[Low molecular weight heparins].
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Anticoagulants↗
Biomedical subjects
F Schröder
Publications and source records attributed to F Schröder.
Cranial neuroendocrine carcinoma primarily diagnosed as malignant paraganglioma with rapid progress to a fatal outcome.
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Carcinoma, Neuroendocrine↗
Murine ventricular L-type Ca(2+) current is enhanced by zinterol via beta(1)-adrenoceptors, and is reduced in TG4 mice overexpressing the human beta(2)-adrenoceptor.
1. The functional coupling of beta(2)-adrenoceptors (beta(2)-ARs) to murine L-type Ca(2+) current (I(Ca(L))) was investigated with two different approaches. The beta(2)-AR signalling cascade was activated either with the beta(2)-AR selective agonist zinterol (myocytes from wild-type mice), or by spontaneously active, unoccupied beta(2)-ARs (myocytes from TG4 mice with 435 fold overexpression of human beta(2)-ARs). Ca(2+) and Ba(2+) currents were recorded in the whole-cell and cell-attached configuration of the patch-clamp technique, respectively. 2. Zinterol (10 microM) significantly increased I(Ca(L)) amplitude of wild-type myocytes by 19+/-5%, and this effect was markedly enhanced after inactivation of Gi-proteins with pertussis-toxin (PTX; 76+/-13% increase). However, the effect of zinterol was entirely mediated by the beta(1)-AR subtype, since it was blocked by the beta(1)-AR selective antagonist CGP 20712A (300 nM). The beta(2)-AR selective antagonist ICI 118,551 (50 nM) did not affect the response of I(Ca(L)) to zinterol. 3. In myocytes with beta(2)-AR overexpression I(Ca(L)) was not stimulated by the activated signalling cascade. On the contrary, I(Ca(L)) was lower in TG4 myocytes and a significant reduction of single-channel activity was identified as a reason for the lower whole-cell I(Ca(L)). The beta(2)-AR inverse agonist ICI 118,551 did not further decrease I(Ca(L)). PTX-treatment increased current amplitude to values found in control myocytes. 4. In conclusion, there is no evidence for beta(2)-AR mediated increases of I(Ca(L)) in wild-type mouse ventricular myocytes. Inactivation of Gi-proteins does not unmask beta(2)-AR responses to zinterol, but augments beta(1)-AR mediated increases of I(Ca(L)). In the mouse model of beta(2)-AR overexpression I(Ca(L)) is reduced due to tonic activation of Gi-proteins.
Adrenergic beta-1 Receptor Agonists↗
[Methotrexate].
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Antimetabolites, Antineoplastic↗
Protein phosphatase activity is increased in a rat model of long-term beta-adrenergic stimulation.
We tested the hypothesis that altered phosphorylation of Ca2+ regulatory proteins contributes to contractile anomalies in cardiac hypertrophy. Cardiac hypertrophy was induced in rats by chronic s.c. administration of isoproterenol (Iso, 2.4 mg/kg/day) via osmotic minipumps. On day 2 of Iso treatment the expression of atrial natriuretic factor was increased, time of relaxation in isolated papillary muscles shortened and protein expression of phospholamban (PLB) and sarcoplasmic reticulum Ca2+-ATPase reduced. In addition, the phosphorylation state of PLB at serine-16 and threonine-17 was decreased from (arbitrary units) 2.3+/-0.3 to 1.1+/-0.2 and from 4.1+/-0.6 to 2.1+/-0.2, respectively. This was not accompanied by altered activity of PLB-phosphorylating protein kinases (protein kinase A or Ca2+/calmodulin-dependent protein kinase II), whereas the activity of types 1 and 2A protein phosphatases (PP1 and -2A respectively) was enhanced from 1.1+/-0.08 to 1.71+/-0.13 nmol/mg/min. Iso treatment did not alter the PP1/PP2A activity ratio and 1 nmol/l okadaic acid, a concentration which completely blocks the catalytic subunit of PP2A, inhibited about 40% of total PP activity in all groups studied. These data indicate that the activity of both PP1 and PP2A were increased. All effects of Iso treatment were abolished by co-administration of propranolol (29.7 mg/kg/day). It is concluded that dephosphorylation of PLB is due to enhanced activity of PP1 and PP2A. We suggest that chronic beta-adrenergic stimulation, which occurs in human cardiac hypertrophy and failure, can lead to increased activity of PPs. This may contribute to altered contractile responses in the hypertrophied heart.
