期刊
JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
卷 16, 期 4, 页码 1149-1158出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1470320314568438
关键词
Lisinopril-tryptophan; pharmacodynamics; angiotensin-converting enzyme; LC-MS; MS; myocardial infarction
资金
- Wellcome Trust [WT088169MA]
- South African Medical Research Council (MRC) [415626]
- South African National Research Foundation (NRF) [R1008575]
- NRF, South Africa
- MRC, South Africa
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.
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