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The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans
Seed, Alison Kuc, Rhoda E. Maguire, Janet J. Hillier, Christopher Johnston, Fiona Essers, Hans de Voogd, Hanka J. McMurray, John Davenport, Anthony P.
Seed, Alison
Kuc, Rhoda E.
Maguire, Janet J.
Hillier, Christopher
Johnston, Fiona
Essers, Hans
de Voogd, Hanka J.
McMurray, John
Davenport, Anthony P.
Abstract
Aims: Inhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased. Main methods: Following oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml− 1 of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg− 1 min− 1 (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured. Key findings: At the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition. Significance: SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease.
Keywords
endothelin converting enzyme (ECE), neutral endopeptidase (NEP), SLV-306, daglutril, atrial natriuretic peptides big endothelin-1, C-terminal fragment (CTF), endothelin-1
Date
2012
Type
Journal article
Journal
Life Sciences
Book
Volume
91
Issue
13-14
Page Range
743-748
Article Number
ACU Department
Collections
Relation URI
Source URL
Event URL
Open Access Status
Open access
License
CC BY-NC-ND 4.0
File Access
Open