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Biomedical subjects

H Heinle

Publications and source records attributed to H Heinle.

At least 19 recordsLinked to original sources
PubMed2006

Intestinal spasmolytic effects of STW 5 (Iberogast) and its components.

Functional gastro-intestinal diseases as the irritable bowel syndrome are very common in the population and are characterized by a broad spectrum of symptoms which mostly are related to spastic or paralytic intestinal function without defined histopathological changes of the tissue. Due to the multifactorial pathogenesis a multifactorial therapy with multi-target action seems to be reasonable. STW 5 (Iberogast), its constituent herbal extracts and some isolated compounds were used in an in vitro model provided by intestinal samples from guinea pig in order to test their activity on histamine-induced contractions and spontaneous motility, respectively. For comparison the known spasmolyticum papaverine was used. The results show that the lytic effect of the phytotherapeuticum on histamine-induced contraction represents additively the actions of the different components and corresponds to approx. 10 microM of papaverine. Spontaneous peristaltic motion was differently modulated by the various constituent extracts. The experiments with silibinin, glycyrrhicine, chelidonine, and protopine showed that the effects of the extracts were not comparable to those of the respective chemical constituents.

Animals↗
PubMed2006

Antioxidative properties of the gastrointestinal phytopharmaceutical remedy STW 5 (Iberogast).

Since inflammation is a common mechanism of many gastrointestinal diseases, reactive oxygen metabolites may play an important role in their pathophysiology. Therefore it is interesting to know, whether phytopharmaceuticals known to modulate gastrointestinal motor function reveal also antioxidative properties. We tested STW 5 (Iberogast), its constituent nine different plant extracts, and some isolated compounds which are present in STW 5 for characterizing their antioxidative and radical quenching activities. The test assays consisted in pure chemical and complex cellular systems in which different types of reactive species were produced. Quantification of the effects was based on chemiluminescence reactions. The results show that all extracts contribute to the effect of the complete remedy STW 5, in the chemical systems in a strongly additive manner, in the cellular systems in a supraadditive manner. The largest contributions resulted from the extracts from peppermint and melissa leaves. Comparison of effects from isolated phytochemical compounds from the extracts with that of the extracts itself shows that usually the extract is more effective than the monosubstance which indicates also the synergism within the whole plant extracts. This means that the plant extracts present in STW 5 provide strong radical quenching activities that could also be involved in the therapeutic gastrointestinal actions.

Free Radical Scavengers↗
PubMed2003

Glimepiride reduces mononuclear activation of the redox-sensitive transcription factor nuclear factor-kappa B.