Adrenergic beta-Agonists↗
Protein kinase G reverses all isoproterenol induced changes of cardiac single L-type calcium channel gating.
OBJECTIVE: cGMP reduces the effect of beta-adrenoceptor agonists on cardiac L-type calcium current by protein kinase G activation. Stimulation of beta-adrenoceptors increases protein kinase A dependent phosphorylation of L-type calcium channels via cAMP. At the single channel level, protein kinase A dependent phosphorylation increases both availability and open probability. The present study investigates how cGMP antagonises protein kinase A induced changes of single L-type calcium channel gating. METHODS: Single L-type calcium channels were recorded in the cell attached configuration of the patch clamp technique in isolated mouse ventricular myocytes. RESULTS: The beta-adrenoceptor agonist isoproterenol (10(-6) M) enhanced single channel peak average current by increasing availability and open probability and decreasing the time constant of long close times. 8-Br-cGMP (10(-3) M) completely reversed these effects. The phosphatase inhibitor okadaic acid (10(-6) M) did not influence the effect of 8-Br-cGMP. The protein kinase G inhibitor Rp-8Br-PET-cGMPS (10(-7) M) abated the effect of 8-Br-cGMP. Activation of protein kinase A by the hydrolysis-resistant cAMP derivative 8-Br-cAMP (10(-3) M) enhanced L-type calcium channel activity like isoproterenol and its effect was also reversed by 8-Br-cGMP. CONCLUSION: 8-Br cGMP diminishes beta-adrenoceptor activation of L-type calcium channels via protein kinase G. It interacts with the beta-adrenoceptor signaling pathway distal of adenylyl cyclase. Our observations suggest that protein kinase G interacts either with protein kinase A or directly with the L-type calcium channel.
8-Bromo Cyclic Adenosine Monophosphate↗
Single-channel activity and expression of atrial L-type Ca(2+) channels in patients with latent hyperthyroidism.
Patients with "latent hyperthyroidism" (suppressed thyroid-stimulating hormone and normal circulating thyroid hormones) are at risk to develop atrial fibrillation. In animal models, hyperthyroidism is associated with increased cardiac L-type Ca(2+) current. Therefore, we assessed L-type channel function and expression in right atria from patients undergoing cardiac surgery. Single L-type channels were studied in the cell-attached condition. Voltage dependence of gating was similar in patients with and without latent hyperthyroidism. With use of a pulse protocol leading to maximum channel availability, single-channel activity was further analyzed. Average peak current was significantly enhanced in latent hyperthyroidism, mainly because of an increased channel availability (P < 0.05). Protein expression was analyzed by Western blot. In latent hyperthyroidism, expression of Ca(2+) channel alpha(1)-subunits was increased more than threefold (P < 0.01). In contrast, sarco(endo)plasmic reticulum Ca(2+)-ATPase and phospholamban levels were not significantly changed. We only observed a trend toward increased sarco(endo)plasmic reticulum Ca(2+)-ATPase expression (P = 0.085). Function and expression of human atrial L-type Ca(2+) channels are increased in latent hyperthyroidism. These endocrine effects on the heart may be clinically relevant.
Blotting, Western↗
Finasteride in association with either flutamide or goserelin as combination hormonal therapy in patients with stage M1 carcinoma of the prostate gland. International Prostate Health Council (IPHC) Trial Study Group.
