Pharmacodynamic Effects of C-domain-specific ACE Inhibitors on the Renin-Angiotensin System in Myocardial Infarcted Rats

J Renin Angiotensin Aldosterone Syst. 2015 Dec;16(4):1149-58. doi: 10.1177/1470320314568438. Epub 2015 Mar 9.

Abstract

Introduction: 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.

Conclusion: 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.

Keywords: LC-MS/MS; Lisinopril-tryptophan; angiotensin-converting enzyme; myocardial infarction; pharmacodynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Angiotensins / blood
  • Animals
  • Lisinopril / pharmacology
  • Male
  • Metabolome / drug effects
  • Myocardial Infarction / blood
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / pathology
  • Oligopeptides / pharmacology
  • Peptides / blood
  • Peptidyl-Dipeptidase A / chemistry*
  • Protein Structure, Tertiary
  • Rats, Wistar
  • Renin-Angiotensin System / drug effects*

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Angiotensins
  • Oligopeptides
  • Peptides
  • Lisinopril
  • Peptidyl-Dipeptidase A
  • goralatide