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Biomedical subjects

J Günther

Publications and source records attributed to J Günther.

At least 37 records · Page 2Linked to original sources
PubMed1998

p53 autoantibodies in the sera, cyst and ascitic fluids of patients with ovarian cancer.

The presence of p53 autoantibodies and p53 protein overexpression in ovarian carcinoma patients were determined and compared. p53 antibodies were detected in sera samples, cyst and/or ascitic fluids of individual patients by two separate techniques (ELISA assay and immunoblot). p53 protein accumulation was assessed immunohistochemically in tissue sections and corresponding tumor effusion cells. The relations between p53 overexpression, the presence of p53 autoantibodies and histology of tumors, grade of differentiation and clinical stage of the disease were considered. p53 expression was found in 20 of 46 (43.5%) ovarian carcinomas and significant relationship between p53 reactivity in tumor tissue and effusion cells in individual patients was evident. In the subset of carcinomas with detectable p53 accumulation only two cases (one serous, one endometrioid) were associated with the presence of p53 autoantibodies (10%). Among 26 p53- negative carcinomas also two cases (7.6%) were seropositive. The strong correlation between the presence of p53 autoantibodies in the sera and respective cyst or ascitic fluids were revealed with no exception of this coincidence. There was no association between the detection of antibodies against p53 and FIGO stage and tumor grade. Our results clearly indicate that p53 overexpression is not sufficient to elicit p53 humoral response in ovarian carcinoma patients. The presence of p53 autoantibodies in this type of cancer is not a frequent event and their importance as independent prognostic factor seems to be very limited.

Ascitic Fluid↗
PubMed1998

The embryoid body as a novel in vitro assay system for antiangiogenic agents.

Tumor progression necessitates the induction of blood vessels that converge upon the tumor and enhance the diffusibility of oxygen and nutrients. Approaches to treat cancer by antiangiogenic therapy are therefore straightforward, and there is a great need for suitable in vitro systems to test antiangiogenic agents. In the present study, embryoid bodies (EBs) differentiated from totipotent mouse embryonic stem (ES) cells and cultivated using the spinner flask technique are introduced as an in vitro system for antiangiogenesis research. ES cells effectively differentiated endothelial cells within the three-dimensional tissue of EBs. The total area of capillary-like structures, which were positive for CD31 (platelet endothelial cell adhesion molecule, PECAM-1), was assessed by confocal laser scanning microscopy and image analysis of a series of optical sections. Endothelial differentiation occurred between Day 4-5 and Day 8 of EB development. Within 7 days, 100% of EBs contained capillary-like structures. Suramin, tamoxifen, tetrahydrocortisol, and a combination of tetrahydrocortisol and heparin were tested for their antiangiogenic capacity in the EB system and were found to efficiently inhibit endothelial differentiation. Diffusion studies of a 10-kd 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF)-dextran and the fluorescent, amphiphilic agent doxorubicin in avascular and vascularized EBs revealed that the endothelial structures formed functional vessels that facilitated diffusion. The diffusion coefficient D for doxorubicin was 296 x 10(-9) cm2 s(-1) in vascularized 8-day-old EBs, ie, about 10-fold larger than in avascular 3-day-old EBs (18 x 10(-9) cm2 s(-1)) and EBs treated with suramin (14 x 10(-9) cm2 s(-1)), tamoxifen (13.5 x 10(-9) cm2 s(-1)), and tetrahydrocortisol/heparin (18.5 x 10(-9) cm2 s(-1)). Consequently, avascular EBs treated with antiangiogenic agents developed central necrosis, which was absent in vascularized EBs. Our findings indicate that EBs are a suitable in vitro model system to study the effects of antiangiogenic agents in a three-dimensional tissue context. Furthermore, EBs provide a unique model to investigate the diffusion of anticancer agents in a tissue in both the avascular and vascularized states.

Animals↗
PubMed1997

Contractile function of papillary muscle from rats with different infarct size after beta-adrenergic blockade and ACE-inhibition.

