Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Significance In failing hearts, norepinephrine (NE) net release and endothelin-1 (ET1) levels are increased. ET1 receptor antagonists were successfully used in preclinical heart failure (HF) studies, but clinical studies did not show beneficial effects in HF patients. We found that mice lacking endothelin receptor A (ET A) only in sympathetic neurons but not in cardiomyocytes were protected from the development of HF. Mechanistically, the presynaptic reuptake of NE within the heart was preserved in mice lacking ET A only in sympathetic neurons. These data provide an explanation of why patients in clinical studies do not benefit from ET1 receptor antagonists, because these patients are usually treated with β blockers, which interfere with the mechanism of action identified here.