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29. Wissenschaftlicher Kongress der Deutschen Hochdruckliga

Deutsche Hochdruckliga e. V. DHL ® - Deutsche Hypertonie Gesellschaft Deutsches Kompetenzzentrum Bluthochdruck

23. bis 25.11.2005, Berlin

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Effects of Endothelin-A-Receptor Antagonism on Systemic Hemodynamic Responses to Exogenous Noradrenaline - Associations with the GNB3 C825T Polymorphism

Effekte einer Endothelin-A-Rezeptor-Blockade auf die hämodynamischen Wirkungen exogenen Noradrenalins - Assoziationen mit dem GNB3 C825T Polymorphismus

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  • A. Mitchell - Universitätsklinikum Essen (Essen, D)
  • A. Zocher - Universitätsklinikum Essen (Essen, D)
  • U. Rushentsova - Universitätsklinikum Essen (Essen, D)
  • J. Nürnberger - Universitätsklinikum Essen (Essen, D)
  • W. Siffert - Universitätsklinikum Essen (Essen, D)
  • R.F. Schäfers - Johanniter Klinikum Oberhausen (Oberhausen, D)
  • T. Philipp - Universitätsklinikum Essen (Essen, D)
  • R. Wenzel - Allgemeines öffentliches Krankenhaus, Zell am See, Österreich

Hypertonie 2005. 29. Wissenschaftlicher Kongress der Deutschen Hochdruckliga. Berlin, 23.-25.11.2005. Düsseldorf, Köln: German Medical Science; 2006. Doc05hochP69

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/hoch2005/05hoch069.shtml

Published: August 8, 2006

© 2006 Mitchell et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

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Objective: The influence of the endothelin system (ETS) on sympathetically mediated hemodynamic responses in humans is largely unknown. Whether any such influence could be genetically determined has not been studied. We investigated the associations of the GNB3 C825T polymorphism with systemic hemodynamic responses to noradrenaline (NA) in the presence and absence of endothelin-A (ETA)-receptor blockade.

Methods: 26 healthy men (n=15 CC, 9 CT, 2 TT) were included in a double blind, placebo controlled cross-over trial. NA was infused (20, 40, 80, 120, 160 ng/kg/min), with either saline or coinfusion of the ETA-antagonist BQ123 (60 ug/min). Impedance cardiography was performed, blood pressure (BP), heart rate (HR) and systolic time intervals were measured. Data were analyzed with ANOVA.

Results: In response to NA diastolic BP rose less in 825T allele carriers (CT/TT vs. CC: +6.3±2 vs. +9.2±3 mmHg, P= 0.022), as did TPR (CT/TT vs. CC: +113±27 vs. +302±74 dyne x sec x cm-5, P= 0.002) and PWV (CT/TT vs. CC: P< 0.001; all results are mean changes from baseline ± SEM). The reduction in QS2c was smaller (P= 0.007) and SV and CO were significantly greater (P= 0.003 and P= 0.023) in 825T allele carriers. BQ123 markedly reduced the NA-induced rise in diastolic BP (NA/BQ123 vs. NA/saline: P= 0.001), TPR (P< 0.0001) and PWV (P< 0.001) and increased CO (P< 0.001) in CC homozygous subjects only. 825T allele carriers showed a greater reduction in QS2c but a lesser reduction in HR (NA/BQ123 vs. NA/saline: P< 0.001 and P= 0.003).

Conclusion: To our knowledge this is the first study to show in man in vivo, that the ETS contributes extensively to vascular and cardiac effects of exogenous NA and that this contribution may vary according to genotype. From our results it could be speculated that in healthy GNB3 825T allele carriers ß-receptor-mediated NA-effects are coupled to endothelin pathways, whereas in CC homozygous individuals alpha-receptor-mediated responses are linked to the ETS.