title: Pharmacodynamic effects of C-domain-specific ACE inhibitors on the renin-angiotensin system in myocardial infarcted rats.
abstract: BACKGROUND
  The renin-angiotensin system (RAS) is a dynamic network that plays a critical role in blood pressure regulation and fluid and electrolyte homeostasis. Modulators of the RAS, such as angiotensin-converting enzyme (ACE) inhibitors, are widely used to treat hypertension, heart failure and myocardial infarction.
  
  
  METHODS
  The effect of ACE inhibitors (lisinopril and C-domain-selective LisW-S) on the constituent peptides of the RAS following myocardial infarction was examined in rats. Ten angiotensin peptides were analysed using a sensitive LC-MS/MS-based assay to examine both the circulating and equilibrium levels of these peptides.
  
  
  RESULTS
  Administration of lisinopril or LisW-S caused a significant decrease in Ang 1-8/Ang 1-10 ratios as determined by circulating and equilibrium peptide level analysis. Furthermore, Ang 1-7 levels were elevated by both ACE inhibitors, but only lisinopril decreased the Ang 1-5/Ang 1-7 ratio. This indicates LisW-S C-domain specificity as Ang 1-5 is generated by hydrolysis of Ang 1-7 by the N-domain. Further corroboration of LisW-S C-domain specificity is that only lisinopril increased the circulating levels of the N-domain ACE substrate Ac-SDKP.
  
  
  CONCLUSIONS
  LisW-S is able to effectively block ACE in vivo by C-domain-selective inhibition. The LC-MS/MS-based assay allows the evaluation of the pharmacologic impact of RAS inhibitors in different pathophysiological conditions.
authors.affiliation: Cardiovascular Research Unit, Division of Cardiothoracic Surgery, University of Cape Town, South Africa.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sharp
authors.affiliation: Attoquant Diagnostics GmbH, Campus-Vienna-Biocenter 5, Austria.
authors.forename: Marko
authors.initials: M
authors.lastname: Poglitsch
authors.affiliation: Cardiovascular Research Unit, Division of Cardiothoracic Surgery, University of Cape Town, South Africa.
authors.forename: Peter
authors.initials: P
authors.lastname: Zilla
authors.affiliation: Cardiovascular Research Unit, Division of Cardiothoracic Surgery, University of Cape Town, South Africa Edward.Sturrock@uct.ac.za.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Davies
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, South Africa.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000809:Angiotensins / Q000097:blood; D000818:Animals; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D055442:Metabolome / Q000187:drug effects; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D009842:Oligopeptides; D010455:Peptides; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; C058504:goralatide
keywords: LC-MS/MS; Lisinopril-tryptophan; angiotensin-converting enzyme; myocardial infarction; pharmacodynamics