Does subclinical hypothyroidism explain the increased susceptibility of women to torsades de pointes?

Among 20 consecutive patients (65% women) with drug-associated torsades de pointes, chemical evidence for hypothyroidism was found in only 10% of both women and men. Subclinical hypothyroidism is therefore unlikely to account for the consistently observed sex difference in the propensity to torsades de pointes.

Glutamic acid decarboxylase antibodies, autonomic nerve antibodies and autonomic neuropathy in diabetic patients.

To clarify whether GAD-ab are associated with diabetic autonomic neuropathy and/or complement fixing antibodies against sympathetic ganglia, adrenal medulla, and vagus nerve, we examined 133 diabetic patients (95 with IDDM). GAD-ab were determined by a radioligand binding assay using in vitro expression of recombinant GAD-65 whereas sympathetic ganglia antibodies, adrenal medulla antibodies, vagus nerve, and ICA were evaluated by indirect immunofluorescence assays. Autonomic nerve function was evaluated by objective tests (heart rate reactions to deep breathing and to tilt). In the total material of 133 patients, GAD-ab were detected in 36 patients, all of whom had IDDM. The frequency of GAD-ab was similar (38%) in IDDM patients with and without signs of autonomic neuropathy (21 of 55 vs 15 of 40). In addition, there were no significant associations between GAD-ab and autonomic nerve antibodies; GAD-ab were detected in 9 of 21 (43%) of patients with and in 27 of 112 (24%) of patients without sympathetic ganglia antibodies, in 5 of 15 (33%) of patients with and 31 of 118 (26%) without adrenal medulla antibodies, and in 5 of 15 (33%) with and 31 of 118 (26%) of patients without vagus nerve antibodies. The frequency of ICA, however, was significantly increased in patients with sympathetic ganglia antibodies compared with those without sympathetic ganglia antibodies (10 of 21 [48%] vs 21 of 112 [19%]; p < 0.01). In conclusion, GAD-ab were neither associated with disturbed autonomic nerve function nor with antibodies against autonomic nerve structures.

POEMS syndrome with myocardial infarction: observations concerning pathogenesis and review of the literature.

A 27-year-old white man with no significant risk factors for coronary artery disease presented with a 9-month history of progressive impotence, gynecomastia, lower extremity paresthesias, and extensive myocardial infarction and subsequently developed ulcerative proctitis. A diagnosis of POEMS syndrome was made based on the clinical presentation; additional physical findings of papilledema, clubbing, and hyperpigmentation; and laboratory findings of an immunoglobulin G M component of the lambda subtype, elevated cerebrospinal fluid protein, and typical sclerotic bone lesions. Abnormal in vitro binding of the patient's serum immunoglobulin to testicular tissue was also seen. Cardiac catheterization showed evidence of diffuse coronary artery narrowing and left ventricular wall motion abnormalities. Diffuse coronary involvement and ulcerative proctitis have not been previously described in POEMS syndrome. It is hypothesized that an abnormal immunoglobin (or fragment) is responsible for both findings. Furthermore, the detection of antitesticular autoantibodies suggests the possibility of an interaction between the antibody and Leydig cells, leading to an alteration in the synthesis and release of sex steroids and thereby explaining the gonadal failure seen in this syndrome. Long-term glucocorticoid therapy for the past 5 years has resulted in marked subjective and objective improvement.

Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia.

The CD33 antigen, identified by murine monoclonal antibody anti-MY9, is expressed by clonogenic leukemic cells from almost all patients with acute myeloid leukemia; it is also expressed by normal myeloid progenitor cells. Twelve consecutive patients with de novo acute myeloid leukemia received myeloablative therapy followed by infusion of autologous marrow previously treated in vitro with anti-MY9 and complement. Anti-MY9 and complement treatment eliminated virtually all committed myeloid progenitors (colony-forming unit granulocyte-macrophage) from the autografts. Nevertheless, in the absence of early relapse of leukemia, all patients showed durable trilineage engraftment. The median interval post bone marrow transplantation (BMT) required to achieve an absolute neutrophil count greater than 500/microL was 43 days (range, 16 to 75), to achieve a platelet count greater than 20,000/microL without transfusion was 92 days (range, 35 to 679), and to achieve red blood cell transfusion independence was 105 days (range, 37 to 670). At the time of BM harvest, 10 patients were in second remission, one patient was in first remission, and one patient was in third remission. Eight patients relapsed 3 to 18 months after BMT. Four patients transplanted in second remission remain disease-free 34+, 37+, 52+, and 57+ months after BMT. There was no treatment-related mortality. Early engraftment was significantly delayed in patients receiving CD33-purged autografts compared with concurrently treated patients receiving CD9/CD10-purged autografts for acute lymphoblastic leukemia or patients receiving CD6-purged allografts from HLA-compatible sibling donors. In contrast, both groups of autograft patients required a significantly longer time to achieve neutrophil counts greater than 500/microL and greater than 1,000/microL than did patients receiving normal allogeneic marrow. CD33(+)-committed myeloid progenitor cells thus appear to play an important role in the early phase of hematopoietic reconstitution after BMT. However, our results also show that human marrow depleted of CD33+ cells can sustain durable engraftment after myeloablative therapy, and provide further evidence that the CD33 antigen is absent from the human pluripotent hematopoietic stem cell.

