Evidence suggests that
endothelin receptor antagonists may have therapeutic potential for the chronic treatment of
heart failure. In the current study, the effects of an orally active mixed
endothelin-A/
endothelin-B (ETA /ETB ) receptor antagonist (
enrasentan) were assessed in a model of
cardiac hypertrophy and dysfunction (spontaneously hypertensive
stroke prone rats) maintained on a high-
salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions.
Enrasentan (1,200 and 2,400 parts per million in the high-
salt/high-fat diet) had no significant effects on
body weight and systolic blood pressure. However, increases in heart rate were not observed in the
enrasentan-treated groups at 12 weeks (p < 0.05).
Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001).
Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively.
Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to
body weight (20% at 12 weeks), and ratio of terminal heart weight to
body weight (16-23%, p < 0.05). Finally, circulating
aldosterone concentration (54-57%) and
proANF fragment (33%) were reduced in
enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates
ventricular remodeling and premature mortality in an aggressive
hypertension model.