38. HYPERTONIE UND PRAVENTION HYPERTONIE UND PRÄVENTION

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1 Hochdruckliga Associated to HYPERTONIE UND PRAVENTION HYPERTONIE UND PRÄVENTION BERLIN Wissenschaftlicher Kongress der Deutschen Hochdruckliga e.v. DHL - Deutschen Gesellschaft für Hypertonie und Prävention in Berlin Dezember 2014 Abstractband

2 [1] 1 Freie Vorträge Freie Vorträge mit Minilecture FV01 Fettverteilung und erhöhter Blutdruck bei Kindern und Jugendlichen aus der PEP Family Hear Study G. Haas 1, T. Bertsch 2, P. Schwandt 3, J. Scholze 4 1 Arteriosklerose-Präventions-Institut, PEP Family Heart Study, München, Deutschland; 2 Klinikum Nürnberg, Inst. für Klinische Chemie, Transfusionsmedizin, Zentrallabor, Nürnberg, Deutschland; 3 Arteriosklerose- Praeventionsinstitut München-Nürnberg, München, Deutschland; 4 Charité - Universitätsmedizin Berlin, Campus Mitte, Medizinische Poliklinik, Berlin, Deutschland FRAGESTELLUNG: Weil Körperfett (BF) in Form der abdominalen Adipositas als stärkerer Prädiktor als generelle Adipositas (body mass index BMI) für kardiovaskuläre Erkrankungen eingeschätzt wird und der BMI auch die Muskel- und Knochenmasse mit erfasst, untersuchten wir bei einer großen Kohorte von Kindern und Heranwachsenden, ob die Körperfettverteilung einhergeht mit Bluthochdruck. MATERIAL UND METHODIK: Nachdem es billig und risikofrei ist, mittels Tallenumfang (WC) und Taillen/Größe-Quotient (WHtR) die abdominale Adipositas und durch Messung der Hautfaltendicke (SFT) geschlechts- und altersabhängige Grenzwerte für Körperfettanteil (BF%) zu errechnen, konnten wir für Kinder und für Jugendliche von 3-18 Jahren den Zusammenhang zwischen Blutdruck und Körperfett errechnen. Dazu wurde SPSS in der Version 18 benutzt. Die statistische Signifikanz wurde mit p<0.05 und für logistische Regressionsmodelle mit p<0.001 bestimmt. ERGEBNISSE: Anthropometrische Charakteristika ergaben bei Kindern kaum Geschlechtsunterschiede, bei den Jugendliche dagegen für Mädchen geringeren Taillenumfang (WC), Taille/Größe-Quotient (WHtR) als Anzeichen abdomineller Adipositas und niedrigere Blutdruckwerte, jedoch signifikant mehr subkutanes Fett als bei männlichen Jugendlichen. Die Prävalenz von Übergewicht, genereller Adipositas, erhöhtem Taillenumfang, Prähypertonie und Hypertonie war vergleichbar bei Kindern und bei Jugendlichen. Die Prävalenz manifester Hypertonie erhöhte sich von normalgewichtigen über übergewichtigen zu adipösen von 5.7% via 10.4% bis zu 18.6% bei Buben und von 5% via 9.1% auf 24.4% in bei Mädchen. Verglichen mit normalgewichtigen war das Prähypertonierisiko von übergewichtigen Buben und Mädchen (OR 1.6 respektive OR 1.8) und bei adipösen (OR 2.4 und OR 3.3). Die stärksten Bezie-hungen zwischen Bluthochdruck und ungünstiger Fettverteilung (Mädchen/Buben), zwischen fanden wir bei BMI >95 th (OR 5.9/ 4.3), SFT Summe >35 cm (OR 5.8/4.6), %BF >95 th (OR 5.6/ 3.4) WHtR >0.5 (OR 3.9/3.8), WC >90 th (OR 3.5/3.1), BMI 85 th - 95 th (OR 2.7/2.1) und %BF 85 th -95 th (OR 2.0, 1.8). SCHLUSSFOLGERUNG: Im Gegensatz zu Erwachsenen scheint bei Jugendlichen die generelle Adipositas ein noch stärkerer Prädiktor für Hypertonie zu sein als die abdominale Adipositas; wobei die Kombination mit vermehrtem Körperfettanteil das stärkste Risiko ausmacht. FV02 The prothrombotic risk of patients with type II diabetes in stable and unstable coronary artery disease M. Berger 1, K. Lysaja 2, M. Lehrke 3, N. Marx 4, K. Heß 5 1 Uniklinik RWTH Aachen, Medizinische Klinik 1, Aachen, Deutschland; 2 Medizinische Klinik I, Aachen, Deutschland; 3 Universitätsklinikum Aachen, Medizinische Klinik I, Aachen, Deutschland; 4 Uniklinik RWTH Aachen, Klinik für Kardiologie, Pneumologie, Angiologie und Internistische Intensivmedizin (Med. Klinik I), Aachen, Deutschland; 5 Uniklinik RWTH Aachen, Klinik für Kardiologie, Pneumologie, Angiologie und Internistische Intensivmedizin, Arbeitsgruppe - Grundlagenforschung, Aachen, Deutschland Background: Diabetes mellitus is associated with increased cardiovascular risk and fibrin clot lysis is a critical factor determing predisposition to atherothrombotic disease. A previous study demonstrated prolonged clot lysis in acute coronary syndrome. However, it is unknown if this holds true in patients with diabetes and whether patient characteristics or medication have any impact in patients with and

3 [2] without diabetes. Therefore, the present study investigates clot lysis in stable and unstable coronary artery disease (SCAD and UCAD respectively) in patients with and without diabetes. Methods and results: Fibrin clot lysis was determined by validated turbidimetric assay in 150 patients, 96 without diabetes (SCAD n=25, UCAD n=23, without CAD n=48) and 54 with diabetes (SCAD n=25, UCAD n=20, without CAD n=9). UCAD was defined as either non-st elevation myocardial infarction with elevated troponin > 50pg/mL or ST elevation myocardial infarction. Clot lysis time data were corrected by a multivariate analysis for potential confounding factors including medication and patient characteristics (sex, age, BMI, height, weight). Clot lysis was significantly increased in UCAD compared to SCAD in patients without diabetes (1422±688 sec and 841±400 sec respectively; p<0.01). Using a multivariate analysis including SCAD/UCAD, anti-fibrinolytic proteins and medication, UCAD was the strongest predictor of clot lysis time in patients without diabetes (p < 0.001). Interestingly, in patients with DM clot lysis was not significantly different between SCAD and UCAD (1368±739 sec and 1365±695 sec respectively; p=0.79). SCAD patients with diabetes exhibited a significantly longer clot lysis compared to SCAD patients without diabetes (1422±688 sec and 841±500 sec respectively; p<0.01). In addition, stable patients with diabetes had a similar clot lysis time compared to patients without diabetes but UCAD (1368±739 sec and 1422±688 sec; p=0.74). Using a multivariate analysis including SCAD/UCAD, medication and antifibrinolytic proteins, a significant prediction was found for PAI-1 (p = 0.03) and statine therapy (p = 0.017). Neither UCAD nor anti-platelet or anti-coagulation was associated with clot lysis time. Similarly, patient characteristics had no influence on clot lysis time in patients with diabetes. Conclusion: In unstable coronary artery disease clot lysis time is increased in patients without diabetes. In addition, in patients with diabetes clot lysis time is no further elevated in the unstable situation. However, in diabetic patients with SCAD clot lysis is already as impaired as in non-diabetic patients with UCAD. This effect is partially explained by PAI-1 plasma levels. Interestingly, in both groups neither anti-platelet therapy nor anti-coagulation did influence clot lysis time suggesting other mechanism to be involved. FV03 Uric acid, hypertension and cardiovascular events - A Mendelian randomisation study M. Kleber 1, G. Delgado 1, T. Grammer 1, G. Silbernagel 2, J. Huang 3, B. Krämer 1, E. Ritz 4, W. März 5 1 Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Deutschland; 2 Department of Angiology, Swiss Cardiovascular Center, Inselspital, University of Bern, Bern, Schweiz; 3 Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; 4 Department of Medicine, Division of Nephrology, University Hospital Heidelberg, Heidelberg, Deutschland; 5 Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, and 5Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, and Synlab Academy, Synlab Services GmbH, Mannheim, Mannheim / Graz, Deutschland Background: Obesity and diet rich in uric acid raising components have been implicated in the high prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension and cardiovascular disease are also increasing. We used Mendelian Randomization to examine whether uric acid represents an independent and causal risk factor for hypertension and cardiovascular events. Methods and results: Uric acid (UA) was measured in patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for UA concentration based on eight non-pleiotropic UA regulating single nucleotide polymorphisms. Causal odds ratios (COR) and causal hazard ratios (CHR) were calculated using a two-stage regression estimate with the GRS as instrumental variable to examine association with hypertension (cross-sectional) or mortality (prospectively) by logistic regression and Cox regression, respectively The GRS was not consistently associated with any biochemical marker except for UA. Uric acid was significantly associated with hypertension with an OR (95% CI) of 1.18 ( ) per 1 mg/dl increase in UA but the COR (95% CI) of 0.86 ( ) was not significant. Uric acid and GRS were both associated with cardiovascular death and sudden cardiac death. Causal hazard ratios were significant for cardiovascular death and sudden cardiac death in a multivariate adjusted model including hypertension and medication with HRs of 1.77 ( ) and 2.41 ( ), respectively, per 1 mg/dl increase in genetically predicted uric acid concentration. Conclusion: This Mendelian Randomization approach suggests that uric acid is not causally involved in hypertension but might play a causal role for adverse cardiovascular outcomes, especially sudden cardiac death.

