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Combinatorial inhibition of Angiotensin converting enzyme, Neutral endopeptidase and Aminopeptidase N by N-methylated peptides alleviates blood pressure and fibrosis in rat model of dexamethasone-induced hypertension.
- Source :
-
Peptides [Peptides] 2020 Jan; Vol. 123, pp. 170180. Date of Electronic Publication: 2019 Nov 10. - Publication Year :
- 2020
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Abstract
- Angiotensin converting enzyme (ACE), neutral endopeptidase (NEP) and aminopeptidase N (APN) are responsible for generation of vasoactive peptides that regulates vasoconstriction, vasodilation and natriuresis, which altogether regulate blood pressure. Cumulative inhibition of ACE, NEP and APN effectively blocks the progression of respective pathways. In this study, N-methylated peptide inhibitors F-N(Me)H-L, V-N(Me)F-R and R-N(Me)V-Y were synthesized against ACE, NEP and APN respectively, using their respective physiological substrates. F-N(Me)H-L inhibited ACE activity with an IC <subscript>50</subscript> of 83 nmol/L, V-N(Me)F-R inhibited NEP activity with an IC <subscript>50</subscript> of 1.173 μmol/L and R-N(Me)V-Y inhibited APN activity with an IC <subscript>50</subscript> of 3.94 nmol/L respectively. Further, the anti-hypertensive effect of N-methylated peptides was evaluated using rat model of dexamethasone-induced hypertension. Individual peptides and their cocktail treatment were started from day 6 of the study period and blood pressure was measured on every alternate day during 15 day study. Administration of F-N(Me)H-L (138 ± 3 mmHg) and cocktail of all the three peptides at a dose of 100 mg/kg significantly reduced systolic blood pressure (SBP) compared to dexamethasone group (SBP of Groups-dexamethasone; (167 ± 5 mmHg), F-N(Me)H-L (138 ± 3 mmHg), and Cocktail (122 ± 3 mmHg). Anti-hypertensive, anti-hypertrophic and anti-fibrotic effects of N-methylated peptides and cocktail was further reflected by the decreased levels of circulating Ang II and increased ANP levels in sera of hypertensive rats along with decrease in collagen deposition in heart and kidney. Though, ACE inhibition is adequate to reduce SBP, targeting NEP and APN along with ACE is beneficial in tackling hypertension and associated fibrosis of heart.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Angiotensin-Converting Enzyme Inhibitors chemistry
Angiotensin-Converting Enzyme Inhibitors pharmacology
Animals
Dexamethasone pharmacology
Disease Models, Animal
Male
Methylation
Rats
Rats, Wistar
Antihypertensive Agents chemistry
Antihypertensive Agents pharmacology
CD13 Antigens antagonists & inhibitors
CD13 Antigens metabolism
Dexamethasone adverse effects
Hypertension chemically induced
Hypertension drug therapy
Hypertension enzymology
Matrix Metalloproteinase Inhibitors chemistry
Matrix Metalloproteinase Inhibitors pharmacology
Neprilysin antagonists & inhibitors
Neprilysin metabolism
Peptides chemistry
Peptidyl-Dipeptidase A metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5169
- Volume :
- 123
- Database :
- MEDLINE
- Journal :
- Peptides
- Publication Type :
- Academic Journal
- Accession number :
- 31715212
- Full Text :
- https://doi.org/10.1016/j.peptides.2019.170180