Aspirin stimulates insulin and glucagon secretion and increases glucose tolerance in normal and diabetic subjects.

Normal subjects and patients with adult-onset diabetes received 10 gm. of aspirin in four days. On the fourth day, the fasting serum glucose and the glucose response to oral glucose were decreased in both groups. These changes were associated with increased levels of serum insulin and pancreatic glucagon, although the glucagon responses to oral glucose were unchanged. In the diabetic patients, aspirin therapy was followed by a decreased glucose response to I.V. glucose and by the appearance of an early insulin peak, which could not be demonstrated before treatment. Aspirin did not affect the I.V. glucose tolerance in normal subjects, although it did enhance the early insulin peak. A decrease in the fasting levels of free fatty acids was noted in both groups, whereas the fasting level of triglycerides decreased only in the diabetic patients. Cholesterolemia did not change in either group. A few preliminary observations indicate that, in normal subjects, ibuprofen and ketoprofen, two other presumed prostaglandin inhibitors, did not affect fasting glycemia, glucose tolerance, or the insulin response to glucose. No changes were noted after the administration of placebo.

Alpha 1 adrenoceptor subtype mediates noradrenaline induced contraction of the human internal mammary artery: radioligand and functional studies.

STUDY OBJECTIVE: The aim was to evaluate the characteristics of alpha adrenergic binding sites on human internal mammary arteries and the alpha adrenoceptor mediated vasoconstrictor response to catecholamines. DESIGN: Human internal mammary arteries were cut longitudinally, the intimal layer was scraped, and the arteries homogenised and centrifuged at 50,000 g to obtain a membrane pellet. Saturation isotherms with [3H]-prazosin were done with 50-100 micrograms plasma membranes per tube and increasing concentrations of [3H]-prazosin (non-specific binding: 2.5 mM noradrenaline plus superoxide dismutase and catalase). Kinetic isotherms were done with 100 micrograms plasma membranes and 1-5 nM [3H]-prazosin for time periods ranging from 1 to 90 min; at the equilibrium, dissociation of [3H]-prazosin was achieved by 10 microM prazosin. alpha 2 Adrenoceptor density on internal mammary artery membranes was assessed with [3H]-rauwolscine (non-specific binding: 1 microM yohimbine). Separation of membrane bound radioactivity was achieved by rapid vacuum filtration through Whatman GF/C fibre filters. Saturation isotherms were evaluated by Scatchard plots and kinetic data, and competition isotherms by Enzfitter analysis. Contractility studies were done with helical strips of artery (without adventitial layer) placed in a thermostated perfusion bath. Data were obtained in the presence of different concentrations of agonists and antagonist to obtain Schild plots. Antagonist drugs were employed at only one concentration for each preparation. SUBJECTS: Mammary arteries were collected from 51 patients (age range 42-65 years) undergoing surgery for coronary grafting. MEASUREMENTS AND MAIN RESULTS: The binding of [3H]-prazosin to arterial plasma membrane was rapid and reversible. The K + 1 was 0.13 (SD 0.03) X 10(9) M.min-1 (n = 5) and the Kd, determined as a ratio between k-1/K + 1, was 0.34(0.01) nM (n = 5). [3H]-Prazosin binding, displaceable by 2.5 mM (-)-noradrenaline, was saturable and disclosed an alpha 1 adrenoceptor density of 30(3) fmol.mg-1 protein with a dissociation constant (Kd) of 215(50) pM (n = 18). The adrenergic agonists competed with [3H]-prazosin in the following order of potency: (-)-adrenaline [Ki = 0.6(0.1) microM; n = 5] greater than (-)-noradrenaline [Ki = 1.05(0.015) microM; n = 12] much greater than (-)-isoprenaline [Ki = 150(10) microM; n = 4]. Specific binding of [3H]-rauwolscine to IMA plasma membranes was negligible (about 2 fmol.mg-1 protein) (n = 15) with an unfavourable ratio of non-specific v specific binding. Catecholamines induced a dose dependent contractile response in arterial strips; (-)-noradrenaline: EC50 = 0.48(0.12) microM, n = 20; (-)-adrenaline: EC50 = 0.15(0.16) microM, n = 10; and methoxamine, a selective alpha 1 adrenergic agonist: EC50 0.67(0.15) microM, n = 10. The alpha 2 adrenoceptor agonists BHT-933, BHT-920, and guanabenz did not contract the arterial strips (up to 10 mM). Prazosin (0.03-0.1 microM) produced concentration dependent right shifts of the (-)-noradrenaline [pA2 = 9.83(0.11), n = 19], (-)-adrenaline [pA2 = 9.50(0.31), n = 10], and methoxamine [pA2 = 8.96(0.18), n = 10] concentration-response curve. CONCLUSIONS - Internal mammary artery plasma membranes possess alpha 1 adrenoceptors which are involved in the vasoconstrictor response to catecholamines. alpha 2 Adrenoceptors seem not to be involved.

Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy.

OBJECTIVES: To investigate the prevalence, metabolic features and risk factors of a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth associated with a wasting of the lower limbs, observed in HIV-infected women treated with combined antiretroviral (ARV) therapy. DESIGN: Cross-sectional study. SETTING: Outpatients attending the Institute of Infectious Diseases, University of Milan, Milan, Italy. PATIENTS AND METHODS: HIV-infected women treated with two or more ARV drugs, observed between December 1997 and February 1998. FR was confirmed by means of a physical examination and dual-energy X-ray absorptiometry (DEXA). The metabolic and endocrinological measurements in patients with FR were compared with those in FR-free women. RESULTS: FR was observed in 32 out of 306 women (10.5%). DEXA revealed more trunk fat (P < 0.01) and less leg fat (P < 0.001) in the patients with FR than in the matched controls. There were no significant differences in laboratory test results between the two groups. All of the FR patients were taking lamivudine-containing regimens; 20 of them were also taking a protease inhibitor (PI). The association of FR with lamivudine-including regimens was statistically significant (P = 0.017). Among the patients taking lamivudine, the risk associated with treatments including PI was 1.8 (95% CI 0.8-3.8, P = 0.12). A total duration of ARV therapy of more than 1000 days was associated with a greater risk of developing FR (OR 10.8; 95% CI 1.4-80.5; P = 0.0207). Stepwise logistic regression analyses indicated that prolonged ARV therapy and a viral load of more than 10000 copies per ml at the beginning of the last ARV regimen were the only variables that significantly and independently correlated with the risk of FR. CONCLUSIONS: The observed body modifications are caused by a redistribution of body fat without fat loss that is apparently not associated with hyperlipidemia, altered glucose metabolism or other endocrinological disorders. The development of FR in patients receiving only reverse transcriptase (RT) inhibitors suggests the presence of a PI-independent mechanism that deserves further investigation.

Serotonergic regulation of cortisol secretion in dogs.

The role of serotonin (5-HT) in the control of serum cortisol secretion was studied in 50 conscious beagle dogs. A significant rise in corticosteroids was observed after 1.5 and 3 mg/kg (P less than 0.01) iv fenfluramine, an indirect serotonergic agonist, as well as after 2 (P less than 0.05) and 3 mg/kg (P less than 0.01) iv quipazine, a direct agonist of 5-HT receptors. Both drugs exhibited a dose-related effect. A lower dose of fenfluramine, 0.5 mg/kg, was ineffective when administered iv, but raised serum cortisol (P less than 0.05) after direct injection into a lateral cerebral ventricle, through a chronically implanted brain cannula. The marked increases in corticosteroid concentration produced by the highest fenfluramine and quipazine doses were completely abolished by pretreatment with ketanserin, an antagonist of 5-HT2 receptors, which did not affect cortisol secretion when administered alone. These data suggest that brain serotonergic system plays a role in the control of cortisol secretion in conscious dogs.

Glucocorticoids and interferon-alpha in the acquired immunodeficiency syndrome.

