RESUMO
Erythrocytes from patients with myotonic muscular dystrophy accumulate calcium at a significantly higher rate than normals do. This increased rate of net accumulation appears related to an enhanced permeability of the membrane to calcium, rather than to an impairment in its active outward transport.
Assuntos
Cálcio/sangue , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Distrofias Musculares/sangue , Transporte Biológico/efeitos dos fármacos , Cálcio/metabolismo , Membrana Celular/metabolismo , Humanos , Distrofias Musculares/metabolismo , Quinina/farmacologiaRESUMO
Extracts of fresh-frozen bovine neurohypophysis were purified by chromatographic techniques to isolate and characterize the components that produce natriuresis in nondiuretic dogs. Two compounds with natiuretic properties similar to those of synthetic arginine vasopressin accounted for most of the natriuretic activity and appeared to be the prevalent vasopressin-like molecules in the extract. These peptides were Ala-Gly-[Arg8]-vasopressin and Val-Asp-[Arg8]-vasopressin; the natriuretic potency of each appeared to be similar to synthetic arginine vasopressin and could be observed with doses in the range of 50 picomoles. In the dog the most conspicuous difference between synthetic arginine vasopressin and the new vasopressin peptides was the smaller pressor responses to natriuretic doses of the new compounds.
Assuntos
Arginina Vasopressina/metabolismo , Natriurese/efeitos dos fármacos , Neuro-Hipófise/metabolismo , Sequência de Aminoácidos , Animais , Arginina Vasopressina/análogos & derivados , Arginina Vasopressina/farmacologia , Bioensaio , Pressão Sanguínea/efeitos dos fármacos , Bovinos , Cães , Masculino , Precursores de Proteínas/metabolismo , Relação Estrutura-AtividadeRESUMO
To define the primary effects of aluminum on bone in the mammalian species, we examined the dose/time-dependent actions of aluminum in normal beagles. Administration of low dose aluminum (0.75 mg/kg) significantly elevated the serum aluminum (151.7 +/- 19.9 micrograms/liter) compared with that in controls (4.2 +/- 1.35 micrograms/liter) but did not alter the calcium, creatinine, or parathyroid hormone. After 8 wk of therapy, bone biopsies displayed reduced bone resorption (2.6 +/- 0.63 vs. 4.5 +/- 0.39%) and osteoblast covered bone surfaces (2.02 +/- 0.51 vs. 7.64 +/- 1.86%), which was indicative of low turnover. In contrast, prolonged treatment resulted in increased bone volume and trabecular number (38.9 +/- 1.35 vs. 25.2 +/- 2.56% and 3.56 +/- 0.23 vs. 2.88 +/- 0.11/mm) which was consistent with uncoupled bone formation. Administration of higher doses of aluminum (1.20 mg/kg) increased the serum aluminum further (1242.3 +/- 259.8 micrograms/liter) but did not affect calcium, creatinine, or parathyroid hormone. However, after 8 wk of treatment, bone biopsies displayed changes similar to those after long-term, low-dose therapy. In this regard, an increased trabecular number (3.41 +/- 0.18/mm) and bone volume (36.5 +/- 2.38%) again provided evidence of uncoupled bone formation. In contrast, in this instance poorly mineralized woven bone contributed to the enhanced bone volume. High-dose treatment for 16 wk further enhanced bone volume (50.4 +/- 4.61%) and trabecular number (3.90 +/- 0.5/mm). These observations illustrate that aluminum may stimulate uncoupled bone formation and induce a positive bone balance. This enhancement of bone histogenesis contrasts with the effects of pharmacologic agents that alter the function of existing bone remodeling units.
