Muhittin Yürekli

Possible role of nitric oxide and adrenomedullin in bipolar affective disorder.

Nitric oxide (NO) has been implicated to play a role in the pathogenesis of depressive disorders. Adrenomedullin (AM) induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of NO. AM immune reactivity is present in the brain, consistent with a role as neurotransmitter. Therefore, it is suggested that these two molecules may play a role together in the brain. We aimed to examine AM and NO in bipolar affective disorder (BPAD). Forty-four patients with BPAD and 21 healthy control subjects were included in this study. DSM-IV diagnosis of bipolar affective disorder (type I, manic episodes) was independently established by two psychiatrists and the Turkish version of the Bech-Rafaelson Mania Scale was administered. Also, a semistructured form was used to ascertain several sociodemographic and clinical variables of the patients. AM and NO were studied in plasma. The mean value of plasma NO levels in the BPAD group of 46.58 ± 13.97 µmol/l was significantly higher than that of controls (31.81 ± 8.14 µmol/l) (z = –4.15, p = 0.000). Mean plasma AM levels were found to be increased in patients with BPAD (35.13 ± 5.26 pmol/l) compared to controls (16.22 ± 3.02 pmol/l) (z = –6.16, p = 0.000). AM levels of BPAD patients were approximately 2-fold higher than controls. AM levels were positively correlated with the duration of hospitalization for the current episode and negatively correlated with the total duration of illness. Both NO and AM may have a pathophysiological role in BPAD (type I, manic episodes) and the clinical symptomatology and prognosis of BPAD.

Increased Levels of Nitric Oxide, Cortisol and Adrenomedullin in Patients with Chronic Schizophrenia

Objective: To investigate the levels of serum cortisol, dehydroepiandrosterone sulfate (DHEA-S), nitric oxide (NO) and adrenomedullin (AM) in schizophrenic patients. Subjects and Methods: Sixty-six male patients with chronic schizophrenia and 28 normal male subjects participated in this study. The duration of disease was 145 ± 120 (mean ± SD) months. Serum levels of cortisol and DHEA-S were measured by electrochemiluminescence; plasma nitrite levels as an index of NO were measured with the Griess reaction, while plasma AM concentration was measured by using high-performance liquid chromatography. Results: Patients (12.48 ± 3.2 µg/dl), as compared to controls (10.31 ± 3.1 µg/dl), had higher levels of baseline cortisol (p < 0.05). DHEA-S levels were lower in patients though this did not reach statistical significance (302 ± 156 µg/dl compared to control, 322 ± 96 µg/dl, p > 0.05). The mean levels of plasma AM and NO in the schizophrenic group (44.33 ± 5.07 pmol/l and 36.27 ± 17.6 µmol/l) were significantly higher than the levels in the control group (14.56 ± 4.03 pmol/l and 32.54 ± 7.14 µmol/l; p < 0.001, p < 0.03, respectively). There was a positive association between duration of disease and cortisol/DHEA-S ratio and cortisol level. Conclusion: The data show that schizophrenia is associated with abnormal levels of cortisol, DHEA-S, NO and AM.

The possible pathophysiological role of plasma nitric oxide and adrenomedullin in schizophrenia

Evidence is accumulating for a possible role of nitric oxide (NO) in schizophrenia. Adrenomedullin (AM) induces vasorelaxation by activating adenylate cyclase and also by stimulating the release of NO. AM immune reactivity is present in the brain consistent with a role as neurotransmitter. We aimed to examine plasma levels of nitrite (a metabolite of NO) and AM in schizophrenic patients. Eighty-two patients with schizophrenia and 21 healthy control subjects were included in this study. DSM-IV diagnosis of chronic schizophrenia was established on the basis of independent structured clinical interviews and review of records by two qualified psychiatrists which included the Brief Psychiatric Rating Scale (BPRS), The Scale for the Assessment of Negative Symptoms (SANS) and The Scale for the Assessment of Positive Symptoms (SAPS). Total nitrite and AM have been studied in plasma. The mean values of plasma nitrite and AM levels in schizophrenic group were significantly higher than control values, respectively (P=0.03, P<0.0001). AM levels of schizophrenic patients were three fold higher than controls. In correlation analyses, there were statistically significant positive correlations between AM level and SAPS-delusion subscale (r=0.27, P=0.04); SAPS-bizarre behavior subscale (r=0.28, P=0.03) and SAPS-total (r=0.36, P=0.005). There is no correlation between total nitrite and AM levels (r=0.11, P=0.31). Both NO and AM may have a pathophysiological role in schizophrenia, and clinically symptomatology and prognosis of schizophrenia. This subject needs further study including treatment response and subtypes of schizophrenia.

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 α1-antitrypsin and α2-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.