AIMS: Glimepiride has the lowest ratio of insulin release to glucose decrease compared with other sulphonylureas. This prompted us to study in vitro and in vivo in a placebo-controlled study the effect of glimepiride on the redox-sensitive transcription factor nuclear factor-kappa B (NF-kappaB). METHODS: Fifteen patients with type 2 diabetes on glibenclamide with a stable HbA1c over the last 6 months were included. After sampling for determination of baseline values, 10 patients were changed to an equivalent dose of glimepiride, while the placebo group was maintained at glibenclamide plus placebo. The glimepiride dose in these patients was adjusted so that no change in glucose control occurred, allowing for direct comparison. The others were kept on glibenclamide and received additional placebo. After 4 weeks of glimepiride or glibenclamide plus placebo, a second blood sample was taken. Mononuclear cells were isolated and assayed in a tissue-culture-independent electrophoretic mobility shift assay (EMSA)-based detection system for NF-kappaB binding activity, and by Western Blot for nuclear localization of NF-kappaB-p65, the cytoplasmic content of IkappaBalpha and the NF-kappaB-controlled haemoxygenase-1. Glimepiride dose-dependent inhibition of carboxymethyllysin (CML) albumin or tumour necrosis factor alpha (TNFalpha)- and H2O2-induced activation of NF-kappaB binding were determined, using isolated peripheral blood mononuclear cells from healthy volunteers, and transcriptional activity of bovine aortic endothelial cells either left untreated or induced with CML albumin incubated with or without glimepiride. Furthermore, in-vitro studies were implemented to demonstrate radical quenching properties of glimepiride in the cell-free 2,2'-azo-bis(2-aminopropane)-dihydrochloride system. RESULTS: Baseline glucose and HbA1c remained stable in the patients switched from glibenclamide to a corresponding dose of glimepiride or kept on glibenclamide plus placebo. While in the group of patients only taking glibenclamide plus placebo the NF-kappaB binding activity did not change significantly (p = 0.58), the NF-kappaB binding activity in the group of patients taking glimepiride was reduced from 19.3 relative NF-kappaB-p65-equivalents to 15.5 relative NF-kappaB-p65-equivalents (p = 0.04). The nuclear translocation of NF-kappaB-p65 was reduced from 100% at baseline to 58% after 4 weeks (p = 0.04); the cytoplasmic localization of NF-kappaB-p65 increased from 100% to 129% (p = 0.03) and the cytoplasmic content of IkappaBalpha increased from 100% to 109% (p = 0.06). The redox-sensitive haemoxygenase-1 antigen was reduced from 100% to 82% (p = 0.04). To prove directly that glimepiride reduces NF-kappaB activation, we isolated peripheral blood mononuclear cells (PBMC) from healthy volunteers. In vitro, glimepiride reduced TNFalpha-(1 nmol/l) and CML albumin (800 nmol/l)-induced NF-kappaB activation dose dependently, being half maximal at 120 micromol/l. H2O2-mediated NF-kappaB activation was only partially reduced. In addition, glimepiride reduced NF-kappaB-dependent gene expression using a NF-kappaB-driven luciferase reporter system. Finally, a cell-free detection system showed that glimepiride has radical quenching properties. CONCLUSION: Glimepiride can affect the activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo.

Aged↗
PubMed2002

Intimal plaque development and oxidative stress in cholesterol-induced atherosclerosis in New Zealand rabbits.

Although oxidative stress is well known in atherogenesis, the origin, nature and kinetics of free radicals involved have not been well described till now. Here, we correlated parameters of oxidative stress with cellular components during induction and stabilization of aortic intimal lesions which were induced in rabbits by feeding a cholesterol-enriched diet for 6 weeks and a normal diet for further 68 weeks. Plasma lipids, aortic plaque size and composition (macrophages, smooth muscle cells, oxidized LDL by morphometry), as well as aortic radical production (by luminol-enhanced chemiluminescence and TEMPO-9AC fluorescence) were measured after various time points. The parameters of oxidative stress were correlated with the different cellular components of the aortic plaques. The plaques increased until week 21, no significant regression was found until week 74, plasma cholesterol was maximal at week 6. Macrophages, oxidized LDL and generation of different species of free radicals were increased during plaque development, yet with different time kinetics. Whereas chemiluminescence correlated only weakly with the amount of intimal macrophages, strong correlations were found between TEMPO fluorescence and smooth muscle cells (r = 0.4778, P < 0.001) and between macrophages and oxidized LDL (r = 0.5896, P < 0.0001). Different indicators of oxidative stress were increased during plaque progression and stabilization. However, the various correlations show, that distinct types of reactive species secreted probably from macrophages and smooth muscle cells contribute to oxidative stress in the different phases of plaque development.

Animals↗
PubMed2000

Effect of urea and osmotic cell shrinkage on Ca2+ entry and contraction of vascular smooth muscle cells.

