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Biomedical subjects

I Wittmann

Publications and source records attributed to I Wittmann.

At least 19 recordsLinked to original sources
PubMed2002

Cigarette smoke and its formaldehyde component inhibit bradykinin-induced calcium increase in pig aortic endothelial cells.

Bradykinin-induced increase in the intracellular concentration of free calcium evokes an activation of the endothelial nitric oxide synthase (eNOS) enzyme, producing nitric oxide (NO). Cigarette smoke inhibits the eNOS-NO-cGMP signaling pathway. The pathomechanism of this deleterious effect of smoke on NO production is unknown. The aim of this study was to investigate the effect of gas phase smoke trapped in a buffer (smoke buffer, SB) on the bradykinin-induced calcium increase in cultured endothelial cells. FURA-2-AM was used to detect bradykinin-induced calcium increase. A sensitive, fluorescent method using O-phthaldialdehyde was used for the determination of intracellular reduced glutathione (GSH) and protein-thiol levels. SB caused a time- and concentration-dependent inhibition of bradykinin-induced calcium increase. Formaldehyde, a component of SB, inhibited bradykinin-induced calcium increase in concentrations characteristic for SB. SB decreased both the intracellular GSH (0.22 +/- 0.06 vs. 2.23 +/- 0.32 mumol/g protein, SB vs. control, p < .001) and protein-thiol levels (4.98 +/- 0.54 vs. 7.31 +/- 0.97 microEqu GSH/g protein, SB vs. control, p < .05) in the endothelial cells. Intracellular GSH and protein-thiol levels were not changed by 80 microM formaldehyde. GSH (4 mM) prevented the effect of SB (p < .001) and formaldehyde (p < .05) on the bradykinin-induced calcium increase. Our data support the premise that SB inhibits bradykinin-induced calcium increase. This inhibition is partially due to protein-thiol oxidation but may also be caused by the formaldehyde content of SB, which inhibits calcium increase in a protein-thiol-independent manner.

Animals↗
PubMed2001

Role of iron in the interaction of red blood cells with methylglyoxal. Modification of L-arginine by methylglyoxal is catalyzed by iron redox cycling.

Diabetes mellitus is characterized by increased methylglyoxal (MG) production. The aim of the present study was to investigate the role of iron in the cellular and molecular effects of MG. A red blood cell (RBC) model and L-arginine were used to study the effects of MG in the absence and presence of iron. Intracellular free radical formation and calcium concentration were measured using dichlorofluorescein and Fura-2-AM, respectively. Effects of MG were compared to the effect of ferrous iron. Reaction of L-arginine with MG was investigated by electron spin resonance (ESR) spectroscopy and by a spectrophotometric method. MG caused an iron dependent oxidative stress in RBCs and an elevation of the intracellular calcium concentration due to formation of reactive oxygen species. Results of co-incubation of MG with ferrous iron in the RBC model suggested an interaction of MG and iron; one interaction was a reduction of ferric iron by MG. A role of iron in the MG-L-arginine reaction was also verified by ESR spectroscopy and by spectrophotometry. Ferric iron increased free radical formation as detected by ESR in the MG-L-arginine reaction; however, ferrous iron decreased it. The reaction of MG with L-arginine yielded a brown product as detected spectrophotometrically and this reaction was catalyzed at a lower rate with ferric iron but at a higher rate with ferrous iron. These data suggest that MG causes oxidative stress in cells, which is due at least in part to ferric iron reduction by MG and to the modification of amino acids e.g. L-arginine by MG, which is catalyzed by iron redox cycling.

Arginine↗
PubMed2001

[Endothelial dysfunction].

The endothelium is a major regulator of vascular tone, releasing vasoconstrictive (endothelin, cyclooxigenase-dependent factors, including prostanoids and oxygen free radicals) and vasodilating (endothelium--derived nitric oxid, endothelium--derived hyperpolarizing factor) mediators. These biologically active substances control not only the vascular tone but the vascular structure and permeability, coagulation and fibrinolysis, as well inflammatory response of the vascular wall. In endothelial dysfunction the balance in the endothelial production of vasodilating and vasoconstricting substances is altered resulting an apparent decrease in endothelium-dependent relaxations. Endothelial dysfunction is an important event in the pathogenesis of the early phase of atherosclerosis and hypertension. The testing and monitoring of endothelial dysfunction include tests of endothelium-dependent vasomotion, as well as circulating markers of endothelial damage. Further methods are needed to build up a panel of tests which measure the extent of endothelial dysfunction (= subclinical atherosclerosis), predict the subsequent risk and response to therapy.

