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The relative importance of sympathetic nerve (SNS) activity and adrenal medullary secretion in various physiological situations has generally been inferred from measurements of norepinephrine (NE) and epinephrine (E), respectively, in urine or plasma. Increasing evidence, however, indicates that under certain conditions the adrenal medulla may release substantial amounts of NE as well as E. In several of these circumstances, estimates of SNS activity based on the measurement of NE turnover in peripheral tissues of experimental animals indicate diminished SNS function, a reduction that is independent of adrenal medullary secretion. These reciprocal alterations in SNS and adrenal medullary activity fall into two patterns. First, when SNS activity is suppressed by fasting, adrenal medullary responses to various stimuli are enhanced. Second, for certain stimuli the SNS response is biphasic, with an initial suppression followed by subsequent stimulation; during the first phase adrenal medullary secretion is markedly increased. The physiological contribution of the adrenal medulla, therefore, would be particularly important under conditions of SNS suppression.

We studied the role of catecholamines in the regulation of potassium homeostasis in nine healthy subjects given intravenous potassium chloride (0.5 meq per kilogram of body weight) in the presence and absence of propranolol. Potassium infusion elevated serum potassium 0.6 +/- 0.09 meq per liter (mean +/-S.E.M.). Addition of propranolol augmented the rise (0.9 +/- 0.05 meq per liter) and prolonged the elevation in serum potassium without decreasing urinary potassium excretion. In a separate study, the same potassium load was administered with a concomitant infusion of epinephrine in five subjects. Epinephrine markedly blunted the increment in serum potassium (0.1 +/- 0.06 meq per liter) while reducing renal potassium excretion. Plasma aldosterone was not altered by the experimental procedures. Serum insulin fell minimally in the presence of propranolol but was unaffected by epinephrine. beta-Adrenergic blockade impairs and epinephrine enhances extrarenal disposal of an acute potassium load. These findings suggest that in patients with impaired potassium disposal, the risk of hyperkalemia may be increased when sympathetic blockade is induced.

Objective. To determine the safety and long-term efficacy of immune ablation and autologous hematopoietic stem cell transplantation (HSCT) in severe systemic lupus erythematosus (SLE).Methods. Fifteen patients with persistently active SLE after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells were mobilized with CYC (2.0 gm/m 2 ) and granulocyte colonystimulating factor (5 g/kg/day). Lymphocytes were depleted from the graft by selection of CD34-positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic features, function of diseased organs, and immunosuppressive medication requirements.Results. Fifteen patients with persistent, severe SLE, 7 of whom were critically ill, were treated. No deaths occurred following treatment. The median followup after HSCT has been 36 months (range 12-66 months). All patients demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to <5 in 12 patients. Complement and anti-doublestranded DNA levels have normalized and marked improvements in end organ function have occurred in all subjects. Of the 12 patients followed up for >1 year after HSCT, 10 have discontinued immunosuppressive medications, and the prednisone dosage has been tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of recurrence of active lupus. One of these patients currently requires no immunosuppressive medication and has a normal performance status. The other patient is currently receiving IV CYC.Conclusion. In patients experiencing the persistence of organ-threatening lupus following standard, aggressive therapy, HSCT may be performed safely, with marked improvement and sustained withdrawal of all immunosuppressive medication for most patients. A phase III randomized trial is warranted to determine the relative efficacy and durability of remission of HSCT compared with standard therapies. Hematopoietic stem cell transplantation (HSCT)is most commonly applied to chemotherapy-sensitive "malignant" hematologic diseases, such as lymphoma or multiple myeloma. These malignancies are characterized by invasive or injurious clonal or oligoclonal lymphocyte proliferation. Diseases for which autologous stem cell transplants are used successfully are believed to be environmentally induced in a setting of genetic susceptibility. HSCT allows for normal, healthy hematopoietic stem cells to repopulate the bone marrow and peripheral blood after chemotherapy-induced elimination of the malignant clones. It may be anticipated that disease-mediating lymphocytes in patients with systemic lupus erythematosus (SLE) should be at least as prone to therapeutic eradication as malignant lymphocytes. If human SLE is also triggered by the hormonal and environmental milieu in a genetically susceptible host, then high-dose chemotherapy and HSCT should also induce sustained lupus-free remissions.