Aggregation of subclinical autonomic nervous system dysfunction and autoantibodies in families with type I diabetes.

The purpose of our study was to evaluate the occurrence of autonomic nervous system autoantibodies (ANS) in the nondiabetic family members of insulin-dependent (type I) diabetic subjects. We studied 24 families, including 45 nondiabetic parents and 53 nondiabetic siblings of a type I diabetic proband. One hundred one nondiabetic population control subjects were also studied. Stored sera from nondiabetic family members and control subjects were evaluated for the presence of complement-fixing (CF) adrenal medullary antibodies (CF-ADM), sympathetic ganglia antibodies (CF-SG), and vagus nerve antibodies (CF-V) by indirect immunofluorescence. HLA-DR3 and -DR4 typing was performed on 42 nondiabetic family members and 104 diabetic subjects. One or more CF-ANS were in 45 of 93 (40%) nondiabetic family members compared to 2 of 70 (2.8%) control subjects. CF-SG were in 28 of 92 (30%) family members compared to 0 of 101 control subjects (P = 0.0001). CF-V were in 25 of 95 (26%) family members compared to 0 of 76 control subjects (P = 0.0001). CF-ADM were in 10 of 83 (12%) family members compared to 2 of 70 (2.8%) control subjects (P = 0.056). There was no HLA-DR3 or HLA-DR4 association with ANS. Subclinical autonomic dysfunction was demonstrated in 3 of 4 family members with autoantibodies compared to 0 of 4 family members without autoantibodies.

Autonomic nerve antibodies and autonomic nerve function in type 1 and type 2 diabetic patients.

Complement-fixing adrenal medulla (CF-ADM), sympathetic ganglion (CF-SG), and vagal (CF-V) nerve antibodies were determined in diabetic patients. Among 74 patients with Type 1 diabetes, CF-ADM was detected in 7 (10%) cases, CF-SG in 14 (19%) cases, and CF-V in 8 (11%) cases. Among 38 patients with Type 2 diabetes, CF-ADM was detected in 5 (13%) cases, CF-SG in 4 (11%) cases, and CF-V in 6 (16%) cases. There were associations between autonomic nerve antibodies and autonomic nerve function. CF-ADM and/or CF-SG were significantly (P less than 0.002) less prevalent in Type 1 diabetic patients with autonomic neuropathy than in those without [5/44 (11%) vs. 14/30 (47%)] and, in agreement with this, the brake index, a sign of parasympathetic and sympathetic autonomic nerve function, was significantly (P less than 0.005) higher (more normal) in these patients (-0.56 +/- 0.13 vs. -1.04 +/- 0.12). In Type 2 diabetic patients, the E/I ratio, an index of parasympathetic nerve function, was significantly (P less than 0.03) lower (more abnormal) in those with CF-V than in those without (-1.81 +/- 0.17 vs. -1.20 +/- 0.11). In conclusion, the frequency of sympathetic nerve antibodies was decreased in Type 1 diabetic patients with autonomic neuropathy, while in Type 2 diabetic patients parasympathetic nerve antibodies were related to severe parasympathetic neuropathy.

Adrenal medullitis in type I diabetes.