Animals↗
PubMed2001

[Analgesics-induced chronic renal failure in patients on dialysis therapy in Hungary].

In recent years elaboration of the diagnosis of analgesic-nephropathy (ANP) with the help of imaging techniques significantly increased the possibility of diagnosing the disease. Therefore, evaluating the prevalence of ANP has become more accurate in our country as well. The prevalence of ANP has been investigated in patients who have newly been taken into the dialysis program due to renal disease of unknown aetiology in 22 dialysis centers between December 1994-December 1997. The diagnosis of ANP has been based on revealing chronic drug abuse in the history and positive results of renal imaging (decrease in length of both kidneys combined with either bumpy contours and/or papillary calcification). Among 284 patients dialysed with unknown diagnosis 42 (14.8% of all cases) proved to have ANP. All patients except 2 took analgesic mixtures containing phenacetin/paracetamol, phenason derivatives, acetilsalysilic acid, caffeine and/or codeine. According to their investigations, ANP is a common disease resulting in end-stage renal failure in Hungary as well.

Acetaminophen↗
PubMed2001

N(epsilon)-(carboxymethyl)lysine levels in patients with type 2 diabetes: role of renal function.

Advanced glycation end products (AGEs) such as N(epsilon)-(carboxymethyl)lysine (CML) have been implicated in the development and progression of diabetic nephropathy. The aim of the present study is to investigate AGE levels in patients with type 2 diabetes with special regard to the role of renal impairment. Serum and urine CML levels (using a newly developed enzyme-linked immunosorbent assay), as well as serum AGE-fluorescence, were measured in 109 patients with type 2 diabetes. Patients were divided into groups with normal and impaired renal function. We found elevated serum fluorescent AGE and CML levels, as well as decreased urinary CML excretion rates, in patients with diabetes with renal impairment, but not those with normal renal function. In the presence of impaired renal function, serum CML and fluorescent AGE levels showed a significant inverse relation with creatinine clearance and a significant direct correlation with each other. No relationship could be found between serum AGE levels and parameters of blood glucose control or the presence of the following clinical complications: ischemic heart disease, diabetic retinopathy, and neuropathy. We conclude that the decline in renal function leads to increased serum AGE levels in patients with type 2 diabetes.

Adult↗
PubMed2001

Insulin-induced peroxynitrite production in human platelet-rich plasma.

Recent data support the possible role of nitric oxide (NO*) in the development of insulin signalling. The aim of this study was to examine the effect of insulin on NO* production by platelets. The chemiluminescence of platelet-rich plasma prepared from the blood of healthy volunteers was measured in the presence of luminol. Indirect detection of NO* by luminol is possible in the form of peroxynitrite produced in the reaction of NO* with a superoxide free radical. Luminol oxidation induced by hydroxyl free radical and lipid peroxidation was prevented by 150 micromol/l of desferrioxamine mesylate. Insulin, in the range of 0.084-840 nmol/l, induced a concentration-dependent increase in chemiluminescence, which was inhibited both by the competitive antagonist of the NO* synthase enzyme. N(omega)-nitro-L-arginine methyl ester (at concentrations of 2.0-4.0 mmol/l, P<0.001), and by the elimination of superoxide free radicals using superoxide dismutase (72-144 IU/ml, P<0.001). In conclusion, we assume that the insulin-induced increase in chemiluminescence of platelet-rich plasma was due to increased production of NO* and superoxide free radicals forming peroxynitrite. The data are consistent with production of peroxynitrite from human platelets under insulin stimulation.

Area Under Curve↗
PubMed2000

[Nephropathy in non-insulin-dependent (type-2) diabetes mellitus].

