The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

[摘要] 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. (c) 2012 Elsevier Inc. All rights reserved.

[发布日期] 2012-10-15

[效力级别]  Proceedings Paper

[关键词] Endothelin converting enzyme (ECE);Neutral endopeptidase (NEP);SLV-306;Daglutril;Atrial natriuretic peptides big endothelin-1;C-terminal fragment (CTF);Endothelin-1