4 [3] FV04 Hausärztliches Hypertonie-Management: Eine Cluster-randomisierte Studie zur Blutdruckkontrolle von Hypertonikern mit Folgeerkrankungen B. Weltermann 1, C. Kersting 2, A. Viehmann 2 1 Institut für Allgemeinmedizin, Universität Duisburg-Essen, Essen, Deutschland; 2 Institut für Allgemeinmedizin, Essen, Deutschland Hintergrund: In randomisiert-kontrollierten Studien wurden durch organisatorisch-strukturelle Maßnahmen wie Recall, die Kombination von nicht-pharmakologischen Maßnahmen und intensivierter Pharmakotherapie signifikante Steigerungen der Blutdruckkontrollraten nachgewiesen. Die vorliegende Analyse soll klären, welche Effekte ein hausärztliches Hypertonie-Management, das solche Elemente in der Regelversorgung anwendet, auf die Blutdruckkontrollrate von Hypertonikern mit kardiovaskulären Folgeerkrankungen und/oder Diabetes mellitus Typ 2 hat. Methode: In einer cluster-randomisierten Studie evaluieren wir die Effekte eines strukturierten Hypertonie-Managements im hausärztlichen Versorgungsalltag. Teilnehmende Praxen werden in eine Interventions- und eine Kontrollgruppe randomisiert. Jede Praxis schließt mindestens 5 Hypertoniker ein. Praxen des Interventionsarms erhalten eine dreiteilige Fortbildung über hausärztliches Hypertonie-Management inklusive Expertenkonsultationen, Fallbesprechungen und Umsetzungsstrategien für die Praxis. Daten werden zu Beginn und nach 9 Monaten erhoben. Prädiktoren auf die Blutdruckkontrolle im Follow-Up wurden mit binär logistischen Regressionen ermittelt. Ergebnisse: Von 142 der 179 Studienpatienten liegen vollständige Langzeitblutdruck- Dokumentationen zu Beginn und bei Follow-Up vor (79%). Von diesen Patienten haben 77 mindestens eine kardiovaskuläre Folgeerkrankung und/oder Diabetes mellitus Typ 2 (54%) und bilden die Analysepopulation. Das Durchschnittsalter beträgt 66,9 Jahre (SD: 13,1 Jahre), 53% sind männlich. Zu Beginn waren 21% der Patienten in der Langzeitblutdruckmessung kontrolliert (<130/80mmHg), bei Follow-Up 34%. Der mittlere Blutdruck betrug 142/79 mmhg zu Beginn und 137/77 mmhg bei Follow-Up. Die ersten Regressionsmodelle zeigen, dass Alter über 66 Jahre ein signifikanter Prädikator für das Erreichen des Blutdruckzielwerts bei Follow-Up war, während Geschlecht, Raucherstatus, Blutdruckselbstmessungen, Übergewicht und die Anzahl Wirkstoffe dies nicht signifikant beeinflussten. Perspektiven: Unsere Cluster-randomisierte Studie führte bei Hypertonikern mit kardiovaskukären Folgeerkrankungen und/oder Diabetes mellitus Typ 2 zu einer Steigerung der Blutdruckkontrollrate um 13% und einer Senkung des mittleren Blutdrucks. Es stehen weitere Analysen aus, um diesen Effekt nach Patienten- und Praxisfaktoren zu differenzieren. FV05 Obstructive respiratory events disturb ventricular repolarization in humans and in pigs by sympathetic dysbalance. D. Linz 1, A. Denner 1, S. Illing 1, M. Hohl 1, F. Mahfoud 1, K. Wirth 1, M. Böhm 1 1 Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Homburg / Saar, Deutschland Introduction: Obstructive sleep apnea (OSA) is associated with sudden cardiac death. Obstructive respiratory events, as occuring in OSA, are associated with negative intrathoracic pressure, which may disturb ventricular repolarization resulting in arrhythmias. Methods: In patients with OSA indices of ventricular repolarization (QT-intervals) and dispersion of repolarization (Tpeak to Tend (TpTe)) were determined during obstructive respiratory events. To identify mechanisms, repetitive tracheal occlusions with applied negative thorathic pressure (OSAmaneuver) were performed in a pig model for OSA before and after the application of atropine (n=7), atenolol (5) and sympathetic renal denervation (RDN, n=7). Results: In patients with OSA, obstructive respiratory events were always temporally associated with a prolongation of QT- as well as TpTe-intervals. In the pig model for OSA, 2 minutes of acute OSAmaneuver resulted in negative thoracic pressure, pronounced hypoxia and hypercapnia and pronounced postapneic blood pressure rises. This was associated with a prolongation in TpTe- (from 48.7±10.6 ms to 89.9±8.8 ms, p<0.01) and QT-interval (426.5±47.0 ms to 472.4±59.2 ms, p<0.01).

5 [4] These changes in ventricular repolarization could be inhibited by atenolol as well as by RDN and were not effected by parasympathetic blockade by atropine. Repetitive obstructive respiratory events over 3 hours caused a prolongation of QT-interval during normal breathing, and increased production of superoxide anions as well as gene expression of the oxidative stress sensitive profibrotic marker CTGF in left ventricular myocardium. Conclusion: Increased dispersion in ventricular repolarisation as well as prolongation of QT-intervals during obstructive respiratory events is mainly driven by sympathetic activation as it could be modulated by atenolol and RDN and may represent mechanisms for increased ventricular arrhythmias and sudden cardiac death in OSA. FV06 Sympathetic denervation depolarizes smooth muscle cell membrane potential and facilitates L- type-ca2+ channel activation in renal resistance arteries P. Heumann 1, A. Koenen 1, A. Steinbach 1, O. Zavaritskaya 2, R. Schubert 2, R. Rettig 1, O. Grisk 1 1 Physiologie, Universitätsmedizin Greifswald, Karlsburg, Deutschland; 2 Zentrum für Biomedizin und Medizintechnik Mannheim, Kardiovaskuläre Physiologie, Mannheim, Deutschland Objective: Sympathetic denervation causes norepinephrine (NE) supersensitivity in renal resistance arteries (RA) and increases their sensitivity to Rho kinase (Rock) inhibition and voltage-dependent L- type Ca 2+ channel blockade without affecting Rock and Cav1.2a1C mrna abundances. Rockdependent Ca 2+ sensitization and Ca 2+ entry mechanisms mutually interact in vascular smooth muscle cells (VSMCs). Therefore, we tested if sympathetic denervation enhances Rock activation or L-type Ca 2+ channel-dependent signaling including a depolarized VSMC resting potential in RA. Methods: Neonatal rats were sympathectomized or sham-treated. Isolated RA from adult rats were investigated by small vessel myography. Rock activation and L-Type Ca 2+ channel expression were studied by Western blot techniques. VSMC membrane potential was recorded in isolated RA. Results: RA from sympathectomized rats showed higher norepinephrine (NE) sensitivity than controls (pd2 6.61±0.16 vs. 6.10±0.09, respectively, p<0.05). Nifedipine significantly reduced pd2 for NE (5.89±0.09 vs. 5.76±0.07, n.s.), and Emax (-20%) in both groups. Additional Rock inhibition did not affect pd2 but reduced Emax for NE by further 20% in both groups. NE did not significantly increase phosphorylation of the Rock substrates ERM and MYPT1 in RA of both groups. There was no evidence for group differences in IP3- and RyR-dependent Ca 2+ release. While L-Type Ca 2+ channel protein expression was similar in RA of both groups, the L-type Ca 2+ channel activator S-(-)-BayK8644 contracted RA from sympathectomized but not from control rats. Rock inhibition or KATP channel activation blocked and depolarization enhanced S-(-)-BayK8644-induced contractions in RA from sympathectomized rats. Depolarization also gave rise to S-(-)-BayK8644-induced contractions in control RA. The membrane potential of RA VSMCs from sympathectomized rats was depolarized compared to controls (-57.5 ± 2.0 mv vs ± 0.3 mv, p < 0.01). Conclusion: Sympathetic denervation causes a depolarization of the VSMC resting potential in RA that facilitates L-type Ca 2+ channel activation and contributes to NE supersensitivity. Our data suggest that the sympathetic nervous system supports the activity of hyperpolarizing ion transport mechanisms in RA VSMCs. FV07 Deficiency of endothelial Cxcr4 reduces reendothelialization and enhances neointimal hyperplasia after vascular injury in atherosclerosis-prone mice H. Noels 1, B. Zhou 1, P. Tilstam 1, W. Theelen 1, X. Li 1, L. Pawig 1, C. Schmitz 2, S. Akhtar 1, S. Simsekyilmaz 1, E. Shagdarsuren 1, A. Schober 3, R. Adams 4, J. Bernhagen 2, E. Liehn 1, Y. Döring 3, C. Weber 3 1 RWTH Uniklinikum Aachen, Institute for Molecular Cardiovascular Research, Aachen, Deutschland; 2 RWTH Uniklinikum Aachen, Institute of Biochemistry and Molecular Cell Biology, Aachen, Deutschland; 3 Ludwig- Maximilians-University Munich, IPEK, München, Deutschland; 4 Max Planck Institute for Molecular Biomedicine, Münster, Deutschland

