Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome.

The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.

The effect of adrenomedullin and cold stress on interleukin-6 levels in some rat tissues.

Stress known to stimulate sympathetic activity, as well as the hypothalamic-pituitary-adrenal axis (HPA), produces a significant increase in adrenomedullin (AdM) levels, suggesting a regulatory or protective role for AdM in countering HPA activation that follows a variety of stressors. Stressors can modulate the secretion of proinflammatory cytokines. Interleukin (IL)-6 is a potent activator of the HPA and appears to play a pathogenic role in conditions related to stress. In the present study, we investigated the administration of AdM on IL-6 levels in cold exposed rats. Male Wistar rats were divided into four groups as control, adrenomedullin treatment, cold stress and cold stress+adrenomedullin-treated groups. In the adrenomedullin-treated group, animals received intraperitoneal (i.p.) injection of adrenomedullin (2000 ng/kg body weight) once a day for a week. For the cold stress exposure the rats were kept in separate cages at 10 degrees C for a week. Control group rats were kept in laboratory conditions. The concentration of IL-6 was determined using an enzyme-linked immunosorbent assay (ELISA) kit. When compared to control, IL-6 levels increased significantly in the cold stress- and adrenomedullin-treated groups (P<0.05). Administration of AdM in addition to cold stress decreased IL-6 levels in lung and liver, but increased in brain and heart when compared to control (P<0.05). The results suggest that cold stress may induce increase of rat proinflammatory cytokine IL-6 and adrenomedullin may play a regulatory or protective role for cold stress.

Adrenomedullin and nitrite levels in children with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is an important cause of chronic congestive cardiac failure in children. In patients with idiopathic DCM, endothelium vasomotor function is disturbed. There are many studies on the roles of nitric oxide (NO) and adrenomedullin (AM) in adult patients with DCM. However, to our knowledge, no studies have investigated the level of AM and NO in children with idiopathic DCM. We determined plasma and urinary AM and total nitrite concentrations in children with idiopathic DCM and investigated the correlation between these and other clinical and laboratory findings. Eleven patients with DCM, ranging in age from 5 month to 14 years, were compared to 10 healthy age- and sex-matched controls. Plasma (pmol/ml) and urinary (pmol/mg creatinine) AM levels were significantly lower than in the healthy controls (19.55 +/- 2.36 vs 51.61 +/- 7.22 and 28.29 +/- 20.66 vs 68.87 +/- 40.23, respectively; p <0.001). Plasma and urinary AM levels were negatively correlated with ejection fraction (EF) and fractional shortening (FS). The plasma (Mmol/L) and urinary nitrite levels (Mmol/mg creatinine) were not different between patients and controls [50.90 +/- 17.50 VS 53.40 +/- 26.05 (P > 0.05) and 1.98 +/- 1.24 vs 2.75 +/- 1.68 (p > 0.05), respectively]. In our study, the first to analyze AM and nitrite levels in children with DCM, plasma and urinary AM levels were found to be decreased. A possible explanation for this reduction could be depletion of the viable myocyte population. However, this hypothesis must be clarified by further studies.

Contribution of adrenomedullin to homeostatic response to cold stress in rat model.

Acute stress known to stimulate sympathetic activity as well as the hypothalamo-pituitary-adrenal (HPA) axis, produces a significant increase in adrenomedullin (ADM) levels in the pituitary gland, plasma and adrenal glands, all of which are key components of HPA axis, suggesting a regulatory or protective role for ADM in countering HPA activation following a variety of physiological and psychological stressors. This study was conducted to assess a rat model for in depth investigation of biochemical mechanisms and consequences of cold stress. Four groups of Sprague-Dawley rats were observed for their serum total protein, glucose, trigliceride and cholesterol levels as well as their blood pressures after housing at room temperature, administration of ADM (1.0 nm/kg), exposing to cold stress (8 degrees C for 48 h) and exposing to ADM injection in addition to cold stress. The results suggest that application of ADM in addition to cold stress may act via receptors on different end-organs and causes altered metabolic regulation taking partial or total occupation of ADM receptors, stimulated in response to cold application induced physiologic ADM release before pharmacological ADM administration.

Adrenomedullin and nitrite levels in children with minimal change nephrotic syndrome.

Nitric oxide (NO) serves many functions within the kidney, and recent evidence suggests that NO contributes to glomerular injury. Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from human pheochromocytoma. Recent studies showed that plasma AM concentrations correlated with the extent of proteinuria. We have examined the possible role of these two agents by studying plasma and urinary total nitrite (NO-2 + NO-3) and AM levels in children with minimal change nephrotic syndrome (MCNS). In comparison with healthy controls, children with MCNS had increased urinary nitrite excretion (micromol/mg urinary creatinine), irrespective of whether the disease was in relapse or remission (3.2+/-0.2 in relapse, n=13; 1.9+/-0.3 in remission, n=12; 1.0+/-0.2 in controls, n=10, P<0.05). Plasma nitrite levels (micromol/l) were high in relapse compared with controls (53.2+/-8.7 vs. 32+/-4.0, P<0.05). Plasma AM levels (pmol/ml) were decreased in relapse (27.6+/-1.4 in relapse, 43.3+/-1.2 in remission, 41.5+/-1.6 in controls, P<0.05). Urinary AM levels (pmol/mg urinary creatinine) were significantly higher in relapse than in remission and in controls (156+/-43 in relapse, 56+/-18 in remission, 36+/-16 in controls, P<0.05). Our data indicate that NO may play a role in mediating the clinical manifestations of MCNS in children. However, changes in AM levels may be the result of heavy proteinuria.

The role of adrenomedullin in varicocele and impotence.

OBJECTIVE: To assess the levels of adrenomedullin (a vasodilatory peptide) in penile blood before and after injection with papaverine in impotent men, and in the internal spermatic vein in infertile patients with varicocele, comparing the results with levels in the brachial vein in the same patients. PATIENTS AND METHODS: Intracavernosal levels of adrenomedullin were determined in 14 impotent men (with no vascular pathology, as assessed by colour Doppler ultrasonography) before and after papaverine-induced penile erection. The effect of needle puncture alone was assessed in eight control patients. The level of adrenomedullin was also measured in the internal spermatic vein and brachial vein in 14 infertile men with varicocele. RESULTS: The mean (SD) intracavernosal adrenomedullin levels in the 14 impotent men were significantly different between the flaccid and papaverine-induced erectile state, at 93.5 (33.0) and 135.8 (34.9) pmol/mL, respectively, (P < 0.05). Needle puncture alone had no effect on adrenomedullin levels. In men with varicocele, the adrenomedullin level of 139.0 (34.3) pmol/mL within the internal spermatic vein was significantly higher than that in the brachial vein, at 103.9 (37.6) pmol/mL (P < 0.05). CONCLUSION: Injection with papaverine increases adrenomedullin release into penile blood; this release may be responsible for the increase in penile blood flow and penile erection. Higher levels of adrenomedullin within the internal spermatic vein of patients with varicocele may result from the retrograde flow of venous blood from the left adrenal gland and kidney. Further studies are needed to determine the role of adrenomedullin in male infertility and impotence.

Increased plasma adrenomedullin levels in patients with Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a chronic systemic inflammatory disorder affecting multiple organs with a generalized vasculitis of arteries and veins. Endothelial dysfunction is one of the prominent features of BD. Adrenomedullin (AM) is a peptide produced not only in normal adrenal medulla but also in the vascular smooth muscle cells and endothelial cells, and its role in the course of BD has not been previously described. OBJECTIVE: To detect changes of plasma AM concentrations in patients with BD compared with age- and sex-matched healthy subjects by using high-performance liquid chromatography (HPCL). We also investigated if disease activity or the duration of BD correlates with AM levels. METHODS: Forty-two consecutive patients with BD (38.5 +/- 11.1 years, 19 male and 23 female) and 20 healthy age- and sex-matched control subjects (39.5 +/- 10.9 years, 8 male and 12 female) were included in this study. We measured plasma AM levels by HPCL, and acute-phase reactants including alpha(1)-antitrypsin and alpha(2)-macroglobulin, neutrophil count and the erythrocyte sedimentation rate. RESULTS: Mean +/- SD plasma AM levels in patients with BD (73.22 +/- 25.55 pmol/l) were significantly higher (p < 0.001) than in healthy control volunteers (21.35 +/- 12.37 pmol/l). Patients with active BD had similar plasma AM concentrations (79.32 +/- 21.89 pmol/l) with patients with inactive disease (67.44 +/- 29.92 pmol/l). On the other hand, patients with longer duration of the disease (mean duration, 13.9 +/- 3.8 years) had significantly higher plasma AM levels (83.99 +/- 19.71 pmol/l; p = 0.005) than patients (62.45 +/- 26.57 pmol/l) with shorter duration of the disease (mean duration, 5. 5 +/- 2.3 years). All acute-phase reaction parameters were found to be significantly increased in the active disease. CONCLUSION: Considering its endothelial cell implications, AM may be involved in reparatory vessel endothelium mechanisms, especially in the chronic disease.

Adrenomedullin and nitrite levels in children with Bartter syndrome.

