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Jerzy Beltowski

Publications and source records attributed to Jerzy Beltowski.

8 recordsLinked to original sources
PubMed2006

Leptin and atherosclerosis.

Leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure. Leptin receptors are expressed in many tissues including the cardiovascular system. Plasma leptin concentration is proportional to body adiposity and is markedly increased in obese individuals. Recent studies suggest that hyperleptinemia may play an important role in obesity-associated cardiovascular diseases including atherosclerosis. Leptin exerts many potentially atherogenic effects such as induction of endothelial dysfunction, stimulation of inflammatory reaction, oxidative stress, decrease in paraoxonase activity, platelet aggregation, migration, hypertrophy and proliferation of vascular smooth muscle cells. Leptin-deficient and leptin receptor-deficient mice are protected from arterial thrombosis and neointimal hyperplasia in response to arterial wall injury. Several clinical studies have demonstrated that high leptin level predicts acute cardiovascular events, restenosis after coronary angioplasty, and cerebral stroke independently of traditional risk factors. In addition, plasma leptin correlates with markers of subclinical atherosclerosis such as carotid artery intima-media thickness and coronary artery calcifications. Inhibition of leptin signaling may be a promising strategy to slow the progression of atherosclerosis in hyperleptinemic obese subjects.

Adipose Tissue↗
PubMed2006

Phosphodiesterase 5 inhibitor ameliorates renal resistance to atrial natriuretic peptide associated with obesity and hyperleptinemia.

BACKGROUND: Abnormal neurohormonal regulation of renal sodium handling plays an important role in obesity-associated hypertension. We investigated the effect of experimental obesity on renal response to atrial natriuretic peptide (ANP). METHODS: The effect of ANP was studied in three groups of rats: (1) lean controls, (2) animals made obese by a highly palatable diet, (3) rats treated with adipose tissue hormone, leptin, for 7 days to reproduce hyperleptinemia observed in obesity. RESULTS: ANP administered at a dose of 50 pmol/kg min(-1) induced about a 3-fold lower increase in Na+ and cGMP excretion in obese and leptin-treated rats than in the control group. ANP decreased Na+,K+-ATPase activity in the renal medulla only in the control group. Natriuretic effect of exogenous cGMP was also impaired in obese and leptin-treated rats. In contrast, hydrolysis-resistant cGMP derivative, 8-bromo-cGMP exerted comparable natriuretic effects in all groups. Neutral endopeptidase inhibitor, phosphoramidon, and ANP clearance receptor antagonist, C-ANP, increased urinary ANP excretion in all groups to a similar level, but their natriuretic effect was impaired in obese and leptin-treated groups. A specific inhibitor of cGMP-degrading phosphodiesterase, zaprinast, had comparable natriuretic and Na+,K+-ATPase-lowering effects in all groups and restored normal sensitivity to ANP. CONCLUSIONS: (1) Dietary-induced obesity is accompanied by impaired natriuretic effect of ANP, (2) ANP resistance in obesity may be accounted for by increased leptin level, (3) accelerated degradation of cGMP may contribute to ANP resistance associated with obesity and hyperleptinemia, suggesting that inhibiting cGMP-specific phosphodiesterases may be useful in the treatment of obesity-associated hypertension.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Time-dependent transition from H(2)O(2)-extracellular signal-regulated kinase- to O(2)-nitric oxide-dependent mechanisms in the stimulatory effect of leptin on renal Na+/K+/-ATPase in the rat.

1. Recent studies suggest that leptin, a peptide hormone secreted by white adipose tissue, is involved in the pathogenesis of arterial hypertension, in part by regulating renal sodium handling. Previously, we have demonstrated that in normal rats leptin has a time-dependent effect on renal Na(+)/K(+)-ATPase that drives tubular sodium reabsorption. Short-term leptin infusion results in a transient decrease in Na(+)/K(+)-ATPase activity, whereas prolonged administration stimulates the enzyme. 2. In the present study, we investigated whether these acute effects of leptin are preserved in rats with experimentally induced chronic hyperleptinaemia. 3. Hyperleptinaemia was induced by administration of exogenous leptin (0.25 mg/kg twice daily, s.c., for 7 days). Acute effects of leptin in anaesthetized control (normoleptinaemic) and hyperleptinaemic animals was investigated. Leptin was infused into the abdominal aorta proximally to the renal arteries for 0.5, 1, 2 or 3 h. 4. Leptin (1 microg/min per kg) had a time-dependent effect on renal Na(+)/K(+)-ATPase in both the control and hyperleptinaemic groups. The inhibitory effect observed after 0.5 h infusion was impaired in the hyperleptinaemic group. However, in both groups this effect was abolished by the Janus kinase inhibitor tyrphostin AG490 (100 nmol/min per kg), as well as by the phosphatidylinositol 3-kinase inhibitors wortmannin (10 nmol/min per kg) and LY294002 (1 micromol/min per kg). 5. The stimulatory effect of leptin on Na(+)/K(+)-ATPase activity was observed after 3 h of infusion and was of similar magnitude in control and hyperleptinaemic groups. In the control group, the stimulatory effect of leptin was abolished by the NADPH oxidase inhibitor apocynin (1 micromol/min per kg), the H(2)O(2) scavenger catalase (1 mg/min per kg) and the extracellular signal-regulated kinase (ERK) inhibitor PD98059 (100 nmol/min per kg). In contrast, in the hyperleptinaemic group, the stimulatory effect of leptin was abolished by the cGMP analogue 8-bromo-cGMP (100 nmol/min per kg) and by the superoxide dismutase mimetic tempol (100 micromol/min per kg) but was not affected by catalase or PD98059. 6. Leptin increased urinary H(2)O(2) excretion and ERK phosphorylation in the renal tissue only in the control group. 7. The results suggest that the acute stimulatory effect of leptin on renal Na(+)/K(+)-ATPase is mediated by divergent mechanisms depending on the chronic leptin level (i.e. by H(2)O(2)-dependent stimulation of ERK in normoleptinaemic animals and by superoxide-dependent impairment of the nitric oxide-cGMP pathway in hyperleptinaemic rats).

Acetophenones↗
PubMed2005

Antioxidant treatment normalizes nitric oxide production, renal sodium handling and blood pressure in experimental hyperleptinemia.

Recent studies suggest that adipose tissue hormone, leptin, is involved in the pathogenesis of arterial hypertension. However, the mechanism of hypertensive effect of leptin is incompletely understood. We investigated whether antioxidant treatment could prevent leptin-induced hypertension. Hyperleptinemia was induced in male Wistar rats by administration of exogenous leptin (0.25 mg/kg twice daily s.c. for 7 days) and separate groups were simultaneously treated with superoxide scavenger, tempol, or NAD(P)H oxidase inhibitor, apocynin (2 mM in the drinking water). After 7 days, systolic blood pressure was 20.6% higher in leptin-treated than in control animals. Both tempol and apocynin prevented leptin-induced increase in blood pressure. Plasma concentration and urinary excretion of 8-isoprostanes increased in leptin-treated rats by 66.9% and 67.7%, respectively. The level of lipid peroxidation products, malonyldialdehyde + 4-hydroxyalkenals (MDA+4-HNE), was 60.3% higher in the renal cortex and 48.1% higher in the renal medulla of leptin-treated animals. Aconitase activity decreased in these regions of the kidney following leptin administration by 44.8% and 45.1%, respectively. Leptin increased nitrotyrosine concentration in plasma and renal tissue. Urinary excretion of nitric oxide metabolites (NO(x)) was 57.4% lower and cyclic GMP excretion was 32.0% lower in leptin-treated than in control group. Leptin decreased absolute and fractional sodium excretion by 44.5% and 44.7%, respectively. Co-treatment with either tempol or apocynin normalized 8-isoprostanes, MDA+4-HNE, aconitase activity, nitrotyrosine, as well as urinary excretion of NO(x), cGMP and sodium in rats receiving leptin. These results indicate that oxidative stress-induced NO deficiency is involved in the pathogenesis of leptin-induced hypertension.

Acetophenones↗
PubMed2005

Differential effect of antioxidant treatment on plasma and tissue paraoxonase activity in hyperleptinemic rats.

