Steven L. Rabinowe

Correction of abnormal renal blood flow response to angiotensin II by converting enzyme inhibition in essential hypertensives.

In 40-50% of patients with essential hypertension, a high sodium intake does not increase renal blood flow (RBF). These patients have been defined as nonmodulators because sodium intake does not modulate renal and adrenal responsiveness to angiotensin II (AII). To define the role of AII in mediating this altered responsiveness, we assessed the effect of a converting enzyme inhibitor (enalapril) on RBF and its responsiveness to AII in 25 patients with essential hypertension--10 modulators and 15 nonmodulators--and 9 normotensive controls. After 5 d of a 200-meq sodium intake, the nonmodulators did not increase RBF, whereas the normotensives (79 +/- 28 ml/min per 1.73 m2) and modulators (75 +/- 26 ml/min per 1.73 m2) did (P less than 0.025). Arterial blood pressure did not change in the modulators with the salt loading, whereas in the nonmodulators, blood pressure rose (P less than 0.004). After enalapril administration for 66 h, there was a significant difference (P less than 0.01, Fisher Exact Test) in the blood pressure response in the two hypertensive subgroups. In the modulators, there was no change; in the nonmodulators, despite the high salt diet, a blood pressure reduction occurred. In parallel, basal RBF and RBF responsiveness to AII were not changed after converting enzyme inhibition in the normotensive control (n = 9) or the hypertensive modulators (n = 10). Conversely, in the nonmodulators (n = 14), the basal RBF increased significantly (83 +/- 25 ml/min per 1.73 m2; P = 0.01), the increment being indistinguishable from the response to salt loading in normal subjects. Furthermore, renovascular responsiveness to infused AII was also significantly enhanced (P = 0.027) in the nonmodulators, suggesting that enalapril-induced increase in RBF reflected a fall in intrarenal AII levels, and not an increase in prostaglandins or kinins, which would have blunted the renal response to AII. Thus, short-term converting enzyme inhibition corrected abnormalities in sodium-mediated modulation of renal vascular responsiveness to AII. The close quantitative relation of the increase in RBF with sodium loading in normal subjects and modulators, and with converting enzyme inhibition in nonmodulators, viewed in the context of the effectiveness of enalapril only in the latter, and parallel shifts in sensitivity to AII, raises the intriguing possibility that converting enzyme inhibition reversed the failure of the renal blood supply to respond to sodium loading. Thus, converting enzyme inhibitors may reduce blood pressure specifically in this subset of patients with essential hypertension, who are sodium sensitive by way of mechanisms more closely related to local than systemic activity of the renin-angiotensin system.

Primary Addison's Disease in a Patient with the Acquired Immunodeficiency Syndrome

Excerpt Disseminated infection involving the adrenal glands has been noted frequently at autopsy in patients with the acquired immunodeficiency syndrome (1, 2). However, results of adrenocorticotro...

Ia-positive T lymphocytes in recently diagnosed idiopathic Addison's disease

The Ia (DR, immune-associated) antigen is absent on normal circulating T lymphocytes, but present on activated T lymphocytes. Utilizing monoclonal antibody L243, the expression of this glycoprotein on circulating T lymphocytes was studied in five patients with recent-onset idiopathic Addisons disease, one patient with recent-onset adrenal hemorrhage, and nine patients with long-standing adrenal insufficiency (five with idiopathic Addisons disease and four after bilateral adrenalectomy for Cushings disease). The patient with adrenal hemorrhage and the nine patients with long-standing adrenal insufficiency had percentages of circulating Ia-positive T cells within the normal range. All five patients with recent-onset idiopathic Addisons disease had an elevated percentage of circulating Ia-positive T cells (7 to 29 percent). The expression of Ia antigen on T cells in recent-onset idiopathic Addisons disease probably reflects immunologic activation, which may be of pathophysiologic importance.

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.

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 insulindependent 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 antibodypositive (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 (≤1 yr duration) 6 of 10 (60%) were CF-SG+; and group 4 (aged 8–59 yr) ICA IDDM subjects (≤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 < .05), and the frequency of CF-SG was greater in the mean to – 2SD group (P < .03) when data were analyzed within mean ± 2SD of the normal blood pressure response.

Complement-Fixing Antibodies to Sympathetic and Parasympathetic Tissuesin IDDM: Autonomic Brake Index and Heart-Rate Variation

We describe herein complement-fixing anti-adrenal medullary (CF-ADM) andanti-sympathetic ganglia (CFSG) antibodies in insulin-dependent diabetes mellitus (IDDM). This study describes complement-fixing antivagus (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 < 0.0001) and CF-SG (r = 0.39, P < 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 (antisympathetic) had higher brake indices than subjects with CF-V (anti-parasympathetic) antibodies (P < 0.03). Subjects with CF-SG had higher brake indices than those with CF-V (P < 0.04). The heart-rate variation with deep breathing was 23.3 ± 10.0 in subjects with CF-V and 45.66 ± 5.1 in the CF-SG+ and/or CF-ADM+ group (P < 0.03). This study demonstrates CF-V antibodies in IDDM and their association with a lower brake index and R-R interval variation compared with patients with sympathetic nervous system autoimmunity.

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 < .03). The means of the 5-min minus basal norepinephrine levels were 88 ± 42 (Ab+) and 207 ± 26 (Ab−) pg/ml (P < .03). Mean epinephrine levels after 5 min of standing were 35 ±16 (Ab+) and 101 ± 44 (Ab−) pg/ml (P < .03). The means of the 5-min minus basal epinephrine levels were 1 ± 5 (Ab+) and 43 ± 38 (Ab) pg/ml (P < .03). Mean change in systolic blood pressure on standing was not different in the two groups. This suggests that CF-ADM and CF-SG are associated with a decreased catecholamine response to change in posture.

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

Previous reports have noted the presence of antiadrenomedullary antibodies in subjects with insulindependent 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 CFADM; 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 < .02) and both control groups (P < .02). CF-ADM were increased in group 3 compared with group 4 (P < .03) and both control groups (P < .03 vs. group 5, P < .05 vs. group 6). Presence of CF-ADM was associated with presence of ICA in group 1 (P < .02) and group 3 (P < .03). In view of these results, adrenomedullary autoimmunity is emerging as a new member of the human organ-specific autoimmune disorders. It occurs before the development of clinically overt diabetes and is associated with the presence of ICAs. The functional significance of adrenomedullary autoimmunity needs to be evaluated.

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.

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.