Some patients with acquired immunodeficiency syndrome (AIDS) develop glucocorticoid resistance characterized by low receptor affinity (Kd) for glucocorticoids in mononuclear, cells and high values of ACTH and cortisol. As glucocorticoids regulate interferon-alpha (IFN alpha) production, we hypothesized that IFN alpha, a cytokine produced predominantly by monocytes in AIDS, should be increased in cortisol-resistant AIDS, attributing the lack of cortisol inhibition to IFN alpha production. Therefore, we examined glucocorticoid receptor characteristics on monocytes by [3H]dexamethasone binding and measured IFN alpha, cortisol, and ACTH in AIDS patients with (AIDS-GR) or without glucocorticoid resistance (AIDS-C) and controls (C). Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/L that was higher than that in the AIDS-C group (2.9 +/- 0.8 nmol/L) and normal subjects (2.0 +/- 0.8 nmol/L; P < 0.01). IFN alpha levels were increased in the AIDS-GR group (17 +/- 6 vs. 4 +/- 1 U/mL in the AIDS-C group and 2 +/- 0.5 U/mL in the C group; P < 0.01). Correlations were found between plasma IFN alpha and receptor Kd on monocytes of AIDS-GR (r = 0.77) and between IFN alpha and plasma cortisol in the same group (r = 0.74). The poly(I)-poly(C)-induced IFN alpha production by monocytes was inhibited by glucocorticoids in the C and AIDS-C groups (approximately 80% inhibition in both groups); the effect was reversed by the receptor antagonist RU-38486. By contrast, glucocorticoids failed to inhibit IFNalpha production from AIDS-GR monocytes (approximately 20% inhibition). In conclusion, elevated IFN alpha levels in AIDS-GR may be due to the lack of inhibitory effect of cortisol on IFN alpha production due to cortisol resistance in monocytes.

Glucocorticoids and the immune function in the human immunodeficiency virus infection: a study in hypercortisolemic and cortisol-resistant patients.

Immunological studies in human immunodeficiency virus (HIV)-positive patients suggest that the disease progression is accompanied by a defective production of type 1 cytokines (interleukin-2 (IL-2) and IL-12], an increased production of type 2 cytokines (IL-4, IL-6, and IL-10), and an increased production of IgE. HIV infection is also associated with activation of the hypothalamo-pituitary-adrenal axis function and increased plasma and urinary cortisol concentrations. As cortisol is involved in the physiological regulation of cytokines, a study was conducted to examine cytokine patterns in two groups of hypercortisolemic patients, one with normal sensitivity to glucocorticoids and the other with glucocorticoid resistance. Ten HIV-infected patients with normal receptor affinity to glucocorticoids (AIDS-C), 10 HIV-infected patients with low receptor affinity to glucocorticoids (AIDS-GR), and 20 healthy subjects were studied. Receptor characteristics of peripheral blood mononuclear cells were evaluated by [3H]dexamethasone binding. Serum cortisol and urinary free cortisol were measured by RIA. Serum ACTH and IgE were measured by immunoradiometric assay, and IL-2, IL-4, and IL-10 cytokines and interferon-gamma were measured by enzyme-linked immunosorbent assay. AIDS-C patients showed low IL-2 and high IL-4, IL-10, and IgE concentratios; conversely, AIDS-GR patients showed high IL-2 and low IL-4 and IgE concentrations. Thus, in HIV infection, elevated cortisol levels suppress cell-mediated immunity and stimulate humoral immunity, whereas this response is not detected in cortisol-resistant patients. These findings indicate that cortisol and its receptors are critically involved in the regulation of immune function in HIV infection.

Indapamide in the treatment of hypertension in non-insulin-dependent diabetes.