To investigate whether cell-mediated immunity against the adrenal medulla occurs in type I diabetes (IDDM), we conducted a retrospective autopsy study of adrenal glands from IDDM and nondiabetic subjects using formalin-fixed tissue. Forty-four IDDM subjects, aged 4-67 yrs (mean +/- SD, 44.8 +/- 15.4) with a duration of IDDM from 0-55 yr (28.6 +/- 14.2), and 29 nondiabetic controls, aged 8-82 yr (51.8 +/- 18.6), were evaluated for a lymphocytic infiltrate using UCHL1, which recognizes a subpopulation of resting T-lymphocytes and most activated T-lymphocytes. Immunohistochemistry using antihuman B-cell antibody (L26) was also performed. Sections were scored for both lymphocytic infiltrates and fibrosis [none (0), small (1), moderate (2), or large (3)]. Blinded scoring was performed. A moderate to severe UCHL1 infiltrate was present in 9 of 44 (20%) IDDM, compared with 1 of 29 (3%) control subjects (P less than 0.04). Mild to severe fibrosis (score 1, 2, or 3) was present in 22 of 42 (52%) IDDM subjects compared with 4 of 25 (16%) control subjects (P = 0.003). Eight of 42 (19%) IDDM subjects had moderate to severe fibrosis (score 2 or 3) compared with 1 of 25 (4%) control subjects. Seventeen of 44 (39%) IDDM subjects had either a moderate to large cellular infiltrate or moderate to severe adrenal medullary fibrosis compared with 2 of 29 (7%) control subjects (P = 0.003). Staining of the adrenal medulla with L26 revealed a large cellular infiltrate in only one subject who was UCHL1 negative. Adrenal medullitis was observed in 20% of IDDM subjects, suggesting that the adrenal medulla may be another immunological target in IDDM.

Complement-fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Autonomic brake index and heart-rate variation.

We describe herein complement-fixing anti-adrenal medullary (CF-ADM) and anti-sympathetic ganglia (CF-SG) antibodies in insulin-dependent diabetes mellitus (IDDM). This study describes complement-fixing anti-vagus (CF-V) nerve antibodies and their relationship to the cardiovascular autonomic brake index (a measure of transient decrease in heart rate during the 1st min after a tilt), and R-R interval variation with deep breathing. CF-V was detectable in 7 of 83 (8.4%) subjects with IDDM aged 1.5-65.5 yr (mean +/- SE 28.7 +/- 1.8 yr) and duration of diabetes 0-47 yr (11.8 +/- 1.4 yr). Seventy-six nondiabetic subjects (aged 10-65 yr) all had negative CF-V scores. CF-V scores correlated with CF-ADM (0-16 yr of IDDM, r = 0.61, P less than 0.0001) and CF-SG (r = 0.39, P less than 0.05). Seventy IDDM subjects (aged 28 +/- 5 yr, duration of diabetes 17 +/- 3 yr) without proteinuria or proliferative retinopathy were screened for CF-ADM, CF-SG, and CF-V antibodies. Five of 70 (7.1%) had CF-SG only (negative for CF-ADM and CF-V). Brake indices ranged from 14.7 to 51.3 (37.3 +/- 6.9). Three of 70 (4.2%) had CF-ADM only, with brake indices from 26.9 to 45.1 (32.9 +/- 6.1). Four of 70 (5.7%) had CF-V antibodies only, with brake indices of 12.7-17.3 (15.1 +/- 1.1). Subjects with CF-SG or CF-ADM (anti-sympathetic) had higher brake indices than subjects with CF-V (anti-parasympathetic) antibodies (P less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

T-cell-depleted autologous bone marrow transplantation therapy: analysis of immune deficiency and late complications.

Fourteen patients with T-cell-derived leukemia and lymphoma underwent high-dose chemoradiotherapy and anti-T-cell monoclonal antibody-treated autologous bone marrow transplantation (ABMT). All patients were either in sensitive relapse or had adverse prognostic features, and five patients had a history of bone marrow involvement with disease. Patients received a median of 2 (1 to 3) prior chemotherapy regimens; 10 patients received local radiotherapy. After high-dose ablative therapy, greater than 500/mm3 granulocytes and greater than 20,000 untransfused platelets/mm3 were noted at a median of 23 (13 to 48) and 26 (15 to 43) days post-ABMT, respectively. Natural killer (NK) cells, T cells (predominantly T8+), and monocytes were noted within the first 1 to 2 months post-AMBT, as seen in other series. Disease-free survival was a median of 10.1 months, 5.9 months for patients with T acute lymphoblastic leukemia or lymphoblastic lymphoma and 25.6 months for patients with T non-Hodgkin's lymphoma (NHL). Toxicities were common and severe. Thirty-six percent of patients developed bacteremias early post-BMT. Late complications included a skin rash consistent with graft versus host disease; infections with Herpes zoster, hepatitis, and Pneumocystis carinii; and the development of Epstein-Barr virus associated lymphoproliferative syndrome. Our findings suggest that patients who have undergone T-depleted ABMT have a profound immunodeficiency not reflected in the phenotypic reconstitution of the T and NK cells. Characterization of the functional deficiency may facilitate the development of methods to reduce the long-term toxicity of AMBT in these patients.

