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34 results on '"Geiger, Klaus K"'

5. Regulation of hepatic blood flow during resuscitation from hemorrhagic shock: role of NO and endothelins

Author

Pannen, Benedikt H.J., Bauer, Michael, Noldge-Schomburg, Gabriele F.E., Zhang, JIan X., Robotham, James L., Clemens, Mark G., and Geiger, Klaus K.

Subjects
Nitric oxide -- Physiological aspects, Regional blood flow -- Physiological aspects, Hemorrhagic shock -- Physiological aspects, Endothelin -- Physiological aspects, Hepatic artery -- Physiological aspects, Biological sciences
Abstract

The role of nitric oxide (NO) and endothelins (ETs) in the regulation of hepatic blood flow was analyzed in anesthetized rats during resuscitation from hemorrhagic shock (HS). Nitric oxide synthase inhibition by Nomega-nitro-L-arginine (L-NAME) in anesthetized rats elevated mean arterial pressure and systemic vascular resistance during resuscitation. However, NO- and HS-mediated vasodilation reduced SVR and preserved hepatic blood flow in anesthetized rats.

Published
1997

9. Hemorrhagic shock primes the hepatic portal circulation for the vasoconstrictive effects of endothelin-1

Author

PANNEN, BENEDIKT H. J., SCHROLL, STEPHAN, LOOP, TORSTEN, BAUER, MICHAEL, HOETZEL, ALEXANDER, and GEIGER, KLAUS K.

Subjects
Vasoconstrictors -- Physiological aspects, Cardiovascular receptors -- Physiological aspects, Microcirculation -- Physiological aspects, Hemorrhagic shock -- Physiological aspects, Biological sciences
Abstract

To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential [ET.sub.A] receptor agonist ET-1 and of the selective [ET.sub.B] receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 x [10.sup.-9] M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 x [10.sup.-9] M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the [ET.sub.B] receptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1. endothelin receptors; microcirculation; portal vein; pressure-flow relationship; sarafotoxin 6c

Published
2001

11. Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Author

Schwer, Christian I., primary, Guerrero, Aida M., additional, Humar, Matjaz, additional, Roesslein, Martin, additional, Goebel, Ulrich, additional, Stoll, Patrick, additional, Geiger, Klaus K., additional, Pannen, Benedikt H. J., additional, Hoetzel, Alexander, additional, and Schmidt, Rene, additional

Published
2008
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12. Carbon Monoxide Inhalation Reduces Pulmonary Inflammatory Response during Cardiopulmonary Bypass in Pigs

Author

Goebel, Ulrich, primary, Siepe, Matthias, additional, Mecklenburg, Anne, additional, Stein, Phillip, additional, Roesslein, Martin, additional, Schwer, Christian I., additional, Schmidt, Rene, additional, Doenst, Torsten, additional, Geiger, Klaus K., additional, Pahl, Heike L., additional, Schlensak, Christian, additional, and Loop, Torsten, additional

Published
2008
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15. Thionamides Inhibit the Transcription Factor Nuclear Factor-κB by Suppression of Rac1 and Inhibitor of κB Kinase α

Author

Humar, Matjaz, primary, Dohrmann, Hannah, additional, Stein, Philipp, additional, Andriopoulos, Nikolaos, additional, Goebel, Ulrich, additional, Roesslein, Martin, additional, Schmidt, Rene, additional, Schwer, Christian I., additional, Loop, Torsten, additional, Geiger, Klaus K., additional, Pahl, Heike L., additional, and Pannen, Benedikt H.J., additional

Published
2007
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16. Repression of T-Cell Function by Thionamides Is Mediated by Inhibition of the Activator Protein-1/Nuclear Factor of Activated T-Cells Pathway and Is Associated with a Common Structure

Author

Humar, Matjaz, primary, Dohrmann, Hannah, additional, Stein, Philipp, additional, Andriopoulos, Nikolaos, additional, Goebel, Ulrich, additional, Heimrich, Bernd, additional, Roesslein, Martin, additional, Schmidt, Rene, additional, Schwer, Christian I., additional, Hoetzel, Alexander, additional, Loop, Torsten, additional, Pahl, Heike L., additional, Geiger, Klaus K., additional, and Pannen, Benedikt H. J., additional

