Kokot F

Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension

Our aim was to investigate systemic nitric oxide (NO) production and its potential determinants such as insulin resistance, dyslipidemia, and circulating methylated analogs of L-arginine in uncomplicated essential hypertension (EH). Nineteen newly diagnosed, untreated male subjects with mild pure uncomplicated EH and 11 normotensive controls were studied at rest after an overnight fast. The groups had comparable age, body mass index, creatinine clearance, cholesterol, fasting glucose, and insulin. In hypertensives, the urinary excretion rate of nitrite plus nitrate (Unox), an index of endogenous NO production, was depressed (56+/-17 vs. 77+/-23 micromol/mmol creatinine; p < 0.05), whereas plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, were increased (2.4+/-1.1 vs. 1.1+/-0.7 microM; p < 0.005). Circulating concentrations of symmetric dimethylarginine were similar in both groups (1.4+/-1.3 vs. 1.5+/-1.1 microM; p = NS). The L-arginine-to-ADMA ratio was reduced in hypertension (3.3+/-0.5 vs. 4.5+/-0.8; p < 0.001 for In-transformed data). There was no correlation between Unox and either the magnitude of insulin resistance or dyslipidemia in EH. Thus in male subjects with EH, endogenous systemic NO formation appears depressed, which is unrelated to accompanying insulin resistance or dyslipidemia. Circulating ADMA levels are increased in uncomplicated EH, which may be of potential relevance.

Decreased plasma adiponectin concentration in patients with essential hypertension

Adipocytes secrete several biologically active substances that are presumed to be involved in obesity-related hypertension. There are no reports that deal with the relationship between plasma adiponectin concentration and blood pressure (BP). To evaluate the role of adiponectin in essential hypertension 33 patients with essential hypertensive (EHP) (12 women, 21 men) and 33 body mass index-matched normotensive healthy subjects (NHS) (13 women, 20 men) were studied. In EHP plasma adiponectin concentration was significantly lower than in NHS (9.1 +/- 4.5 v 13.7 +/- 5.2 microg/mL, respectively). In all subjects a significant negative correlation was found between plasma adiponectin concentration and mean, systolic, and diastolic BP, suggesting that adiponectin contributes to the clinical course of essential hypertension.

Plasma Immunoreactive Leptin and Neuropeptide Y Levels in Kidney Transplant Patients

Leptin and neuropeptide Y (NPY) seem to play an important role in food intake and energy expenditure. Leptin is secreted by adipose tissue in proportion fo fat stores and is presumed to be an important anorectic hormone. NPY is produced by the hypothalamus, and in contrast to leptin, is one of the most potent appetite stimulants yet demonstrated. On the other hand, in most patients increased appetite is present after successful kidney transplantation. Finally, a stimulatory effect of glucocorticoids on leptin secretion was reported. The present study aimed to assess the relationship between plasma leptin and NPY levels and body mass index (BMI) in haemodialyzed patients (HDP) with chronic renal failure and in kidney transplant patients (KTP). In both groups, BMI was of the same magnitude as in healthy controls. Despite the presence of a normal BMI, leptin levels in KTP (25.2 ± 3.6 ng/ml) and in HDP with chronic renal failure (25.3 ± 4.2 ng/ml) were higher than in controls (11.7 ± 1.8 ng/ml). The mean plasma NPY level in KTP (168.0 ± 10.3 pg/ml) was significantly higher (p < 0.01) than in controls (70.7 ± 5.9 pg/ml) and in HDP (77.0 ± 5.7 pg/ml). In all examined groups, a significant positive correlation was found between leptinaemia and BMI. Conclusions: (1) KTP are characterized by significantly elevated leptinaemia in spite of a normal BMI. In KTP this increased leptinaemia does not seem to be dependent only upon the fat mass and the kind and dosis of immunosuppressive therapy. (2) Similarly to healthy subjects, female KTP and HDP show markedly higher leptinaemia than males. (3) In contrast to healthy subjects and HDP, KTP are characterized by significantly elevated plasma NPY levels.

Relationship between plasma renin profile and leptinaemia in patients with essential hypertension