Different effects of duration on prevalence of anti-adrenal medullary and pancreatic islet cell antibodies in type I diabetes mellitus.

Autoimmunity is a known factor in the pathogenesis of islet cell destruction, but little is known of its role in the pathogenesis of the neuronal complications of diabetes. We carried out a cross-sectional study of 94 subjects with Type I diabetes mellitus (DM) to examine the relationship between duration and presence of complement fixing anti-adrenal medullary antibodies (CF-ADM). CF-ADM were present in 19% of subjects (n = 62) with duration of DM less than or equal to 16 years and 3% of subjects (n = 32) with duration of DM greater than 16 years. All subjects with CF-ADM+ and duration of DM 0-5 years (n = 7) were islet cell antibody positive (ICA+). Among subjects with duration of DM 6-16 years who were CF-ADM+, 4 of 5 subjects were ICA- and 1 of 5 subjects was ICA+. The only CF-ADM+ subject with duration of DM greater than 16 years was ICA-. Absorption of ADM+ and ICA+ sera with upper phase glycolipid extract blocks ICA but not ADM binding to tissue. This study suggests: 1) CF-ADM positivity is associated with ICA positivity in subjects with duration of DM 0-5 years. CF-ADM positivity persists after 5 years duration of DM when islet cell antibodies have disappeared. Therefore, the antigenic target of the adrenal medulla and pancreatic islets may be different. 2) There is an increased prevalence of CF-ADM in subjects with duration of DM 0-16 years (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal medullary fibrosis in IDDM of long duration.

We conducted a retrospective pathology study to determine whether subjects with long-standing insulin-dependent diabetes mellitus (IDDM) have abnormalities of the adrenal medulla compared with subjects with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic individuals. Slides were scored from 0 (no fibrosis) to 3+ (complete fibrosis). Nineteen IDDM subjects aged 30-60 yr (mean +/- SE 44.9 +/- 2.5 yr) at autopsy and with duration of diabetes 13-45 yr (26.8 +/- 1.8 yr) were studied. Twelve NIDDM subjects aged 61-84 yr (73.3 +/- 2.5 yr) with duration of diabetes 17-33 yr (22.8 +/- 1.9 yr) were studied. Twenty-two nondiabetic subjects aged 32-77 yr (53.7 +/- 2.9 yr) were studied. Four of 19 (27%) IDDM subjects had moderate to severe fibrosis compared to 1 of 12 (8.3%) NIDDM subjects and 1 of 22 (4.5%) control subjects. Thirteen of 19 (68%) IDDM subjects had a score of 1, 2, or 3 compared to 3 of 22 (13.6%) control subjects (P less than .0005). There was an association between duration of IDDM and fibrosis score (r = .46, P less than .05) and between age and fibrosis score among IDDM subjects (r = .57, P = .01). No association between age or duration of diabetes and fibrosis score was observed for NIDDM or control subjects. Adrenal medullary fibrosis may be an anatomical correlate of the diminished epinephrine secretion that occurs in response to insulin-induced hypoglycemia in some IDDM subjects.

Anti-sympathetic nervous system autoantibodies. Diminished catecholamines with orthostasis.