We tested whether ACE-inhibition with ramipril (A), beta-adrenergic blockade with metoprolol (beta) or combined treatment (beta A) for 6 weeks after inducing myocardial infarction in rats by left coronary artery ligation modifies contractile function of hypertrophied papillary muscle from left ventricles with different infarct size (IS) compared to a placebo group (P). At IS<40% of left ventricle, contraction and relaxation were less impaired than at IS>40% compared to sham operated rats (SO). Isometrically developed peak force and calcium sensitivity of myofilaments, measured in skinned fibres, were significantly higher in beta. Treatment with ramipril or metoprolol improved contraction rate and force development, respectively, mainly at IS<40%, but deteriorated relaxation rate. ACE-inhibition and beta-adrenergic blockade had no significant improving effect on the relaxation rate and further characteristics of the contractile function at IS>40%, although combined treatment reduced the infarct size and ramipril treatment suppressed the development of hypertrophy. Post-extrastimulatory potentiation was increased in beta and beta A at IS>40%. Post-rest potentiations were influenced hardly at IS<40% and were significantly smaller in A at IS>40%. The twitch-to-twitch decay of the potentiations was faster at IS>40%. Increase in the degree of post-extrastimulatory potentiation, steeper twitch-dependent decay of the potentiations and loss of rest-dependent potentiation at IS>40% indicate relatively increased trans-sarcolemmal Ca2+ transports via Ca2+ channels and Na+/Ca2+ exchange, partly modified by ramipril and metoprolol. The results demonstrate that ACE-inhibition and beta-adrenergic blockade induce a dissociation between trophic effects and phenotypic effects on contractile function after chronic infarction.

Adrenergic beta-Antagonists↗
PubMed1995

Alterations of cardiac contractile function are related to changes in membrane calcium transport in spontaneously hypertensive rats.

OBJECTIVE: Transport activities of cardiac sodium-calcium exchange and sarcoplasmic reticulum calcium ATPase were measured biochemically in spontaneously hypertensive rats (SHR) with hypertrophied myocardium and in normotensive Wistar-Kyoto (WKY) rats and it was tested whether possible differences have consequences for the contractile properties of papillary muscle. METHODS: Sarcolemmal sodium-dependent calcium transport via sodium-calcium exchange and oxalate-supported sarcoplasmic reticulum calcium uptake were measured in left ventricular membranes of 22-week-old rats. Postextrastimulatory potentiated contractions, postrest potentiated contractions, the twitch-to-twitch decay of those potentiations and the response to increasing stimulation frequency of left ventricular papillary muscles were analysed. RESULTS: Compared with WKY rats we found in SHR: a significant increase in sodium-calcium exchange (65%) and in sarcoplasmic reticulum calcium uptake (24%); a steeper twitch-to-twitch decay in postextrastimulatory potentiated contractions and postrest potentiated contractions, suggesting a lower calcium fraction recirculating between myofilaments and sarcoplasmic reticulum and, consequently, a relatively higher calcium efflux via sodium-calcium exchange; a stronger rest-dependent decrease in recirculating calcium fraction in postrest potentiated contractions accompanied by accelerated relaxation, suggesting an increasing driving force for calcium extrusion via sodium-calcium exchange, probably caused by decreasing intracellular sodium during rest; a greater transient decrease in peak force of subsequent twitches after postrest potentiated contractions below pre-interventional level, indicating higher cellular calcium loss; and a smaller negative inotropic effect in response to doubling of stimulation rate as a manoeuvre to increase the intracellular sodium level. CONCLUSION: In SHR, the contractile properties suggest an increased contribution of sodium-calcium exchange to cellular calcium removal, which is strongly supported by the enhanced sodium-calcium exchange activity in cardiac membrane vesicles.

Animals↗
PubMed1994

Interpretation of the inotropic effect of 2,3-butanedione monoxime on the isometric twitch of guinea-pig papillary muscle.