6 [5] Objective: The Cxcl12/Cxcr4 chemokine ligand/receptor axis mediates the mobilization of smooth muscle cell progenitors, driving injury-induced neointimal hyperplasia. This study aimed to investigate the role of endothelial Cxcr4 in neointima formation. Methods and Results: β-galactosidase staining using Bmx-CreER T2 reporter mice and double immunofluorescence revealed an efficient and endothelial-specific deletion of Cxcr4 in Bmx-CreER T2 + compared to Bmx-CreER T2 - Cxcr4-floxed Apoe -/- mice (referred to as Cxcr4 EC-WT ApoE -/- and Cxcr4 EC- KO ApoE -/-, respectively). Endothelial Cxcr4 deficiency significantly increased wire injury-induced neointima formation in carotid arteries from Cxcr4 EC-KO ApoE -/- mice. The lesions displayed a higher number of macrophages, whereas the smooth muscle cell and collagen content were reduced. This was associated with a significant reduction in reendothelialization and endothelial cell proliferation in injured Cxcr4 EC-KO ApoE -/- carotids compared to Cxcr4 EC-KO ApoE -/- controls. Furthermore, stimulation of human aortic endothelial cells with CXCL12 significantly enhanced their wound-healing capacity in an in vitro scratch assay, an effect that could be reversed with the CXCR4 antagonist AMD3100. Also, flow cytometric analysis showed a reduced mobilization of Sca1 + Flk1 + Cd31 + and of Lin - Sca1 + progenitors in Cxcr4 EC-KO ApoE -/- mice following vascular injury, although Cxcr4 surface expression was unaltered. No differences could be detected in plasma concentrations of Cxcl12, Vegf, S1P or Flt3- ligand, all cytokines with an established role in progenitor cell mobilization. Nonetheless, double immunofluorescence revealed a significant reduction in local endothelial Cxcl12 staining in injured carotids from Cxcr4 EC-KO ApoE -/- mice. Conclusion: Endothelial Cxcr4 is crucial for efficient reendothelialization following vascular injury through endothelial wound-healing and proliferation, and through the mobilization of Sca1 + Flk1 + Cd31 + cells, often referred to as circulating endothelial progenitor cells. FV08 TLR4 mediiert den Anstieg des systolischen Blutdruckes mit dem Alter - eine translationale Studie M. Baumann 1, S. Schneider 2, S. Kemmner 1, C. Aoqui 1, P. Hoppmann 2, S. Chmielewski 1, K. Laugwitz 2, A. Kastrati 2, U. Heemann 1 1 Kinikum rechts der Isar, Technische Universität München, Abt. für Nephrologie, München, Deutschland; 2 1. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, München, Deutschland Background: Systolic blood pressure (SBP) increases steadily with age. More than 50% of people aged 60+ are hypertensive. One suspected pathomechanism of SBP increase with age is aortic stiffness reflecting vascular aging. Oxidative stress contributes to aortic stiffness. An important regulator of oxidative stress is Toll-like receptor 4 (TLR4). We hypothesized that life-long TLR4 mediated oxidative stress increases aortic stiffness and contributes to SBP increase with age. Methods: We investigated adult (3-6 months of age) aged (9-12 months of age) and advance aged (15-18 months of age) male C57Bl/6j and TLR4 null-mice mice. We assessed SBP, aortic stiffness (aortic pulse wave velocity, apwv) and aortic oxidative burden with malondialdehyde (MDA) in aging. In a translational study we analyzed in a cohort of 2679 patients with myocardial infarction the effect of TLR4 896A/G single nucleotide polymorphism on SBP, pulse pressure and hypertension in dependency on age. Results: C57Bl/6j and TLR4 null-mice had in adulthood similar SBP, apwv and similar oxidative burden. During aging in C57Bl/6j mice SBP, apwv and MDA increased (15mmHg, 2m/s, 30%, respectively). Aged TLR4 null-mice did not show these changes. In the upper age tertile of the patient cohort (age >70 years), patients with a TLR4 896A/G single nucleotide polymorphism had lower SBP and pulse pressure (7mmHg) and less hypertension (79% versus 60%). The TLR4 SNP remained a significant predictor for SBP in univariate and multivariate regression analysis. Discussion: We propose that TLR4 signaling causes oxidative stress within the vascular wall and participates in SBP increase with age by inducing vascular aging.

7 [6] FV09 Identification of VEGF-R2 as dinucleoside polyphosphate generating enzyme V. Jankowski 1, M. van der Giet 2, W. Zidek 3, J. Jankowski 4 1 RWTH Aachen, IMCAR, Aachen, Deutschland; 2 Charite, Med. Klinik IV, Berlin, Deutschland; 3 Charité CBF - CC 10, Medizinische Klinik für Nephrologie, Berlin, Deutschland; 4 Institute for Cardiovascular Research, Aachen, Deutschland Recently, interest in uridine (5)-adenosine (5) tetraphosphate (Up4A) has increased after its identification some years ago [1]. Several lines of evidence strongly suggest that Up4A has a functional role in the cardiovascular system, including its vasoactive effects, plasma concentrations, and its release upon endothelial stimulation. Since physiologic and pathophysiologic effects as well as metabolism of Up4A have been studied in detail, the endogenous synthesis of Up4A has not been elucidated so far. Since endothelial cells released the dinucleoside polyphosphate Up4A, we tested cytosolic proteins of human endothelial cells obtained from dermal vessels elicited for enzymatic activity. When incubated with mononucleotides containing purine and pyrimidine base these cells showed increasing concentrations of Up4A. The underlying enzyme was isolated and identify by chromatography and the mass-spectrometric analysis revealed that the enzymatic activity was caused by the vascular endothelial growth factor receptor 2 (VEGFR2). The simultaneous biosynthesis of dinucleoside polyphosphates could amplify the response to VEGF, since dinucleoside polyphosphates induce cellular growth via P2Y purinergic receptors. Thus the biosynthesis of dinucleoside polyphosphates by VEGFR2 may enhance the proliferative response to VEGF. Given that VEGFR2 is primarily expressed in endothelial cells, the biosynthesis of Up4A is mainly located in the vascular system. Since the vasculature is also the main site of action of Up4A, activating vascular purinoceptors, blood vessels appear as an autocrine system with respect to dinucleoside polyphosphates. We conclude that VEGFR2-receptor is capable of synthesizing dinucleoside polyphosphates. Up4A may modulate the effects of VEGFR2 due to their proliferative effects. Reference [1] Jankowski V, Tölle M, Vanholder R, Schönfelder G, van der Giet M, Henning L, Schlüter H, Paul M, Zidek W, Jankowski J (2005) Identification of uridine adenosine tetraphosphate (Up4A) as an endothelium-derived vasoconstrictive factor. Nature Medicine 11: Track Experimentelle Hypertonie-Forschung für Junge Hypertensiologen Immunologie und Experimentelle Hypertensiologie FV10 High salt (NaCl) reduces the activation and function of alternatively activated (M2) macrophages via epigenetic modifications M. Gebhardt 1, K. Binger 1, C. Rintisch 2, M. Heinig 2, A. Schröder 3, W. Neuhofer 4, K. Hilgers 3, A. Manzel 3, C. Schwartz 3, M. Kleinewietfeld 5, R. Linker 3, F. Lang 6, D. Vöhringer 3, N. Hübner 7, R. Dechend 8, J. Jantsch 3, J. Titze 3, D. Müller 1 1 MDC und ECRC, Berlin, Deutschland; 2 MDC, Berlin, Deutschland; 3 FAU Erlangen, Erlangen, Deutschland; 4 LMU München, München, Deutschland; 5 TU Dresden, Dresden, Deutschland; 6 Universität Tübingen, Tübingen, Deutschland; 7 Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Deutschland; 8 Universitätsklinikum, Experimental and Clinical Research Center, Berlin, Deutschland High intake of dietary salt (sodium chloride; NaCl) is attributed to the development of hypertension and cardiovascular disease, and has been proposed to be a cause for the rapid increase in autoimmune diseases in western civilisations. We have recently shown that NaCl has a pro-inflammatory effect and boosts the activation of Th17 cells in vitro, with mice fed a high salt diet having an accelerated and more severe experimental autoimmune encephalomyelitis. In this study, we examine how the activation of alternatively activated (M2) macrophages is affected by NaCl. In stark contrast to our study with Th17 cells, we find that high salt dose-dependently decreased M2 activation in IL-4+IL-13 stimulated BM-derived mouse macrophages. Genes important for M2 activation, including Mrc1, Arg1, Ym1, Fizz1 and PD-L2, all had a blunted expression in the presence of NaCl; an effect which was not observed in tonicity controls (mannitol or urea), implying a specific action of NaCl. Transcription factors important for modulating M2 function (Irf4 and Klf4) were similarly affected. In contrast to our previous