The etiology of autonomic neuropathy in insulin-dependent diabetes mellitus (IDDM) is unknown. Previous studies have noted the presence of anti-adrenal medullary antibodies in IDDM. Recently, we have also demonstrated the presence of anti-sympathetic ganglia antibodies in IDDM. We initiated a study to evaluate whether subjects with complement-fixing anti-adrenal medullary (CF-ADM) and anti-sympathetic ganglia (CF-SG) antibodies have a decreased catecholamine response to change in posture. Seven IDDM subjects aged 19-41 yr with duration of disease 5-21 yr at the time of the posture study were evaluated. Serums collected longitudinally were evaluated for the presence of CF-ADM and CF-SG antibodies. Three IDDM subjects were CF-ADM- and CF-SG- at all testing intervals (Ab- group). Four IDDM subjects were CF-ADM+ and/or CF-SG+ on at least one testing date (Ab+ group). Baseline mean norepinephrine and epinephrine levels were not significantly different in Ab+ and Ab- subjects. Norepinephrine levels 5 min after standing were mean +/- SD 227 +/- 16 and 419 +/- 48 pg/ml for Ab+ and Ab- subjects, respectively (P less than .03). The means of the 5-min minus basal norepinephrine levels were 88 +/- 42 (Ab+) and 207 +/- 26 (Ab-) pg/ml (P less than .03). Mean epinephrine levels after 5 min of standing were 35 +/- 16 (Ab+) and 101 +/- 44 (Ab-) pg/ml (P less than .03). The means of the 5-min minus basal epinephrine levels were 1 +/- 5 (Ab+) and 43 +/- 38 (Ab-) pg/ml (P less than .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Premature menopause: monoclonal antibody defined T lymphocyte abnormalities and antiovarian antibodies.

The presence of other organ-specific autoimmune disorders in some patients with premature menopause has supported the concept of an autoimmune etiology. The authors analyzed the peripheral blood of 23 women with the diagnosis of premature menopause to detect the presence of monoclonal antibody-defined T-lymphocyte abnormalities and/or antiovarian antibodies. All subjects were less than 40 years of age with the duration of menopause ranging from less than 1 year to 11 years at the time of study. Thirty-five percent of the subjects had an elevated percentage of Ia+ (Dr-activated) T cells using monoclonal antibody L243. The percent T4 (helper) T8 (suppressor/cytotoxic) T cells and T4/T8 ratio were normal in the study group. Four subjects (approximately 17%) had elevated percentages of the age-related 3G5+ T cell subset. Two of the subjects with increased 3G5+ T cells also exhibited increased Ia+ T cells. Antiovarian steroid cell antibodies and antiadrenal cortical antibodies were present in approximately 9% of subjects. Anti-islet cell antibodies were not present. Thyroid antimicrosomal antibodies were present in 17% of subjects. Study subjects exhibited immunologic abnormalities that the authors hypothesize may play a role in the development of premature menopause in a larger percentage of patients than was previously suspected.

Trisomy 21 (Down's syndrome): autoimmunity, aging and monoclonal antibody-defined T-cell abnormalities.

Down's syndrome has been associated with organ-specific autoimmunity and 'premature aging'. We studied 27 individuals with Down's syndrome (all trisomy 21, no translocations aged 0.5 to 50 years). Subjects were not preselected for autoimmunity. Six subjects had a history of hypothyroidism and three additional subjects had anti-microsomal antibodies (euthyroid). Three subjects had insulin-dependent diabetes mellitus and one additional subject had islet cell autoantibodies (non-diabetic). The percentage Ia (Dr) positive T cells exceeded the normal range in 7/26 (27%). The percent CD4+ and CD8+ T cells were not significantly different from control. A subgroup of Down's syndrome subjects (less than age 10) had a premature increase in the percentage of 3G5+ (age-related) T cells. Normal individuals express a similar percentage of 3G5+ T cells at age 50 to 70 years. The presence of T-cell activation and 'premature T-cell aging' may predispose Down's syndrome subjects to organ-specific autoimmunity and age-related disorders.

Anti-sympathetic ganglia antibodies and postural blood pressure in IDDM subjects of varying duration and patients at high risk of developing IDDM.

We examined the sera of 94 subjects with insulin-dependent diabetes mellitus (IDDM) for the presence of complement-fixing sympathetic ganglia (CF-SG) antibodies. In a cross-sectional analysis (duration 0-43 yr), 22% had detectable CF-SG antibodies. Subjects at high risk for IDDM were also studied. Four groups were studied: group 1 (aged 4-64 yr) islet cell antibody-positive (ICA+) prediabetic subjects, 10 of 19 (53%) were CF-SG+; group 2 (aged 6-14 yr) ICA- prediabetic subjects (first-degree relatives of IDDM subjects with either transient hyperglycemia, impaired oral glucose tolerance, and/or first-phase insulin release after intravenous glucose tolerance testing), 4 of 9 (44%) were CF-SG+ (2 of the 4 ICA- CF-SG+ subjects have progressed to IDDM); group 3 (aged 1.5-43 yr) ICA+ IDDM subjects (less than or equal to 1 yr duration) 6 of 10 (60%) were CF-SG+; and group 4 (aged 8-59 yr) ICA- IDDM subjects (less than or equal to 1 yr duration), 2 of 11 (18%) were CF-SG+. All groups had increased CF-SG compared with controls. Postural blood pressure and simultaneous CF-SG antibody measurements were performed in 28 IDDM subjects. The drop in systolic blood pressure was greater in the CF-SG+ subjects (P less than .05), and the frequency of CF-SG was greater in the mean to -2SD group (P less than .03) when data were analyzed within mean +/- 2SD of the normal blood pressure response.