The present study was performed to elucidate the effects of urea on vascular smooth muscle cells (SMC). Addition of urea (20, 50, 100 mM) to physiological salt solution blunted the vasoconstrictory effect of phenylephrine (by 17, 25 and 30%, respectively) and of an increased extracellular K+ concentration (by 7, 14 and 19%, respectively) without affecting the basal tone of rabbit arterial rings. According to Fura-2 fluorescence in cultured SMC (A7r5), urea had no effect on basal intracellular calcium activity ([Ca2+]i), but significantly blunted the increase of [Ca2+]i following an increase of extracellular K+. Whole-cell patch-clamp studies revealed that the Ca2+ current through voltage-sensitive Ca2+ channels is significantly inhibited in the presence of urea. As evident from calcein fluorescence, addition of urea leads to sustained cell shrinkage. The effects of urea on vascular tone, [Ca2+]i activity, voltage-gated Ca2+ channels and cell volume are mimicked by addition of raffinose or NaCl. However, the cell shrinkage induced by urea is sustained, whereas the addition of equiosmolar NaCl is only transient and followed by a regulatory cell volume increase. Moreover, hypertonic NaCl increases, whereas urea decreases, the transcription of cell-volume-regulated kinase hsgk. In conclusion, urea leads to sustained shrinkage of vascular smooth muscle cells, which is followed by inhibition of voltage-gated Ca2+ channels, a decrease of [Ca2+]i and thus blunts the vasoconstrictory action of phenylephrine and increased extracellular K+ concentration.

Animals↗
PubMed2000

Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo.

OBJECTIVE: The aim of this study was to evaluate the potential of paclitaxel to prevent restenosis in vivo. BACKGROUND: Paclitaxel (Taxol) is a microtubule-stabilizing compound with potent antitumor activity. It influences the cytoskeleton equilibrium by increasing the assembly of altered microtubules, thereby inducing cellular modifications that result in reduced proliferation, migration and signal transduction. METHODS: Before the in vivo study, delivery efficiency was determined with radiolabeled paclitaxel in porcine hearts. After induction of a defined plaque in the right carotid arteries of 76 New Zealand rabbits by electrical stimulation, 27 animals underwent balloon dilation and subsequent local paclitaxel delivery (10 ml, 10 micromol/liter) with a double-balloon catheter. Twenty-nine animals served as control with angioplasty only, 10 animals underwent local delivery of vehicle only (0.9% NaCl solution) and 10 animals were solely electrostimulated. Vessels were excised one, four, and eight weeks after intervention. RESULTS: The extent of stenosis in paclitaxel-treated animals was significantly reduced compared with balloon-dilated control animals (p = 0.0012, one, four and eight weeks after intervention: 14.6%, 24.6% and 20.5%, vs. 24.9%, 33.8% and 43.1%, respectively). Marked vessel enlargement compared with balloon-dilated control animals could be observed (p = 0.0001, total vessel area after one, four and eight weeks: paclitaxel group: 1.983, 1.700 and 1.602 mm2, control: 1.071, 1.338 and 1.206 mm2, respectively). Tubulin staining and electron microscopy revealed changes in microtubule assembly, which were limited to the intimal area. Vasocontractile function after paclitaxel treatment showed major impairment. CONCLUSIONS: Local delivery of paclitaxel resulted in reduced neointimal stenosis and enlargement in vessel size. Both these effects contribute to a preservation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton.

Animals↗
PubMed2000

Chronically elevated endothelin-1 concentrations modulate the beta-adrenergic receptor system in vitro and in vivo.

In atherosclerosis and heart failure chronically elevated endothelin-1 (ET-1) plasma concentrations have been found which correlate with an increased mortality. The aim of this study was to determine the effects of chronically elevated ET-1 concentrations in vitro on the expression of the beta-adrenergic receptor (betaAR), the alpha-subunit of the stimulatory guanine-nucleotide-binding protein (G(s alpha)), and to determine betaAR's ability to activate adenylyl cyclase. In order to elucidate the effects of elevated ET-1 concentrations in vivo, male rats were infused with ET-1 and betaAR density was measured. Smooth muscle cells were incubated with ET-1 (10(-7) mol/l) for 6 to 48 h. Densities of betaARs were determined by radioligand binding studies and the G(s alpha) was analyzed by Western blotting. Isoproterenol-mediated adenylyl cyclase activity was measured. Additionally male rats were infused with ET-1 for 3 weeks. In vitro the betaAR density increased by 52% (p < 0.05, n = 5). The G(s alpha) increased to 260%. The isoproterenol-stimulated adenylyl cyclase activity was increased to 228%. In vivo, the pulmonary and myocardial betaAR density was elevated by 43% and 97%, respectively. Chronic ET receptor activation induces a transregulation of betaARs in vitro and in vivo.

