title: 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.
authors.affiliation: Department of Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406-0939, USA. robert_willette@gsk.com
authors.forename: R N
authors.initials: RN
authors.lastname: Willette
authors.forename: K M
authors.initials: KM
authors.lastname: Anderson
authors.forename: A H
authors.initials: AH
authors.lastname: Nelson
authors.forename: A R
authors.initials: AR
authors.lastname: Olzinski
authors.forename: T
authors.initials: T
authors.lastname: Woods
authors.forename: R W
authors.initials: RW
authors.lastname: Coatney
authors.forename: N
authors.initials: N
authors.lastname: Aiyar
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: F C
authors.initials: FC
authors.lastname: Barone
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002264:Carboxylic Acids / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D017379:Hypertrophy, Left Ventricular / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011498:Protein Precursors / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D015996:Survival Rate; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans; D011498:Protein Precursors; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; C098288:enrasentan