8 [7] findings in Th17 cells, the effect of salt on M2 activation was not mediated via Sgk-1. To explore the mechanism for the effect of NaCl on M2 activation we performed gene expression analysis simultaneously with genome wide epigenetic modification analysis (ChIP-seq for H3K4me3 and H4ac). The results of this revealed that NaCl modulated epigenetic marks at genes important for M2 activation. Finally, we asked if these salt-mediated changes in M2 gene profiles, translated into effects on their function. Using an in vitro assay, we found that NaCl-treated M2 macrophages have a reduced ability to suppress the activation of effector T cells. Our study reveals a novel effect of NaCl on M2 activation and function, and gives support to the notion that the modulation of immune cell function by high dietary salt is relevant to hypertension and autoimmune diseases. FV11 Cytosolic renin exerts anti-necrotic effects under ischemic conditions in an angiotensinindependent manner D. Staar 1, H. Wanka 1, P. Lutze 1, I. Bäumgen 1, A. Albers 1, T. Beck 1, J. Peters 1 1 Institut für Physiologie / Universitätsmedizin Greifswald, Karlsburg, Deutschland Objective: The classical renin-angiotensin system (RAS) increases oxidative stress and exerts proinflammatory effects through angiotensin generation by secretory renin. However, after myocardial infarction an alternative renin transcript is expressed that encodes for a non-secretory intracellular renin with presumably protective functions. The aim of the present study was to investigate these protective functions in detail under the ischemia-related condition glucose depletion in the presence of the renin inhibitor CH732. Methods: H9c2 rat cardiomyoblast control cells (un-transfected or empty pires vector-transfected) and cells overexpressing cytosolic renin [E(2-9)renin cells] were cultured under control conditions as well as under glucose depletion for 24 hours in the presence or absence of the rat renin inhibitor CH732 (10-6 M). Transcript levels of secretory renin [E(1-9)renin] and cytosolic renin [E(1A-9)renin] were quantified by real-time PCR and western blot. Functionally, we examined early and late necrotic events [propidium iodide uptake and LDH ratio (release/content), respectively]. Results: Control cell lines exposed to glucose depletion exhibited a marked increase of cytosolic renin transcript as well as renin protein levels (4-5fold, p 0.05). Furthermore, after glucose depletion the late necrosis rate was increased significantly (1,8fold, p 0.05). In contrast, cytosolic renin overexpression in E(2-9)renin cells protected the cells from late necrosis after glucose depletion. These protective effects of cytosolic renin overexpression were seen even under renin inhibition by CH732. Conclusions: Cytosolic renin is cardioprotective by reducing the rate of necrosis under ischemiarelated conditions such as glucose depletion. The effects are independent of angiotensin generation. FV12 Einfluss von endogenen Immunzellen auf extrazellulärer Matrix und Remodelierung nach Myokardinfarkt A. Schuh 1, S. Simsekyilmaz 2, A. Curaj 2, O. Bucur 3, I. Kanzler 2, X. Li 2, M. Staudt 2, V. Jankowski 2, N. Marx 1, J. Jankowski 2, E. Liehn 2 1 Uniklinik RWTH Aachen, Klinik für Kardiologie, Pneumologie, Angiologie und Internistische Intensivmedizin (Med. Klinik I), Aachen, Deutschland; 2 Institute for Molecular Cardiovascular Research, Aachen, Deutschland; 3 Beth Israel Diacones Medical Center, Boston, USA Im Rahmen der Entwicklung neuer Strategien zur Optimierung kardialer Reparationsprozesse nach Myokardinfarkt legen aktuelle Studien nahe, dass im Gegensatz zur bisherigen Überzeugung und Studienlage auch ein erhöhter Kollagengehalt der Infarktnarbe nicht zwangsläufig zu einer Verschlechterung der myokardialen Funktion führen muss. Ziel dieser Studie war es, erstmals eine vollständige Charakterisierung aller bekannter Kollagensubtypen zu unterschiedlichen Zeitpunkten nach Myokardinfarkt im Infarktareal durchzuführen und den Einfluss unterschiedlicher inflammatorischer Zellen auf das Kollagenmuster und die funktionelle Stabilität/Elastizität der Narbe zu untersuchen. Im Rahmen dieser Studie quantifizierten wir die Produktion extrazellulärer Matrix von kultivierten Myofibroblasten in vitro, welche wir anschließend mit unterschiedlichen inflammatorischen Zellen ko-

9 [8] kultivierten. Die quantitative Darstellung der exprimierten Matrix Proteine durch mrna-nachweise zeigte eine erhöhte Fibrinproduktion nach Kokultur mit Neutrophilen, während Kokultur mit Monozyten die Kollagenproduktion erhöhte. Nach Analyse der Signalisierungswege, konnten wir feststellen dass die Neutrophile in den Myofibroblasten das Remodelierung (TGF-ß1, IL1ß), Proliferation, Migration, Differenziation, und Angiogenese-Gene aktivieren, während die Monozyten die Remodelierung (AngII, NFkB) und Apoptose-Gene aktivieren konnten. Diese Befunde wurden auch in weiteren Experimenten bestätigt (Proliferation Teste, TUNEL). Weiterhin, führten wir zur Darstellung der Elastizität der extrazelullären Matrix in allen Gruppen atomic force microscopy (AFM)-Messungen durch. Es zeigte sich, dass die Kokultutr mit Neutrophilen eine deutlich erhöhte Elastizität nachweisen, während die Monozyten-Kokultur die Steifheit der Myofibroblasten in vitro signifikant erhöhen. Interessanterweise, ist diese biomechanistic Befund auch reversibil, wenn die Kokultur ausgelöst ist. Zusammenfassend, konnten wir nachweisen dass die inflammatorischen Zellen signifikanten Einfluss auf die Ausprägung unterschiedlicher Kollagenexpressionsmuster im Infarktnarbengewebe nehmen können, sowie die andere Matrix Proteine. Dies hat weiterhin Veränderungen der Stabilität/Elastizität der Narbenareale, der Narbenfunktion und auch der myokardialen Funktion zur Folge. Ein Eingriff in die Migrationsprozesse von Entzündungszellen nach Myokardinfakt könnte somit in Zukunft kardiale Reparationsprozesse therapeutisch beeinflussen. Freie Vorträge mit Minilecture FV13 Charakterisierung der translationalen Profile von Myofibroblasten bei chronischer Nierenerkrankung und Hypertonie I. Grgic 1, A. Hofmeister 1, M. Krautzberger 2, J. Duffield 3, A. McMahon 2, B. Humphreys 4 1 Philipps-Universität Marburg, Klinik für Innere Medizin und Nephrologie, Marburg, Deutschland; 2 Broad CIRM Center, University of Southern California, Los Angeles, USA; 3 University of Washington, Division of Nehprology, Seattle, USA; 4 Brigham and Women's Hospital, Renal Division, Boston, USA Fibroseprozesse in der Niere führen zur Entwicklung von chronischem Nierenversagen und Bluthochdruck. Myofibroblasten spielen eine Schlüsselrolle bei der Umstrukturierung von funktionellem Nierengewebe und Entwicklung von Fibrose. Eine detaillierte Analyse der Genexpression von Myofibroblasten insbesondere in der frühen Phase der Fibrogenese könnte dabei helfen, neue Biomarker und Therapiestrategien für die Behandlung von chronischen Nierenerkrankungen zu entwickeln. Das Herauslösen und spezifische Anreichern einzelner Zelltypen aus ganzem Nierengewebe ist allerdings schwierig. Aus diesem Grund haben wir uns zum Ziel gesetzt, durch Weiterentwicklung und Nutzung der TRAP (translational ribosome affinity purification) Technologie zellspezifische mrna aus Myofibroblasten und ihren Vorläuferzellen bei renaler Fibrose zu isolieren und zu charakterisieren. Wir haben hierzu eine transgene Maus generiert, in der ein egfp-markiertes ribosomales L10a Protein (egfp-l10a) unter der Kontrolle des Collagen1α1 Promotors exprimiert wird, welches eine selektive Extraktion von polysomal-gebundener mrna von (Myo)Fibroblasten aus ganzen Nieren ermöglicht. Es erfolgte die Gewinnung von polysomaler mrna aus gesunden und fibrosierenden Nieren (unilaterale ureterale Obstruktion, UUO) von Collagen1α1-eGFP-L10a Mäusen und anschließende Analyse und Validierung der resultierenden translationalen Profile. Die Analyse offenbarte Genexpressionssignaturen, die eine starke Assoziation mit Prozessen der Zellproliferation, Migration und Zellformänderung hatten. Es konnten zahlreiche neue Gene und potentielle Kandidaten für Biomarker identifiziert werden, die spezifisch in Myofibroblasten während Fibrose hochreguliert wurden. Die Validierung der Ergebnisse erfolgte mittels quantitativer PCR, in-situ Hybridisierung und Immunblot Analyse. Zusammenfassend konnte hier durch Adaptation und Anwendung der neuartigen TRAP Methode in der Niere eine umfassende Charakterisierung der frühen Genexpressionsveränderungen in Myofibroblasten bei renaler Fibrose in vivo gezeigt werden. Der hieraus resultierende Genatlas eröffnet neue Einsichten in die Pathophysiologie von chronischen Nierenerkrankungen und Hypertonie.

