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Deutsche Gesellschaft Für Experimentelle Und Klinische Pharmakologie Und Toxikologie E.V Naunyn-Schmiedeberg´s Arch Pharmacol (2013 ) 386 (Suppl 1):S1–S104 D OI 10.1007/s00210-013-0832-9 Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie e.V. Abstracts of the 79 th Annual Meeting March 5 – 7, 2013 Halle/Saale, Germany This supplement was not sponsored by outside commercial interests. It was funded entirely by the publisher. 123 S2 S3 001 003 Multitarget approach in the treatment of gastroesophagel reflux disease – Nucleoside Diphosphate Kinase B is a Novel Receptor-independent Activator of comparison of a proton-pump inhibitor with STW 5 G-protein Signaling in Clinical and Experimental Atrial Fibrillation Abdel-Aziz H.1,2, Khayyal M. T.3, Kelber O.2, Weiser D.2, Ulrich-Merzenich G.4 Abu-Taha I.1, Voigt N.1, Nattel S.2, Wieland T.3, Dobrev D.1 1Inst. of Pharmaceutical & Medicinal Chemistry, University of Münster Pharmacology, 1Universität Duisburg-Essen Institut für Pharmakologie, Hufelandstr. 55, 45122 Essen, Hittorfstr 58-62, 48149 Münster, Germany Germany 2Steigerwald Arzneimittelwerk Wissenschaft, Havelstr 5, 64295 Darmstadt, Germany 2McGill University Montreal Heart Institute, 3655 Promenade Sir-William-Osler, Montréal 3Faculty of Pharmacy, Cairo University Pharmacology, Cairo Egypt Québec H3G 1Y6, Canada 4Medizinische Poliklinik, University of Bonn, Wilhelmstr. 35-37, 53111 Bonn, Germany 3Medizinische Fakultät Mannheim der Universität Heidelberg Institutes für Experimentelle und Klinische Pharmakologie und Toxikologie, Maybachstr. 14, 68169 Gastroesophageal reflux disease (GERD) was the most common GI-diagnosis (8.9 Mannheim, Germany million visits) in the US in 2012 (1). Proton pump inhibitors (PPI) are presently the mainstay of therapy, but in up to 40% of the patients complete symptom control fails. Background: Chronic atrial fibrillation (cAF) is associated with abnormal atrial Ca2+ and STW5 was shown to relief coconcomitant reflux symptoms in patients with functional protein-kinase signaling, with G-protein related, cyclic AMP (cAMP)-mediated protein dyspepsia (2) and to prevent inflammation in an acute model of GERD without affecting kinase A hyperphosphorylation playing a significant role. Nucleoside diphosphate kinase the pH of the refluxate (3). In the present study, the efficacy of STW5 compared to B (NDPK-B) increases ventricular cAMP levels through receptor-independent Gs-protein omeprazole was assessed in a sub-chronic model of GERD. Rats were pre-treated for activation involving direct Gs-protein β-subunit interaction/phosphorylation. Here, we 7d either with STW5 (0.5 or 2 ml) or omeprazole (as reference drug). Esophagitis was assessed NDPK-B expression and Gs-protein signaling in atria from sinus rhythm (SR) induced surgically. Rats were treated for a further 10d with STW5 or omeprazole and vs cAF patients, in canine atria with atrial tachycardia remodeling (ATR), and in isolated sacrificed. The esophagi of the 5 groups (STW5, omeprazole, Sham, Control) were canine atrial myocytes. excised and evaluated. Both treatments improved macroscopic parameters to a similar Methods: NDPK-B and G-protein expression was assessed in atria from 23 SR and 23 extent. Proteom-profiling of the tissue homogenates revealed a stronger and dose- cAF patients, in atria from 7 control (Ctl) and 7 ATR (1-wk at 400 bpm) canines and in dependent down-regulation of proinflammatory parameters like IL-1ß, thymuschemokine isolated canine atrial myocytes paced at 1-Hz (P1) and 3-Hz (P3) by immunoblotting. or Cinc2 in the STW5 groups compared to omeprazole. Agilent whole genome cAMP levels were measured by immunoassay. microarrays of tissue and blood samples supported these findings (downregulation of Results: NDPK-B was robustly expressed in atria from both canines and patients. In IL1, IL1r, IL6r, IL-17, VCAM-1). In addition both, STW5 and omeprazole, strongly cAF patients, the protein levels of NDPK-B were increased by 96%* (cAF, 1.96±0.23*- modulated cerulosporin (CP; 63, 62 fold), prostacyclin synthase 1 (PS1; 51, 62fold) and fold n=7 vs SR, 1.0±0.13-fold n=6; *P<0.05) and this was accompanied by 80%* CD163 (58, 54 fold). increases in both Gαs and Gβ1 proteins. Protein levels of Gαi2, Gαi3 and Gβ2 were Gastric acid appears to be not the only causative agent in GERD. Since CP, PS1 and unchanged. Similarly, protein abundances of NDPK-B (increased by 161%*), Gαs (by CD163 are recently discovered inflammatory and immune-modulators they may 45%*) and Gβ1 (by 120%*) were higher in ATR than in Ctl, whereas Gαi2 and Gαi3 were represent novel therapeutic targets of the inflammatory processes in GERD. The present unaltered. NDPK-B (by 81%*) and Gαs (by 62%*) protein levels were higher in P3 findings might pave the way for the clinical use of multi-target anti-inflammatory agents compared to P1 myocytes. In addition cAMP content was higher in P3 than in P1 atrial like STW 5 in the treatment of GERD, especially in patients not adequately controlled by myocytes (P3, 39.0±4.7*, n=6 vs P1, 56.1±7.8, n=6 pmol/mg). In cAF, Gβ1 PPIs. immunoprecipitation resulted in enhanced co-immunoprecipitation of NDPK-B and immunoprecipitation of NDPK-B yielded in increased Gβ1 co-immunoprecipitation, 1- Perry, et al. Gastroenterology 2012; 143:1179-1187 pointing to augmented complex formation between NDPK-B and Gβ1 in cAF patients. 