There is a dramatic increase in the incidence of end-stage renal disease in non-insulin dependent diabetes mellitus (NIDDM) requiring renal replacement therapy. The most important risk factors of the onset of nephropathy in NIDDM are genetic predisposition (history of diabetes, hypertension and cardiovascular events in first-degree relatives), hypertension, quality of glycaemic control and smoking. These risk factors play an important role also in the progression of diabetic nephropathy. In about 20-25% of NIDDM patients nondiabetic renal diseases cause the renal damage (other primary nephropathies, ischaemic nephropathy). NIDDM is mainly the part of metabolic x syndrome (hypertension, obesity, dyslipidaemia, impaired glucose tolerance or NIDDM) and, for this reason, all members of metabolic x syndrome has to be involved in treatment strategies e.g. blood pressure "subnormalization", aggressive glycaemic control, cessation of smoking, the treatment of obesity and dyslipidaemia with diet, physical activity and antilipidaemic drugs, as well as restriction of dietary protein and salt intake. The successful prevention and treatment of diabetic nephropathy needs the development of an interdisciplinary interaction that involves general practitioners, diabetologists and nephrologists.

Albuminuria↗
PubMed1999

[Detection of glycation end products in the urine of diabetic patients].

Advanced glycation end products play an important role in the development of tissue damage in diabetes mellitus. The aim of the present study was the investigation of the excretion of different glycation end products in the urine. Methylglyoxal, an intermediate product of the glycation, formed with L-arginine in an in vitro model two fluorescent peaks. These peaks can be characteristic for imidazolone-like product(s) which are produced also in the reaction of methylglyoxal with proteins described in the literature, suggesting modification of proteins with methylglyoxal at the guanidino group of the L-arginine amino acid. Using the fluorescent characteristics of these (excitation/emission: 320/400 nm and 340/425 nm) and the generally accepted wavelength of the so called non-specific advanced glycation end product (370/440 nm) could be identified these glycation end products in the urine of 98 patients with diabetes mellitus (21 type I., 77 type II., 51 female and 47 male, mean age: 56.6 years). These three particular glycation end products showed significant intercorrelations in the urine (p < 0.001). Concentrations of these glycation end products in the urine correlated negatively with the serum creatinine in the range between 120-240 mumol/l (p < 0.001). Data presented here verify that non-specific glycation end product and imidazolone-like glycation end products can be detected in the urine of diabetic patients. Elimination of these products by the urine is markedly decreased in the stage of early renal insufficiency. These decrease in the secretion can cause an elevation of the advanced glycation end products in the circulation leading progression of diabetic complication.

Diabetes Mellitus, Type 1↗
PubMed1999

[Detection of carbonyl stress markers in the urine of diabetic patients].

Carbonyl stress-induced tissue damage is caused by reactive aldehydes produced by non-enzymatic glycation, oxidative stress and metabolic processes. The aim of this study was the detection of the major markers of carbonyl stress in the urine of diabetic patients (21 type 1, 77 type 2, 51 female, 47 male, 56.6 +/- 13.7 year of age; mean +/- SD). Oxidative stress was detected by using the reaction of malondialdehyde, the end product of free radical damage of the tissues, with L-arginine. This reaction produced a fluorescent compound, pyrimidinyl-L-ornithine. Thus, pyrimidinyl-L-ornithine, as well as pentosidine, an advanced glycation end product, and the non-specific advanced glycation end product, which is thought to be partially as a result of lipid peroxidation, could be detected simultaneously by using the fluorescent method. Correlation coefficients among the concentrations of these products in the urine of 98 diabetic patients were as follows: pyrimidinyl-L-ornithine vs. non-specific advanced glycation end product: r = 0.72, p < 0.001; pentosidine vs. non-specific advanced glycation end product: r = 0.68, p < 0.001; pentosidine vs. pyrimidinyl-L-ornithine: r = 0.60, p < 0.001. Strong negative correlations were found between the serum creatinine levels of these patients, between 120-240 mumol/l, and the urinary concentration of these products: r = -0.88 for non-specific advanced glycation end products, r = -0.86 for pentosidine and r = -0.89 for pyrimidinyl-L-ornithine (p < 0.001 for all three). These data support a closer relation of the so-called non-specific glycation end product to oxidative stress than to non-enzymatic glycation. Results presented here suggest an early retention of the products of carbonyl stress in the patients with moderate renal insufficiency, which can play a role in the development of diabetic complications.