Adenylyl Cyclases↗
PubMed1999

Oxidizability of low density lipoprotein and total antioxidative capacity of plasma are differently altered during induction and regression of hypercholesterolemia in rabbits.

Oxidizability of isolated low density lipoprotein (LDL) and total antioxidative capacity of plasma were measured in rabbits fed for 6 weeks a cholesterol-rich diet and for further 34 weeks a normal diet. Whereas the time to induce copper ion-mediated lipid peroxidation in LDL was prolonged during hypercholesterolemia, total antioxidative capacity as determined by a radical-trapping assay was increased at 6 weeks, but decreased during the time when the plasma cholesterol levels declined slowly to normal. Since aortic plaque progression was continued also during the first 15 weeks of normal diet, increased atherogenicity of hypercholesterolemia might be better reflected by the antioxidant capacity of plasma rather than by oxidation of isolated LDL.

Animals↗
PubMed1998

Downregulation of beta-adrenergic receptors by low density lipoproteins and its prevention by beta-adrenergic receptor antagonists.

OBJECTIVE: Vasodilation by beta-adrenergic receptors of smooth muscle cells appears to be impaired early after the onset of hypercholesteremia. The aim of this study was to analyze the modulation of beta-adrenergic receptor density and adenylyl cyclase activity in the presence of moderately elevated concentrations of LDL. The effects of beta 1- and beta 2-adrenergic receptor antagonists on LDL-induced receptor changes were studied. METHODS AND RESULTS: Media explants of porcine coronary arteries were incubated with moderately elevated LDL concentrations (0.7-3.9 mmol/l). The density of beta-adrenergic receptors was determined in plasma membranes using the radioligand [125I]iodocyanopinodolol. LDL (3.9 mmol/l) resulted in a decrease of beta-adrenergic receptor density (control 137 +/- 5 vs. 89 +/- 7 fmol/mg protein, P < 0.01). After removal of LDL and cultivation for an additional 3 days beta-adrenergic receptors increased to 129 +/- 5 fmol/mg. In the presence of the beta 1- or beta 2-adrenergic receptor antagonists the LDL-mediated decrease was inhibited. Addition of metoprolol after 3 days of LDL incubation caused a restoration of receptor density. The basal, isoproterenol- and forskolin-stimulated adenylyl cyclase activities were increased after LDL incubation by 180, 110 or 80%, respectively. CONCLUSION: Moderately elevated LDL levels decreased beta-adrenergic receptor density while adenylyl cyclase activity was simultaneously increased. beta 1- or beta 2-adrenergic receptor antagonists prevented this receptor decrease and might preserve the beta-adrenergic receptor density in the presence of moderately elevated LDL levels.

Adenylyl Cyclases↗
PubMed1997

Inhibition of Fas-induced apoptotic cell death by osmotic cell shrinkage.

Apoptosis is an active physiological mechanism permitting the elimination of cells by triggering an intracellular signalling cascade. Here, we tested whether osmotic alterations of cell volume interfere with apoptotic cell death in Jurkat T-lymphocytes. Apoptotic cell death of Jurkat cells was elicited by activation of the Fas receptor which results in sphingomyelinase stimulation, release of ceramide, activation of Ras, Rac-proteins and formation of O2. Osmotic cell shrinkage inhibited apoptotic cell death induced by the Fas receptor in Jurkat T-lymphocytes. Osmotic cell shrinkage did not interfere with Fas induced activation of the acidic sphingomyelinase or activation of Ras but impaired the formation of O2 suggesting an important function of cell volume in the synthesis of reactive oxygen intermediates upon Fas receptor ligation.

