Enrasentan Improves Survival, Limits Left Ventricular Remodeling, and Preserves Myocardial Performance in Hypertensive Cardiac Hypertrophy and Dysfunction

Abstract

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.

Novel Neurohormonal Antagonist Strategies: Vasopressin Antagonism, Anticytokine Therapy, and Endothelin Antagonism in Patients Who Have Heart Failure

“…Enrasentan, another nonselective ET-A/ET-B receptor-antagonist, was evaluated in a rat model of hypertensive cardiac hypertrophy and dysfunction [149]. Sixteen-week survival was significantly better than controls, and improvements in SV and CI, indices of LV mass, and circulating aldosterone were observed, again suggesting that combined ET-A/ ET-B receptor antagonism has the potential to attenuate ventricular remodeling in the experimental setting.…”

Enrasentan, an Antagonist of Endothelin Receptors

“…Cosenzi et al have demonstrated that the drug normalizes blood pressure and protects target organs in rats with hypertension induced by a high fructose diet (14). In SHR-stroke prone rats with high-salt, high fat diet the reduction in blood pressure was not significant (68).…”

Comparison of the dual receptor endothelin antagonist enrasentan with enalapril in asymptomatic left ventricular systolic dysfunction: a cardiovascular magnetic resonance study

“…Enrasentan treated rats with cardiac hypertrophy and dysfunction induced by banding had higher stroke volume and cardiac index, improved survival, and reduced LV mass index, aldosterone, and pro-atrial natriuretic peptide concentrations. 7 The present study is the first to have compared an endothelin antagonist, enrasentan, directly with an ACE inhibitor, enalapril, in asymptomatic patients with LV dysfunction. The goal was to determine whether treatment with an endothelin receptor antagonist may have an early role in slowing the progression of HF.…”