untreated diabetic rats and in those that received low-dose (2 U/day) insulin therapy. In contrast, hepatic IR mRNA levels did not differ significantly from controls in those that received moderate doses of insulin (3-8 U/day) and were significantly less than controls in those that received the highest doses (6-10 U/day). Renal IR mRNA levels also were increased significantly in the untreated diabetic rats but not in those that received low- or moderate-dose insulin therapy, and were significantly less than controls in those that received the highest doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diabetes Mellitus Experimental/genética , RNA Mensageiro/análise , Receptor de Insulina/genética , Animais , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Química Encefálica , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Insulina/sangue , Insulina/metabolismo , Insulina/uso terapêutico , Rim/química , Rim/metabolismo , Rim/ultraestrutura , Fígado/química , Fígado/metabolismo , Fígado/ultraestrutura , Masculino , Hibridização de Ácido Nucleico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos , Receptor de Insulina/metabolismo , EstreptozocinaRESUMO
BACKGROUND: Therapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition. METHODS: Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy. RESULTS: Fasting glucose (4.9 +/- 0.1 versus 5.2 +/- 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 +/- 12.2 versus 83.9 +/- 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 +/- 1.7 versus 15.9 +/- 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 +/- 0.3 versus 2.8 +/- 0.5;P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 +/- 0.4 versus 6.5 +/- 0.6 mmol/l; P < 0.05) and insulin levels (223.1 +/- 48.8 versus 390.3 +/- 108.8 pmol/l;P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 +/- 1.4 versus 8.6 +/- 1.2 mg/kg x min per microU/ml insulin; 95% confidence interval 0.6--.0;P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 +/- 1.4 versus 15.2 +/- 1.4 kg;P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography. CONCLUSIONS: In the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.
Assuntos
Inibidores da Protease de HIV/metabolismo , Soronegatividade para HIV/fisiologia , Indinavir/metabolismo , Adulto , Idoso , Glicemia/análise , Teste de Tolerância a Glucose , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Nível de Saúde , Humanos , Indinavir/administração & dosagem , Indinavir/efeitos adversos , Insulina/sangue , Ácido Láctico/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
Plasma 18-hydroxycorticosterone (180HB) concentration was measured in 23 patients with primary aldosteronism. After overnight recumbency, the levels were markedly elevated and were 6 times higher in patients with aldosterone-producing adenomas than in patients with hyperplasia. A value of 100 ng/dl or greater at 0800 h after overnight recumbency distinguished an adenoma from hyperplasia. There was no overlap of values, as was observed with plasma aldosterone concentration (PAC) at 0800 h and after 4 h of upright posture at 1200 h. There was a significant negative correlation between the ratio of 180HB to PAC and the potassium concentration in patients with primary aldosteronism due to hyperplasia. Potassium repletion with potassium chloride and/or spironolactone in patients with aldosterone-producing adenomas decreased the 180HB:PAC ratio by decreasing 180HB and increasing PAC. 180HB is an effective discriminator of an adenoma and may be a useful marker of the events in late aldosterone synthesis.
Assuntos
18-Hidroxicorticosterona/sangue , Corticosterona/análogos & derivados , Hiperaldosteronismo/sangue , Adenoma/sangue , Neoplasias das Glândulas Suprarrenais/sangue , Hiperfunção Adrenocortical/sangue , Aldosterona/sangue , Humanos , Hiperaldosteronismo/etiologia , Postura , Potássio/sangue , Cloreto de Potássio/farmacologia , Renina/sangue , Espironolactona/farmacologiaRESUMO
