TY - JOUR
T1 - Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure
AU - Andersen, Stine
AU - Axelsen, Julie Birkmose
AU - Ringgaard, Steffen
AU - Nyengaard, Jens Randel
AU - Hyldebrandt, Janus Adler
AU - Bogaard, Harm Jan
AU - de Man, Frances S.
AU - Nielsen-Kudsk, Jens Erik
AU - Andersen, Asger
PY - 2019/10/15
Y1 - 2019/10/15
N2 - 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.
AB - 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.
KW - Angiotensin II
KW - Animal models
KW - Natriuretic peptides
KW - Pulmonary hypertension
KW - Right ventricular failure
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068748353&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31307846
UR - http://www.scopus.com/inward/record.url?scp=85068748353&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ijcard.2019.06.065
DO - https://doi.org/10.1016/j.ijcard.2019.06.065
M3 - Article
C2 - 31307846
SN - 0167-5273
VL - 293
SP - 203
EP - 210
JO - International journal of cardiology
JF - International journal of cardiology
ER -