Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia

Abstract

1Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2 One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3 Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NClO) and all other animals were placed in a normobaric hypoxic chamber (Fi 02 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-', twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4 Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5 CHClO rats had significant right ventricular hypertrophy (0.53 ± 0.08) and pulmonary vascular remodelling (29.0 0.01%) and had gained significantly less body weight (33.2 ± 5.5 g) than NC1O rats (0.31 ± 0.04, 10.9 0.01%, and 59.2 ± 11.9 g respectively). CHC1O rats had significantly elevated plasma ANP levels (58.4 ± 9.9 pM) compared with NClO rats (23.9 ± 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 ± 0.01%) and right ventricular hypertrophy (0.52 ± 0.09) in CHT20 rats compared with CHV20 controls (33.0 ± 0.02% and 0.61 ± 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals. 6 Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.

Current and future treatments of pulmonary arterial hypertension

“…ClinicalTrials.gov identifier: NCT03229499). Furthermore, the effect of oestrogen inhibition with tamoxifen will be investigated in patients with PAH in a small randomised controlled trial (RCT; (Dempsey et al, 2009), pharmacological inhibition of neprilysin alone or in combination with PDE5 inhibition attenuated PH in chronic hypoxic rats without affecting systemic circulation (Baliga et al, 2008;Thompson, Sheedy, & Morice, 1994).…”

“…Studies of neprilysin in animal models of PH showed conflicting results. While neprilysin‐deficient mice exhibited an exaggerated response to chronic hypoxia (Dempsey et al, 2009), pharmacological inhibition of neprilysin alone or in combination with PDE5 inhibition attenuated PH in chronic hypoxic rats without affecting systemic circulation (Baliga et al, 2008; Thompson, Sheedy, & Morice, 1994). Recently, the efficacy and safety of the neprilysin inhibitor racecadotril was tested in an RCT in PAH.…”

The Regulation of Pulmonary Vascular Tone by Neuropeptides and the Implications for Pulmonary Hypertension

“…NEPs appear to have an underlying role in the pathogenesis of PH ( Dempsey et al, 2009 ). NEP inhibitors have produced promising results in models of PH, both as monotherapy ( Klinger et al, 1993 ; Thompson et al, 2012 ) or in combination with PDE5 inhibition ( Baliga et al, 2008 ). This is largely due to their ability to increase circulating atrial natriuretic peptide.…”

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double‐blind, placebo‐controlled, proof‐of‐concept trial

“…NEP is a membrane bound zinc metallopeptidase responsible for the metabolism and inactivation of an array of vasodilator (e.g., natriuretic peptides, adrenomedullin, vasoactive intestinal peptide) and vasoconstrictor (e.g., angiotensin II, endothelin-1 [ET-1]) peptides (Erdos & Skidgel, 1989;Kenny & Stephenson, 1988). Indeed, preclinical evidence indicates that NEP −/− mice are less susceptible to hypoxiainduced pulmonary oedema (Irwin, Patot, Tucker, & Bowen, 2005) and that inhibition of NEP attenuates hypoxia-induced PH by potentiating the action of natriuretic peptides Thompson, Sheedy, & Morice, 1994;Winter, Zhao, Krausz, & Hughes, 1991). These observations fit with the up-regulation of NEP in the pulmonary circulation during acute lung injury and heart failure (Abassi, Kotob, Golomb, Pieruzzi, & Keiser, 1995;Hashimoto, Amaya, Oh-Hashi, Kiuchi, & Hashimoto, 2010).…”