Apoptosis↗
PubMed1997

Effects of indapamide on Ca2+ entry into vascular smooth muscle cells.

Part of the antihypertensive action of indapamide has been attributed to a direct inhibitory action on Ca2+ entry into vascular smooth muscle cells. The present study has been performed to identify the possible mechanisms involved. To this end the effect of indapamide on intracellular Ca2+ activity - [Ca2+]i - has been tested under control conditions and under conditions known to increase [Ca2+]i such as osmotic cell swelling (mimicking mechanical stress), depolarization (increase of extracellular K+ concentration) and oxidative stress (H2O2). Indapamide (10 micromol/l) was without effect on control [Ca2+]i, but significantly blunted the increase of [Ca2+]i following potassium-induced depolarization or following osmotic cell swelling. It did not significantly modify the increase of [Ca2+]i induced by H2O2. The effects on cell membrane potential induced by increased [K+], osmotic cell swelling, or H2O2 were not significantly modified by indapamide (10 micromol/l). Voltage-gated Ca2+ currents were not significantly modified by 10 micromol/l indapamide, but were significantly reduced by 100 micromol/l and blunted by 1 mmol/l. In conclusion, indapamide at high concentrations (100 micromol/l) inhibits voltage-gated Ca2+ channels, an effect which blunts the increase of [Ca2+]i during depolarization of the cell membrane at increased extracellular [K+] or osmotic stress. Whether these effects at high concentrations of indapamide are relevant to the antihypertensive action, however, cannot be established from these in vitro studies.

Animals↗
PubMed1996

Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.

Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death.

Acetylcysteine↗
PubMed1996

Lipid islands in human gastric mucosa: morphological and immunohistochemical findings.

BACKGROUND & AIMS: Lipid islands are a common finding in the gastric mucosa, but their pathogenesis has not yet been established. The aim of this study was to investigate the morphology and immunophenotype of the various cells in lipid islands and to consider the possible mechanisms involved in the pathogenesis of these lesions. METHODS: Morphological and immunohistochemical investigations using antibodies against macrophages, smooth muscle cells, and lymphocytes were performed. Unfixed tissue was available for immunostaining for low-density lipoprotein (LDL) and oxidized LDL in one case. RESULTS: The lipid islands were composed of KP1-, KiM1p-, and cathepsin D-positive foam cells that were only weakly reactive for lysozyme. In cryostat sections, the foam cells were found to contain LDL and oxidized LDL. A few smooth muscle cells, plasma cells, lymphocytes, pericytes, fibroblasts, and Schwann cells that contained lipid droplets were also found. CONCLUSIONS: In gastric lipid islands, the presence of oxidized LDL, which is taken up by macrophages and smooth muscle cells via scavenger receptors, suggests that oxidized LDL is of key significance in the development and persistence of these lesions. Because the metabolism of LDL to oxidized LDL may occur by various mechanisms, various different initial conditions, including gastritis, may precede the development of lipid islands. Thus, anti-inflammatory treatment may be appropriate.

Foam Cells↗
PubMed1996

Effects of the new antioxidant nicanartine in an experimental model of atherosclerosis.

Transmural direct current (DC) stimulation of rabbit carotid arteries for 4 weeks was used for induction of atherosclerotic lesions. Ten animals received nicanartine (5-(3,5-di-tert-butyl)-4-hydroxyphenyl-1-(3-pyridyl)-2-oxapentane CAS 150443-71-3, Mrz 3/124) which reveals antioxidative as well as cholesterol-lowering properties supplemented to the diet containing 0.1% cholesterol. Controls were 10 rabbits without drug. Effects on plaque growth were determined by comparing the thickness of the DC induced intimal lesions in both groups. Furthermore, using non-stimulated segments of carotid arteries vasoprotecting effects were characterized by measuring H2O2-enhanced contractility of KCI-induced contraction as well as relaxation caused by acetylcholine induced liberation of endothelial derived relaxing factors. The results show decreased plaque growth during DC stimulation, diminished effectivity of H2O2 on contractility and improved endothelial function in the drug treated group. Since plasma cholesterol was only marginally increased under these feeding conditions, the plaque-reducing effect is most probably due to the antioxidative properties of nicanartine. Similar effects on neointima formation were also shown for other antioxidants.

