Enrasentan improves survival, limits left ventricular remodeling, and preserves myocardial performance in hypertensive cardiac hypertrophy and dysfunction

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 hyper trophy and dysfunction (spontaneously hypertensive stroke prone rats) maint ained on a high-salt/high-fat diet. Echocardiography was used to quantify c ardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2 ,400 parts per million in the high-salt/high-fat diet) had no significant e ffects on body weight and systolic blood pressure. However, increases in he art rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved surviva l (90-95% vs. 30% [control rats] at 18 weeks: p < 0.001). Enrasentan treatm ents also increased stroke volume (at 8, 12, and 16 weeks) and cardiac inde x (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatment s 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 termin al heart weight to body weight (16-23%, p < 0.05). Finally, circulating ald osterone concentration (54-57%) and proANF fragment (33%) were reduced in e nrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA/ETB rece ptor antagonism improves cardiac performance and attenuates ventricular rem odeling and premature mortality in an aggressive hypertension model.