Sacubitril/valsartan alleviates sepsis-induced myocardial injury in rats via dual angiotensin receptor-neprilysin inhibition and modulation of inflammasome/caspase 1/IL1β pathway.

Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE

Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.

Aminobutyrates*/pharmacology ; Aminobutyrates*/therapeutic use ; Biphenyl Compounds*/pharmacology ; Biphenyl Compounds*/therapeutic use ; Caspase 1*/metabolism ; Drug Combinations* ; Inflammasomes*/metabolism ; Interleukin-1beta*/metabolism ; Neprilysin*/antagonists & inhibitors ; Neprilysin*/metabolism ; Sepsis*/complications ; Sepsis*/drug therapy ; Sepsis*/metabolism ; Tetrazoles*/pharmacology ; Tetrazoles*/therapeutic use ; Valsartan*/pharmacology ; Valsartan*/therapeutic use; Animals ; Male ; Rats ; Angiotensin Receptor Antagonists/pharmacology ; Angiotensin Receptor Antagonists/therapeutic use ; Cardiomyopathies/drug therapy ; Cardiomyopathies/etiology ; Cardiomyopathies/metabolism ; Cardiomyopathies/pathology ; Myocardium/pathology ; Myocardium/metabolism ; Oxidative Stress/drug effects ; Rats, Wistar ; Receptors, Angiotensin/metabolism ; Signal Transduction/drug effects

Sepsis is a life-threatening situation that ultimately affects cardiac function, leading to cardiomyopathy and myocardial injury as a result of uncontrolled response to infection.Till now, there is limited effective treatment to rescue those cases. Thus, novel therapeutic strategies should be identified to achieve better outcomes for septic patients. For the first time, we aimed to evaluate the effect of sacubitril/valsartan (Sac/Val) on sepsis-induced cardiac injury. Wistar male adult albino rats were randomly divided into four groups; Group I received the vehicle; Group II was given the vehicle plus 1 ml saline containing viable Escherichia coli (E. coli) (2.1 × 10 ⁹  cfu) by intraperitoneal (i.p.) injection on the 1st and 2nd days; Group III received i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) and Nitro- ω-L-arginine (L-NNA) (25 mg/kg/day) for 7 days. Group IV was administered i.p. injection as group II plus oral administration of Sac/Val (30 mg/kg/day) for 7 days. Our data (n = 10) revealed successful induction of sepsis as it showed a significant increase in the measured cardiac enzymes, malondialdehyde (MDA), angiotensin II (Ang II), neprilysin, inflammasome, caspase 1, interleukin (IL)1β, and caspase 3 with cardiac histopathological changes, but there was a significant decrease in the antioxidants and blood pressure (BP). Co-administration of Sac/Val could obviously improve these changes. Interestingly, L-NNA given group showed a decrease in the cardioprotective effect of Sac/Val. Sac/Val could ameliorate sepsis induced cardiac damage via inhibition of Ang II and neprilysin with anti-inflammatory, anti-oxidant and anti-apoptotic properties.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)

Keywords: Angiotensin; Inflammasome; Interleukin1β; Neprilysin; Sacubitril/valsartan; Sepsis

0 (Aminobutyrates)
0 (Angiotensin Receptor Antagonists)
0 (Biphenyl Compounds)
EC 3.4.22.36 (Caspase 1)
0 (Drug Combinations)
0 (Inflammasomes)
0 (Interleukin-1beta)
EC 3.4.24.11 (Neprilysin)
0 (Receptors, Angiotensin)
WB8FT61183 (sacubitril and valsartan sodium hydrate drug combination)
0 (Tetrazoles)
80M03YXJ7I (Valsartan)

Date Created: 20240722 Date Completed: 20240816 Latest Revision: 20240822

20240823

10.1016/j.ejphar.2024.176834

39038638