In previous studies, treatment with recombinant human GH (rhGH) produced sustained increases in weight and lean body mass (LBM) and decreases in fat mass in patients with human immunodeficiency virus (HIV)-associated wasting. To evaluate the effects of chronic rhGH treatment on components of energy balance, we recruited separate subgroups of HIV-positive patients with an involuntary weight loss of 10% or more to undergo paired measurements of resting energy metabolism (n = 6) or food intake (n = 11) before and during the final week of a 3-month rhGH (0.1 mg/kg.day) treatment period. In the energy metabolism subset, resting energy expenditure (REE) and substrate oxidation rates were measured by indirect calorimetry during brief admissions to a metabolic ward. Patients in the energy intake subset prepared written 4-day food intake diaries. Body composition was measured in both groups by bioelectrical impedance analysis. Changes in weight (+2.2 +/- 0.9 and +2.2 +/- 0.6 kg), LBM (+3.2 +/- 0.6 and +3.8 +/- 0.5 kg), and fat (-1.0 +/- 0.5 and -1.6 +/- 0.5 kg) in the energy metabolism and energy intake subsets, respectively, did not differ between groups and were comparable to changes seen in a larger group of patients who received rhGH in a randomized, double blind, placebo-controlled multicenter study. In the energy metabolism subset, REE (+232 +/- 69 Cal/day; P = 0.020) and lipid oxidation (+3.1 +/- 1.0 Cal/kg LBM.day; P = 0.016) increased, whereas protein oxidation decreased (-1.3 +/- 1.0 Cal/kg LBM.day; P = 0.027) during rhGH therapy. These changes in REE and substrate oxidation are comparable to changes we noted previously in a study of the effects of short term rhGH treatment in patients with HIV-associated wasting. Moreover, the sustained increases in lipid oxidation are consistent with the decreases in body fat content that occur with rhGH treatment. In the energy intake subset, a trend for increased daily energy intake (+203 +/- 262 Cal; P = 0.456) is obviated when adjustments for changes in weight or LBM are made (+1.3 +/- 4.0 and -0.5 +/- 5.0 Cal/kg BW and LBM, respectively). Taken together, these results demonstrate that increases in weight and LBM that occur with chronic rhGH therapy are accompanied by sustained increases in REE and lipid oxidation and decreases in protein oxidation. These changes in body composition occur without a significant increase in energy intake and may, instead, represent a redistribution of body energy stores.
Assuntos
Ingestão de Energia , Metabolismo Energético , Síndrome de Emaciação por Infecção pelo HIV/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adulto , Composição Corporal , Calorimetria Indireta , Método Duplo-Cego , Impedância Elétrica , Feminino , Síndrome de Emaciação por Infecção pelo HIV/metabolismo , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Metabolismo dos Lipídeos , Masculino , Oxirredução , Proteínas/metabolismo , Aumento de PesoRESUMO
Cytosol binding of [3H]aldosterone was measured after incubation of the hormone at 37 C with slices of human kidney obtained after surgical removal. High affinity [3H]aldosterone binding with an apparent equilibrium dissociation constant (Kd) of approximately 0.5 nM was observed to probably "mineralo-corticoid receptors." [3H]aldosterone binding of lower affinity and higher capacity (probably to "glucocorticoid receptors") was also observed. Binding of other steroids by the mineralocorticoid receptors was determined by competitive analysis using a low concentration of [3H]aldosterone (so that [3H] binding is predominantly by the mineralocorticoid receptors). The binding activities relative to aldosterone (100%) were: deoxycorticosterone, 48%; cortisol, 1.5%; 18-hydroxy-deoxycorticosterone, 1.2%; and 18-hydroxy-corticosterone, 0.2%. The relative sodium-retaining potencies of these steroids in vivo correlate well with their binding activities. These data provide further support to the view that the major high affinity [3H]aldosterone binding is by mineralocorticoid receptors. Two steroids, 16beta-hydroxy-dehydroepiandrosterone and 16-oxo-androstenediol, recently shown to have sodium-retaining activity in the rat, and also implicated in low-renin "essential" hypertension in man, showed no competitive binding activity. The affinity of [3H]aldosterone for binding to these mineralocorticoid receptors and the relative steroid binding activities are similar to the values previously reported in the rat. Thus, human and rat mineralocorticoid receptors appear to be similar in their affinity for aldosterone and their specificity for binding a number of other steroids.
