Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor Sacubitril/Valsartan
| Autor: | Krishna Mallem, Alexander Vang, Alan R. Morrison, Thomas Mancini, Richard T. Clements, Gaurav Choudhary, Danielle J. McCullough, Ana Fernandez-Nicolas, Nouaying R. Kue |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Angiotensin receptor Hypertension Pulmonary Ventricular Dysfunction Right Tetrazoles 030204 cardiovascular system & hematology Pulmonary Artery Vascular Remodeling Article Muscle hypertrophy Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Afterload Internal medicine Renin–angiotensin system Medicine Animals Arterial Pressure Protease Inhibitors Neprilysin Antihypertensive Agents 030304 developmental biology 0303 health sciences Hypertrophy Right Ventricular Ventricular Remodeling business.industry Aminobutyrates Biphenyl Compounds medicine.disease Angiotensin II Pulmonary hypertension Fibrosis Disease Models Animal Drug Combinations Cardiology Ventricular Function Right Valsartan Female Cardiology and Cardiovascular Medicine business Angiotensin II Type 1 Receptor Blockers Sacubitril Valsartan |
| Zdroj: | Circ Heart Fail |
| ISSN: | 1941-3297 |
| Popis: | Background: Angiotensin II has been implicated in maladaptive right ventricular (RV) hypertrophy and fibrosis associated with pulmonary hypertension (PH). Natriuretic peptides decrease RV afterload by promoting pulmonary vasodilation and inhibiting vascular remodeling but are degraded by neprilysin. We hypothesized that angiotensin receptor blocker and neprilysin inhibitor, sacubitril/valsartan (Sac/Val, LCZ696), will attenuate PH and improve RV function by targeting both pulmonary vascular and RV remodeling. Methods: PH was induced in rats using the SU5416/hypoxia model (Su/Hx), followed by 6-week treatment with placebo, Sac/Val, or Val alone. There were 4 groups: CON—normoxic animals with placebo (n=18); PH−Su/Hx rats+placebo (n=34); PH+Sac/Val (N=24); and PH+Val (n=16). Results: In animals with PH, treatment with Sac/Val but not Val resulted in significant reduction in RV pressure (mm Hg: PH: 62±4, PH+Sac/Val: 46±5), hypertrophy (RV/LV+S: PH: 0.74±0.06, PH+Sac/Val: 0.46±0.06), collagen content (µg/50 µg protein: PH: 8.2±0.3, PH+Sac/Val: 6.4±0.4), pressures and improvement in RVs (mm/s: PH: 31.2±1.8, PH+Sac/Val: 43.1±3.6) compared with placebo. This was associated with reduced pulmonary vascular wall thickness, increased lung levels of ANP (atrial natriuretic peptide), BNP (brain-type natriuretic peptide), and cGMP, and decreased plasma endothelin-1 compared with PH alone. Also, PH+Sac/Val animals had altered expression of PKC isozymes in RV tissue compared with PH alone. Conclusions: Sac/Val reduces pulmonary pressures, vascular remodeling, as well as RV hypertrophy in a rat model of PH and may be appropriate for treatment of pulmonary hypertension and RV dysfunction. |
| Databáze: | OpenAIRE |
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