Protective role of caffeic acid phenethyl ester in the liver of rats exposed to cold stress

Cold exposure can induce a form of environmental stress. Cold stress (CS) alters homeostasis, results in the creation of reactive oxygen species and leads to alterations in the antioxidant defense system. The caffeic acid phenethyl ester (CAPE), an active component of propolis, has an antioxidant capacity. We investigated the effect of CS on oxidative stress and antioxidant defense system and the possible protective effect of CAPE in rat liver tissue. Twenty‐four female Wistar Albino rats were divided into four groups: Control, CAPE‐treated, CS, and CAPE‐treated CS (CS + CAPE) group. Catalase (CAT), glutathione peroxidase (GSH‐Px), superoxide dismutase (SOD) activities and total glutathione (GSH) and malondialdehyde (MDA) levels were measured. In addition, histological changes in liver tissue were examined by light microscopy. SOD, CAT and GSH‐Px activities and total GSH level were significantly declined in the CS group. In the CS + CAPE group, the activities of these three enzymes and GSH level significantly raised with regard to the CS group. MDA levels increased in the CS group and decreased in the CS + CAPE group. The tissues of the CS group showed some histopathological changes such as necrosis, hepatocyte degeneration, sinusoidal dilatation, hemorrhage and vascular congestion and dilatation. In the CS + CAPE group, the histopathological evidence of hepatic damage was markedly reduced. Histological parameters were consistent with biochemical parameters. In this study, CS increased oxidative stress in liver tissue. CAPE regulated antioxidant enzymes, inhibited lipid peroxidation and reduced hepatic damage.

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.

Adrenomedullin and Leptin Levels in Diabetic Retinopathy and Retinal Diseases

Purpose: Proliferative and vascular retinal diseases are important cause of irreversible blindness. Consistent features of these diseases are endothelial dysfunction and angiogenesis. Adrenomedullin (ADM) is a multifunctional vasorelaxant peptide. Leptin is a recently discovered metabolic peptide that regulates energy metabolism in human. In the present study, we aimed to investigate the possible roles of adrenomedullin and leptin in the pathophysiology of diabetic and proliferative diseases. Methods: Ten patients with proliferative diabetic retinopathy (57.1 years, 5 female and 5 male) and 8 patients (51 years, 5 female and 3 male) with other retinal diseases including macular hole and epiretinal membrane were included in this study. All the patients had undergone pars plana vitrectomy for complications of the diseases. Vitreous samples were collected by vitreous tap during the vitrectomy. Adrenomedullin analysis was made by using reverse-phase high-performance liquid chromatography (HPLC). Leptin was measured by enzyme-linked immunosorbent assay (ELISA). Body mass index (BMI) [weight (kg)/height (m2)] was calculated for each group. The Mann-Whitney U test was used for statistics. Results: The age, gender ratio and BMI were not substantially different between the two groups. The mean vitreous adrenomedullin levels (63.9 ± 7.1 pmol/l) were significantly higher (p < 0.05) in group I than in group II (34.25 ± 3.0 pmol/l). Leptin levels in vitreous (4.54 ±1.6 ng/ml) were also significantly higher (p < 0.05) in patients with diabetic retinopathy than in those without diabetes (1.83 ± 0.5 ng/ml). Conclusion: Increased adrenomedullin and leptin levels in vitreous humor might be a possible newly associated factor in the course of vascular and proliferative retinal diseases.

Adrenomedullin and nitrite levels in children with minimal change nephrotic syndrome

Abstract 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 (µmol/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 (µmol/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.

Adrenomedullin and nitrite levels in children with Bartter syndrome

Abstract 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 (µmol/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 (µmol/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.

Adrenomedullin reduces antioxidant defense system and enhances kidney tissue damage in cadmium and lead exposed rats.

Adrenomedullin (AdM) is synthesized and secreted by a number of cells and tissue. AdM is a potent vasodilator but it is also considered a neuromodulator, an angiogenic factor, and a hormone regulator. AdM possess antiapoptotic, antioxidant, and antimicrobial properties. Heavy metals such as cadmium and lead are found widely in the environment and they have important biological functions. Lead (Pb) and cadmium (Cd) can accumulate in the lungs, liver, bone, and kidneys and cause serious organ damage. In the present study, we investigated the effect of AdM, Pb + AdM, and Cd + AdM treatments on superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px) activities as well as the level of malondialdehyde (MDA) in the kidney. Heavy metal accumulation was determined in kidney with and without AdM infusion and kidney damage was evaluated by light and electron microscopy. Increased heavy metal accumulation was observed in the heavy metal and AdM treated groups. SOD, CAT, GSH‐Px activities, and MDA levels were significantly different in the treatment groups when compared with the control group. Tubular degeneration, necrosis, cell swelling, mononuclear cell infiltration, and degenerated organelles were observed in the kidney following treatment. Therefore, AdM infusion has no beneficial and/or compensatory role in cadmium and lead toxicity in the kidney. We conclude that heavy metal accumulation in the kidney in conjunction with AdM infusion is cytotoxic despite the known beneficial effects of adrenomedullin.