This Article Full Text Full Text (PDF) All Versions of this Article: 109/2/249    most recent 01.CIR.0000109139.69775.EBv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schirger, J. A. Articles by Burnett, J. C. Search for Related Content PubMed PubMed Citation Articles by Schirger, J. A. Articles by Burnett, J. C., Jr Related Collections Related Article

(Circulation. 2004;109:249-254.)
© 2004 American Heart Association, Inc.

Basic Science Reports

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

John A. Schirger, MD; Horng H. Chen, MB, BCh; Michihisa Jougasaki, MD, PhD; Ondrej Lisy, MD, PhD; Guido Boerrigter, MD; Alessandro Cataliotti, MD; John C. Burnett, Jr, MD

From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to John A. Schirger, MD, Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905. E-mail schirger.john{at}mayo.edu

Received February 24, 2003; de novo received July 22, 2003; revision received September 12, 2003; accepted September 20, 2003.

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.

Key Words: endothelin • heart failure • receptors • sodium

Related Article:

Endothelin Expression and the Progression of Heart Failure: Exemplifying the Vagaries of Therapeutic Development

Marvin A. Konstam and David DeNofrio
Circulation 2004 109: 143-145. [Extract] [Full Text]

This article has been cited by other articles:

				H. H. Chen, B. K. Huntley, J. A. Schirger, A. Cataliotti, and J. C. Burnett Jr Maximizing the Renal Cyclic 3'-5'-Guanosine Monophosphate System with Type V Phosphodiesterase Inhibition and Exogenous Natriuretic Peptide: A Novel Strategy to Improve Renal Function in Experimental Overt Heart Failure J. Am. Soc. Nephrol., October 1, 2006; 17(10): 2742 - 2747. [Abstract] [Full Text] [PDF]

				N. Emoto, S. B. Raharjo, D. Isaka, S. Masuda, S. Adiarto, A. Y. Jeng, and M. Yokoyama Dual ECE/NEP Inhibition on Cardiac and Neurohumoral Function During the Transition From Hypertrophy to Heart Failure in Rats Hypertension, June 1, 2005; 45(6): 1145 - 1152. [Abstract] [Full Text] [PDF]