Endopeptidase-24.11 and its inhibitors: Potential therapeutic agents for edematous disorders and hypertension

Endopeptidase-24.11 (E-24.11) is a zinc-dependent cell-surface enzyme. First characterized as a peptidase of the brush border of the renal proximal tubule and purified from rabbit kidneys [1, 2], it has since been identified immunologically in a number of tissues, including other brush borders (intestine, placenta, choroid plexus), gonads, epithelia of the genital tracts, peripheral nerves and brain [3–14]. It therefore has a wide, but by no means ubiquitous, tissue distribution and is capable of hydrolyzing many natural and synthetic peptide substrates, such as neuropeptides, the natriuretic peptides and the endothelins [15–25], attributes that suggest that it may have multiple physiological functions. Therapeutic interest first focused on its action in the brain, where E-24.11 (enkephalinase) had been shown to participate in the metabolism of endogenous opioid peptides, such as the enkephalins. It was reasoned that inhibitors of the enzyme might be useful as analgesics by increasing endogenous enkephalin levels, but so far no clinically useful compounds have emerged. More recently, attention has been given to the role of this enzyme in clearing peptides with natriuretic actions, in particular atrial and brain natriuretic peptide (ANP and BNP). The demonstration that both ANP and BNP are good substrates for E-24.11 [22, 26–28] has raised the possibility that E-24.11 inhibitors might be used to potentiate their natriuretic and hypotensive actions and have a place in the management of heart failure and hypertension. This review will focus on the renal and cardiovascular pharmacology of E-24.11 inhibitors and their potential use as therapeutic agents.