Assuntos
Alumínio/farmacologia , Desenvolvimento Ósseo/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Animais , Análise Química do Sangue , Osso e Ossos/anatomia & histologia , Cães , Relação Dose-Resposta a DrogaRESUMO
To examine the influence of osteoblast function on aluminum-induced neo-osteogenesis in the mammalian species, we compared the effects of aluminum in sham-operated and thyroparathyroidectomized (TPTX) beagles. TPTX dogs received sufficient calcium carbonate and calcitriol to maintain normal plasma calcium and calcitriol levels, but developed evidence of decreased osteoblast recruitment and activity, including diminished osteoid-covered trabecular bone surface (3.22 +/- 0.21 vs. 10.95 +/- 1.30%) and a decreased osteoblast number (27.8 +/- 8.1 vs. 139.0 +/- 26.0/mm). Administration of aluminum (1.25 mg/kg i.v., three times/wk) increased the serum aluminum levels in both sham (1,087.0 +/- 276.0 vs. 2.7 +/- 0.8 micrograms/liter) and TPTX animals (2,786.0 +/- 569.0 vs. 3.6 +/- 0.8 micrograms/liter) above normal but did not alter the plasma calcium, creatinine, or PTH from control levels in either sham or TPTX dogs. After 8 wk of therapy, however, bone biopsies from sham-operated beagles displayed evidence of neo-osteogenesis including an increased bone volume (47.0 +/- 1.0 vs. 30.4 +/- 0.9%) and trabecular number (4.1 +/- 0.2 vs. 3.2 +/- 0.2/mm). Much of the enhanced volume resulted from deposition of poorly mineralized woven bone (9.9 +/- 2.7%). In contrast, biopsies from aluminum-treated TPTX animals exhibited significantly less evidence of ectopic bone formation. In this regard, bone (35.5 +/- 1.7%) and woven tissue volume (1.4 +/- 0.8%) as well as trabecular number (3.3 +/- 0.1/mm) were significantly less than those of the aluminum-treated controls. These observations illustrate that aluminum reproducibly stimulates neo-osteogenesis and induces a positive bone balance. However, this effect apparently depends on the availability of a functional osteoblast pool which, if depleted by TPTX, limits the expression of aluminum-induced new bone formation.
Assuntos
Alumínio/administração & dosagem , Hormônio Paratireóideo/fisiologia , Animais , Osso e Ossos/patologia , Contagem de Células , Cães , Injeções Intravenosas , Masculino , Osteoblastos/patologia , Osteoblastos/fisiologia , Osteogênese , Glândulas Paratireoides/cirurgia , TireoidectomiaRESUMO
Magnesium-deficient rats develop significant hypercalcemia, hypophosphatemia, and hyperphosphaturia. These changes suggest a state of hyperparathyroidism. This study examines the regulation of parathyroid gland activity in magnesium-deficient rats. Magnesium deficiency was induced in intact and chronically parathyroidectomized animals by feeding them a diet free of this cation. Control animals were pair fed and treated identically except for the inclusion of magnesium in their gavage solution.Magnesium-deficient rats with intact parathyroid glands developed significant hypercalcemia and hypophosphatemia. In addition, the concentration of ionic calcium in plasma was significantly elevated. In contrast, magnesium-deficient parathyroidectomized animals did not have a higher level of calcium in plasma than their nondeficient controls; they developed a decreased concentration of ionic calcium in the absence of a difference in the concentration of phosphate in plasma when compared with appropriate controls. The increased urinary excretion of phosphate was independent of the parathyriod status of the animals.It can be concluded that the hypercalcemia and hypophosphatemia of magnesium deficiency demands parathyroid gland activity and that the regulation of this activity is modified in the magnesium-deficient state to permit the maintenance of an elevated concentration of ionic calcium in plasma. Additional explanations must be found for the hyperphosphaturia.
RESUMO
Myotonic muscular dystrophy (MyD) is a systemic genetic disorder that is thought to result from a generalized cellular membrane defect although the exact nature of this defect is unknown. This study examines two calcium-dependent membrane processes that have been observed in erythrocytes from healthy individuals: calcium-stimulated phosphatidic acid accumulation and calcium-induced potassium leak. We find that erythrocytes from MyD patients, in contrast to controls, have markedly impaired phosphatidic acid accumulations while maintaining normal potassium leaks. The calcium uptakes and ATP contents of MyD erythrocytes are not different from controls. We conclude that phospholipid metabolism is altered in MyD erythrocytes. The specificity of this abnormality and its relationship to altered muscular function are not known.