The negative inotropic effect of 2,3-butanedione monoxime (BDM) on the isometric twitch of guinea-pig papillary muscle was analysed by parameters characterizing the time course of the mechanogram. BDM at concentrations of up to 4 mmol/l produced a clear negative inotropic effect, whereas the Ca transient measured in isolated cardiomyocytes was only slightly affected. Peak force was more reduced than dF/dtmax and dF/dtmin. This led to an earlier, more narrow peak and a shortening of twitch duration. Based on a reaction scheme for the cross-bridge cycle, a mathematical model using a Ca transient and mechanograms as input data has been developed. The kinetic parameters were estimated by fitting the model to various time courses of force obtained at rising concentrations of BDM. BDM decreased the ratio of rate constants for cross-bridge attachment and detachment in a concentration-dependent manner: the formation of cross-bridges became inhibited, whereas dissociation was promoted. Above 4 mmol/l BDM the more marked alterations of the parameters of the mechanogram indicated an additional suppressing effect on intracellular Ca supply. The computer analysis suggests how the cellular mechanism(s) of the BDM-induced negative inotropic effect are reflected in the time course of the mechanogram.

Animals↗
PubMed1992

Binding and action of insulin-like growth factors and insulin in bovine luteal tissue during the oestrous cycle.

The effect of insulin-like growth factors (IGFs) and insulin on the release of progesterone and oxytocin from bovine corpus luteum was investigated at early (days 5-7), mid- (days 8-12) and late (days 15-18) luteal phases of the oestrous cycle in an in vitro microdialysis system. The expression of specific receptors was evaluated in bovine corpora lutea of the respective luteal stages. A 30 min infusion of IGF-1, IGF-2 (1.3, 13 and 130 nmol l-1) or insulin (13, 130 and 1300 nmol l-1) caused a stimulation of the release of progesterone (P < 0.05). IGF-1 was most effective in releasing progesterone. Oxytocin release from corpora lutea was stimulated by insulin at all doses tested (13-1300 nmol l-1), whereas the IGFs were only effective at the highest dose (130 nmol l-1) applied. The high doses of IGFs (130 nmol l-1) and insulin (1300 nmol l-1) stimulated the release of progesterone and oxytocin throughout the luteal phase (P < 0.05). For all three peptides, greatest stimulation was seen during the late luteal phase (days 15-18 of the oestrous cycle) with the peak of progesterone release directly related to peptide infusion (P < 0.05). In addition, IGF-1 stimulated total release of progesterone (units in 4 h) after the beginning of the stimulation during this phase (P < 0.05). IGF-1 caused a gradual increase of progesterone even beyond the time of peptide perfusion, whereas IGF-2 and insulin stimulated progesterone release only during the peptide perfusion. Distinct receptors for IGF-1 and IGF-2 were present in corpora lutea membrane preparations at all stages investigated. Specific binding for insulin was also seen in all stages of the cycle without any cycle-dependent changes in the amount of binding. The displacement of labelled insulin by unlabelled IGF-1 and IGF-2 did not show the rank of order that has been described as typical for insulin receptors (i.e. insulin > IGF-1 > IGF-2), but comparable binding affinities were observed for the three unlabelled ligands. Specific binding of IGF-2 was markedly higher than that of IGF-1 or insulin throughout the cycle (1.9- and 4.9-fold higher compared with IGF-1 and insulin, respectively). Receptor specificity did not change during luteal development. Binding affinity and capacity of IGF-1 receptor was constant throughout the oestrous cycle. Specific IGF-2 binding increased and showed a positive co-operativity towards the end of the cycle. Specific binding of insulin was not significantly different in the three luteal stages examined.

Animals↗
PubMed1990

Adverse immune reactions to gold. I. Chronic treatment with an Au(I) drug sensitizes mouse T cells not to Au(I), but to Au(III) and induces autoantibody formation.

