title: The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: British Heart Foundation Research Centre, University of Glasgow, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Seed
authors.forename: Rhoda E
authors.initials: RE
authors.lastname: Kuc
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Maguire
authors.forename: Christopher
authors.initials: C
authors.lastname: Hillier
authors.forename: Fiona
authors.initials: F
authors.lastname: Johnston
authors.forename: Hans
authors.initials: H
authors.lastname: Essers
authors.forename: Hanka J
authors.initials: HJ
authors.lastname: de Voogd
authors.forename: John
authors.initials: J
authors.lastname: McMurray
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Davenport
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D009320:Atrial Natriuretic Factor / Q000097:blood*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D001552:Benzazepines; D019332:Endothelin-1; C405520:SLV 306; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes