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 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.
Willette
R N
RN
Department of Cardiovascular Pharmacology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406-0939, USA. robert_willette@gsk.com
Anderson
K M
KM
Nelson
A H
AH
Olzinski
A R
AR
Woods
T
T
Coatney
R W
RW
Aiyar
N
N
Ohlstein
E H
EH
Barone
F C
FC
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
D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans; D011498:Protein Precursors; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; C098288:enrasentan