Endothelin in heart failure: a promising therapeutic target?

The results of early acute haemodynamic studies with anti-endothelin agents are promising. Much still needs to be done, however, before endothelin antagonism is established as a therapeutic strategy in heart failure. We need to know, for example, whether the haemodynamic effects of anti-endothelin drugs are sustained. We need to ensure that there is no reflex activation of other neuroendocrine systems and, preferably, to demonstrate neuroendocrine suppression. Characterisation of the renal actions of endothelin receptor antagonists will also be important. Perhaps the most pressing issue in the development of these agents is elucidation of the role of the endothelial ETB receptor in heart failure. It is now clearly shown that vascular smooth muscle ETB receptors can mediate vasoconstriction in human blood vessels and that these receptors may be particularly important in heart failure. The effect of selective ETB receptor blockade in humans in vivo is not currently known, however, and whether endothelial ETB receptors might tonically offset ETA and ETB receptor mediated smooth muscle contraction remains conjectural. This question is directly relevant to whether selective ETA or non-selective ETA and ETB receptor antagonism might be the better therapeutic strategy in heart failure. ECE inhibition may become another therapeutic option in due course, but at present no specific and selective inhibitors of the enzyme have been developed. The recent demonstration that the selective ETA receptor antagonist BQ-123 improves long term survival in rats with heart failure induced by myocardial infarction suggests that anti-endothelin strategies may hold great therapeutic promise in heart failure.