Both leptin and the renin-angiotensin system (RAS) can influence the activity of the sympathetic nervous system, water and electrolyte metabolism as well as vascular remodelling, which are all involved in the regulation of arterial blood pressure. Thus leptin and the RAS may act together in the pathogenesis of essential hypertension. The present study aimed to answer the following question: does an interrelationship exist between leptinaemia and the plasma renin activity (PRA) profile in normotensive and hypertensive subjects? Forty-three patients with essential hypertension (EHP) (23 females, 20 males, mean age 39.0 ± 1.8 years, mean body mass index (BMI) 26.8 ± 0.6 kg/m2, mean arterial pressure (MAP) 123 ± 2 mm Hg) and 32 healthy subjects (NTS) (18 females, 14 males, mean age 38.6 ± 2.2 years, mean BMI 25.4 ± 0.5 kg/m2, MAP 95 ± 1 mm Hg) were examined. Plasma leptin levels were estimated once after the administration of a diet containing 100–120 mmol Na/day and after overnight 8-h recumbency. PRA was estimated twice: first after the administration of a diet containing 100–120 mmol Na day and overnight 8-h recumbency (PRA I), and a second time after 3 days of sodium restriction (20 mmol Na/day), and 3 h of upright position (PRA II). Antihypertensive drugs were withdrawn 7 days before the study. In EHP plasma leptin concentration was insignificantly higher than in NTS (14.0 ± 2.0 vs10.8 ± 1.5 ng/ml respectively). Only females with hypertension showed a significant positive correlation between plasma leptin concentrations (expressed as the logarithmic values) and PRA I. Using the multiple regression analysis, in all studied subjects (EHP and NTS together), logarithm (log) of plasma leptin concentrations was significantly related to gender, BMI and MAP. Multiple regression analysis performed separately for EHP or NTS revealed a significant relation of log plasma leptin concentrations with gender and BMI. A significant correlation was found between log leptinaemia values and BMI, mean and systolic blood pressure respectively if the whole group of subjects (EHP+NTS) or EHP and NTS separately were analysed. Especially in hypertensive women a highly significant correlation was found between log plasma leptin concentrations and MAP. We conclude that a significant relationship between leptinaemia and PRA does exist in females with EH and that participation of both PRA and leptin in the pathogenesis of EH in females seems to be likely.

Hormonal regulation of appetite and body mass in patients with advanced prostate cancer treated with combined androgen blockade.

Cachexia is rarely observed in patients with advanced prostate cancer treated with combined androgen blockade. Androgens play an important role in the regulation of body mass composition and influence the secretion of leptin, the appetite regulating hormone. The aim of the study was to assess the influence of a combined treatment with nonsteroidal antiandrogen and LH-RH analogue on the hormonal regulation of appetite and changes in body mass in patients with advanced prostate cancer (Whitmore-Jewett stage D1 or D2). Eighteen patients with prostate cancer and 17 healthy subjects matched for age and body mass index were included. In all patients serum concentrations of leptin, neuropeptide Y (NPY), insulin, testosterone and estradiol were measured before and after four and twelve weeks of androgen blockade. Pretreatment serum leptin levels were similar in patients with prostate cancer and in the controls. In a multiple regression analysis only body mass index and testosterone significantly contributed to the variation of plasma leptin. During the treatment body mass and plasma leptin significantly increased while NPY decreased. The change of plasma NPY was significant only after 4 weeks of therapy. This study shows that the afferent regulation of leptin secretion is unchanged in advanced prostate cancer. Androgen ablation significantly increases body mass and influences secretion of appetite regulating hormones. Testosterone appears to play a significant role in the regulation of leptin secretion.

Steroid withdrawal at 3 months after kidney transplantation: a comparison of two tacrolimus-based regimens.

The 6 month prospective, randomized study compared the steroid‐sparing potential of two tacrolimus‐based regimens after renal transplantation. A total of 489 patients were randomized (1:1) to receive tacrolimus/mycophenolate mofetil (MMF)/steroids (n = 243; group Tac/MMF/S) or tacrolimus/azathioprine/steroids (n = 246; group Tac/Aza/S). At 3 months, steroids were tapered off in 267 (54.6%) patients free from steroid‐resistant acute rejection and with serum creatinine concentrations <160 μmol/l. The incidence of biopsy‐confirmed acute rejection at month 3 was lower in group Tac/MMF/S compared with group Tac/Aza/S (18.1% vs. 26.0%,P = 0.035). Moreover, more patients in the Tac/MMF/S group met the criteria for steroid withdrawal than in the Tac/Aza/S group (60.5% vs. 48.8%; P < 0.01). The incidence of acute rejection during months 4–6 was low in all groups, both for patients on steroid‐free dual therapy (Tac/MMF: 2.7%, Tac/Aza: 0.8%) and for patients who continued steroid maintenance therapy (Tac/MMF/S: 3.5%, Tac/Aza/S: 7.1%). Moreover, kidney function was well preserved in steroid‐free patients with month 6 median serum creatinine levels of 119.5 μmol/l (Tac/MMF), and 115.1 μmol/l (Tac/Aza). For patients who continued to receive steroids, month 6 median creatinine levels were 130.5 μmol/l (Tac/MMF/S) and 132.8 μmol/l (Tac/Aza/S). The criteria for the selection of patients to discontinue steroids were adequate. Both tacrolimus‐based regimens allowed the safe discontinuation of steroids in low‐risk patients at month 3. The Tac/MMF combination was superior in the prevention of acute rejections and more patients met the chosen criteria for steroid withdrawal.

