Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure.
Aminobutyrates
/ pharmacology
Angiotensin II Type 2 Receptor Blockers
/ pharmacology
Animals
Antihypertensive Agents
/ pharmacology
Biphenyl Compounds
Disease Models, Animal
Drug Combinations
Heart Ventricles
/ drug effects
Hypertension, Pulmonary
/ drug therapy
Hypertrophy, Right Ventricular
/ drug therapy
Pulmonary Circulation
/ drug effects
Rats
Tetrazoles
/ pharmacology
Valsartan
Vascular Remodeling
/ drug effects
Ventricular Dysfunction, Right
/ drug therapy
Angiotensin II
Animal models
Natriuretic peptides
Pulmonary hypertension
Right ventricular failure
Journal
International journal of cardiology
ISSN: 1874-1754
Titre abrégé: Int J Cardiol
Pays: Netherlands
ID NLM: 8200291
Informations de publication
Date de publication:
15 10 2019
15 10 2019
Historique:
received:
18
02
2019
revised:
03
06
2019
accepted:
24
06
2019
pubmed:
17
7
2019
medline:
10
7
2020
entrez:
17
7
2019
Statut:
ppublish
Résumé
Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure. Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks. In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function. Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.
Sections du résumé
BACKGROUND
Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure.
METHODS
Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks.
RESULTS
In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function.
CONCLUSIONS
Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.
Identifiants
pubmed: 31307846
pii: S0167-5273(19)30876-9
doi: 10.1016/j.ijcard.2019.06.065
pii:
doi:
Substances chimiques
Aminobutyrates
0
Angiotensin II Type 2 Receptor Blockers
0
Antihypertensive Agents
0
Biphenyl Compounds
0
Drug Combinations
0
Tetrazoles
0
Valsartan
80M03YXJ7I
sacubitril and valsartan sodium hydrate drug combination
WB8FT61183
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
203-210Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.