Children with Bartter syndrome have lower than normal vascular reactivity with normotension in spite of biochemical and hormonal abnormalities which are typical of hypertension. Nitric oxide (NO) is a potent endogenous vasodilator, and plays an important role in the control of vascular tone. Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from human pheochromocytoma. The possible role of NO and AM in maintaining this reduced vascular reactivity was examined by studying plasma and urinary nitrite, a stable metabolite of NO, and AM levels in ten children with Bartter syndrome, ten healthy controls, and five children with hypokalemia of causes other than Bartter syndrome (pseudo-Bartter). Urinary excretion of nitrite (mumol/mg urinary creatinine) was 8.9 +/- 1.2 in children with Bartter syndrome, 4.7 +/- 0.9 in healthy controls, and 2.9 +/- 0.8 in pseudo-Bartter (P < 0.05). Plasma nitrite levels (mumol/l) were 101.9 +/- 23.4, 59.9 +/- 14.7, and 65.0 +/- 29.7, respectively (P < 0.05), in the three groups. Urinary excretion of AM (pmol/mg urinary creatinine) was 187 +/- 40, 65 +/- 10, and 160 +/- 50, respectively (P < 0.05), in the three groups. Plasma AM levels were 47.4 +/- 1.8, 39.9 +/- 5.9, and 42.4 +/- 3.9, respectively (P > 0.05), in the three groups. The same parameters were repeated in the two groups of controls and in the Bartter patients in the 6th month of therapy. Urinary nitrite and AM levels were still higher in the Bartter patients than in the other groups. We conclude that in Bartter syndrome the increased NO production may be responsible for the reduced vascular response of the disease. Initially, increased levels of AM in Bartter syndrome and pseudo-Bartter may be a compensatory response to acute hypokalemia; however, continuation of a high level of urinary excretion of AM in children with Bartter syndrome may suggest also the possible role of AM in the reduced vascular response of the disease.

Subacute toxicity of uranyl acetate in Swiss-Albino mice.

Subacute effects of uranyl acetate were investigated in laboratory mice (Mus musculus, Swiss-Albino). Uranyl acetate was administrated to mice during a period of 5 days with dietary consumption ad libitum. Effects of uranyl acetate on food and water consumption, body weight changes; plasma urea nitrogen (BUN), creatinine concentrations and activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assayed by time-course experiment. Glutathione S-transferase (GST) and catalase (CAT) activities were also determined in liver tissues on day 5. Distribution of radioactivity in liver, kidney and brain was detected by scintillation spectrometry. The results indicated that uranyl acetate was accumulated in examined tissues, with highest accumulation being in brain. Some of the biochemical biomarkers (BUN, creatinine, ALP) were significantly increased (P<0.05) in the exposure group compared to control animals. Also, BUN and/or creatinine levels and/or ALT and AST activities significantly increased (P<0.01 or P<0.05) with UA exposure on day 3 and/or day 5 compared with results of day 1.

Exercise training reverses the age-related decline in tyrosine hydroxylase expression in rat hypothalamus.

Tyrosine hydroxylase (TH) is the rate-limiting enzymatic step in the catecholamine biosynthesis pathway. Some studies have demonstrated that aging is associated with a decrease in TH activity and TH mRNA in rat hypothalamus. We previously demonstrated that exercise training can decrease TH gene expression in the adrenal medulla of young but not senescent rats. This study was designed to examine the effects of endurance training on the TH expression in hypothalamus with aging. To this end, we assessed TH mRNA, TH immunoreactivity, and TH activity with or without exercise training. Young and old F-344 female rats were trained by treadmill running for 8 weeks. All parameters examined were significantly lower in hypothalamus of old (25-month) compared with young (5-month) control animals (p < .05). Exercise training significantly elevated TH mRNA (n = 5-7 in each group), TH immunoreactivity (n = 5-8 in each group), and TH activity (n = 12-13 young groups and n = 6 old groups) in the hypothalamus of old animals (p < .05), but there was no significant change in any of these parameters in young animals following training. These data indicate that endurance training can reverse the age-related decline in catecholamine biosynthesis in the hypothalamus.

Effect of chronic treatment with prazosin and L-arginine on the elevation of blood pressure during cold exposure.

Chronic exposure to cold (5 degrees C) is well known to increase both tyrosine hydroxylase (TH) activity in brown adipose tissue and systemic blood pressure. The effect of chronic dietary administration of the alpha-adrenergic antagonist, prazosin, and the amino acid, L-arginine, on both the elevation of blood pressure during exposure to cold and on TH activity and expression of TH mRNA in the adrenal glands of rats was studied. As observed previously, chronic exposure to cold increased systolic blood pressure significantly and induced cardiac hypertrophy. Chronic dietary treatment with prazosin (8 mg/kg food) and arginine (20 g/kg food) returned blood pressure to control levels, did not affect body weight significantly, but failed to prevent cardiac hypertrophy. Both prazosin and L-arginine reduced the drinking response to administration of angiotensin II. Treatment with arginine and prazosin was accompanied by a significant increase in the urinary outputs of dopamine and L-DOPA. The 3 cold-treated groups (control, L-arginine and prazosin) had increases in plasma T3 and decreases in plasma T4 and plasma renin activity. Plasma concentrations of epinephrine and norepinephrine were increased significantly in the L-arginine-treated group. TH mRNA and TH activity in the adrenal glands were increased in the 3 cold-treated groups and these measures were correlated directly and significantly with plasma norepinephrine and epinephrine concentrations. Although both prazosin and arginine prevented the cold-induced elevation of blood pressure, they did not prevent the increase in TH mRNA, TH activity or epinephrine in plasma. The protective effect of arginine and prazosin in cold-induced hypertension may be related both to their reduction in plasma renin activity and to a reduced responsiveness to angiotensin II, as well as to their abilities to increase the secretion of dopamine.