Assuntos
Aldosterona/metabolismo , Rim/metabolismo , Receptores de Esteroides/metabolismo , Animais , Citosol/metabolismo , Humanos , Rim/ultraestrutura , Cinética , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
A role for hormonal substances and other biochemical messengers in the regulation of the glomerular filtration rate has been inferred from the results of micropuncture studies in the rat and from the demonstration of hormone-responsive adenylate cyclase activity in glomeruli isolated from the renal cortex of rats and rabbits. To investigate whether such hormonal factors may contribute to the regulation of glomerular function in humans, we studied the response of adenylate cyclase activity to the administration of human PTH-(1-34) and prostaglandins (PG) by glomeruli isolated from the renal cortex of four human kidneys. PTH and PGs (PGE2, PGI2, and, to a lesser extent, PGF2 alpha) stimulated human glomerular adenylate cyclase activity. Basal adenylate cyclase activity ranged from 0.2-1.2 nmol 20 min-1 mg-1. For each agonist, the percent increase above basal values (at the maximum concentration tested) and the concentration of the agonist that elicited 50% of the maximum stimulation (ED50) were as follows: for PTH 300-460% (10,000 mIU/ml); ED50, 100-550 mIU/ml; for PGE2, 160-380% (10 microM); ED50, 0.4-1.6 microM; and for PGI2, 180-650% (10 microM); ED50, 0.09-0.46 microM. The synthetic guanylnucleotide 5'-guanylylimidodiphosphate [Gpp(NH)p] potentiated the effect of PTH and PGI2, since the combined effects were greater than the sums of the effects of the individual agonists, and there was a significant interaction between Gpp(NH)p and PTH or PGI2, as indicated by three-factor analysis of variance. Additivity, but not potentiation, was observed for PGE2. The effects of PTH plus PGE2 or PGI2 were also additive, a finding that suggests that PTH and PGs are not linked to the same pool of adenylate cyclase. In contrast, the combination of PGE2 and PGI2 resulted in a significantly lower effect than the sum of their individual effects, a finding indicating that these PGs share in part a common pool of adenylate cyclase. Demonstration of PTH- and PG-dependent adenylate cyclase activity in human isolated glomeruli suggests a role for these agonists in the regulation of the glomerular filtration rate in man.
Assuntos
Adenilil Ciclases/metabolismo , Glomérulos Renais/enzimologia , Hormônio Paratireóideo/farmacologia , Fragmentos de Peptídeos/farmacologia , Prostaglandinas/farmacologia , Adulto , Dinoprosta , Dinoprostona , Interações Medicamentosas , Epoprostenol/farmacologia , Guanilil Imidodifosfato/farmacologia , Humanos , Técnicas In Vitro , Glomérulos Renais/efeitos dos fármacos , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologia , TeriparatidaRESUMO
Spironolactone (SPL) corrects hypertension, hypokalemia, and hyporeninemia in patients with primary hyperaldosteronism (PHA) by blocking mineralocorticoid (MCH) receptors. We evaluated the effect of continuous SPL treatment (100 to 300 mg/day for 7 days to 9 years) on plasma renin (PRC), potassium, aldosterone (PA), 18-hydroxycorticosterone (18-OHB), deoxycorticosterone (DOC), and corticosterone (B) concentrations and 24-hour urinary excretion of aldosterone (UA) in 24 patients with PHA (15 with an aldosterone-producing adenoma [APA] and nine with idiopathic PHA [IHA]). Despite the normalization of PRC and K in both APA and IHA patients by SPL, UA and PA failed to increase in APA (55.8 +/- 8.8 to 51.4 +/- 7.3 micrograms/24 hr and 54.0 +/- 9.4 to 44.6 +/- 6.2 ng/dl, respectively) in contrast to rises in IHA patients (22.3 +/- 2.5 to 69.3 +/- 10.3 micrograms/24 hr and 16.0 +/- 1.0 to 49.9 +/- 9.9 ng/dl). Similar corrections with amiloride (20-40 mg/day for 2 months) in one patient with APA produced a three- to fourfold increase in UA and PA. In addition, while on SPL the characteristic fall or no change in PA and 18-OHB during upright posture persisted in all APA patients despite further increases in PRC (4.48 +/- 1.15 to 7.86 +/- 1.89) and K (4.0 +/- 0.1 to 4.3 +/- 0.1). The patterns of the aldosterone precursors, DOC, B, and 18-OHB, and their ratios to acute stimulation with cosyntropin were not altered by SPL. Thus, SPL treatment causes a sustained impairment of the aldosterone secretory response to normalized PRC and K, but not to ACTH stimulation, only in patients with APA.