Adult↗
PubMed1997

In vivo blocking of L-selectin rescues BALB/c mice from fatal Leishmania major infection.

Susceptibility and resistance to experimental Leishmania major (L. major) infection in mice are associated with a Th2- or Th1-type response, respectively. We have previously shown that immunological events occurring within the first 24 h after infection in the lymph node (LN) draining the site of parasite challenge are critical for the development of either type of T-cell responses. In the present study we manipulated these events by preventing the entry of naive lymphocytes into the draining LN by injecting BALB/c mice with a single dose of the anti-L-selectin mAb MEL-14 one day prior to infection with L. major. In contrast to control BALB/c mice, in MEL-14 treated animals the primary lesion healed 12 weeks after infection. The parasite load in the spleen and lymph nodes of MEL-14 treated mice was significantly reduced. The healing was found to be associated with an increased production of IFN-gamma and with a decrease in IL-4 production by LN cells. We observed a dramatic decrease in cellularity in the draining LN in Mel-14 treated L. major-infected mice within the first week of infection. Moreover, the cells in the LN of MEL-14 treated mice were highly enriched in activated cells as well as in cell influx in the draining LN after local L. major infection of BALB/c mice prevents fatal disease. The data suggest the MEL-14-induced enrichment of the draining LN in memory and activated cells is fundamental for the initiation of a protective Th1-type response.

Animals↗
PubMed1997

Control of Leishmania major infection in BALB/c mice by inhibition of early lymphocyte entry into peripheral lymph nodes.

A single i.p. injection with the anti-CD62L (anti-L-selectin) mAb Mel-14 before parasite challenge protected BALB/c mice from the otherwise lethal infection with Leishmania major. The Mel-14 mAb treatment resulted in a significant (>90%) decrease in cellularity of the popliteal lymph node (PLN) with a decrease in the proportion of CD4+ cells and an increase of the proportion of B220+ cells. Furthermore, both activated cells (CD25+ and CD69+) and cells of the memory phenotype (CD45RBdull CD44high) were significantly enriched in PLN from Mel-14-treated BALB/c mice. After infection with L. major, the otherwise massive cellular infiltration in the draining PLN was completely blocked in the Mel-14-treated mice, and in these animals the high representation of both activated and memory cells in PLN remained characteristic for the first days of infection. The protective effect was found to be associated with a markedly increased production of IFN-gamma and with a decrease in IL-4 production upon restimulation of PLN and spleen cells with L. major Ag in vitro. The cured mice were found to be resistant against a secondary challenge with the parasites. These data suggest that the induction of a nonprotective Th2 response to L. major is associated with the entry of lymphocytes from the recirculating pool into the draining LN. The Mel-14-induced changes in the lymphoid microenvironment of the draining peripheral LN appear to favor the development of a protective Th1 cell-mediated immune response against the parasite.

Animals↗
PubMed1997

Possible role of free radicals generated by pseudohypoxia in the regulation of hepatic glucose output. An in vitro model using rat liver microsomal glucose 6-phosphatase.