The antihypertensive effect of indapamide, a new thiazide derivative, has a low diuretic effect and a primary action on vascular smooth muscle. It was evaluated in a series of 20 patients with non-insulin-dependent diabetes (age range 47-75 years) who had arterial hypertension of mild to moderate degree treated with hypoglycemic agents and/or diet. Indapamide, 2.5 mg, was given as a single daily dose for 6 months. A statistically significant reduction of systolic and diastolic pressures was observed in both supine and upright positions. This decrease was significant beginning in the first month of therapy (p less than 0.001). No significant modifications of fasting glycemia, postprandial glycemia, and glycosylated hemoglobin were noted. No significant changes were observed in serum sodium, potassium, chloride, calcium, and uric acid. Indapamide is an effective and practical treatment of hypertension of mild to moderate degree in patients with diabetes. The absence of effect on glucose metabolism makes it an especially interesting drug.

Metoclopramide increases plasma aldosterone concentration in man.

Plasma Aldosterone (PA) response to metoclopramide (10 mg i.v.) was studied in 11 normal, 2 hypophysectomized subjects and in one patient with bilateral adrenal hyperplasia. All the subjects were kept on a normal sodium and potassium intake. Four normal subjects were pretreated with 1 mg of dexamethasone in order to inhibit endogenous ACTH. In all subjects metoclopramide elicited a prompt rise of PA comparable to that obtained with angiotensions or ACTH. No significant change of blood pressure, serum electrolytes, plasma renin activity, Plasma Cortisol (PC) was detected. The lack of PC response to metoclopramide and the PA increase in dexamethasone pretreated subjects rule out an ACTH mediated effect. The increase of PA in hypophysectomized subjects, in whom metoclopramide did not stimulate any prolactin release, rules out a prolactin mediated effect. Metoclopramide increases plasma aldosterone concentration probably via a direct action on the adrenal glomerular zone or throught another unknown mechanism.

Osmotic and nonosmotic control of vasopressin release in the elderly: effect of metoclopramide.

The study was undertaken to define the relationships between the arginine vasopressin (AVP) response to a pressure-volume stimulus (upright posture test), an osmolar challenge, and metoclopramide injection (20 mg, iv) in normal young and elderly subjects. Besides confirming previous findings of increased AVP responsiveness to osmolar challenge and reduced AVP responsiveness to upright posture in the elderly, we found that metoclopramide stimulated AVP release in both young [from 1.09 +/- 0.05 (mean +/- SD) to 1.77 +/- 0.05 pmol/L; P less than 0.05] and elderly subjects (from 1.54 +/- 0.18 to 4.73 +/- 1.82 pmol/L; P less than 0.01). The response was much greater in the elderly (P less than 0.01). The AVP responses to upright posture and metoclopramide were inversely correlated (r = -0.77; P less than 0.01), suggesting that the elderly have increased sensitivity to stimuli, such as metoclopramide, to counteract their reduced sensitivity to baroreceptor stimulation of AVP release.

Short-term variations in bone remodeling biochemical markers: cyclical etidronate and alendronate effects compared.

Bone-remodeling markers have been proposed to monitor antiosteoporotic therapy, as substantial changes in these markers usually occur in a relatively short time interval. In this study we have evaluated the short term effects of two bisphosphonates on bone-remodeling markers with the aim of 1) defining the shortest reliable time interval after which markers should be measured, and 2) comparing the effects of different bisphophonates. To do so, 74 postmenopausal women with a lumbar spine t score of at least -1 were randomly allocated to 4 different treatments: calcium carbonate (500 mg/day; n = 18), 5 mg/day alendronate (A5; n = 18), 10 mg/day alendronate (A10; n = 20), and cyclical etidronate (CE; n = 18). Serum and 24-h urine samples were collected at baseline and 14, 28, 56, and 84 days after the beginning of therapy. Type I collagen N-terminal (NTx) and C-terminal (CTx) telopeptides and total deoxypyridinoline (tDPD) were measured in urine and normalized for urinary creatinine excretion. Osteocalcin and bone alkaline phosphatase in serum were measured. Alendronate (at both doses) and CE significantly decreased bone-remodeling markers, whereas calcium carbonate did not. Bone resorption markers reduction reached a plateau 14 (A10) or 28 (A5 and CE) days after the beginning of treatment, whereas osteocalcin and bone alkaline phosphatase were significantly reduced at 56 (A10) and 84 (CE) days. The global effects of alendronate and CE on NTx and CTx (calculated as the area under the curve) were significantly different from those of calcium (P < 0.05), but were not significantly different from each other. The percent change from baseline obtained with tDPD, NTx, or CTx during bisphosphonate treatment were significantly different (P < 0.05), but this difference disappeared when the variability in the calcium carbonate group was taken into account. In conclusion, this study shows that 1) etidronate and alendronate induce a significant and rapid reduction in bone-remodeling markers; 2) the changes in NTx, CTx, and tDPD urinary excretions reach a plateau after 2-4 wk of treatment; and 3) short term treatments with CE or alendronate induce similar changes in the urinary excretion of NTx and CTx.

