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

Savitha, Mysuru Natarajan and Suvilesh, Kanve Nagaraj and Siddesha, Jalahalli Mariswamy and Gowda, M. D. Milan and Choudhury, Manisha and Velmurugan, Devadasan and Umashankar, Muddegowda and Vishwanath, Bannikuppe Sannanaik (2020) 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. Peptides, 123.

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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 IC50 of 83 nmol/L, V-N(Me)F-R inhibited NEP activity with an IC50 of 1.173 mu mol/L and R-N(Me)V-Y inhibited APN activity with an IC50 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.

Item Type: Article
Uncontrolled Keywords: Angiotensin converting enzyme; Neutral endopeptidase; Aminopeptidase N; F-N(Me)H-L; V-N(Me)F-R; R-N(Me)V-Y; Atrial natriuretic peptide
Subjects: C Chemical Science > Biochemistry
Divisions: Department of > Biochemistry
Depositing User: Mr Umendra uom
Date Deposited: 30 Jan 2021 11:05
Last Modified: 01 Feb 2021 06:02
URI: http://eprints.uni-mysore.ac.in/id/eprint/15680

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