Endothelin antagonism in experimental ischemic heart failure: hemodynamic, structural and neurohumoral effects

P Mulder, V Richard, C Thuillez
Heart Failure Reviews 2001, 6 (4): 295-300
Heart failure is characterized both by an activation of the endothelin system and an increased vasoconstrictor contractile response to the peptide. Given its pharmacological profile, it is likely that endothelin (ET-1) plays a deleterious role in the development of heart failure, and that blockers of the endothelin system are beneficial in this disease. Indeed, in rats with heart failure, ET(A) and dual ET(A)-ET(B) receptor antagonists reduce arterial pressure as well as left ventricular end diastolic pressure. The same antagonists also prevent the degradation of left ventricular function, as evidenced by the increased left ventricular fractional shortening and wall thickening. ET(A) and ET(A)-ET(B) antagonists also reduce LV dilatation and LV fibrosis, but do not affect LV hypertrophy. Moreover, comparison between selective ET(A) and combined ET(A)-ET(B) antagonists reveal no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. However, only combined ET(A)-ET(B) antagonists significantly decreased heart rate. ET(B) antagonists alone do not affect blood pressure or LV hemodynamics, but reduce LV fibrosis. With regard to survival, we have shown that long term treatment with the dual ET(A)-ET(B) antagonist bosentan increased survival to the same extent as an angiotensin converting enzyme inhibitor. However, the effect of selective ET(A) antagonists on survival is more controversial, since we found that the non-peptide ET(A) antagonists LU 135252 did not affect survival of rats with myocardial infarction, while others have shown that the peptide ET(A) antagonist BQ-123 increased survival in the same model. These conflicting data regarding the efficacy of selective ET(A) vs dual ET(A)-ET(B) blockade points out the need for controlled long term studies comparing the effects of theses two pharmacological approaches on survival.

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