Metoclopramide increases vasopressin secretion.

The possibility that metoclopramide (MCP), a potent stimulator of aldosterone secretion, might influence vasopressin secretion in man was studied. MCP (10 mg, iv) increased plasma vasopressin (mean +/- SD) from 1.3 +/- 0.1 to 2.4 +/- 0.1 pg/ml at 10 min and to 2.65 +/- 0.1 pg/ml at 20 min (P less than 0.01) in 10 recumbent normal subjects. No changes in plasma osmolality or peripheral hemodynamics, which might have accounted for the increase in vasopressin, were found. Sulpiride (100 mg iv), haloperidol (2 mg, iv), and domperidone (20 mg, iv), three chemically unrelated antidopaminergic agents, as well as TRH (200 micrograms, iv), failed to modify plasma vasopressin, thus suggesting that the MCP effect on vasopressin is not linked to its antidopaminergic and/or PRL-releasing properties. MCP also was effective in releasing vasopressin in 5 dehydrated subjects, in whom plasma vasopressin increased from 1.9 +/- 0.2 to 3.1 +/- 4 pg/ml (P less than 0.05), and in 5 subjects during steady state water diuresis, in whom free water excretion decreased from 9 to 1 ml/min (P less than 0.01) and plasma vasopressin increased from 0.3 +/- 0.1 to 1.2 +/- 0.2 pg/ml (P less than 0.05). No changes in either vasopressin secretion or free water excretion occurred in 4 patients with severe central diabetes insipidus. These results suggest that MCP stimulates the release of biologically active vasopressin in man.

Cortisol resistance in acquired immunodeficiency syndrome.

This study concerns 9 iv drug abusers with acquired immunodeficiency syndrome (AIDS) who developed hypercortisolism without the clinical signs or metabolic consequences of hypercortisolism. All patients were characterized by an Addisonian picture (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis). An acquired form of peripheral resistance to glucocorticoids was suspected. We, therefore, examined glucocorticoid receptor characteristics on mononuclear leukocytes by measuring [3H]dexamethasone binding and the effect of dexamethasone on [3H]thymidine incorporation, which is one of the effects of glucocorticoid receptor activation. Glucocorticoid receptor density was increased in AIDS patients with an Addisonian picture (group 1; 16.2 +/- 9.4 fmol/million cells) compared to values in 12 AIDS patients without an Addisonian picture (group 2; 6.05 +/- 2.6 fmol/million cells; P less than 0.01) and sex- and age-matched controls (3.15 +/- 2.3 fmol/million cells; P less than 0.01). The affinity of glucocorticoid receptors (Kd) was strikingly decreased (9.36 +/- 3.44 nM in group 1; 3.2 +/- 1.5 nM in group 2; 2.0 +/- 0.8 nM in controls; P less than 0.01). [3H]Thymidine incorporation was decreased dose-dependently by dexamethasone in controls and patients; the effect was significantly blunted (P less than 0.05) in group 1 patients, which suggests that activation of glucocorticoid receptor is impaired as a result of the glucocorticoid receptor abnormality. In conclusion, AIDS patients with hypercortisolism and clinical features of peripheral resistance to glucocorticoids are characterized by abnormal glucocorticoid receptors on lymphocytes. Resistance to glucocorticoids implies a complex change in immune-endocrine function, which may be important in the course of immunodeficiency syndrome.