BACKGROUND: It was very reasonable to consider that the combination of the 5alpha-reductase, finasteride, and a pure antiandrogen such as flutamide should provide an effective form of maximal androgen blockade (MAB). Finasteride decreases intraprostatic levels of 5alpha-dihydrotestosterone (DHT), and the antiandrogen would restrain the biological action of the residual DHT by interfering with its association with androgen receptor. This form of MAB should sustain the concentration of testosterone in plasma, thereby maintaining sexual function and reasonable quality of life. In order to investigate this, a randomized multicenter phase II clinical trial of patients with untreated M1 cancer of the prostate was developed and undertaken. METHODS: Patients were randomly allocated to one of three treatment schedules: 1) goserelin, 3.6 mg, s.c., monthly in combination with flutamide, 250 mg., t.i.d. and a placebo, daily, in the image of 2 x 5 mg finasteride; 2) goserelin, 3.6 mg., s.c., monthly in combination with finasteride, 10 mg (2 x 5 mg, daily) and a placebo (t.i.d.) in the image of flutamide; and 3) finasteride, 10 mg (2 x 5 mg, daily) in combination with flutamide (250 mg, t.i.d.). The reduction in concentration of serum PSA at 24 weeks was the endpoint of interest. RESULTS: Baseline prostate-specific antigen (PSA) levels of the patients in the three groups were very similar. There was a substantial decrease in levels of PSA in the three groups prior to the end of the study, the percent decrease in the groups being: 1) goserelin and flutamide combination, 99.1% (95% Confidence interval (CI), 97.7, 99.6); 2) goserelin and finasteride combination, 98.75% (95% CI, 97.1, 99.5); and 3) finasteride and flutamide combination, 97.6%, 95% CI, 94.5, 98.9). In the Generalized linear model (GLM) analysis, there was no center by treatment group interaction (P = 20), and there were no significant differences between centers (P = 0.059) nor among the three treatment groups (P = 0.16). CONCLUSIONS: The decrease in levels of PSA in such a group of patients with M1 cancer of the prostate over a 24-week period was surprisingly large, and the differences in these decreased levels between the three treatment arms were remarkably small. There were no apparent differences in bone scan scores, World Health Organization (WHO) performance status, and pain scores between the arms. With regard to sexual function associated with quality of life, there were the understandable difficulties of data collection from patients treated with goserelin.
5-alpha Reductase Inhibitors↗
Effects of beta2-adrenergic stimulation on single-channel gating of rat cardiac L-type Ca2+ channels.
Cardiac L-type Ca2+ channels can be stimulated by activation of beta2-adrenoceptors. We intended to determine how the gating behavior at the single-channel level (cell-attached configuration) is affected after selective stimulation of beta2-adrenoceptors. Rat cardiomyocytes were exposed to zinterol, a beta2-agonist (n = 7), isoproterenol (n = 6), a nonselective agonist, 8-bromo-cAMP (n = 6), and a combination of isoproterenol and ICI-118551 (n = 8), a selective beta2-receptor antagonist, or isoproterenol and CGP-20712A, a beta1-selective antagonist (n = 7). In all groups the ensemble-average current and the availability of the channels to open on depolarization were increased in a similar fashion. In addition, the open probability (Po) within active sweeps was elevated. However, zinterol exerted this effect in a unique manner. It elevated Po not by shortening closed times but solely by reducing active sweeps with very low Po and a short burst duration. All zinterol effects were abolished by ICI-118551 (n = 5) and mimicked by isoproterenol plus CGP-20712A (n = 7). We conclude that beta2-adrenoceptor activation of L-type channels differs qualitatively from the classical cAMP-dependent mechanism.
Adrenergic beta-Agonists↗
Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle.