Plasma potassium rises during muscular exercise and falls rapidly when exercise is stopped. Since the sympathoadrenal system is stimulated with exertion and both alpha- and beta-adrenergic agonists affect internal potassium homeostasis, we studied the influence of catecholamines on potassium shifts during and after exercise. Six healthy subjects were given maximal exercise stress tests under three conditions: with no medication (control), during beta-blockade with propranolol, and during alpha-blockade with phentolamine. Compared with a peak rise in plasma potassium of 1.23 +/- 0.27 mmol per liter (mean +/- S.E.M.) during the control study, propranolol caused a rise of 1.89 +/- 0.35 (P less than 0.01) and a sustained elevation during recovery. Phentolamine diminished the rise of potassium (0.70 +/- 0.21 mmol per liter; P less than 0.01) and lowered the potassium level throughout recovery. These effects of catecholamines were independent of the venous pH, the plasma bicarbonate and serum glucose levels, and urinary potassium excretion, and they did not appear to be due to insulin. High norepinephrine and epinephrine levels confirmed the release of catecholamines capable of stimulating alpha- and beta-receptors. Exercise work did not differ among the groups. beta-Adrenergic receptors appear to moderate the acute hyperkalemia of exercise, whereas alpha-adrenergic receptors act to enhance hyperkalemia and may protect against hypokalemia when exertion ceases.

SUMMARY To test the hypothesis that normal age-related limitations in cardiovascular homeostasis may become clinically significant under stress, the cardiovascular response to postural change was assessed in six young and six old healthy subjects before and after modest diuretic-induced sodium depletion. Before diuresis, systolic blood pressure was maintained (from 110 ± 4 to 113 ± 6 mm Hg) while heart rate increased 22% (from 67 ± 2 to 82 ± 5 beats/min) at 3 minutes after 60-degree upright tilt in young subjects. After a significant diuretic-induced weight reduction and natriuresis, the young again maintained systolic blood pressure (from 110 ± 4 to 110 ± 6 mm Hg) and increased heart rate 49% (from 68 ± 2 to 101 ± 5 beats/min; p < 0.05, compared with prediuresis values) in response to the same postural stimulus. During the prediuresis tilt, the older subjects showed no change in systolic blood pressure (from 132 ± 4 to 134 ± 6 mm Hg) and a 9% increase in heart rate (from 68 ± 3 to 74 ± 2 beats/min). After a similar significant weight reduction and sodium loss, the older subjects showed a significant reduction in systolic blood pressure (from 132 ± 6 to 108 ± 6 mm Hg; p < 0.05) and a 17% increase in heart rate (from 69 ± 4 to 81 ± 3 beats/min; p < 0.05) during tilt compared with values in young subjects. Three of six elderly subjects noted postural symptoms. These results suggest that, although the healthy old may appear well compensated under optimal conditions, decreased cardiovascular reserve renders them susceptible to postural change following mild sodium depletion. founded by inclusion of subjects with varying degrees of illness in addition to advanced age. To test the hypothesis that the normal age-related limitation in cardiovascular homeostasis may become clinically significant under stress, we characterized the time course and magnitude of blood pressure and heart rate response to upright tilt in carefully screened, healthy, community-dwelling young and old volunteers before and after mild diuretic-induced sodium depletion. Subjects and MethodsSix young (age, 23-35 years) and six old (age, 65-80 years) healthy, community-dwelling subjects participated in this study. Nine subjects were men and three were elderly women. Eleven subjects were white and one young subject was black. The protocol was approved by the Human Experimentation Committee of the Beth Israel Hospital, and all participants gave informed consent before the study. All were thoroughly screened by history, physical examination, labora-

Because the formation of sickle cells is dependent on the intracellular concentration of deoxyhemoglobin S, we investigated the possibility of altering or preventing sickle-cell crises by reducing serum sodium so as to cause red cells to swell. In three patients with sickle-cell anemia who had been disabled by recurrent painful crises, sustained dilutional hyponatremia was induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in combination with a high fluid intake. Mean corpuscular hemoglobin concentration fell, and the degree of sickling at low partial oxygen pressure was reduced, as determined by morphologic criteria and by increased oxygen affinity of blood. Chronic hyponatremia (serum sodium, 120 to 125 mmol per liter) reduced the frequency of painful crises, whereas acutely induced hyponatremia abbreviated the duration of crises. These results, although preliminary, are encouraging enough to warrant further study of the safety and effectiveness of induced hyponatremia in the prevention and treatment of sickle-cell crises.