Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts

Objective: Although interest in diastolic heart failure is growing because of its clinical frequency, little is known about this type of heart failure. Our laboratory recently developed a diastolic heart failure model using Dahl salt-sensitive rat. In this model, gene expression of angiotensin-converting enzyme and endothelin (ET) system in the left ventricle was enhanced at heart failure stage without downregulation of angiotensin type 1a receptor mRNA level. However, the roles of these humoral systems in the transition to diastolic failure remain unclear. Methods: Subdepressor doses of angiotensin II type 1 (AT1) receptor and ET type A (ETA) receptor antagonists were administered in this model just after onset of hypertension, and their effects were investigated. Results: Neither AT1 nor ETA receptor blockade inhibited the early (13 weeks) compensatory left ventricular (LV) hypertrophy. This form of compensatory hypertrophy is associated with subnormal LV end-systolic stress, which was normalized by AT1 receptor blockade but not by ETA receptor blockade. Progression of LV hypertrophy and fibrosis and transition to heart failure (19 weeks) in the untreated rats were prevented by both antagonists, resulting in normalization of LV end-diastolic pressure and lung weight. AT1 receptor blockade, but not ETA receptor blockade, normalized time constant of LV relaxation. Enhanced gene expression for ET system in the left ventricle observed in the untreated rats was suppressed with AT1 receptor antagonist administration. ETA receptor blockade slightly but significantly elevated the AT1a receptor mRNA level as compared with the untreated rats. Conclusions: RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart diseases, however, neither RAS nor ET system is mandatory for normal compensation for pressure overload. RAS apparently causes such diastolic effects at least partly through the ET system.