Upon weekly i.m. injections of disodium gold thiomalate (Na2AuTM) 100% of A.SW mice produced IgG autoantibodies to antinuclear Ag and nucleolar Ag, respectively; about 70% of C57BL/6 mice produced IgG antinuclear Ag, whereas DBA/2 mice were resistant. Moreover, C57BL/6 mice, but not DBA/2 mice, showed increased mesangial deposits of IgG. These alterations were due not to disodium thiomalate, but to the gold ion of Na2AuTM. An assumed T cell reactivity of susceptible mouse strains to Na2AuTM was tested by means of the direct popliteal lymph node (PLN) assay. However, no distinct PLN reaction to Na2AuTM was detectable. Likewise, AuCl did not induce a PLN reaction. Both Na2AuTM and AuCl contain gold in the Au(I) state. The poor PLN responses to Au(I) contrasted with the strong PLN responses to Au(III) compounds. PLN reactions to Au(III) were dose dependent, T cell dependent, and specific. When Au(III) was reduced to Au(I) by addition of Na2TM or methionine before testing in the PLN assay its sensitizing capacity was significantly decreased. Thus, the oxidation state of gold, i.e., Au(III) vs Au(I), plays a major role for its sensitizing capacity. Therefore, we propose that the Au(I) of Na2AuTM is oxidized to Au(III) before T cells are sensitized and adverse immunologic reactions develop. Results obtained with the adoptive transfer PLN assay indicated that, indeed, repeated i.m. injections of Na2AuTM sensitized A.SW and C57BL/6 splenic T cells to Au(III).

Animals↗
PubMed1989

The isometric twitch of rabbit papillary muscle: reflection of the cellular calcium movements?

The cycling of the activator-Ca of the myocardium is mediated by the sarcolemma (SL) and the sarcoplasmic reticulum (SR). Both the extent and the time course of the release as well as of the removal of the activator-Ca by the SL differ from that by the SR. The visualization of these differences in the isometric myograms of isolated myocardium (Bogdanov et al. 1979; Günther et al. 1986; King and Bose 1983; Malecot et al. 1986) prompted the conclusion that distinct cellular Ca movements determine distinct parts of the isometric contraction-relaxation cycle. To test this hypothesis the effects of Ca, isoprenaline and ouabain on the isometric contraction-relaxation cycle of rabbit papillary muscles were re-evaluated. The similarities and differences in the effects of the interventions on the twitch measures could be explained by their effects on the cellular Ca movements.

Animals↗
PubMed1989

Postrest contractions as an example for the regulation of the course of isometric twitch.

Postrest contractions (PRC) of isometrically contracting rabbit papillary muscles are used to analyse how the shape of the twitch can be explained by existing models for the accompanying Ca-regulation. By the change of the extracellular Ca concentration (Cae) potentiated or depressed PRC were produced. The course of the twitch is separated by mechanical indices commonly used. The results fit some biochemical and electro-physiological findings, as the regulatory role of the sarcoplasmic reticulum and the Na-Ca exchange, but do not reflect others. The sharp separation between an early and late phase of the contraction and relaxation, respectively, is limited by the overlapping of different Ca regulating processes.

Animals↗
PubMed1988

The complement membrane attack complex stimulates the prostanoid production of cultured glomerular epithelial cells.

Incubation of cultured rat glomerular epithelial cells (GEC) with sublytic amounts of the purified complement components C5b6, C7, C8 and C9 greatly stimulated the release of the prostanoids prostaglandin E (PGE) and thromboxane B2. Incubation of GEC with C5b-8 was also stimulatory, whereas omission of C7 abolished the enhanced prostanoid production. These effects were dose-dependent. The increased release of PGE was biphasic with peaks at 5 min and 24 h of incubation. The second peak could be prevented by treatment with cycloheximide, suggesting its dependence on protein synthesis. The observations on cultured GEC provide evidence that terminal complement components alter the metabolism of glomerular cells, resulting in increased production of prostanoids. The results are consistent with the concept that deposition of nonlytic amounts of complement in the glomerular capillary wall may affect the GEC in vivo and may indirectly contribute to abnormalities of the glomerular filter as it is seen in glomerular disease.

Animals↗
PubMed1986

Modification of relaxation of isometrically contracting rabbit papillary muscle by calcium, isoprenaline, ouabain and amiloride.

The influence of isoprenaline, ouabain, amiloride, as well as enhanced extracellular Ca on the time course of relaxation of the isometrically contracting papillary muscle was investigated. Under the experimental conditions used the relaxation rate shows different phases, which are modified characteristically. It is concluded that this reflects the different involvement of the Ca transport mechanisms for the relaxation.