Assuntos
Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Lipídeos de Membrana/metabolismo , Miotonia Congênita/metabolismo , Ácidos Fosfatídicos/metabolismo , Transporte Biológico Ativo/efeitos dos fármacos , Cálcio/metabolismo , Cálcio/farmacologia , Humanos , Técnicas In Vitro , Potássio/metabolismoRESUMO
Although aluminum excess is an apparent pathogenetic factor underlying osteomalacia in dialysis-treated patients with chronic renal failure, the mechanism by which aluminum impairs bone mineralization is unclear. However, the observation that aluminum is present at osteoid-bone interfaces in bone biopsies of affected patients suggests that its presence at calcification fronts disturbs the cellular and/or physiochemical processes underlying normal mineralization. Alternatively, aluminum at osteoid-bone interfaces may reflect deposition in preexistent osteomalacic bone without direct effects on the mineralization process. We investigated whether aluminum accumulates preferentially in osteomalacic bone and, if so, whether deposition of aluminum occurs at calcification fronts and specifically inhibits mineralization. Aluminum chloride (1 mg/kg) was administered intravenously three times per week for 3 wk to five normal and five vitamin D-deficient osteomalacic dogs. Before administration of aluminum the vitamin D-deficient dogs had biochemical and bone biopsy evidence of osteomalacia. Bone aluminum content in the osteomalacic dogs (15.1 +/- 2.2 micrograms/g) and the plasma aluminum concentration (10.4 +/- 2.1 micrograms/liter) were no different than those of normal dogs (10.5 +/- 3.5 micrograms/g and 11.9 +/- 1.2 microgram/liter, respectively). After the 3 wk of aluminum administration the plasma phosphorus, parathyroid hormone, and 25-hydroxyvitamin D concentrations were unchanged in normal and vitamin D-deficient dogs. Similarly, no alteration in bone histology occurred in either group. In contrast, bone aluminum content increased to a greater extent in the vitamin D-deficient dogs (390.3 +/- 24.3 micrograms/g) than in the normal dogs (73.6 +/- 10.6 micrograms/g). Moreover, aluminum localized at the osteoid-bone interfaces of the osteomalacic bone in the vitamin D-deficient dogs, covering 42.9 +/- 9.2% of the osteoid-bone surface. Further, in spite of continued aluminum chloride administration (1 mg/kg two times per week), vitamin D repletion of the vitamin D-deficient dogs for 11 wk resulted in normalization of their biochemistries. In addition, while normal dogs maintained normal bone histology during the period of continued aluminum administration, vitamin D repletion of the vitamin D-deficient dogs induced healing of their bones. Indeed, the appearance of aluminum in the cement lines of the healed bones indicated that mineralization had occurred at sites of prior aluminum deposition. These observations illustrate that aluminum deposition in osteomalacic bone may be a secondary event that does not influence bone mineralization. Thus, although aluminum may cause osteomalacia in chronic renal failure, its presence at mineralization fronts may not be the mechanism underlying this derangement.
Assuntos
Alumínio/metabolismo , Osso e Ossos/metabolismo , Osteomalacia/metabolismo , Deficiência de Vitamina D/metabolismo , Envelhecimento , Alumínio/farmacologia , Animais , Osso e Ossos/patologia , Cães , Minerais/metabolismo , Osteogênese , Osteomalacia/etiologia , Osteomalacia/fisiopatologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/fisiopatologiaRESUMO
Intact human erythrocytes can be readily loaded with calcium by incubation in hypersomotic media at alkaline pH. Erythrocyte calcium content increases from 15-20 to 120-150 nmol/g hemoglobin after incubation for 2 h at 20 degree C in a 400 mosmol/kg, pH 7.8 solution containing 100 mM sodium chloride, 90 mM tetramethylammonium chloride, 1 mM potassium chloride, and 10 mM calcium chloride. Calcium uptake is a time-dependent process that is associated with an augmented efflux of potassium. The ATP content in these cells remains at more than 60% of normal and is not affected by calcium. Calcium uptake is influenced by the cationic composition of the external media. The response to potassium is diphasic. With increasing potassium concentrations, the net accumulation of calcium initially increases, becoming maximal at 1 mM potassium, then diminishes, falling below basal levels at concentrations above 3 mM potassium. Ouabain inhibits the stimulatory effect of low concentrations of potassium. The inhibitory effects of higher concentrations of potassium are ouabain insensitive and independent of the external calcium concentration. Sodium also inhibits calcium uptake but this inhibition can be modified by altering the external concentration of calcium. The effux of calcium from loaded erythrocytes is not significantly altered by changes in osmolality, medium ion composition, or ouabain. It is concluded that hypertonicity increases the net uptake of calcium by increasing the influx of calcium and that some part of the sodium potassium transport system is involved in this influx process.