BACKGROUND: The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings. METHODS AND RESULTS: We investigated the properties of L-type calcium channels in left ventricular myocytes isolated from nonfailing donor hearts (n= 16 cells) or failing hearts of transplant recipients with dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel recording technique was used (70 mmol/L Ba2+). Peak average currents were significantly enhanced in heart failure (38.2+/-9.3 fA) versus nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation of channel availability (55.9+/-6.7% versus 26.4+/-5.3%, P=0.001) and open probability within active sweeps (7.36+/-1.51% versus 3.18+/-1.33%, P=0.04). These differences closely resembled the effects of a cAMP-dependent stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow gating shows that channels from failing hearts remain available for a longer time, suggesting a defect in the dephosphorylation. Indeed, the phosphatase inhibitor okadaic acid was unable to stimulate channel activity in myocytes from failing hearts (n=5). Expression of calcium channel subunits was measured by Northern blot analysis. Expression of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements did not reveal an increase of current density in heart failure. CONCLUSIONS: Individual L-type calcium channels are fundamentally affected in severe human heart failure. This is probably important for the impairment of cardiac excitation-contraction coupling.
8-Bromo Cyclic Adenosine Monophosphate↗
Mirasorvone: a masked 20-ketopregnane from the defensive secretion of a diving beetle (Thermonectus marmoratus).
The sunburst diving beetle, Thermonectus marmoratus, ejects a milky fluid from its prothoracic defensive glands when disturbed. Two major volatile components of this secretion are steroids; cybisterone (structure 7) constitutes about 20% of the volatiles, and a new steroid, mirasorvone, about 50%. Mirasorvone is assigned an 18-oxygenated pregnane structure (structure 9) on the basis of extensive spectroscopic data. Although no 18-oxygenated steroid has been described previously from an insect source, a closely related hormone with mineralocorticoid activity, 18-hydroxydeoxycorticosterone (structure 13), has been isolated from the adrenal glands of rats.
Animals↗
[Cyclosporine].
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Bone Marrow Transplantation↗
Single-channel properties of L-type calcium channels from failing human ventricle.
OBJECTIVE: The aim of our study was to analyse the single-channel properties of L-type calcium channels from failing human heart and to compare them to the respective animal data. Furthermore, we intended to evaluate the feasibility of future single-channel studies on the role of calcium channels in the pathophysiology of heart failure. METHODS: Single L-type calcium channels were recorded in ventricular myocytes from explanted failing human heart, using the cell-attached configuration of the patch-clamp technique. RESULTS: One or more successful registrations of calcium channels could be obtained in 11 of 19 cell isolations. Determination of single-channel conductance yielded a mean value of 16.6 +/- 1.2 pS (70 mM Ba2+ as the charge carrier) under control conditions and 23.7 +/- 2.8 pS in presence of the calcium-channel agonist FPL 64176. The rapid gating process could be described by a C<-->C<-->O gating scheme. Slow gating analysis revealed a highly significant clustering of active and non-active sweeps. CONCLUSION: Single-channel measurements of L-type calcium channels in human failing ventricle are feasible and reproducible despite the varying patient characteristics. Their channel properties are qualitatively comparable to those found in other mammals. Whether there are quantitative differences due to the underlying heart failure can be elucidated in further studies.
Adult↗
[Asymptomatic cerebral aneurysms--surgical and endovascular therapy options].
Aneurysmal subarachnoid hemorrhage carries a risk of 50% mortality. Therefore it is recommended to also treat asymptomatic, previously unruptured aneurysms. Deciding whether to treat or to observe depends on the consideration of risk of hemorrhage and the surgical risk. Such decision could be facilitated if predisposing factors affecting the outcome were known. 15 Patients with 19 unruptured aneurysms managed in a period when both, surgical and endovascular treatment options were available, were selected from a group of 47 asymptomatic patients documented since 1984. The patients were either operated (n = 9) or were treated by endovascular occlusion with GDC coils (n = 6). In most cases, a long history of headaches eventually lead to a CT-scan or MRI in which a suspicious abnormality was found. Upon subsequent angiography, 8 middle cerebral, 6 carotid, 3 basilar and 1 pericallosal, and ophthalmic artery aneurysm(s), respectively, were found. The aneurysms varied from 4 to 30 mm in diameter. The patients were followed between 9 months and 2.5 years. Treatment results in this small series were independent from size, location, age or sex of the patient. The initial, mostly unrelated symptoms persisted after treatment in most cases. The morbidity according to GOS in this small series (3 out of 19 patients deteriorated) is not representative of the complete series where morbidity and mortality was 5.4% and 1.2% respectively). In agreement with the literature reviewed herein, we recommend surgical treatment of previously unruptured aneurysms, especially when the patients are below 60 years of age. In patients with posterior circulation aneurysms, endovascular coil occlusion is a valid alternative, especially in older patients with concurrent medical problems.
