Key result
Endothelin pathway inhibitors show cardiorenal promise but face clinical limits from fluid retention.
Why the study?
Endothelin-converting enzymes catalyze the final step in endothelin biosynthesis, and inhibitors of these enzymes may represent novel therapeutic agents for cardiovascular and related diseases.
Hypothesis-generating in animal models of hypertension and HF; leaves open clinical translation given fluid retention.
Endothelins (ETs) are potent vasoconstrictors, promitogens, and inflammatory mediators. They have been implicated in the pathogenesis of various cardiovascular, renal, pulmonary, and central nervous system diseases. Since the final step of the biosynthesis of ETs is catalyzed by a family of endothelin-converting enzymes (ECEs), inhibitors of these enzymes may represent novel therapeutic agents. Currently, seven isoforms of these metalloproteases have been identified; they all share a significant amino acid sequence identity with neutral endopeptidase 24.11 (NEP), another metalloprotease. Therefore, it is not surprising that the majority of ECE inhibitors also possess potent NEP inhibitory activity. To date, three classes of ECE inhibitors have been synthesized: dual ECE/NEP inhibitors, triple ECE/NEP/ACE inhibitors, and selective ECE inhibitors. Potential clinical applications of these compounds in hypertension, chronic heart failure, restenosis, renal failure, and cerebral vasospasm deduced from studies with relevant animal models are reviewed.
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Jeng et al. (2002) conducted a review in Cardiovascular, renal, and pulmonary diseases. Endothelin-converting enzyme (ECE) inhibitors and endothelin receptor antagonists was evaluated. Endothelin-converting enzyme inhibitors and receptor antagonists show therapeutic potential in cardiovascular and renal diseases, though clinical use is often limited by fluid retention.
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