Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats

Klinger, James R.; Petit, R; Warburton, Rod R.; Wrenn, David S.; Arnal, F; Hill, Nicholas S.

doi:10.1152/jappl.1993.75.4.1615

Cited by 22 publications

(17 citation statements)

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“…ANP activity is associated with an increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) (Tremblay et al, 1985). In the study by Klinger et al (1993b), SCH 42495 reduced pulmonary and renal NEP activity by 50% but as in our study, plasma ANP was significantly decreased. The significant increase in urinary levels of cyclic GMP seen by Klinger et al suggests that the biological activity of ANP is increased by NEP inhibition.…”

Section: Discussionsupporting

confidence: 44%

“…Similarly, Klinger et al (1993b) showed that rats treated with the less potent NEP inhibitor, SCH 34826 (90 mg kg-'; twice daily) during 3 weeks of chronic hypoxia had a significantly lower degree of right ventricular hypertrophy, and less pulmonary vascular remodelling, despite a significant reduction in plasma ANP levels. How then does NEP inhibition lead to modification of the cardio-pulmonary response to hypoxia without elevation of plasma ANP?…”

Section: Discussionmentioning

confidence: 92%

“…We and others have previously found that NEP inhibition caused a significant reduction in the cardio-pulmonary remodelling associated with the development of pulmonary hypertension in rats exposed to chronic hypoxia Stewart et al, 1992;Klinger et al, 1993b;Thompson et al, 1994). Unfortunately, these models are of limited clinical relevance in that they study the development of pulmonary hypertension.…”

Section: Introductionmentioning

confidence: 99%

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

Thompson

Sheedy

Morice

1994

British J Pharmacology

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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.

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Section: Discussionsupporting

confidence: 44%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

Thompson

Sheedy

Morice

1994

British J Pharmacology

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“…Neutral endopeptidase is a major enzymatic pathway for the degradation of BNP and also plays a role in kinin and adrenomedulin breakdown. 193 Inhibition of NEP increases plasma levels of BNP 193 and has been shown to inhibit hypoxic pulmonary hypertension in rats, 194 although the mechanism by which this was achieved is not known.…”

Section: Dovepressmentioning

confidence: 99%

Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent

Casserly

Klinger²

2009

DDDT

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B-type natriuretic peptide (BNP) is a member of the natriuretic peptide family, a group of widely distributed, but evolutionarily conserved, polypeptide mediators that exert myriad cardiovascular effects. BNP is a potent vasodilator with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. Circulating levels of BNP correlate with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH). Elevated plasma BNP levels are associated with increased mortality in patients with PAH and a fall in BNP levels after therapy is associated with improved survival. These findings have important clinical implications in that a noninvasive blood test may be used to identify PAH patients at high-risk of decompensation and to guide pulmonary vasodilator therapy. BNP also has several biologic effects that could be beneficial to patients with PAH. However, lack of a convenient method for achieving sustained increases in circulating BNP levels has impeded the development of BNP as a therapy for treating pulmonary hypertension. New technologies that allow transdermal or oral administration of the natriuretic peptides have the potential to greatly accelerate research into therapeutic use of BNP for cor pulmonale and pulmonary vascular diseases. This review will examine the basic science and clinical research that has led to our understanding of the role of BNP in cardiovascular physiology, its use as a biomarker of right ventricular function and its therapeutic potential for managing patients with pulmonary vascular disease.

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“…Early studies, conducted with inhibitors of NEP, suggested that this peptidase may contribute to chronic hypoxic PHTN. 24,25 However, recent observations in other systems support the possibility that NEP could actually be protective against PHTN, through both peptidase-dependent (eg, degradation of selected vasoactive neuropeptides) and peptidase-independent (eg, complex formation of NEP's intracellular cytosolic domain with signaling molecules) mechanisms. 26 Even the peptidase-dependent effects may extend beyond neuropeptide targets.…”

mentioning

confidence: 99%

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Dempsey

Wick

Karoor³

et al. 2009

The American Journal of Pathology

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Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder. Chronic hypoxic pulmonary hypertension (PHTN) is a major clinical problem, complicating most lung and heart disorders. 1,2 In large animal models of chronic hypoxic PHTN that closely resemble human disease, the earliest pulmonary artery (PA) smooth muscle cell (SMC) proliferative changes occur at the medial/adventitial border. 3 Growth and migration of SMC and myofibroblasts in distal vessels is also a prominent feature. 4,5 These structural changes, together with derangements in vascular tone, are major contributors to the severity of chronic hypoxic PHTN. [1][2][3][4][5][6] However, mechanisms that regulate susceptibility to, and severity of, chronic hypoxic PHTN and vascular remodeling remain poorly understood. Currently available treatments for chronic hypoxic PHTN are also inadequate.

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Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats

Cited by 22 publications

References 0 publications

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

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

Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

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