Adult↗
Migration of human glioma cells in response to tumour cyst fluids.
Glial tumours often show high degrees of local invasion that lead to local recurrence of the disease. Extracellular matrix components as well as soluble factors may play a critical role in this poorly understood process. Cyst fluid from human brain tumours may accumulate such autocrine produced factors and may represent a source were those factors may be easily obtained and studied. We have studied the effect of cyst fluids harvested from 17 glial tumours, 3 meningiomas, and three metastases on the motility of established human glioma cell lines. Both cyst fluids of high grade and low grade gliomas contained varying degrees of motility enhancing activity. No such activity was identified in cyst fluids obtained from meningiomas. The relation of mitogenic and motogenic activity in three selected cyst fluids was analysed using a quantitative monolayer migration assay. Quantitative analysis of cyst fluid effects on both proliferation and migration indicate that tumour cyst fluids contain factors that strongly stimulate cell migration and that maximum stimulation of migration did not occur at concentrations optimal for cell proliferation. Our findings indicate that glial tumours in fact produce and secrete soluble factors that may contribute to their dissemination in brain tissue.
Adult↗
Double-lung transplantation in the rat: an acute, syngeneic in situ model.
BACKGROUND: The high rate of reperfusion injury in clinical lung transplantation mandates significant improvements in lung preservation. Innovations should be validated using standardized and low-cost experimental models. METHODS: The model introduced here is analyzed by comparing global lung function after varying ischemic times (2, 4, 8, 16, and 24 hours). A rat double-lung block is flush-perfused, and the main pulmonary artery and left atrium are connected to the left pulmonary artery and vein of a syngeneic recipient using a T-shaped stent. With pressure side ports and incorporated flow crystals, measurement of vascular resistance and graft oxygenation can be performed. The transplant is ventilated separately, and compliance and resistance are determined. RESULTS: The increase in the ischemic interval from 2 to 24 hours caused an increase in the alveolar arterial oxygen difference from 220 +/- 20 to 600 +/- 34 mm Hg, pulmonary vascular resistance from 198 +/- 76 to 638 +/- 212 mm Hg.mL-1.min-1, and resistance to airflow from 274 +/- 50 to 712 +/- 30 cm H2O/L H2O, and a decrease in pulmonary compliance from 0.4 +/- 0.05 to 0.12 +/- 0.06 mL/cm H2O. CONCLUSIONS: This in situ, syngeneic rat lung transplantation model offers an alternative to large animal models for verification of lung preservation solutions and for modification of donor or recipient treatment regimens.
Airway Resistance↗
Identification and synthesis of new bicyclic acetals from the mountain pine beetle, Dendroctonus ponderosae Hopkins (Col.: Scol.).
Head-space volatiles obtained from male mountain pine beetles, Dendroctonus ponderosae, were analyzed by coupled GC-MS and chiral gas chromatography. 5-Ethyl-7-methyl-6,8-dioxabicyclo[3.2.1]octane (6) was found as a new naturally occurring isomer of brevicomin (1). In addition, several stereoisomers of 7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octan-2-ol (11) and 1-(5-methyl-6,8-dioxabicyclo[3.2.1]octyl)ethanol (12) could be identified. Relative and absolute configurations of the compounds were determined by unambiguous syntheses, which are described.
Animals↗
Successful application of high dose intravenous immunoglobulins in Sjögren's syndrome associated arthritis.
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Adult↗