Recent studies suggest that adipose tissue hormone, leptin, is involved in atherogenesis, especially in obese subjects. Previously, we have demonstrated that experimentally induced hyperleptinemia decreases plasma paraoxonase 1 (PON1) activity. The aim of this study was to investigate whether treatment with synthetic antioxidant, Tempol, modulates the effect of leptin on plasma and tissue PON1 in the rat. Leptin was administered at a dose of 0.25 mgkg-1 s.c. twice daily for 7 days and Tempol was added to the drinking water at a concentration of 2 mM. Leptin reduced plasma PON1 activity toward paraoxon, phenyl acetate and gamma-decanolactone to 71.1, 72.3 and 57.1% of control, respectively. In addition, leptin decreased PON1 activity toward paraoxon in aorta, renal cortex and medulla to 78.6, 49.2 and 48.0% of control, respectively, but had no effect on PON1 in heart, lung and liver. PON1 activity toward phenyl acetate was lower following leptin treatment only in aorta. Leptin increased plasma concentration and urinary excretion of isoprostanes as well as malonyldialdehyde + 4-hydroxyalkenals level in aorta, renal cortex and renal medulla. Coadministration of Tempol prevented leptin-induced oxidative stress and normalized PON1 activity in aorta and kidney. However, Tempol had no effect on plasma PON1 in leptin-treated rats. These data indicate that hyperleptinemia decreases tissue PON1 activity through oxidative stress-dependent mechanism. In contrast, leptin-induced downregulation of plasma PON1 is not mediated by oxidative stress.

Animals↗
PubMed2004

Oxidative stress, nitric oxide production, and renal sodium handling in leptin-induced hypertension.

Chronic hyperleptinemia induces arterial hypertension in experimental animals and may contribute to the development of hypertension in obese humans; however, the mechanism of hypertensive effect of leptin is not completely elucidated. We investigated the effect of leptin on whole-body oxidative stress, nitric oxide production, and renal sodium handling. The study was performed on male Wistar rats divided into 3 groups: 1) control, fed standard chow ad libitum, 2) leptin-treated group, receiving leptin injections (0.25 mg/kg twice daily s.c. for 7 days), 3) pair-fed group, in which food intake was adjusted to the leptin group. Leptin caused 30.5% increase in systolic blood pressure. Plasma concentration and urinary excretion of 8-isoprostanes in animals receiving leptin was 46.4% and 49.2% higher, respectively. The level of lipid peroxidation products, malonyldialdehyde + 4-hydroxyalkenals, increased by 52.5% in the renal cortex and by 48.4% in the renal medulla following leptin treatment, whereas aconitase activity decreased in these regions of the kidney by 45.3% and 39.2%, respectively. Urinary excretion of nitric oxide metabolites (NOx) was 55.0% lower, and fractional excretion of NOx was 55.8% lower in the leptin-treated group. Urinary excretion of cGMP decreased in leptin-treated rats by 26.3%. Following leptin treatment, absolute and fractional sodium excretion decreased by 35.0% and 41.2%, respectively. These results indicate that hyperleptinemia induces systemic and intrarenal oxidative stress, decreases the amount of bioactive NO possibly due to its degradation by reactive oxygen species, and causes renal sodium retention by stimulating tubular sodium reabsorption. NO deficiency and abnormal renal Na+ handling may contribute to leptin-induced hypertension.

Animals↗
PubMed2002

Human leptin stimulates systemic nitric oxide production in the rat.

OBJECTIVE: Apart from having an effect on energy balance, leptin is also involved in cardiovascular regulation and in the pathogenesis of obesity-associated hypertension. We investigated the effect of leptin on nitric oxide (NO) production. RESEARCH METHODS AND PROCEDURES: Wistar rats were placed in metabolic cages, and urine was collected in 2-hour periods. After the control period, leptin (1 mg/kg intraperitoneal) was administered, and urine collection was continued for up to 6 hours. Blood was obtained 0.5, 1, 2, 4, and 6 hours after hormone injection. RESULTS: Leptin increased plasma concentrations of NO metabolites (nitrates + nitrites, NO(x)) by 32.5%, 58.0%, and 29.7% at 1, 2, and 4 hours, respectively. Urinary NO(x) excretion increased by 28.8% in the first and by 20.1% in the second 2-hour period after injection. The plasma concentration of the NO second messenger, cyclic guanosine 3',5'-monophosphate (cGMP), increased by 83% and 50.6% at 2 and 4 hours after leptin administration, respectively. Urinary excretion of cyclic GMP increased by 36.1% in the first and by 43.1% in the second 2-hour period. Leptin had no effect on the plasma concentration of atrial natriuretic peptide (ANP). The effect of leptin on plasma and urinary NO(x) was abolished by the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg intraperitoneal) administered 15 minutes before leptin injection. L-NAME alone caused a 32.2% increase in systolic blood pressure, but this increase was not observed in rats receiving L-NAME and leptin. DISCUSSION: The results indicate that leptin stimulates systemic NO production; leptin prevents blood pressure elevation induced by acute NO blockade, suggesting that leptin also triggers additional hypotensive mechanisms; and ANP is not involved in renal and vascular effects of leptin.

Animals↗