Published
2007
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20. Volatile Anesthetics Induce Caspase-dependent, Mitochondria-mediated Apoptosis in Human T Lymphocytes In Vitro

Author

Loop, Torsten, primary, Dovi-Akue, David, additional, Frick, Michael, additional, Roesslein, Martin, additional, Egger, Lotti, additional, Humar, Matjaz, additional, Hoetzel, Alexander, additional, Schmidt, Rene, additional, Borner, Christoph, additional, Pahl, Heike L., additional, Geiger, Klaus K., additional, and Pannen, Benedikt H. J., additional

Published
2005
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22. Sevoflurane Inhibits Phorbol-Myristate-Acetate-induced Activator Protein-1 Activation in Human T Lymphocytes in Vitro : Potential Role of the p38-Stress Kinase Pathway

Author

Loop, Torsten, primary, Scheiermann, Patrick, additional, Doviakue, David, additional, Musshoff, Frank, additional, Humar, Matjaz, additional, Roesslein, Martin, additional, Hoetzel, Alexander, additional, Schmidt, Rene, additional, Madea, Burkhard, additional, Geiger, Klaus K., additional, Pahl, Heike L., additional, and Pannen, Benedikt H. J., additional

Published
2004
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23. Inhibition of Activator Protein 1 by Barbiturates Is Mediated by Differential Effects on Mitogen-Activated Protein Kinases and the Small G Proteins Ras and Rac-1

Author

Humar, Matjaz, primary, Andriopoulos, Nikolaos, additional, Pischke, Soeren E., additional, Loop, Torsten, additional, Schmidt, Rene, additional, Hoetzel, Alexander, additional, Roesslein, Martin, additional, Pahl, Heike L., additional, Geiger, Klaus K., additional, and Pannen, Benedikt H. J., additional

Published
2004
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32. Heterocyclic Thioureylenes Protect from Calcium-Dependent Neuronal Cell Death

Author

Humar, Matjaz, Graetz, Christine, Roesslein, Martin, Goebel, Ulrich, Geiger, Klaus K., Heimrich, Bernd, and Pannen, Benedikt H.J.

Abstract

Calcium-dependent cell death occurs in neurodegenerative diseases and ischemic or traumatic brain injury. We analyzed whether thioureylenes can act in a neuroprotective manner by pharmacological suppression of calcium-dependent pathological pathways. In human neuroblastoma (SK-N-SH) cells, thioureylenes (thiopental, carbimazole) inhibited the calcium-dependent neuronal protein phosphatase (PP)-2B, the activation of the proapoptotic transcription factor nuclear factor of activated T-cells, BAD-induced initiation of caspase-3, and poly-(ADP-ribose)-polymerase cleavage. Caspase-3-independent cell death was attenuated by carbimazole and the protein kinase C (PKC) δ inhibitor rottlerin by a PP-2B-independent mechanism. Neuroprotective effects were mediated by the redox-active sulfur of thioureylenes. Furthermore, we observed that the route of calcium mobilization was differentially linked to caspase-dependent or independent cell death and that BAD dephosphorylation did not necessarily induce intrinsic caspase activation. In addition, a new 30- to 35-kDa caspase-3 fragment with an unknown function was identified. In organotypic hippocampal slice cultures, thioureylenes inhibited caspase-3 activation or reduced N-methyl-d-aspartate and kainic acid receptor-mediated cell death that was independent of caspase-3. Because prolonged inhibition of caspase-3 resulted in caspase-independent cellular damage, different types of cell death must be taken under therapeutic consideration. Here we show that thioureylenes in combination with PKCδ inhibitors might represent a promising therapeutic approach to attenuate neuronal damage.

Published
2009
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33. Thionamides inhibit the transcription factor nuclear factor-kappaB by suppression of Rac1 and inhibitor of kappaB kinase alpha.