Assuntos
Cálcio/sangue , Eritrócitos/metabolismo , Trifosfato de Adenosina/sangue , Transporte Biológico , Relação Dose-Resposta a Droga , Humanos , Ouabaína/farmacologia , Potássio/sangue , Potássio/farmacologia , Sódio/sangue , Sódio/farmacologiaRESUMO
Swelling-activated [K-Cl] cotransport and shrinkage-activated Na/H exchange were studied in dog red cells with altered internal Mg or Li content. The two pathways responded in a coordinated fashion. When cells were depleted of Mg, [K-Cl] cotransport was stimulated and Na/H exchange was inhibited. Raising internal Mg had the opposite effect: [K-Cl] cotransport was inhibited and Na/H exchange was stimulated. Li loading, previously shown to stimulate Na/H exchange, inhibited [K-Cl] cotransport. From these reciprocal effects and from other evidence, we surmise that the regulation of Na/H exchange and [K-Cl] cotransport is conducted and coordinated by a discrete mechanism that responds to changes in cell volume and is sensitive to cytoplasmic Mg and Li concentrations.
Assuntos
Proteínas de Transporte/sangue , Cloretos/sangue , Eritrócitos/metabolismo , Potássio/sangue , Simportadores , Animais , Calcimicina/farmacologia , Cães , Cinética , Lítio/farmacologia , Magnésio/farmacologia , Trocadores de Sódio-Hidrogênio , Cotransportadores de K e Cl-RESUMO
Dog red blood cells (RBC) are shown to regulate their volume in anisosmotic media. Extrusion of water from osmotically swollen cells requires external calcium and is associated with net outward sodium movement. Accumulation of water by osmotically shrunken cells is not calcium dependent and is associated with net sodium uptake. Net movements of calcium are influenced by several variables including cell volume, pH, medium sodium concentration, and cellular sodium concentration. Osmotic swelling of cells increases calcium permeability, and this effect is diminished at acid pH. Net calcium flux in either direction between cells and medium is facilitated when the sodium concentrations is low in the compartment from which calcium moves and/or high in the compartment to which calcium moves. The hypothesis is advanced that energy for active sodium extrusion in dog RBC comes from passive, inward flow of calcium through a countertransport mechanism.
Assuntos
Cálcio/fisiologia , Eritrócitos/fisiologia , Animais , Transporte Biológico , Cães , Eritrócitos/metabolismo , Concentração de Íons de Hidrogênio , Concentração Osmolar , Sódio/metabolismo , Fatores de Tempo , Água/metabolismoRESUMO
A 48-year-old man receiving maintenance hemodialysis underwent coronary artery bypass surgery with good results for intractable angina. No complications were observed that could be attributed to the hemodialysis treatment. There appear to be no cogent reasons to arbitrarily exclude this population of patients from consideration for coronary artery bypass surgery.
Assuntos
Angina Pectoris/cirurgia , Ponte de Artéria Coronária , Falência Renal Crônica/terapia , Diálise Renal , Angina Pectoris/complicações , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversosRESUMO
The successful application of any analytical technique involves a balance between the performance characteristics of the method and the data requirements of the problem. As has been discussed, the electrothermal procedure for the determination of aluminum imposes some constraints on the clinical application of the methodology. These include detection limits in the same range as normal serum values, the possibility of interference from sample constituents, and the potential for contamination. In addition, reference standards are not currently available. Nevertheless, electrothermal procedures have received broad acceptance. This can be attributed to several factors. Electrothermal procedures tend to be inherently simple. Second, an understanding of the potential limitations of the technique has led to procedures that minimize these negative aspects and provide accurate measurements of aluminum in biological fluids. These factors, in conjunction with the reliability and relative ease of application of the technique, have led to an acceptance of electrothermal atomic absorption as the method of choice for the measurement of aluminum in biological samples.
Assuntos
Alumínio/análise , Espectrofotometria Atômica/métodos , Alumínio/sangue , Humanos , Padrões de ReferênciaRESUMO
Occupational exposure to aluminum can be associated with increases in both urinary aluminum excretion and serum aluminum. In most studies, the increases in urinary aluminum are proportionately greater than the changes in serum aluminum. A similar pattern of response follows increases in dietary aluminum intake. Thus, there is ample evidence for systemic aluminum absorption from occupational exposure to airborne aluminum as well as dietary intake. Although both circumstances are accompanied by a similar renal response, there is little information explaining how normal kidneys augment renal excretion with only trivial changes in serum aluminum concentrations. In addition, it is not understood how airborne exposure to microgram amounts of aluminum produces significant increases in urinary aluminum. The latter observation suggests the presence of a sensitive uptake process for aluminum from airway exposure.