Assuntos
Adenoma/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Aldosterona/metabolismo , Hiperaldosteronismo/tratamento farmacológico , Potássio/sangue , Renina/sangue , Espironolactona/farmacologia , Glândulas Suprarrenais/patologia , Adulto , Cosintropina , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Postura , Espironolactona/administração & dosagem , Fatores de TempoRESUMO
Urodilatin is a recently described member of the atrial natriuretic peptide family, thought possibly to be synthesized in the kidney. To determine if urodilatin binding sites are present in rat and human kidney, we evaluated the effect of urodilatin on iodine-125-labeled atrial natriuretic peptide (ANP) (100 pM) binding to tissue sections using an in situ autoradiographic technique. 125I-ANP binding occurred primarily in glomeruli and medullary structures of both rat and human kidney. Increasing concentrations of urodilatin yielded a monophasic displacement of 125I-ANP binding with an IC50 of 4.2 nM, a value nearly identical to that achieved with unlabeled ANP (7.2 nM). In additional experiments, rat glomeruli and inner medullary collecting duct cells were isolated and incubated in vitro with either ANP or urodilatin (10(-11) to 10(-6) M) and cyclic guanosine-3',5'-monophosphate accumulation measured by radioimmunoassay. Dose-response curves for the two peptides were superimposable in each tissue; at 10(-6) M, ANP generated 613 +/- 41 and urodilatin 603 +/- 55 fmol cyclic guanosine monophosphate per 10 minutes per milligram protein in inner medullary collecting duct cells (p = NS). Thus, urodilatin is as effective as ANP in displacing 125I-ANP binding to both rat and human renal tissue and in generating cyclic guanosine monophosphate in renal target cells in the rat, suggesting that its physiological effects may occur through the same receptors and signaling pathways that mediate the actions of ANP.
Assuntos
Fator Natriurético Atrial/metabolismo , Fator Natriurético Atrial/farmacologia , GMP Cíclico/metabolismo , Diuréticos/metabolismo , Rim/metabolismo , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Receptores do Fator Natriurético Atrial/fisiologia , Animais , Autorradiografia , Ligação Competitiva , Diuréticos/farmacologia , Radioisótopos do Iodo , Rim/efeitos dos fármacos , Glomérulos Renais/metabolismo , Medula Renal/metabolismo , Túbulos Renais Coletores/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
Insulin resistance is present in some strains of rats with genetic hypertension. To determine whether this abnormality is present at the level of the insulin receptor, we compared insulin sensitivity, insulin receptor binding, and mRNA levels in tissues of 10-week-old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. Because we have previously demonstrated an inverse relationship between dietary sodium intake and renal insulin receptor density and mRNA levels in normal Sprague-Dawley rats, the two rat strains in the current experiment were fed either low salt (0.07% NaCl) or high salt (7.5% NaCl) chow until the SHR became hypertensive. Fasting plasma glucose and plasma insulin levels did not differ between SHR and WKY and were not affected by salt intake. When the rats were maintained on the low salt diet, the rate of glucose infusion required to main euglycemia during a hyperinsulinemic clamp was significantly lower in SHR than WKY. High salt diet decreased the rate of glucose utilization during the hyperinsulinemic clamp in WKY but not SHR. During the low salt diet, insulin infusion decreased sodium excretion in both WKY and SHR. When the rats were maintained on the high salt diet, the antinatriuretic response to insulin was blunted in WKY but not SHR. Both the density and mRNA levels of insulin receptor were comparable in the kidney of WKY and SHR, but only WKY had the previously demonstrated decrease in receptor number and mRNA levels when fed the high salt chow. Hepatic insulin receptor mRNA levels were significantly lower in SHR than WKY fed the low salt diet. High salt diet decreased significantly insulin receptor mRNA levels in the liver of WKY but not of SHR. Thus, SHR appear to have lost the feedback mechanism that normally limits insulin-induced sodium retention when extracellular volume is expanded. A decreased expression of insulin receptor in the liver of SHR provides a possible explanation for the insulin resistance and decreased insulin clearance present in this strain.
