Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention.
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.


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.
Schirger
John A
JA
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases and Department of Physiology, Mayo Clinic and Foundation, Rochester, Minn 55905, USA. schirger.john@mayo.edu
Chen
Horng H
HH
Jougasaki
Michihisa
M
Lisy
Ondrej
O
Boerrigter
Guido
G
Cataliotti
Alessandro
A
Burnett
John C
JC
D000818:Animals; D018450:Disease Progression; D004285:Dogs; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006333:Heart Failure / Q000097:blood / Q000503:physiopathology* / Q000652:urine*; D006439:Hemodynamics; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System; D012964:Sodium / Q000652:urine*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan; D012964:Sodium; D012083:Renin