Hepatic glucose output is decreased by hyperglycaemia through an unknown mechanism. We hypothesize that free radicals generated by hyperglycaemic pseudohypoxia might cause glucose output to decrease by inhibiting glucose 6-phosphatase - a key enzyme of gluconeogenesis. To prove this a model experiment was performed on a microsome fraction of rat liver. One of the characteristic features of pseudohypoxia due to hyperglycaemia is an increase in the ratio of NADH/NAD+, so in the present study the changes in NADH - induced glucose 6-phosphatase activity were investigated as related to the release of inorganic phosphate (Pi) derived from glucose 6-phosphate. After incubation for 50 min, Pi release was significantly reduced by NADH (4.026 +/- 0.189 vs 2.696 +/- 0.429 micromol x l(-1) x mg protein(-1), control vs NADH samples, p < 0.01). The decrease in the activity of glucose 6-phosphatase generated by NADH was prevented by using desferrioxamine, an irreversible ferric chelator, butylated hydroxytoluene and Trolox, two agents which inhibit lipid peroxidation, and reduced glutathione, a non-specific radical scavenger. Superoxide dismutase, catalase and the hydroxyl radical scavenger dimethyl sulphoxide proved to be ineffective. When the above investigations were carried out in the presence of a ferric-EDTA complex the inhibition of glucose 6-phosphatase was found to be inducible by hydrogen peroxide and/or hydroxyl free radicals. These investigations seem to indicate that pseudohypoxia due to hyperglycaemia can inhibit the activity of glucose 6-phosphatase both by lipid peroxidation and by inducing hydrogen peroxide and/or hydroxyl free radicals and thus it may play a part in the glucose-induced decrease of hepatic glucose output.

Adenosine Triphosphate↗
PubMed1997

Induction of endothelial cell injury by cigarette smoke.

Cigarette smoke contains different populations of free radicals which may be responsible for endothelial cell (EC) injury of smokers. The purpose of this study was to examine the effects of gas-phase cigarette smoke on EC endothelium-derived relaxing factor (EDRF)/NO-guanylate cyclase (GC)-cGMP pathway and on EC detachment-type injury after incubation with smoke. Furthermore, we examined whether different kind of antioxidants can prevent smoke-caused EC injury. We measured cGMP pathway using direct (sodium nitroprusside, SNP) and indirect (A23187, the calcium ionophore and bradykinin, BK) activators of GC. Directly and indirectly stimulated EC cGMP production dose-dependently decreased and EC detachment increased after incubation with smoke. Externally added thiols (glutathione, GSH; D-Penicillamine, DP; N-acetylcysteine, NAC) protected EC from damage of cGMP production and cell detachment. Other antioxidants (catalase, deferoxamine and superoxide dismutase) were ineffective. These results suggest that the thiol containing GC in EC is destroyed or inactivated or thiol like species responsible for activation of GC is incomplete in EC after incubation with smoke. It is also possible that externally added thiols bind an unknown component of smoke and this way, EC is protected. EC injury may contribute to vascular diseases associated with cigarette smoking.

Animals↗
PubMed1990

Redox agents modulate a(K+)0 changes evoked by acetylcholine and adrenaline in frog heart.

It was observed earlier, that in the presence of oxidizing agents the acetylcholine exerted a positive ino- and chronotropic effect, while the positive ino- and chronotropic action of adrenaline was decreased. In the presence of reducing agents both the negative inotropic effect of acetylcholine and the positive inotropic action of adrenaline was increased. Analyzing the ionic mechanism background of these correlations, the changes of extracellular K(+)-activity (a(K+)0) were followed and it was established that; In relation to slow transient changes (in min time ranges) an oxidant decreased the a(K+)0 following acetylcholine, while it increased the a(K+)0 after adrenaline application. A reductant increased the a(K+)0 with acetylcholine, but decreased a(K+)0 in the presence of adrenaline. Because of the inverse character of redox modulation on a(K+)0 levels, a reverse change in a(K+)0 should be (at least one of) the site of action of the opposite effects of oxidants or reductants exerted on ino- and chronotropism of acetylcholine or adrenaline.

Acetylcholine↗
PubMed1989

Free radicals and their interpretations.

Oxygen free radicals can be blamed for evoking gastric mucosal damage, because of the protective effect of some lipid soluble free radical scavengers (vitamin A related compounds, Vitamin E). Direct determination of free oxygen radicals related chemical entities in the gastric tissue during ulcerogenesis yielded controversial results. Aluminum antacid compound together with acid binding property exhibited cytoprotection too, elevating the tissue PGE2 level substantially. Magnesium containing antacid according to our model experiments on red blood cells damage by free radicals, is capable to bind free radicals as well as to counteract with the dangerous intracellular calcium accumulation. It has been concluded that aluminum-magnesium antacid has a cytoprotective effect via: 1. acid binding; 2. prostaglandin generation; 3. free radical scavenging; 4. calcium antagonist activity.

Aluminum Hydroxide↗