Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor Sacubitril/Valsartan

Abstract

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.

Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury

“…ACE-I and ARB are cornerstone not only for hypertension but also for HF treatment. An emerging topic of interest is the potential role of angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/ valsartan in patients with pulmonary vascular remodeling, pulmonary hypertension, and right ventricular overload related to lung diseases (10). The synergistic effects of RAS and neprilysin inhibition, versus RAS inhibition alone, may magnify the protective benefits of natriuretic peptides by reducing fibrosis and vascular remodeling and promoting vasodilation and natriuresis (80).…”

“…The synergistic effects of RAS and neprilysin inhibition, versus RAS inhibition alone, may magnify the protective benefits of natriuretic peptides by reducing fibrosis and vascular remodeling and promoting vasodilation and natriuresis ( 80 ). Given the prevalence and the negative prognostic role of myocardial injury in COVID-19 patients ( 11 ), ARNI may not only be effective in reducing morbidity and mortality in patients with chronic symptomatic HF with reduced ejection fraction (HFrEF) ( 55 ) but may also counterbalance the Ang II-AT 1 R pathway, which has been implicated in maladaptive right ventricular hypertrophy and fibrosis associated with pulmonary hypertension ( 10 ). Indeed, neprilysin inhibition is intimately related to RAS activation, but it is unclear whether ARNI has any impact on ACE2 or in COVID-19 patients.…”

ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism

“…Local tissue-based RAS exacerbates pulmonary hypertension, acute lung injury and experimental lung fibrosis [8]. Thus, blocking of the Angiotensin II receptor type I (AT1R) was associated with reduced SARS-CoV spike protein mediated lung injury [6] and reduced pulmonary hypertension in experimental models [9]. The AT1R blocker valsartan has recently been reported to improve clinical outcomes for patients with chronic obstructive pulmonary disease (COPD) complicated with pulmonary hypertension (DOI:10.1183/13993003.congress-2019.PA2469).…”

Dual Angiotensin Receptor and Neprilysin Inhibitor Ameliorates Portal Hypertension in Portal Hypertensive Rats

“…It is worth noting that neprilysin inhibition upregulated the ET-1 level, particularly in neprilysin-rich organs like the kidney [21]. However, another study showed that ARNI reduced the plasma ET-1 level in rats with pulmonary hypertension [22]. The various findings may be related to different research subjects and experimental settings.…”