2- Gundermann, et al. Adv Ther 2003; 20:43–49 cAMP content was higher in cAF than in SR (cAF, 20.2±1.8*, n=16 vs SR, 13.1±0.9, 3- Abdel-Aziz, et al. J Pharmacol Sci 2010; 113:134-42 n=16 pmol/mg), indicating an increase in receptor-independent Gs activation and thus cAMP formation in cAF. Conclusion: NDPK-B is expressed in human and canine atria, is upregulated in both clinical and experimental AF, and enhances Gs and cAMP signaling. NDPK-B may constitute a novel pathway for abnormal atrial G-protein/cAMP signaling, with potentially important implications for AF pathophysiology. 002 Peak levels of cyanide after consumption of foods containing cyanogenic glycosides: A cross-over study on bioavailability in humans Abraham K., Buhrke T., Lampen A. 004 Bundesinstitut für Risikobewertung Abt. Lebensmittelsicherheit, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany Phosphorylation-dependent receptor memory of the human β1-adrenergic Background: The toxicity of cyanide after its release from cyanogenic glycosides in receptor 1 2 1 1 3 1,4 plants eaten as food (e.g. bitter almonds) is well-known. However, in terms of risk Ahles A. , Rochais F. , Hinz L. , Rodewald F. , Bünemann M. , Engelhardt S. assessment, data is missing on the velocity of surge of cyanide levels in blood: In this 1Technische Universität München Institut für Pharmakologie und Toxikologie, special case of peracute toxicity, for a given dose, this surge determines the resulting Biedersteiner Straße 29, 80802 München, Germany peak levels and therefore the risk of toxic effects. In humans, clinical data of cyanide 2Universität Würzburg Rudolf-Virchow-Zentrum / DFG-Forschungszentrum für levels is available, but its use in risk assessment is an overly conservative approach, as Experimentelle Biomedizin, Josef-Schneider-Str. 2, Haus D15, 97080 Würzburg, the surge of cyanide after ingestion of inorganic salts is very rapid. In case of foods with Germany cyanogenic glycosides, especially the velocity of the release of cyanide and the duration 3Philipps-Universtität Marburg Institut für Pharmakologie und Klinische Pharmazie, Karl- of the digestion processes are expected to cause a delay of this surge, leading to lower von-Frisch-Straße 1, 35032 Marburg, Germany toxicity of the same dose. 4DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung) Standort Munich Heart Study design: Cross-over study in healthy adults (n=12), consumption of persipan (100 Alliance, Biedersteiner Straße 29, 80802 München, Germany and 200 g, equivalent total cyanide: 68 mg/kg), linseed (30.9 g, cyanide: 220 mg/kg) and bitter apricot kernels (6 pieces, about 2.1 g, cyanide about 3200 mg/kg). Measurements Signaling properties of G protein-coupled receptors are affected by receptor of cyanide in whole blood (at least n=15 points of time), using a GC/MS method with polymorphisms, yet the molecular basis for the functional differences of individual K13C15N as internal standard. receptor variants is poorly understood. Recent structural data suggest that the frequent Results: Mean peak levels of cyanide were highest after consumption of bitter apricot Arg389Gly polymorphism in the proximal carboxy terminus of the human β1-adrenergic kernels (14.2 µM, after 20 min, n=10), followed by linseed (5.7 µM, after 40 min) and receptor (β1AR) presumably affects the stability of the receptor protein by specific 100 g persipan (1.3 µM, after 105 min). All these “meals” contained equivalents of about interaction of arginine (but not glycine) with transmembrane helix 1. 6.8 mg cyanide. The double dose eaten with 200 g persipan resulted in a mean peak To investigate a possible impact of the Arg389Gly polymorphism on receptor level of 2.9 µM (after 150 min). Interindividual variability was considerable; critical conformation we developed fluorescence resonance energy transfer (FRET)-based cyanide levels above 20 µM (maximum: 22.5 µM) were reached in a few individuals after sensors for the β1AR-variants at position 389. These sensors retained the consumption of bitter apricot kernels. pharmacological and functional characteristics of the native receptors. Upon stimulation Conclusion: In case of foods containing cyanogenic glycosides, not only the dose, but of the sensors we determined
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