Pharmacologic data reveal the heterogeneity of angiotensin-converting enzyme according to its source (lung versus heart).

Angiotensin-converting enzyme (ACE) has 2 different active sites: a C-site (in the carboxy terminal region) and an N-site (in the amino terminal part). Some ACE inhibitors have a relatively greater affinity for the C-sites, whereas others bind to the 2 sites with equal affinity. The different ontogenesis of lung and heart endothelial cells can be related to binding differences to the C- and N-sites. We labeled Ro31-8472, a clizapril derivative, which has the same affinity for the 2 ACE sites. Binding of 125I-Ro31-8472 to human left ventricle and lung plasma membranes was saturable, inhibited by ethylene diaminetetraacetic acid and displayed affinities of 360 +/- 41 pM in heart and 320 +/- 51 pM in lung. For captopril the Hill slope was 0.57 +/- 0.03 for heart and 0.48 +/- 0.05 for lung; for delaprilat, a nonsulfhydryl analogue of captopril, the slope was 0.43 +/- 0.05 for heart and 0.55 +/- 0.05 for lung. These drugs were characterized by biphasic competition isotherms. The Hill slope of enalaprilat was 1.01 +/- 0.06 for heart and 0.93 +/- 0.06 for lung, and Ro31-8472 had a slope of 0.97 +/- 0.04 for heart and 0.93 +/- 0.03 for lung. The affinity of ACE inhibitors with Hill slope different from unity varied according to the source of ACE; in fact, delaprilat had greater affinity for the high-affinity sites of heart than lung (pKi, 9.89 and 9.47, respectively), whereas captopril had greater affinity for the high-affinity sites of lung than heart (9.40 and 8.85, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the Frank-Starling mechanism in maintaining cardiac output during increasing levels of treadmill exercise in beta-blocked normal men.

To determine the effects of beta blockade on hemodynamics during increasing levels of treadmill exercise, 10 healthy volunteers were studied after 1 week of placebo, and then after 1 week of treatment with oral propranolol, 80 mg twice daily, or dilevalol, 400 mg once daily. The study was randomized and double-blind, with a crossover sequence. Hemodynamics were measured by CO2 rebreathing at rest and at 25, 50, 75 and 100% of VO2 max. After placebo, cardiac output increased from 5.8 +/- 2.1 (rest), to 19.4 +/- 6.4 liters/min (100% VO2 max), mainly due to an increase in heart rate from 84 +/- 6 to 169 +/- 15 beats/min. Stroke volume increased from 70 +/- 27 (rest), to 137 +/- 65 ml (25% VO2 max), and then leveled off to 116 +/- 41 at 100% VO2 max. After both beta blockers, exercise cardiac output was maintained at 100% VO2 max: 20.1 +/- 9.3 liters/min with propranolol and 19.1 +/- 8.6 with dilevalol. However, a significant reduction versus placebo values was observed for cardiac output at 25% VO2 max, from 13.7 +/- 5.9 during placebo, to 9.4 +/- 2.5 during propranolol, and to 9.6 +/- 2.3 during dilevalol (both p less than 0.01 vs placebo). Maintenance of cardiac output with both beta blockers at higher levels of exercise came from an increased stroke volume (p less than 0.05 vs placebo), while heart rate (in beats/min) was greatly reduced (propranolol 61.6 +/- 9.4 rest, 90.1 +/- 10.7 at 100% VO2 max; dilevalol 70.8 +/- 6.4 rest, 99.2 +/- 11.8 at 100% VO2 max, p less than 0.01 vs placebo for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.

This randomized, double-blind, placebo-controlled study shows that 20-week fluvastatin treatment induces beneficial changes in the lipid panel and a shift in the fibrinolytic pathway toward activation through a decrease in tissue plasminogen activator antigen. Fluvastatin treatment causes no variation in lipoprotein(a) circulating levels.

Angiotensin converting enzyme binding sites in human heart and lung: comparison with rat tissues.

