In a canine model of congestive heart failure, 7 days of ET-A receptor antagonism with LU135252 did not improve sodium excretion and increased plasma renin activity and ET-1 levels.
Does chronic oral ET-A receptor antagonism improve sodium excretion and neurohumoral function in a canine model of pacing-induced congestive heart failure?
In a canine model of CHF, ET-A receptor antagonism increased plasma renin activity and ET-1 without improving sodium excretion, offering a potential mechanism for worsening symptoms observed in clinical trials.
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.
Schirger et al. (Tue,) conducted a other in Congestive heart failure (n=13). ET-A receptor antagonism (LU135252) vs. Untreated CHF was evaluated on Sodium excretion, neurohumoral function, and renal hemodynamics. In a canine model of congestive heart failure, 7 days of ET-A receptor antagonism with LU135252 did not improve sodium excretion and increased plasma renin activity and ET-1 levels.