10 [9] FV15 Sympathetic nervous system drives renal inflammation by alpha(2a)- adrenoceptors H. Hoch 1, L. Hering 1, L. Hein 2, L. Rump 3, O. Vonend 4, J. Stegbauer 5 1 Uniklinik Düsseldorf, Klinik für Nephrologie, Düsseldorf, Deutschland; 2 Universitätsklinikum Freiburg, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Freiburg, Deutschland; 3 Heinrich-Heine-Universität Düssseldorf, Klinik für Nephrologie, Düsseldorf, Deutschland; 4 Zentrum für Nieren- und Hochdruckerkrankungen, Wiesbaden, Deutschland; 5 Universitätsklinikum Düsseldorf, Klinik für Nephrologie, Düsseldorf, Deutschland Chronic kidney disease (CKD) is one of the major health issues. Inflammatory processes play a pivotal role in the pathogenesis of CKD. It is well-known that CKD is associated with an activation of the sympathetic nervous system (SNS). The activated SNS in turn leads to a progression of CKD. Alpha(2A)-adrenoceptors (α2a-ar) regulate sympathetic nerve activity by controlling norepinephrine (NE) release from sympathetic nerve endings by a negative feedback mechanism. There is increasing evidence that α2a-ars on non-adrenergic cells, like immune cells, modulate pro-inflammatory processes during tissue damage. Here we tested the impact of α2a-ar on the progression of renal fibrosis. Unilateral ureteral obstruction (UUO) a model of renal fibrosis - was performed in FVB mice lacking the α2a-ar (KO) and compared to its wild-type (WT). Renal NE tissue content was measured by HPLC. 7d after UUO immunohistochemistry and gene expression analysis by real-time PCR analyses were carried out. Murine macrophages were isolated from the peritoneal cavity, subsequently cultured and stimulated. Renal sympathetic neurotransmission and renal NE tissue content was significantly exaggerated in KO compared to WT mice indicating an increased tone of SNS. Despite of the increased tone of SNS, renal fibrosis, assessed by sirius red/ fast green collagen staining (p=0.0428) and renal collagen-1 expression (p=0.001), was significantly attenuated in KO compared to WT mice 7 days after UUO. Moreover, the expression of the pro-inflammatory and pro-fibrotic cytokines TNF-α (p<0.05) and TGFβ (p<0.05) as well as the chemokines CCL2 (p<0.05) and CCL5 (p<0.05) were significantly reduced in mice lacking the α2a-ar compared to WT indicating a pro-inflammatory role of α2a-ar on immune cells in the progression of renal fibrosis. Analyzing immune cells α2a-ars could be detected in macrophages. A dramatically infiltration of macrophages could be observed into the obstructed kidney. Interestingly, the infiltration of macrophages was significantly attenuated in kidneys of KO mice compared to WT. To test a direct impact of α2a-ars on immune cells driving renal fibrosis, we isolated macrophages from WT mice and stimulated them with the α2-ar-agonist UK (0.1 µm). Stimulation of α2a-ar, expressed on macrophages induced a 5-fold expression of TNF-α (p<0.001). Our results show, that alpha2a-ars appear not only to be key players in regulating renal sympathetic activity, but also promote inflammation and the progression of renal fibrosis in response to kidney injury. SNS possibly drives renal inflammation by activation of α2a-ars on immune cells. Further studies are necessary to test wether α2a-ars in non-adrenergic cells mediate renal fibrosis and inflammation. Therefore we will use a transgenic mouse where the α2a-ar was deleted only from non-adrenergic cells. Track: Experimentelle Hypertonie-Forschung für Junge Hypertensiologen Sitzung 2 - NO- vom reinen Vasodilator zum komplexen Regulator von Blutdruck und Gefäßfunktion FV16 ENaC is involved in endothelial shear stress sensing M. Maase 1, A. Tarjus 2, P. Jeggle 3, V. Drüppel 1, C. Fassot 4, S. El Moghrabi 2, H. Oberleithner 1, D. Henrion 4, N. Farman 2, F. Jaisser 2, K. Kusche-Vihrog 1 1 Universität Münster, Institut für Physiologie II, Münster, Deutschland; 2 Centre de Recherches des Cordeliers, Inserm U872 equipe 1, Paris, Frankreich; 3 University of Cambridge, Department of Pharmacology, Cambridge, United Kingdom; 4 Université d'angers, UMR CNRS 6214, UMR Inserm 1083, Angers, Frankreich Purpose: Besides kidney, the epithelial sodium channel (ENaC) is also found in vascular endothelial and smooth muscle cells, suggesting an additional role in vascular function. Endothelial cells are exposed to shear forces generated by the blood flow. The resulting deformation of the endothelial cells is an important stimulus for the secretion of nitric oxide (NO), which in turn leads to relaxation of the underlying vascular smooth muscle cells. We recently demonstrated that an increased ENaC

11 [10] abundance in the endothelial membrane stiffens the cell cortex indicating that endothelial ENaC (EnNaC) is a crucial determinant of endothelial nanomechanics (see figure). Dysfunction of endothelial cells, which is hallmarked by a reduced NO release, might lead to atherosclerosis and hypertension. In addition, aennac accumulates with aging indicating a link to age-related cardiovascular disease. The (patho-)physiological role of EnNaC in the endothelium, however, remains to be investigated. Material and Methods: Mice with conditional endothelial aenac KO (aennac KO) compared to WT were studied. (i) Renal function was explored using metabolic cages, (ii) vascular reactivity was assessed in mesenteric arteries, (iii) endothelial cell stiffness was analyzed by Atomic Force Microscopy using endothelial cells from ex vivo aorta preparations and (iv) western blots were performed for detection of (phospho-) enos, Akt and MLCK. Results: Renal function and Na + excretion were unaffected in the KO mice, indicating EnNaC not being involved in sodium balance. Ex vivo vascular contraction (induced by phenylephrine/kcl) and dilation (induced by acetylcholine) were unaffected in aennac KO. However a striking difference was observed regarding flow-mediated vasodilation that was found blunted in aennac KO. Similar results were observed after benzamil treatment in WT arteries. Ex vivo endothelial stiffness was decreased by acute EnNaC blockage (15min benzamil, 1µM) in the WT whereas no effect in the aennac KO could be observed. Western Blot analysis showed that the phosphorylation of enos, Akt and MLCK is increased in aennac KO compared to WT. Discussion and Conclusion: Based on these observations the following sequence of events can be postulated: EnNaC inhibition (using genetic or pharmacological approaches) reduces endothelial stiffness. This results in a higher amount of phospho-enos and subsequently in a higher release of NO. Since no flow-induced dilation of the vessel could be observed under these conditions, a state of saturated dilation is concluded. Our results demonstrate that aennac is part of the flow-sensing machinery in the vessel in that its presence is linked to the ability of a vessel to dilate. Thus, it can be concluded that pharmacological control of aennac abundance might be a therapeutic strategy in the prevention of hypertension.

12 [11] FV17 Major Role of Ryanodine Type 2 Receptors in Global and Local Intracellular Calcium Release in Arterial Smooth Muscle M. Kaßmann 1, J. Schleifenbaum 1, I. Szijártó 1, Y. Anistan 1, M. Gollasch 2 1 Charité, Experimental and Clinical Research Center, Berlin, Deutschland; 2 Charité Campus Virchow,, Nephrologie/Intensivmedizin, Berlin, Deutschland Objective: Ryanodine receptors (RyR) are calcium-sensitive ion channels in the sarcoplasmic reticulum (SR) membrane, and are important effectors in arterial smooth muscle excitation-contraction (EC) coupling. While three different RyR isoforms are expressed in arterial smooth muscle cells (SMCs), the relative contribution of each RyR isoform to vascular function remains unresolved. Methods: We generated tamoxifen-inducible SMC specific knock-out mice of RyR2 to test the hypothesis of RyR2 contributing in arterial EC coupling, vasoregulation, and systemic blood pressure. Myography and videomicroscopy of isolated arteries, calcium imaging and patch clamp current recordings on isolated SMCs, and radiotelemetric blood pressure measurements were used. Results: Targeted deletion of the gene for RyR2 resulted in a loss in functional coupling of calcium sparks to associated BK potassium channel activation, and increased arterial tone and systemic blood pressure. Aortas, femoral, cerebral and mesenteric arteries from RyR2 deficient mice showed no contraction in response to RyR activation by 10 mmol/l caffeine. Conclusion: Our data demonstrate that RyR2 are key elements in Cav1.2 channel-induced EC coupling in large and small arteries. Furthermore, RyR2, by activating BK channels, are important molecular SR calcium release components in translating local calcium signals (Ca 2+ -sparks) to vasoregulation and arterial blood pressure. FV18 Salz erleichtert die Adhäsion von Monozyten während vaskulärer Inflammation F. Schierke 1, M. Wyrwoll 1, V. Drüppel 1, K. Kusche-Vihrog 1 1 Universität Münster, Institut für Physiologie II, Münster, Deutschland Purpose: Inflammatory processes are hallmarked by binding of monocytes to adhesion molecules at the surface of endothelial cells and subsequent transmigration into the subendothelial matrix. There is evidence that synergistic effects of salt (NaCl) and aldosterone support vascular inflammation An important target of inflammatory processes is the endothelial glycocalyx (egc), a negatively charged mesh of proteoglycans, covering the surface of endothelial cells. Recently, it was shown that the egc functions as a Na + buffer barrier with protective effects on the endothelium. Since high Na + /aldosterone leads to a collapse of the egc, we tested the hypothesis that under such conditions the binding of monocytes to the endothelial surface is altered. Material and Methods: Human endothelial cells (EA.hy 926) were grown for 24 hours in low (130 mm) and high (150 mm) Na + concentrations in the presence of aldosterone (1 nm), TNFα (0.57 nm) and with/without the aldosterone antagonist spironolactone (100 nm). To test the adhesion of monocytes to the endothelial surface fluorescently labeled monocytes (anti-cd14) were seeded onto confluent endothelial monolayers for 5h and quantified afterwards. To test the barrier function of the egc, the adhesion forces between immobilized monocytes and the egc were quantified with a specialized Atomic Force Microscope (CellHesion). Changes in the conformation of the egc, in response to low and high Na +, were detected by using quantum dot (QD)-mediated immunofluorescence staining of heparan sulfates (HS) on the endothelial cell surface. Results: In the presence of high Na + /aldosterone the number of adherent monocytes on the endothelial cell surface was significantly increased by 49% while the adhesion forces between monocyte and egc were significantly decreased by 26%. In addition high Na + diminished the number of detectable HS, the major component of the egc, by 34%, indicating either shedding or conformational changes of the egc. All effects could be prevented by treatment with the aldosterone receptor antagonist spironolactone. Discussion: The data provide evidence for a two-step mechanism of monocyte adhesion. In a first step, monocytes bind to the egc and in a second step to the surface of the endothelial cell. Treatment with high Na + /aldosterone collapses the egc leading to a decreased binding of the monocytes to the egc. The collapsed egc in turn facilitates the access of the monocytes to the plasma membrane and binding to adhesion molecules (VCAM). Conclusion: The egc is involved in the adhesion process of monocytes and serves as an important protective barrier. High Na + /aldosterone enhance the process of vascular inflammation.