1. Angiotensin converting enzyme (ACE), a dipeptidyl carboxypeptidase which catalyzes the final activation step in the formation of angiotensin II, was identified by radioligand studies in rat heart and lung. In this work we identified ACE binding sites in human left ventricle and lung by radioligand binding using the ACE inhibitor [3H]-ramiprilat in all tissues tested was saturable, temperature and zinc-dependent, and inhibited by EDTA. In human left ventricle homogenate we found a density of binding sites of 121 +/- 15 fmol mg-1 protein (n = 4) with an affinity (Kd) of 850 +/- 55 pM, whereas in rat left ventricle the same values were 23 +/- 4 fmol mg-1 protein and 315 +/- 30 pM, (n = 4), respectively. 3. [3H]-ramiprilat binding to rat (n = 4) and human lung (n = 4) showed a binding site density of 2132 +/- 155 and 1085 +/- 51 fmol mg-1 protein respectively with an affinity of 639 +/- 54 and 325 +/- 22 pM. The lung:heart ratio of ACE binding site density was about 9:1 in man and 100:1 in rat. 4. The binding affinities of 13 ACE inhibitors were evaluated on human heart and lung: the drugs tested showed a wide range of affinities for the ACE binding sites in both tissues, and the affinity for lung was significantly greater than for heart for most of the drugs. 5. The greater potency of some ACE inhibitors in displacing [3H]-ramiprilat in human lung compared with the heart indicates differences between ACE binding sites in these tissues and suggests the possibility of a selective organ-targeted therapeutic approach.

Glucocorticoids and the immune system in AIDS.

An interesting aspect of HIV disease is the immunoendocrine dialogue, via the hypothalamo-pituitary-adrenal axis, between glucocorticoids and cytokines and its potential role in HIV disease progression. This study reports recent data on the interaction between glucocorticoids and the immune system in AIDS patients with an acquired form of glucocorticoid resistance. Clinically, glucocorticoid-resistant AIDS patients (AIDS-GR; about 12% in our series of patients) present Addisonian symptoms (weakness, weight loss, hypotension, hyponatremia and intense mucocutaneous melanosis) in spite of elevated values of plasma cortisol and urinary free cortisol. Monocytes from these patients have a significantly lower receptor affinity (higher Kd) for glucocorticoids and a higher receptor density than other patients and controls. Such receptor alteration is associated with higher values of plasma interferon alpha (IFN alpha). In AIDS-GR there is a significant correlation between the values of receptor Kd and of plasma IFN alpha (r = 0.77). After poly(I):poly(C) stimulation, monocytes from AIDS-GR produce much more IFN alpha than other AIDS patients. While in patients with no resistance and in control patients, monocyte production of IFN alpha is inhibited by dexamethasone (the effect being reversed by RU-486), a very slight inhibition of dexamethasone on IFN alpha production is observed in monocytes from AIDS-GR. In conclusion, these data demonstrate that the immunosuppressive mechanisms acting in AIDS may be reversed, as shown by the increased stimulus on IFN alpha production found in cortisol-resistant patients. These data also suggest that antiglucocorticoid drugs may be helpful in HIV disease as they antagonize the excessive immunosuppression induced by the increased production of glucocorticoids found at every stage of HIV disease.

Glucocorticoid resistance and the immune function in the immunodeficiency syndrome.