Author

Humar, Matjaz, Dohrmann, Hannah, Stein, Philipp, Andriopoulos, Nikolaos, Goebel, Ulrich, Roesslein, Martin, Schmidt, Rene, Schwer, Christian I, Loop, Torsten, Geiger, Klaus K, Pahl, Heike L, and Pannen, Benedikt H J

Abstract

Thionamides, inhibitors of the thyroid peroxidase-mediated iodination, are clinically used in the treatment of hyperthyroidism. However, the use of antithyroid drugs is associated with immunomodulatory effects, and recent studies with thionamide-related heterocyclic thioderivates demonstrated direct anti-inflammatory and immunosuppressive properties. Using primary human T-lymphocytes, we show that the heterocyclic thionamides carbimazole and propylthiouracil inhibit synthesis of the proinflammatory cytokines tumor necrosis factor (TNF)alpha and interferon (IFN)gamma. In addition, DNA binding of nuclear factor (NF)-kappaB, a proinflammatory transcription factor that regulates both TNFalpha and IFNgamma synthesis, and NF-kappaB-dependent reporter gene expression were reduced. Abrogation of NF-kappaB activity was accompanied by reduced phosphorylation and proteolytic degradation of inhibitor of kappaB (IkappaB)alpha, the inhibitory subunit of the NF-kappaB complex. Carbimazole inhibited NF-kappaB via the small GTPase Rac-1, whereas propylthiouracil inhibited the phosphorylation of IkappaBalpha by its kinase inhibitor of kappaB kinase alpha. Methimazole had no effect on NF-kappaB induction, demonstrating that drug potency correlated with the chemical reactivity of the thionamide-associated sulfur group. Taken together, our data demonstrate that thioureylenes with a common, heterocyclic structure inhibit inflammation and immune function via the NF-kappaB pathway. Our results may explain the observed remission of proinflammatory diseases upon antithyroid therapy in hyperthyroid patients. The use of related thioureylenes may provide a new therapeutic basis for the development and application of anti-inflammatory compounds.

Published
2008
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34. Dobutamine inhibits phorbol-myristate-acetate-induced activation of nuclear factor-kappaB in human T lymphocytes in vitro.

Author

Loop T, Bross T, Humar M, Hoetzel A, Schmidt R, Pahl HL, Geiger KK, and Pannen BHJ

Subjects
Adrenergic Agents pharmacology, CD3 Complex metabolism, Cell Nucleus drug effects, Cell Nucleus metabolism, Clenbuterol pharmacology, DNA metabolism, Electrophoretic Mobility Shift Assay, Humans, Jurkat Cells, NF-kappa B genetics, Receptors, Adrenergic, alpha drug effects, T-Lymphocytes drug effects, Xamoterol pharmacology, Adrenergic beta-Agonists pharmacology, Anti-Inflammatory Agents, Dobutamine pharmacology, NF-kappa B antagonists & inhibitors, NF-kappa B metabolism, T-Lymphocytes metabolism, Tetradecanoylphorbol Acetate pharmacology
Abstract

Adrenergic drugs are often used for hemodynamic support of cardiac output and vasomotor tone in critically ill patients. Recent evidence shows that the administration of these vasoactive drugs may affect cytokine release and could influence the inflammatory response. However, the mechanism of this immunomodulatory effect remains unknown. The nuclear transcription factor-kappaB (NF-kappaB) regulates the expression of many cytokines and plays a central role in the immune response. Therefore, we examined the effects of various adrenergic drugs (dobutamine, xamoterol, clenbuterol, epinephrine, norepinephrine, and phenylephrine) on the activation of NF-kappaB, on the NF-kappaB-driven reporter gene activity, and on the expression of the NF-kappaB target gene interleukin (IL)-8. In addition, we quantified the amount of the NF-kappaB inhibitors IkappaBalpha and IL-10. Here we report that dobutamine inhibited the activation of NF-kappaB in primary human CD3(+) T lymphocytes. Suppression of NF-kappaB involved the stabilization of its inhibitor, IkappaBalpha. The effect appears to be beta(2)-receptor specific, because beta(1)-adrenergic and alpha-adrenergic substances (i.e., xamoterol, epinephrine, norepinephrine, and phenylephrine) did not affect NF-kappaB activation and because dobutamine-mediated inhibition of NF-kappaB could be prevented by a specific beta(2)-antagonist. Our results demonstrate that dobutamine is a potent and specific inhibitor of NF-kappaB, and they thus provide a possible molecular mechanism for the immunomodulation associated with beta-adrenergic therapy.

Published
2004
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