19 February 2018 by Gaurav Choudhary

Treatment of pulmonary hypertension in rats with Angiotensin II Receptor Blocker Neprilysin Inhibitor.

Introduction

Angiotensin II has been implicated in the development of maladaptive RV hypertrophy and fibrosis associated with PH. Neprilysin degrades natriuretic peptides, increased levels of which may promote improved pulmonary vascular dilation, remodeling and decreased afterload. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, LCZ696, will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling.

Methods

PH was induced in rats using the Sugen/hypoxia model (3 weeks, 10% FiO2), followed by 6-week treatment (daily oral gavage) with placebo or LCZ696 (68 mg/kg). There were 3 groups- Con: normoxic animals with placebo (n=18), PH: Su/Hx rats + placebo (n=24), and PH +LCZ696: Su/Hx rats + LCZ696 (n=24). Animals were evaluated for differences in hemodynamics, cardiac function, RV hypertrophy and fibrosis, pulmonary vascular remodeling, and natriuretic peptide levels.

Results

Before treatment, both PH and PH +LCZ696 groups had changes consistent with PH as shown by echocardiography including increased PA pressures, RV wall thickness, and reduced RV function (RV s’). Treatment with LCZ696 resulted in significant improvements in PAT, RV wall thickness, and RV s’ as well as reductions in RV systolic pressure. There was significant RV hypertrophy in PH+placebo (compared to Con) that was normalized in the PH+LCZ696 group (p<.05, RV/LV weight ratio PH vs PH+LCZ696). PH animals had increased pulmonary vascular wall thickness that was reduced with LCZ696 (PH vs PH+LCZ, p=.05). PH+LCZ696 animals had increased ANP, BNP, and cGMP levels in serum and lung tissue compared to PH alone (P<.05) and altered expression of PKC isozymes in RV tissue.

Conclusion

LCZ696 reduces pulmonary pressures, vascular remodeling as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of RH failure associated with pulmonary hypertension.

Key Contributors

Richard Clements PhD, Alexander Vang, Richard Kue, Thomas Mancini, Gaurav Choudhary MD Vascular Research Laboratory, Providence VA Medical Center, Providence RI and Department of Medicine, Alpert Medical School of Brown University, Providence RI.


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