Glucocorticoids, the final product of HPA axis, and their receptors (GRs) on mononuclear cells are crucial mediators in the endocrine-immune interaction. An alteration in GRs involving a lower receptor affinity (Kd) for glucocorticoids has been found in a group of advanced AIDS patients, who developed Addisonian symptoms (weakness, weight loss, hypotension, hyponatremia, and intense mucocutaneous melanosis) in spite of hypercortisolism and normal or slightly elevated values of ACTH (AIDS-GR). In these patients, data for the suppression test showed decreased cortisol and ACTH suppression in response to exogenous dexamethasone. The inhibitory effect of dexamethasone on radiolabeled-thymidine incorporation in mononuclear cells from these patients was also reduced. Monocytes of AIDS-GR patients had a receptor Kd of 10.5 +/- 4.2 nmol/l that was higher than that of other AIDS patients (AIDS-C) (2.9 +/- 0.8 nmol/l) and normal subjects (2.0 +/- 0.8 nmol/l: p < 0.01). Correlations were found between plasmatic IFN-alpha and receptor Kd on monocytes of AIDS-GR (r = 0.77). Poly (i)-poly (c)-induced IFN-alpha production by monocytes was inhibited by glucocorticoids in the AIDS-C group and controls (approx. 80% in both groups): The effect was reversed by the receptor antagonist RU-486. By contrast, glucocorticoid did not inhibit IFN-alpha production in AIDS-GR group. In conclusion, levels of plasmatic IFN-alpha, a cytokine with antiviral properties, may be increased several times, and dexamethasone fails to inhibit monocytes' IFN-alpha production only in AIDS with cortisol resistance, a disturbance that confirms an important immunoregulatory role of glucocorticoids in HIV disease.

Fat redistribution in HIV-infected patients. A new hormonal-immune disorder?

Multidrug antiretroviral regimes in HIV-infected patients may have side effects. The most frequent side effects are changes in fat metabolism and distribution. We describe a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth and fat loss in the lower limbs, which occurs in approximately 10% of HIV-infected women treated with combined antiretroviral therapy. To elucidate the metabolic, endocrine, and immunologic consequences of the observed disturbance, we measured serum lipids, glucose, C-peptide, ACTH, plasma, urinary cortisol, and cytokines IL-2, IFN gamma, Il-4, IL-10, Il-12, and TNF alpha in 36 patients with FR and in a control group without FR. There were no significant differences in hormonal and metabolic laboratory testing between the two groups. Immunology studies showed that in vitro production of TNF alpha and IL-10 was lower and IL-12 production higher in SR patients. Whether or not such immune alterations may be reponsible or be caused by fat redistribution remains to be explained. One year after the follow up, 50% of the patients treated with triple therapy developed lipodystrophy, characterized by weight loss, face-wasting, and hyperglycemia; the remaining 50% remained unchanged. In 13 patients the 3TC withdrawal was followed by improvements of the syndrome in 50% and of lipodystrophy in about 25%. These data suggest that the FR syndrome is frequent in patients treated with 3TC and that it is associated with characteristic changes in the cytokine production.

Immunoendocrinologic abnormalities in human immunodeficiency virus infection.

Alterations in the production of adrenal steroids and a complex pattern of dysregulation in cytokine profiles accompany the progression of HIV infection. Cortisol levels increase in HIV infection, while those of dehydroepiandrosterone (DHEA), a physiologic antagonist of the immunoregulatory activities of cortisol, decrease. A shift from type-1 to type-2 cytokine production is also detected in most patients during disease progression. This shift is summarized as a defective production of interferon gamma (IFN gamma), interleukin-2 (IL), and IL-12 accompained by increased production of IL-4, IL-5, IL-6, and IL-10. IFN gamma and IL-2 are suppressed, while the generation of IL-4 is stimulated by cortisol and pharmacological doses of glucocorticoids (GC). GC and IL-4 stimulate the differentiation of B lymphocytes into IgE-producing plasma cells, the concentration of which augments in HIV infection. Finally, GC induces programmed cell death (PCD) in a variety of different cells, including mature T lymphocytes. Because (1) TH1 but not TH2 undergo rapid Fas-mediated PCD upon antigen-stimulation, and (2) TH2 clones preferentially survive in vitro cell cultures, the progressive shift from type-1 to type-2 cytokine production observed in HIV infection could be at least partially provoked by the increase in the production of cortisol and the reduction of DHEA. Progression of HIV infection to AIDS can be controlled by highly active antiretroviral therapy (HAART); HAART drastically reduces HIV plasma viremia, but is less effective in immune reconstitution. Additionally HAART is associated in a sizable portion of patients by complex lypodistropyc phenomena that often involve the endocrine system.