Type I diabetes as a chronic autoimmune disease.

The realization that Type I diabetes is an autoimmune disease and, in particular, a chronic autoimmune disease is beginning to impact on clinical care and research directed at elucidating the cause and prevention of diabetes. For example, specialized laboratory evaluation can now be used to exclude potential renal donors who are at high risk of developing diabetes (by screening renal donor candidates who are relatives of Type 1 diabetics for cytoplasmic islet cell antibodies and evaluating first phase insulin secretion on intravenous glucose tolerance testing). The most important long-term consequence of the ability to predict Type 1 diabetes may be the development of effective immunotherapy to prevent the disease. Finally, the realization that Type 1 diabetes is an auto-immune disease and that some of the antigens expressed by islets (e.g., specific gangliosides identified with monoclonal antibodies) are expressed by renal glomerular cells, retinal microvascular pericytes, and neurons has renewed interest in searching for immunologic factors contributing to secondary complications.

Anti-adrenal medullary antibodies in IDDM subjects and subjects at high risk of developing IDDM.

Previous reports have noted the presence of anti-adrenomedullary antibodies in subjects with insulin-dependent diabetes mellitus (IDDM). We initiated a study to evaluate the presence of complement-fixing anti-adrenomedullary antibodies (CF-ADM) in the following subjects: group 1 (age 4-60 yr), anti-islet cell antibody-positive (ICA+) subjects at high risk of developing diabetes, in which 9 (32%) of 28 were positive for CF-ADM; group 2 (age 6-41 yr), anti-ICA negative (ICA-) subjects at high risk of developing diabetes, in which 0 (0%) of 15 were positive for CF-ADM; group 3 (age 1-58 yr), ICA+ diabetic subjects, in which 7 (30%) of 23 were positive for CF-ADM; group 4 (age 5-68 yr), ICA- diabetic subjects, in which 1 (4%) of 24 was positive for CF-ADM; group 5 (age 20-56 yr), volunteer blood bank donor controls, in which 2 (6%) of 32 were positive for CF-ADM; and group 6, known healthy controls, in which 0 (0%) of 14 were positive for CF-ADM. CF-ADM were increased in group 1 compared with group 2 (P less than .02) and both control groups (P less than .02). CF-ADM were increased in group 3 compared with group 4 (P less than .03) and both control groups (P less than .03 vs. group 5, P less than .05 vs. group 6). Presence of CF-ADM was associated with presence of ICA in group 1 (P less than .02) and group 3 (P less than .03).(ABSTRACT TRUNCATED AT 250 WORDS)

Renin suppression by saline is blunted in nonmodulating essential hypertension.

We have reported that 50% of subjects with normal renin essential hypertension have both delayed suppression of the renin-angiotensin-aldosterone axis following sodium infusion and a delayed rate of excretion of an acute salt load. In another study we have also described a subset of patients with essential hypertension (called nonmodulators) who have several abnormalities, including a pressor response to salt loading. To evaluate whether the abnormalities described in these different groups of patients actually occur in the same patient, we assessed the renin-angiotensin-aldosterone axis response to short-term saline loading in 38 hypertensive patients. Their ability to modulate was determined by their renal vascular response to infused angiotensin II on a high salt diet (200 mEq Na). In response to a 3-hour infusion of saline, 75 mEq/hr, the reduction in plasma renin activity at both 60 and 120 minutes was significantly greater (p less than 0.008) in patients with normal modulation than in the nonmodulators. Plasma aldosterone levels were also significantly lower (p less than 0.001) in those with intact modulation. Thus, nonmodulating essential hypertensive patients have abnormalities in several systems that influence sodium homeostasis, including altered adrenal and renal vascular response to angiotensin II, altered renal blood flow response to salt loading, and a delayed suppression of the renin-angiotensin-aldosterone system with short-term saline infusion.