Assuntos
Hipertensão/metabolismo , Insulina/análise , RNA Mensageiro/análise , Receptor de Insulina/análise , Animais , Insulina/metabolismo , Masculino , Ensaio Radioligante , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Autoregulatory mechanisms ensure relatively small fluctuations of blood pressure with postural changes in healthy people. Although orthostatic hypotension is well recognized and commonly encountered, there are only a few reports of orthostatic hypertension. Most of the reported cases of orthostatic hypertension were related to excessive venous pooling, with an initial drop in cardiac output followed by overcompensation with an excessive release of catecholamines, or to nephroptosis with orthostatic activation of the renin-angiotensin system. We describe a 44-year-old woman with normal supine blood pressure and severe orthostatic hypertension who did not demonstrate an initial decrease in cardiac output and had normal plasma and urinary catecholamines and renin release. Pharmacological tests of autonomic nervous system function showed an increased pressor sensitivity to norepinephrine (11 to 14 times normal), normal sensitivity to isoproterenol, diminished baroreceptor reflex sensitivity, and exquisite sensitivity to alpha-adrenergic blockers. This unusual case of orthostatic hypertension appears to be secondary to vascular adrenergic hypersensitivity.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Postura , Pressorreceptores/fisiologia , Receptores Adrenérgicos/fisiologia , Resistência Vascular , Antagonistas Adrenérgicos alfa/uso terapêutico , Adulto , Barorreflexo/fisiologia , Catecolaminas/sangue , Catecolaminas/urina , Exercício Físico , Feminino , Hemodinâmica , Humanos , Hipertensão/sangue , Renina/sangue , Decúbito DorsalRESUMO
The effect of circadian rhythm and alterations in posture on plasma aldosterone concentration was studied in 13 patients with primary aldosteronism (six adenoma, five idiopathic hyperplasia, two carcinoma) to define the regulatory mechanism in each of these pathologic subtypes. Blood samples for aldosterone, cortisol, renin, and potassium concentrations were obtained every 4 h during prolonged recumbency (32 h) and upright posture (16 h). During recumbency, aldosterone and cortisol followed a normal circadian pattern in patients with adenoma and hyperplasia, with peak values at 0400-0800 h and the nadir at 1600-2400 h. Normalized aldosterone and cortisol values correlated significantly in both groups (adenoma r=+0.66, P less than 0.001; hyperplasia r=+0.42, P less than 0.01). With upright posture, aldosterone levels declined parallel to the normal circadian fall in cortisol in patients with adenoma (r=+0.68, P less than 0.001); whereas aldosterone levels increased in patients with hyperplasia parallel to small increments in renin (r=+0.65, P less than 0.001) and potassium (r=+0.64, P less than 0.001). During the administration of dexamethasone, aldosterone no longer correlated with cortisol in patients with adenoma but continued to correlate with renin during upright studies in patients with hyperplasia (r=+0.77, P less than 0.01). Aldosterone circadian rhythm was abnormal in patients with carcinoma and no effect of posture was noted. Unilateral adrenalectomy restored the normal postural relationship in four patients with adenoma. These studies suggest that aldosterone secretion is under continuous ACTH control regardless of posture in patients with adenoma, whereas persistent adrenal responsiveness to small increments in renin and/or potassium mediate the postural increase in plasma aldosterone in patients with hyperplasia. True adrenal autonomy occurs only in patients with adrenal carcinoma and when ACTH is suppressed in those with adenoma.
Assuntos
Aldosterona/sangue , Ritmo Circadiano , Hiperaldosteronismo/sangue , Postura , Adulto , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Renina/sangue , Fatores de TempoRESUMO
Body wasting, characterized by disproportionate loss of body cell mass, is a feature of many chronic diseases, including infection with the human immunodeficiency virus (HIV). Therapies that merely increase energy intake do not consistently restore body cell mass in patients with the wasting syndrome. Because treatment with GH has induced nitrogen (N) retention in catabolic patients after surgery, burns, cancer, and hypocaloric feeding, we designed this study to determine whether GH could also produce an anabolic response in persons with HIV-associated weight loss. Six HIV-positive (HIV+) men with an average weight loss of 19% and six healthy weight-stable controls (HIV-) were hospitalized on a metabolic ward, where they consumed a constant metabolic diet during successive 5-day precontrol, 7-day baseline, and 7-day treatment [recombinant human GH (rhGH), 0.1 mg/kg.day] periods. The effects of rhGH on body weight, N and electrolyte excretion, energy expenditure, substrate oxidation, and integrated lipid and carbohydrate metabolism were assessed. Body weight increased promptly and progressively during treatment (2.0 +/- 0.3 and 1.6 +/- 0.2 kg in HIV+ and HIV-, respectively). Urinary N excretion decreased by 288 +/- 17 and 287 +/- 42 mmol/day in HIV+ and HIV-, respectively. Resting energy expenditure increased by 7.5% in both groups. Protein oxidation decreased, whereas lipid oxidation increased significantly. Glucose flux increased, and modest increases in fasting plasma triglyceride, glucose, and insulin levels were observed. Thus, short term rhGH treatment increased both protein anabolism and protein-sparing lipid oxidation, effects that should increase body cell mass if sustained during chronic therapy.
