Endothelin A Receptor Antagonism in Experimental Congestive Heart Failure Results in Augmentation of the Renin-Angiotensin System and Sustained Sodium Retention

John A. Schirger, Horng H. Chen, Michihisa Jougasaki, Ondrej Lisy, Guido Boerrigter, Alessandro Cataliotti, John C. Burnett

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Background-While both the endothelin-1 (ET-1) and renin-angiotensin systems (RAS) are activated in congestive heart failure (CHF), the temporal sequence of this activation remains unclear. Understanding this pattern of neurohumoral activation may aid in understanding the significance of ET-1 in CHF and provide strategies for ET-1 antagonism. Although acute endothelin (ET) receptor antagonism improves systemic hemodynamics in CHF, clinical trials with chronic ET receptor antagonism report worsening CHF symptoms. Methods and Results-In a canine model of progressive left ventricular dysfunction, we demonstrated activation of myocardial and plasma ET-1 without activation of the RAS during transition to overt CHF, suggesting that ET-1 contributes to this transition. We next evaluated the effects of chronic oral ET-A receptor antagonism on neurohumoral function, renal hemodynamics, and sodium excretion in pacing-induced CHF. After 7 days of treatment (n=7) with ET-A receptor antagonism (with LU135252), sodium excretion did not improve in treated versus untreated CHF (n=6). Furthermore, both plasma renin activity and plasma ET-1 increased with ET-A receptor blockade. Conclusions-Activation of the myocardial and plasma ET-1 systems precedes activation of the myocardial and plasma RAS in CHF. ET-A receptor antagonism in experimental CHF further activates the RAS without improving sodium excretion. These findings suggest an important role for ET-1 in the progression of CHF and a potential mechanism for the exacerbation of CHF symptoms observed in clinical trials with chronic ET receptor antagonism. Further studies with combined modulation of the ET and other neurohumoral systems in CHF are required.

Original languageEnglish (US)
Pages (from-to)249-254
Number of pages6
JournalCirculation
Volume109
Issue number2
DOIs
StatePublished - Jan 20 2004

Keywords

  • Endothelin
  • Heart failure
  • Receptors
  • Sodium

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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