Animals↗
PubMed1995

The relationship between habitual anger coping style and serum lipid and lipoprotein concentrations.

The relationship between habitual anger coping styles, especially anger expression in a socially assertive manner and serum lipid concentrations was examined in 86 healthy subjects. Habitual anger expression was measured by the Müller Anger Coping Questionnaire (MAQ) on four scales: Aggression, Controlled Affect, Guilt, and Social Inhibition. A positive correlation between serum cholesterol and Aggression was found, as was a negative correlation between LDL/HDL ratio and Controlled Affect. These correlations remained significant after adjustments for age, Body Mass Index (BMI), athletic activity, alcohol, nicotine and coffee consumption. After these adjustments, significant negative partial correlations between Controlled Affect and both total cholesterol and LDL were also found. We found no significant gender differences on any lipid measure. This study demonstrated that unfavourable lipid profiles are linked to a predominantly aggressive anger coping style, whereas favourable lipid profiles are associated with more socially assertive anger coping (Controlled Affect). Thus the expression of anger in a socially assertive manner can be seen as health promoting. The MAQ scales were better predictors of total serum cholesterol concentrations than the health related behaviors and characteristics. Results are discussed in terms of a psychophysiological risk model of inadequate anger coping.

Adaptation, Psychological↗
PubMed1995

Benign supraclavicular tumorous lymphangiectasia--a new disease?

We describe an isolated recurrent non-inflammatory tumorous swelling of the supraclavicular fossa in four premenopausal women. Ultrasonography, magnetic resonance imaging and computer tomography of the neck each suggested an inhomogeneous mass consistent with "lymphangioma." In each patient the clinical course and histopathologic findings suggested that the swellings were due to chronic localized lymph stasis with subsequent lymphangiectasia, possibly initiated by intermittent obstruction of the juncture of the thoracic or right lymph duct with the internal jugular vein. Enlargement may have been hormonally triggered by estrogens as each woman was taking oral contraceptive pills at the onset of the disease. To characterize this unique entity, we have termed the disorder benign supraclavicular tumorous lymphangiectasia.

Adult↗
PubMed1994

Effects of dietary garlic supplementation in a rat model of atherosclerosis.

In the present study possible antiatherogenic effects of dietary garlic were investigated in an experimental model which consists in the deendothelialisation by ballooning of the a. carotis communis of rats. 3 experimental groups were established: group I received a standard diet; the diet of group II was supplemented with 2% cholesterol and group III received 2% cholesterol and 5% dried garlic powder. Four weeks after ballooning plasma cholesterol, the average thickness of the neointima as well as the DNA content and the expression of collagens type I, III and IV in the ballooned arterial segment were determined. Furthermore, the specific activities of the enzymes glutathione peroxidase, glutathione disulfide reductase, glutathione-S-transferase and glucose 6 phosphate dehydrogenase were measured in homogenates of liver, heart and aorta. Hypercholesterolemia induced by cholesterol-feeding (group II 92 +/- 18 mg/100 ml) was significantly reduced by garlic (group III 53 +/- 19 mg/100 ml). Only little effects of garlic were seen in inhibiting neointima after ballooning. However, significant effects were found in protecting the enzymes of the glutathione dependent peroxide detoxification system, which is strongly impaired under hypercholesterolemia. Generally a normalisation, in some cases even an improvement beyond that, of the enzyme activities occurred in the garlic treated group. This indicates that in the model of atherosclerosis used here garlic is effective in lowering plasma cholesterol and in improving peroxide detoxification, however, it has only little influence on the wound healing reaction and does not significantly inhibit the development of intimal thickenings after ballooning.

Animals↗