Assuntos
Emaciação/etiologia , Hormônio do Crescimento/farmacologia , Infecções por HIV/fisiopatologia , Redução de Peso/efeitos dos fármacos , Adulto , Análise de Variância , Glicemia/análise , Emaciação/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Hormônio do Crescimento/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Lipídeos/sangue , Masculino , Nitrogênio/urina , Oxirredução , Potássio/sangue , Potássio/urina , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Sódio/sangue , Sódio/urina , Ureia/urinaRESUMO
GH has been proposed as a therapy for patients with HIV-associated fat accumulation, but the pharmacological doses (6 mg/d) used have been associated with impaired fasting glucose and hyperglycemia. In contrast, physiologic doses of GH ( approximately 1 mg/d) in HIV-negative men reduced visceral adiposity and eventually improved insulin sensitivity, despite initially causing insulin resistance. We conducted an open-label study to evaluate the effects of a lower pharmacologic dose of GH (3 mg/d) in eight men with HIV-associated fat accumulation. Oral glucose tolerance, insulin sensitivity, and body composition were measured at baseline, and 1 and 6 months. Six patients completed 1 month and 5, 6 months of GH therapy. IGF-I levels increased 4-fold within 1 month of GH treatment. Over 6 months, GH reduced buffalo hump size and excess visceral adipose tissue. Total body fat decreased (17.9 +/- 10.9 to 13.5 +/- 8.4 kg, P = 0.05), primarily in the trunk region. Lean body mass increased (62.9 +/- 6.4 to 68.3 +/- 9.1 kg, P = 0.03). Insulin-mediated glucose disposal, measured by a euglycemic hyperinsulinemic clamp, declined at month 1 (49.7 +/- 27.5 to 25.6 +/- 6.6 nmol/kg(LBM).min/pmol(INSULIN)/liter, P = 0.04); values improved at month 6 (49.2 +/- 22.6, P = 0.03, compared with month 1) and did not differ significantly from baseline. Similarly, the integrated response to an oral glucose load worsened at month 1 (glucose area under the curve 20.1 +/- 2.3 to 24.6 +/- 3.7 mmol.h/liter, P < 0.01), whereas values improved at month 6 (22.1 +/- 1.5, P = 0.02, compared with month 1) and did not differ significantly from baseline. One patient developed symptomatic hyperglycemia within 2 wk of GH initiation; baseline oral glucose tolerance testing revealed preexisting diabetes despite normal fasting glucose. In conclusion, GH at 3 mg/d resulted in a decrease in total body fat and an increase in lean body mass in this open-label trial. While insulin sensitivity and glucose tolerance initially worsened, they subsequently improved toward baseline. However, the dose of GH used in this trial was supraphysiologic and led to an increase in IGF-I levels up to three times the upper normal range. Because there are known adverse effects of long-term GH excess, the effectiveness of lower doses of GH should be studied. We also recommend a screening oral glucose tolerance test be performed to exclude subjects at risk for GH-induced hyperglycemia.
Assuntos
Tecido Adiposo/fisiopatologia , Glicemia/metabolismo , Composição Corporal/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Hormônio do Crescimento Humano/uso terapêutico , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/efeitos dos fármacos , Adulto , Idoso , Constituição Corporal , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Contagem de Linfócito CD4 , Seguimentos , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Infecções por HIV/sangue , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Hiperglicemia/induzido quimicamente , Hiperinsulinismo , Insulina/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
We recently reported that renin, angiotensinogen, and angiotensin-converting enzyme were present in normal human pituitary lactotroph cells and PRL-secreting adenomas. Angiotensin-II and -III have also been shown to modulate PRL release in vitro. The present study was designed to determine whether angiotensin modulates PRL secretion in vivo. In 36 hypertensive patients with widely varying renin levels, active renin and basal PRL levels did not correlate. In 10 normal volunteers, both a sustained infusion of angiotensin-II and a graded infusion of angiotensin-III induced a 2- to 3-fold increase in aldosterone levels, but had no effect on PRL secretion. Administration of the angiotensin-converting enzyme inhibitor captopril had no effect on PRL circadian rhythm in 10 normal subjects or on PRL concentrations in 11 patients with PRL-secreting adenomas. Cross-over administration of placebo and captopril did not affect the peak PRL level measured after TRH treatment in 10 hypertensive men (placebo, 43.1 +/- 5.4; captopril, 40.0 +/- 6.2 micrograms/L; P = NS) or the rise in PRL induced by doperidone in 6 normal women (placebo, 129.5 +/- 16.2; captopril, 150.0 +/- 35.7 micrograms/L; P = NS). Further, administration of enalapril for 30 days to 6 hypertensive patients did not alter basal PRL concentrations or the peak concentrations induced by TRH. These data indicate that in humans the circulating renin-angiotensin system does not interact with diurnal PRL release or with the response to TRH or domperidone.