13 [12] Since aldosterone receptor antagonism has protective effects on the egc and attenuates the adhesion of monocytes this could be a useful strategy in the prevention of Na + /aldosterone-mediated inflammatory processes of the vasculature. Freie Vorträge mit Minilecture FV19 Untersuchung eines neuen Kandidatengens für die linksventrikuläre Hypertrophie am Knockout-Maus-Modell L. Herlan 1, K. Grabowski 1, A. Schulz 1, R. Kreutz 1 1 Charité - Universitätsmedizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Deutschland Fragestellung: Die linksventrikuläre (LV) Hypertrophie (LVH), die als Umbauprozess des Herzens in Folge eines Bluthochdrucks entstehen kann, stellt eine der häufigsten Risikofaktoren weltweit für Herzversagen dar. Wir konnten kürzlich im Rattenmodell eine Carboxypeptidase (CE) als neues Kandidatengen für die LVH identifizieren. Zur Bestätigung der Relevanz des Gens für das LV Remodeling züchteten wir eine CE-Knockout (KO)-Maus-Kolonie für weiterführende Untersuchungen. Methode: Heterozygote CE-KO-Mäuse wurde vom Mutant Mouse Regional Resource Center (MMRRC, erworben und als Stamm B6;129S5-Cpxm2 tm1lex /Mmucd/rk zu homozygoten Wildtyp (WT)- und KO-Tieren weiter gezüchtet. Mittels unilateraler Nephrektomie und Implantation eines subkutanen Desoxycorticosteronacetat (DOCA)-Pellets und gleichzeitiger erhöhter NaCl-Aufnahme im Trinkwasser soll eine salzsensitive Hypertonie und LV Funktionsstörung im Mausmodell induziert werden. Die Tiere sollen telemetrisch und echokardiographisch monitorisiert werden. Nach Beendigung der Beobachtungszeit werden Blutdruck, Herzfrequenz und die LV Funktion charakterisiert. Die LV Endorganschädigung (Remodeling) und insbesondere die inflammatorischen Veränderungen im linken Ventrikel werden anschließend histomorphologisch, immunhistochemisch und auf Genexpressionsebene weitergehend untersucht. Ergebnisse: Der KO des Gens konnte auf DNA und mrna-ebene konfirmiert werden. In Vorversuchen haben wir bereits eine Basalcharakterisierung des neuen CE-KO-Stamms durchgeführt. Die Tiere zeigen normales Paarungsverhalten und normale Wurfgrößen (n=6-11) und keine offensichtlichen Entwicklungsstörungen. In der 12. Woche zeigen männliche homozygote KO-Tiere unter Normalbedingungen tendenziell geringere Indizes für das Verhältnis LV Gewicht/Körpergewicht im Vergleich zu WT- und heterozygoten Tieren (P=0,06). Im DOCA/NaCl-Versuch erwarten wir unter hypertensiven Bedingungen für WT-Tiere eine stärkere Ausbildung von LVH und Fibrose im Vergleich zu KO-Tieren und scheinoperierten Tieren. Diskussion: Unsere vorläufigen Befunde belegen, dass mit der Etablierung der CE-KO-Maus die Relevanz des Gens für die Ausbildung einer LVH als Folge eines Bluthochdrucks in sinnvoller Weise untersucht werden kann. Weiterhin kann so der Einfluss der CE bzw. der CE-Defizienz auf molekulare Pathways analysiert und damit neue Erkenntnisse über die weitgehend unbekannte Funktion des Gens erlangt werden. FV20 Cardiac and vascular tissue properties determine the central blood pressure waveform: Consequences for pulse wave analysis M. Heusinkveld 1, B. Spronck 1, J. Lumens 1, A. Hughes 2, K. Reesink 1, T. Delhaas 1 1 Maastricht University Medical Centre, CARIM School for Cardiovascular Diseases, Department of Biomedical Engineering, Maastricht, Niederlande; 2 University College London, Faculty of Population Health Sciences, London, United Kingdom Background Various methods exist to estimate central blood pressure (BP) waveforms from noninvasive peripheral BP measurements. Most methods consider only vascular effects and are based on population reference data and over-simplified boundary conditions. Because contractile properties of the heart may play a role as well, we investigated by means of a computational model the isolated and combined influences of cardiac properties as well as vascular stiffening on the central BP

14 [13] waveform. Methods A model of the circulation (Arts et al.2005, AJP-HCP) was used to simulate central and peripheral BP waveforms from the left ventricle (LV) to femoral and radial arteries. We investigated the effect on BP waveform of 1) a 50% reduction in the shortening velocity (v-s) of LV sarcomeres and 2) a vascular stiffness increase, corresponding to an increase in carotid-femoral pulse wave velocity from 8.6m/s to 10.2m/s. Central BP waveforms were characterized using augmentation index (AIx, based on the 2nd derivative) and pulse pressure (PP). Results We obtained realistic BP waveforms for LV, central and peripheral vessels. Vascular stiffening (all else equal) resulted in an AIx increase from 16% to 36% and an increase in PP from 60 to 100mmHg. Reducing v-s (all else equal) caused AIx to increase from respectively 16% (PP=60mmHg) to 30% (PP=60mmHg). Combined reduced v and vascular stiffening resulted in an AIx of 42% with a PP of 80mmHg. Discussion Not only vascular, but also cardiac properties influence the central BP waveform. We conclude that heart-vessel interaction should be considered in pulse wave analysis. FV21 Doxorubicin-induced toxicity in rats: Effect of melatonin and compound 21. R. Rajkovicova 1, K. Arendasova 1, J. Hrenak 1, K. Repova 1, A. Barta 2, K. Krajcirovicova 1, F. Simko 1, L. Paulis 1 1 Comenius University in Bratislava, Faculty of Medicine, Institute of Pathological Physiology, Bratislava, Slowakei; 2 Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, Bratislava, Slowakei In the cardiovascular system, chemotherapeutic agents may cause adverse effects by compromising myocardial function or by changing vascular hemodynamics. The standard (although unspecific) treatment for consequences of anthracycline-induced damage is represented by inhibition of the AT1 receptor activation by ACE inhibitors or ARBs. In this condition, introducing exogenous antioxidants or AT2 receptor stimulation with anti-inflammatory and antifibrotic effects might be beneficial. Therefore, we aimed to investigate the effects of the antioxidant melatonin and an AT2 receptor agonist compound 21 (C21) in an animal model of doxorubicine-induced toxicity and compare these effects to those of olmesartan and captopril. Six groups of male Wistar rats were treated for four weeks. The first group served as a control. The remaining groups were injected with a single dose of doxorubicin (5 mg/kg i.v.) at the same day as oral administration of either vehicle or captopril (100 mg/kg/day) or olmesartan (10 mg/kg/day) or melatonin (10 mg/kg/day) or C21 (0.3 mg/kg/day) was initiated. The blood pressure was measured by tail-cuff plethysmography. Fibrosis and histomorphometric parameters were evaluated in the left ventricle, aorta and kidney. Captopril, olmesartan and melatonin prevented the doxorubicin-induced increase in systolic blood pressure and prevented loss of glomeruli, though without any effect on left ventricular mass. Hypertrophic remodelling of aorta was prevented by olmesartan and captopril, while melatonin prevented aortic fibrosis. Finally, only compound 21 attenuated body weight loss, hypotrophy of left ventricle and the decline in numerical glomerular density, yet without affecting blood pressure. Melatonin and compound 21 seem to elicit protective effects different from those by captopril or olmesartan. Combinations of these putative protective subsatnces with established cardiovascular treatment should be investigated. (APVV , VEGA 1/0380/14, UK558/2014)