Does leptin play a role in the pathogenesis of essential hypertension

Background: Leptin is produced and released by adipocytes in proportion to fat stores. Leptin as an anorectic hormone plays an important role in the regulation of food intake, energy expenditure, and insulin secretion. In contrast, neuropeptide Y, insulin, cortisol, and growth hormone are presumed to be appetite modulators. Leptin and neuropeptide Y are both involved in the activation of sympathetic tone. Increased body fat stores in obese patients are involved in the pathogenesis of some metabolic disorders (e.g., hyperinsulinaemia, glucose intolerance) and arterial hypertension. Methods and Results: Based on this pathophysiological background, we tried to assess the relationship between plasma leptin and blood pressure in 41 patients with essential hypertension (EHP; 20 females, 21 males, mean age 38.7±1.9 years, mean body mass index – BMI – 25.8±0.5 kg/m2) and in an appropriately sex– and BMI–matched control group of 27 normotensive healthy subjects (NHS; 11 females, 16 males, mean age 39.7±2.5 years, mean BMI 24.8±0.6 kg/m2). The plasma leptin concentration did not differ significantly between EHP and NHS (13.0±1.9 vs. 8.1±1.0 ng/ml, respectively). In both groups a significant positive correlation was found between BMI and plasma leptin concentration (p<0.0001). A significant positive correlation (p<0.02) was found between leptinaemia and mean (MAP), systolic and diastolic blood pressures, if data were analyzed for all examined subjects or separately only for women. Such a correlation could not be confirmed for male NHS and EHP subjects. The plasma neuropeptide Y concentration was higher in EHP than in NHS (77.1±23.0 vs. 63.6±9.8pg/ml, p = 0.05). In contrast to neuropeptide Y plasma insulin, cortisol, and growth hormone concentrations were similar in EHP and in NHS. Conclusion: Both EHP and NHS are characterized by a positive correlation between BMI and leptinaemia. Leptin may be indirectly involved in blood pressure regulation, especially in women of both NHS and EHP.

Effects of Neuropeptide Y on Appetite

Neuropeptide Y (NPY) is a polypeptide containing 36 amino acids. Circulating NPY originates predominantly from the sympatho-adrenomedullary nervous system. It has a vasoconstrictive and mitogenic effect on blood vessels and seems to be involved in blood pressure regulation and angiogenesis. NPY is a potent orexigenic agent and is presumed to play a leading role in the regulation of eating behavior. Stimulation of the NPY-ergic arcuate – paraventricular nucleus (ARC–PVN) pathway by exercise, fasting, energy loss (glucosuria) is followed by increased appetite and food intake and increased parasympathetic activity, but suppression of sympathetic activity and energy expenditure. The end result of this process is an increase of energy stores. Activity of the NPY-ergic ARC–PVN pathway is suppressed by leptin – a polypeptide produced by adipocytes. Although functioning of an NPY–leptin feedback was found in rodents, it seems likely that also in man the NPY–leptin axis is involved in the regulation of food intake and energy expenditure.

Influence of Erythropoietin Treatment on Follitropin and Lutropin Response to Luliberin and Plasma Testosterone Levels in Haemodialyzed Patients

Plasma levels of follitropin (FSH), lutropin (LH) and testosterone (TE) were estimated in 5 anaemic haemodialyzed patients before and after 3 months of erythropoietin treatment (EPO group), in 5 male haemodialyzed patients with a haematocrit value of 33% (which was of the same magnitude as the post-treatment haematocrit value in the EPO group) and in 15 male healthy subjects. After EPO treatment, haematocrit values rose from 23.0 +/- 0.9 to 34.6 +/- 0.75%. EPO treatment induced a significant suppression of basal plasma FSH and LH levels, while plasma TE levels slightly increased. After EPO treatment, the response of plasma FSH and LH to luliberin administration was significantly reduced. As the endocrine profile of EPO-treated patients differed from that of haemodialyzed patients showing a similar haematocrit value, it seems that EPO-induced hormonal changes are not or not only related to improvement of anaemia. Normalization of the pituitary-gonadal feedback in EPO treatment seems to participate in the pathogenesis of improved sexual activity in these patients.

Effects of Naloxone Administration on Endocrine Abnormalities in Chronic Renal Failure

In 72 patients with end-stage renal failure and 70 healthy subjects, the influence of blockade of opioid receptors by naloxone on secretion of prolactin, lutropin (LH), follitropin (FSH), adrenocorticotropin (ACTH), somatotropin (HGH), insulin (IRI), glucagon (IR-G), parathyroid hormone (PTH) and calcitonin (CT) was studied. Administration of naloxone stimulated luliberin-induced LH and FSH secretion quantitatively equally in patients and controls. Blockade of opioid receptors was followed by a less marked suppression of chlorpromazine-induced prolactin secretion but by a higher response of hypoglycemia-induced ACTH secretion in uremic patients than in controls. In addition, a less marked suppressive effect of naloxone was noted on hypoglycemia-induced HGH secretion in chronic renal failure as compared with controls. Blockade of opioid receptors improved significantly glucose tolerance and glucose-induced insulin secretion in uremic patients and suppressed nearly completely glucagon secretion response during the second phase of a glucose tolerance test. Finally, administration of naloxone was followed by a blunted response of Ca-induced CT secretion and suppression of PTH. Data presented in this paper suggest the existence of hyperendorphinism in end-stage renal failure.