Amiloride↗
PubMed1986

Stimulation pattern dependent contractions of myocardial preparations after lipid diets.

Lipid diets modify the electro-mechanical coupling. To characterize the regulation of the supply of Ca for the activation of the contraction the influence of the stimulation pattern on the development of tension was investigated after diets containing cholesterol (Ch), rape oil (RO) and cholesterol-oil (ChO). The sequence of increasing inotropic states produced was compared with a control group (C). In ChO high resting potentiation, low postextrastimulatory potentiation (PEP) and a delayed Ca supply for interpolated extra contractions (EC) are typical features. The positive inotropic effect of rising extracellular Ca grows parallel to the sequence of the inotropic states. The maximum rate of contraction and relaxation correlates linearly with the tension development. Some of the results are similar in RO. In both groups a more pronounced involvement of the sarcoplasmic reticulum in the Ca regulation should be responsible for the effects. Especially in C the Ca loading effect of paired stimulation shortens the latent period and increases the rate of contraction and relaxation. In Ch the highest values of PEP are reached. These results reflect the involvement of a high sarcolemmal fraction of Ca in the activation.

Animals↗
PubMed1984

K-p-nitrophenylphosphatase activity, Na and K content, Na permeability and membrane lipid composition in rabbit myocardium after cholesterol rich diet.

The aim of the present study was to investigate the effects of a cholesterol-rich diet on membrane function and lipid composition in rabbit myocardium. The activity and the ouabain sensitivity of the K-p-nitrophenylphosphatase (K-pNPPase), a partial reaction of the Na, K-ATPase, were diminished after a cholesterol/oil or pure cholesterol diet. The content of cholesterol, cholesterol esters and of several classes of phospholipids was enhanced in microsomes. A causal relationship is assumed between cholesterol accumulation and a decrease in membrane fluidity as well as in Na, K-ATPase activity. The intracellular Na content and the Na-Li-exchange rate were higher after the cholesterol diet. The increase in the Na content is supposed to be induced by a lower Na transport and a higher Na permeability. An enhanced Ca flux via the sarcolemma could be the consequence.

4-Nitrophenylphosphatase↗
PubMed1984

[Time dependence of Ca supply in rat and rabbit myocardium].

The time dependence of Ca supply in rat (R) and rabbit myocardium (K) for the activation was analyzed by the action potential area up to 50% of repolarization (APA50) of the action potential (AP) during the electrical restitution as well as by extra contractions (EC) during the mechanical restitution and subsequent postextrastimulatory contraction (PEC) or potentiation (PEP) in isometrically contracting papillary muscle at different extracellular Ca concentrations (Cae). In K a considerable increase in APA50 of the EC-AP during the electrical restitution within the interval of rhythmical contraction (T) strongly correlates with the subsequent PEP. In R both the alteration of the APA50 and the PEP are smaller than in K. Compared with K in R the mechanical restitution is delayed, but accelerated by rising Cae as demonstrated by increasing EC/T. The course of mechanical restitution and the low PEP are regarded to be connected with the fact that the sarcoplasmic reticulum is the main source of activator Ca in R. Differences in both electrical and mechanical restitution and, especially the higher PEP, agree with the sarcolemma as the main source of activator Ca in K.

Action Potentials↗
PubMed1982

[Fatty acid patterns of triglycerides in serum and skeletal muscles of rabbits on a cholesterol diet].

In 18 rabbits a hypercholesterolaemia was produced by a 12-week dietetic load with cholesterol. The hypercholesterolaemic rabbits had increased proportions of saturated and simply unsaturated fatty acids in the triglycerides of the serum and the skeletal muscle. The content of eicosapentaenic acid was lowered. The alterations in the fatty acid pattern are equal to those of patients with hyperlipoproteinaemia and arteriosclerosis. On the basis of these findings rabbits seems to be a suitable model, in order to investigate the connections between fatty acid patterns and the development of arteriosclerosis by experiments on animals.

Animals↗