15 [14] FV22 Arterial Hypertension and Risk of Stent Thrombosis in Patients with Coronary Artery Disease A. Lahmann 1, P. Groha 1, S. Kufner 1, T. Kessler 1, T. Tada 1, R.A. Byrne 1, S. Cassese 1, M. Joner 1, M. Fusaro 1 P. Hoffmann 1, C. Burgdorf 1, S. Schneider 1, S. Schüpke 1, T. Ibrahim 1, L. Ott 1, K.L. Laugwitz 1, C. Hengstenberg 1, H. Schunkert 1, A. Kastrati 1 1 Deutsches Herzzentrum München, Klinik für Herz- und Kreislauferkrankungen,München,Deutschland Aims: Stent thrombosis is a serious complication after percutaneous coronary intervention. The association of arterial hypertension with stent thrombosis has not been assessed in large cohorts of patients with coronary artery disease. The aim of this study was to investigate the impact of hypertension on stent thrombosis and survival. Methods: A total of 17,133 patients undergoing successful coronary stent implantation from 1998 to 2011 at 2 centres in Munich, Germany, were included in this study. The definition of hypertension was a permanent systolic or diastolic blood pressure higher than 140 respectively 90 mmhg or an antihypertensive medication. The patients underwent routine control angiography 6-8 months after intervention. Results: We included 17,133 patients that underwent successful coronary stenting. Hypertension was present in 11,239 patients (65,6%). Overall, there were 1558 (9.1%) deaths and 218 (1.3%) cases of stent thrombosis after 3 years. In a multivariate adjusted analysis, patients with hypertension had a significantly lower risk of stent thrombosis (hr 0.61 (95% CI ), p<0.001). Moreover, hypertension was associated with a significantly lower mortality (hr 0.74 (95% CI ). Discussion: In our study, hypertension was associated with a significant lower risk of stent thrombosis and mortality. Severity of hypertension as measured by number of antihypertensive drugs was not associated with aforementioned. Further studies are needed to elucidate the underlying mechanisms of the genesis of stent thrombosis in patients with coronary artery disease. Conclusion: In this large cohort, hypertension was associated with a lower risk of stent thrombosis and mortality after three years follow up. FV23 Kardiovaskuläre Effekte vom aeroben und isometrischen Training bei arterieller Hypertonie: eine prospektive, randomisierte, placebo-kontrollierte Studie N. Pagonas 1, S. Vlatsas 2, F. Seibert 1, F. Bauer 1, W. Zidek 2, T. Westhoff 1 1 Universitätsklinik Marienhospital Herne, Ruhr-Universität Bochum, Medizinische Klinik I, Herne, Deutschland 2 Charité CBF - CC 10, Medizinische Klinik für Nephrologie, Berlin, Deutschland Einleitung: Das aerobe Ausdauertraining und das dynamische Widerstandstraining werden durch die aktuellen Leitlinien im Rahmen der nicht-pharmakologischen Behandlung von Bluthochdruck empfohlen. Das isometrische Training wird wegen fehlenden Daten aus kontrollierten Studien nicht empfohlen. Die vorliegende Arbeit führt im Rahmen einer randomisierten, prospektiven, kontrollierten Studie erstmalig einen direkten Vergleich des kardiovaskulären Effektes von aerobem Training und isometrischem Faustschlusstraining durch. Material und Methoden: 70 Patienten mit bekannter medikamentös behandelter arteriellen Hypertonie oder einem Blutdruck = 140/90 ohne medikamentöse Therapie wurden in drei Gruppen randomisiert. In der ersten Gruppe wurden 25 Patienten eingeschlossen, die über einen Zeitraum von 12 Wochen ein isometrisches Training 5 Mal pro Woche durchgeführt haben (Faustschlusskontraktionen mit 30% der maximalen Kraft). In der zweiten Gruppe (Placebo) wurden 23 Patienten eingeschlossen, die dasselbe Protokoll wie die aktive Gruppe durchgeführt haben, allerdings mit einem Placebo-Gerät (Kontraktionen mit 5% der maximalen Kraft). In der dritten Gruppe wurden 22 Patienten motiviert, entsprechend der Leitlinien 5 Mal pro Woche Minuten aerobes Ausdauertraining über ebenfalls 12 Wochen zu betreiben. In allen 3 Gruppen, erfolgten in dem Zeitraum der Studie keine zusätzliche Intervention und keine Änderung der Vormedikation. Ergebnisse: Zum Studienbeginn zeigten sich keine Unterschiede zwischen den Gruppen.

16 [15] Vier Patienten in der Gruppe mit aeroben Training haben das Studienprotokoll verletzt (n=1) oder die Teilnahme in der Studie abgebrochen (n=3) und wurden von der Auswertung ausgeschlossen. Das aerobe Training führte zu einer statistisch signifikanten Senkung sowohl des systolischen, als auch des diastolischen Blutdrucks in der ambulanten 24-Stunden-Blutdruckmessung (systolisch von 129.1±10.4 mmhg auf 122.7±11.7, p = und diastolisch von 79.5±8.9 auf 76.7±10.9, p = 0.009). Zusätzlich wurde eine Verbesserung der Elastizita tsindices der kleinen und der großen Gefäße und ein Abfall des totalen peripheren Widerstands gesehen. Das isometrische Training hatte keinen Einfluss auf die ambulante 24-Stunden-Blutdruckmessung (jeweils p > 0.05) und zeigte keine statistisch signifikante Verbesserung der Gefäßelastizitätsparameter (p > 0.05). Schlussfolgerung: Die vorliegenden Daten bestätigen den blutdrucksenkenden Effekt des aeroben Trainings, selbst als ein unbeaufsichtigtes Training. Das isometrische Training zeigte keinen blutdrucksenkenden Effekt bei hypertensiven Patienten.

17 [16] FV24 Potenzial der renalen Denervierung diffuse, interstitielle myokardiale Fibrose zu reduzieren. A. Doltra 1, D. Messroghli 1, P. Stawowy 1, R. Gebker 1, J. Hassel 1, C. Schneeweis 1, B. Schnackenburg 1, E. Fleck 1, S. Kelle 1 1 Deutsches Herzzentrum Berlin, Klinik für Innere Medizin/Kardiologie, Berlin, Deutschland Purpose: Hypertensive cardiomyopathy is characterized by myocyte hypertrophy and interstitial fibrosis. It is estimated, that up to 30% of patients suffer from resistant hypertension. In these patients, renal denervation (RD) has emerged as a novel therapeutic option, however its effects on the heart are poorly understood. Today, new magnetic resonance (MR) techniques (myocardial extracellular volume (ECV) fraction) permit a quantitative assessment of myocardial fibrosis and have been correlated with mortality and events. Thus, our aim was to study the effects of RDN on myocardial fibrosis. Methods: 23 patients with resistant hypertension undergoing RD and 5 resistant hypertensive controls were prospectively included. 1.5T cardiac MR including left ventricle (LV) cine imaging and T1 mapping pre- and post- contrast were performed before RD and at 6 months follow-up. Indexed LV mass, septal ECV fraction, and indexed absolute extracellular volume (a quantitative measure of extracellular matrix) were quantified at both time points. Results: Indexed LV mass decreased significantly at 6 months follow-up (41.83 ± (41.59) vs ± 7.44 (38.49) g/m 1.7, p = 0.001) only in RDN patients. Regarding ECV, no significant differences were observed between baseline and 6 months follow-up (26.24 ± 3.92 (26.06) vs ± 4.53 (25.63) %, p = 0.605). However, when absolute extracellular volume was quantified, a significant decreases were observed after 6 months in RDN patients exclusively (10.36 ± 2.25 (10.79) vs ± 2.38 (9.79) ml/m 1.7, p = 0.031). Conclusions: RD is associated with a decrease in LV mass independent of blood pressure reduction. We observed no significant changes in ECV fraction, although a significant decrease in absolute extracellular volume was noted. Our results suggest that renal denervation leads to regression of interstitial fibrosis. Total extracellular volume quantification is the biomarker of choice to monitor LV hypertrophy. FV25 Blutdruck, Fitness und Body-Mass-Index von Hundebesitzern im Vergleich zu Nichthundebesitzern A. Wilhelm 1, S. Mahler 1, B. Weisser 1 1 Christian-Albrechts-Universität zu Kiel, Institut für Sportwissenschaft, Kiel, Deutschland Fragestellung: Eine regelmäßige körperliche Aktivität senkt den Blutdruck. Hundebesitzer gehen regelmäßig mit ihrem Hund spazieren. Unklar ist, ob diese Aktivität den Blutdruck beeinflusst und ob ein möglicher Einfluss über das Körpergewicht oder die körperliche Fitness vermittelt wird. Material und Methode: Insgesamt wurden 40 Versuchspersonen untersucht (m: 20, w: 20, mittleres Alter 50,5 ± 5,5 Jahre), davon 20 Nichthundebesitzer und 20 Hundebesitzer. Erhoben wurden Fitness, Ruheblutdruck und Body-Mass-Index (BMI). Die Fitness wurde mittels des UKK Walkingtests (2 km) gemessen. Der Fitnessindex wird mittels Walkingzeit, Belastungspuls und BMI über alters- und geschlechtsspezifischer Formeln ermittelt. Ergebnisse: Die Gruppen unterschieden sich bezüglich des Alters nicht. Hundebesitzer hatten einen signifikant niedrigeren Blutdruck als Nichthundebesitzer (132 ± 15,5 mm Hg / 84 ± 11,0 mm Hg vs. 143 ± 17,6 mm Hg / 95 ± 11,2 mm Hg; p <.05 / p <.01). Gleichzeitig war auch der BMI signifikant niedriger (24,8 ± 2,9 kg/m 2 vs. 28 ± 5,3 kg/m 2, p <.05) und der UKK Fitnessindex signifikant besser (86 ± 18,2 vs. 54 ± 27,3, p <.01). Es ergab sich eine positive Korrelation zwischen BMI und Blutdruck (r =.40 / r =.40, p <.05) und gleichzeitig eine negative Korrelation zwischen Fitness und Blutdruck (r =-.32 / r =-.44, p<.05 / p<.01). Diskussion: Die beim Spaziergang mit dem Hund niedrigen Intensitäten körperlicher Aktivität könnten den Blutdruck schon positiv beeinflussen. Dieser blutdrucksenkende Effekt ist möglicherweise über das Körpergewicht und/oder die körperliche Fitness vermittelt, die bekannter Weise beide für sich alleine das kardiovaskuläre Risiko auch unabhängig beeinflussen. Hundebesitzer wurden auch seltener antihypertensiv behandelt (23 vs. 30%), d.h. Unterschiede in einer medikamentösen Therapie sind nicht für die gezeigten Blutdruckdifferenzen verantwortlich. Über den Belastungspuls beim Walkingtest in der Bestimmung des Index wird eine unterschiedliche subjektive Anstrengung

18 [17] weitgehend herausgerechnet. Schlussfolgerung: Schon gering-intensive körperliche Aktivitäten wie regelmäßiger Spaziergang mit dem Hund scheinen den Blutdruck zu senken. Unklar bleibt der kausale Zusammenhang und ob auch ein insgesamt gesünderer Lebensstil bei Hundebesitzern diesen Effekt unterstützt. FV26 Central pulse pressure predicts BP reduction after renal denervation in patients with treatment resistant hypertension C. Ott 1, A. Schmid 2, S. Toennes 3, T. Ditting 1, R. Veelken 1, M. Uder 2, R. Schmieder 1 1 University of Erlangen-Nuremberg, Department of Nephrology and Hypertension, Erlangen, Deutschland; 2 University of Erlangen-Nuremberg, Department of Radiology, Erlangen, Deutschland; 3 Institut of Legal Medicine, Goethe University, Forensic Toxicology Department, Frankfurt/Main, Deutschland Background: Enhanced vascular aging is associated with elevated central pulse pressure (cpp), which is an independent predictor for cardiovascular (CV) events. Although many antihypertensive treatment strategies are effective, high residual CV risk remains indicative of an advanced and largely irreversible vascular damage. Renal denervation (RDN) has been shown to reduce blood pressure (BP) to various extent in patients with treatment-resistant hypertension (TRH). We hypothesized that cpp predicts BP reduction after RDN. Methods: Sixty-three patients with TRH (office BP 140/90 mmhg and 24-h ABPM 130/80 mmhg, despite treatment with at least 3 antihypertensive drugs including a diuretic) underwent catheter-based RDN using the Symplicity Flex TM catheter and followed for 6 months. At baseline cpp was assessed by pulse wave analysis (SphygmoCor TM ). Patients were stratified according their median cpp (55 mmhg). Medication adherence was assessed using toxicological urine analyses. Results: Office BP reduction 6 months after RDN was greater (-22±19/-13±11 vs. -9±20/-5±13 mmhg, p=0.038/0.014) and 24-h ABP reduction tended to be greater (-11±13/-8±10 vs. -3±18/-4±10 mmhg, p=0.070/0.112) in patients with cpp below median compared to those above median of cpp. In accordance, in patients with full compliance to drug therapy (>80% of prescribed drugs detected in the urine) office systolic and diastolic BP was more reduced in patients below median than in those above median of cpp (p = 0.049/0.020). Only, cpp (β= 0.687, p=0.001) and baseline systolic BP (β= , p<0.001) were independent determinants of office systolic BP reduction after RDN. Conclusion: Our data suggest that central PP, the pulsatile component of BP, indicative of the degree of large arterial stiffening, predicted BP response after RDN. FV27 Potential Cost-Effectiveness of Therapeutic Drug Monitoring in Patients with Resistant Hypertension O. Chung 1, K. Bonaventura 2 1 Facharzt für Pharmakologie und Toxikologie, Kiel, Deutschland; 2 Klinikum Ernst von Bergmann ggmbh, Potsdam, Deutschland Background: Non-adherence to drug therapy poses a significant problem in patients with presumed resistant hypertension (RH). Therapeutic drug monitoring (TDM) is a useful tool to identify nonadherence, leading to effective blood pressure (BP) control. However, cost-effectiveness of TDM in the management of RH has not been investigated. Method: A Markov model was used to evaluate lifeyears, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios in RH patients receiving either TDM optimized therapy or standard best medical therapy. The model ran from the age of years or death, using a cycle length of 1 year. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality. Cost analyses were performed from a payer s perspective. Deterministic and probabilistic sensitivity analyses were conducted. Results: In the 60-year olds, TDM gained 1.07 QALYs (men) and 0.97 QALYs (women) at additional costs of 3,854 and 3,922, respectively. Given a willingness-to-pay threshold of 35,000 per QALY gained, probability of TDM being cost-effective was =95% in all age groups from years. Results were influenced mostly by the frequency of TDM testing, the rate of non-responders to TDM, and the magnitude of effect of TDM on BP. Conclusion: Therapeutic drug monitoring presents a potential cost-

19 [18] effective health care intervention in patients diagnosed with RH. Importantly, this finding is valid for a wide range of patients, independent of gender and age. Track: Experimentelle Hypertonie-Forschung für Junge Hypertensiologen Sitzung 4 - Die Präeklampsie als pathophysiologisches Modell der Hypertonie FV27 Chronic p38 MAPK inhibition improves vascular function and remodeling in Angiotensin II dependent hypertension S. Potthoff 1, S. Stamer 1, M. Thieme 1, S. Sivritas 1, L. Hering 1, L. Rump 1, J. Stegbauer 1 1 Heinrich-Heine-Universität Düssseldorf, Klinik für Nephrologie, Düsseldorf, Deutschland AngiotensinII (AngII) dependent AngII-Typ1-receptor activation causes vasoconstriction and vascular injury leading to hypertension. The activation of mitogen activated protein kinase p38 (p38-mapk) plays a substantial role in AngII dependent endorgan damage. Recently, we showed that AngII dependent p38-mapk activation increased vasoreactivity through phosphorylation of the myosin-lightchain (MLC20). In this study, we evaluate the effect of chronic p38-mapk inhibition in AngII dependent hypertension on vascular function and remodeling. C57Bl/6 mice were infused with AngII (1000ng/kg/min) for 14 days via osmotic minipump and treated either with an oral p38-mapk inhibitor (BIRB769; 50mg/kg/day) or a placebo. Chronic p38-mapk inhibition did not alter blood pressure at baseline but attenuated the development of AngII-dependent hypertension significantly (placebo vs. BIRB796: 120.7±2.6 vs ±3.0 (baseline); 147±4.2 vs ±2.2 (after 1 week of AngII)P<0.01; 176.3±5.2 vs ±3.2 (after 2 weeks of AngII)P<0.001; values in mmhg). Additionally,in BIRB769 treated mice a significant reduction of aortic media-to-lumen ratio after AngII infusion was observed (placebo: 0.65±0.05; BIRB796: 0.46±0.02; P<0.05). Evaluating relative expression of genes involved in aortic hypertrophy and remodeling revealed a significant down regulation of MMP1, MMP9 and fibronectin in BIRB769 treated mice (P<0.05). In these mice, vascular function was tested in the isolated perfused kidney. AngII dependent pressor was significantly attenuated in BIRB769 treated mice. NO-dependent vasorelaxation was significantly improved in BIRB769 treated compared to placebo treated hypertensive mice. To rule out the possibility that the improved vascular function to chronic p38-mapk inhibition could be ascribed to blood pressure reduction or vascular remodeling, p38-mapk was inhibited by SB (5µM) ex vivo in the isolated perfused kidney. Acute p38-mapk inhibition attenuated AngII-dependent pressor response similar to that seen in mice chronically treated with BIRB769. In summary, chronic p38-mapk inhibition improves blood pressure and vascular injury in AngIIdependent hypertension. These effects could be assigned to blood pressure independent effects as acute p38-mapk inhibition improves vascular function. Thus, our findings indicate an important role of the p38-mapk in regulating blood pressure and vascular injury and highlights its potential as a pharmaceutical target. FV29 Leptin sensitivity remained preserved in diet-induced obese rats by blocking angiotensin II AT1 receptors M. Lau 1, H. Müller-Fielitz 1, C. Geißler 1, L. Werner 1, M. Piehl 1, W. Raasch 1 1 Universität Lübeck, Institut für Eperimentelle und Klinische Pharmakologie und Toxikologie, Lübeck, Deutschland BACKGROUND AND PURPOSE: AT1 receptor blockers (ARB) such as telmisartan (TEL) were demonstrated in experimental studies to reduce of body weight. Weight loss was mostly found after high ARB dosing and was not related to blood pressure reduction. The mechanism underlying ARBinduced weight loss is still unclear. A leptin dependent mechanism is thought to be involved since ARB failed to reduce body weight in animals with an impaired leptin signaling. Here, we mainly investigated leptin sensitivity, taking a functional approach by measuring food intake and body weight after leptin exposure. We additionally performed immunohistochemical staining experiments against phosphorylation of signal transducer and activator of transcription (pstat3) to attribute function to

20 [19] leptin signaling. METHODS: Normotensive Sprague Dawley rats could choose freely between standard chow and a cafeteria diet (CD), which both were abundantly offered. Leptin resistance tests (LRT) were conducted to determine whether TEL (8 mg/kg/d, 14 days) enhances leptin sensitivity. pstat staining was performed in arcuate nucleus (AC) of hypothalami to estimate leptin transport across the blood-brain barrier. mrna levels of (an-)orexigenic peptide levels were determined in hypothalami. RESULTS: Weight gain, energy intake, and plasma leptin were reduced by TEL but blood pressure remained unchanged. The 24-h profiles of plasma leptin were similar between controls and TELtreated rats after saline injections, but were higher after leptin injections in controls and slightly lower in TEL-treated animals. After TEL, energy intake during LRT was lower in leptin- than in salinepretreated rats, but remained unchanged in controls, irrespectively of whether rats received saline or leptin. The area under the curve of plasma leptin levels correlated positively with the energy intake in controls, independently of whether rats received leptin or saline, which strongly supports leptin resistance in these rats. In contrast, this correlation was negative in TEL-treated rats, irrespectively of whether saline or leptin was administered, indicating that leptin sensitivity is retained. Leptin minimized the gain in body weight during LRT in rats treated with TEL as compared to saline-treated animals. pstat3-positive cells in AC were higher after injecting leptin than after saline. When rats were fed with CD, cell numbers of pstat3 were reduced in AC compared to chow-fed controls. TEL treatment tended (p=0.054) to normalize pstat3-positive cell numbers despite CD feeding Hypothalamic mrna levels of the orexigenic peptides melanin-concentrating hormone and preproorexin were reduced by TEL. CONCLUSIONS: Rats develop leptin resistance due to the cafeteria diet after 2 weeks. Leptin sensitivity is preserved by TEL treatment despite feeding with cafeteria diet. This pleiotropic effect is not related to the hypotensive action of TEL.

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