Long-term treatment with neutral endopeptidase inhibitor improves cardiac function and reduces natriuretic peptides in rats with chronic heart failure

Maki, Toshihide; Nasa, Yoshihisa; Yamaguchi, Fuminari; Yoshida, Hiroyuki; Mori, Masaya; Takada, Taku; Horikawa, Eriko; Okano, Kaori; Takeo, Satoshi

doi:10.1016/s0008-6363(01)00258-9

Cited by 25 publications

(12 citation statements)

References 25 publications

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“…Our studies also demonstrate that the pulmonary and systemic circulations of NEP Ϫ/Ϫ mice do not respond to hypoxia in the same manner. The cardiac findings in our study are consistent with observations made with more specific NEP antagonists alone and in combination with ACE inhibitors 29,30,53 and with the original description of the cardiac phenotype of the NEP Ϫ/Ϫ mouse. 33 There was no evidence of differential structural change in the left ventricle of NEP ϩ/ϩ or NEP Ϫ/Ϫ mice following chronic hypoxia, making increased cardiac dysfunction an unlikely explanation for the pulmonary vascular and right heart findings here.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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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“…Finally, BNP level is, to a great extent, degraded by clearance receptors and neutral endopeptidase mostly located in the kidney but also found in the lungs, brain, heart, and peripheral vasculature. [32][33][34] Adipose tissue may afford another source of available clearance receptors and neutral endopeptidase, leading to more rapid degradation of BNP. In addition, natriuretic peptides have recently been found 35,36 to be lipolytic in adipose tissue; hence, higher BNP levels may have potentially facilitated weight loss and the lower body weights we observed in individuals with high BNP levels.…”

Section: Commentmentioning

confidence: 99%

Relationship Between Obesity and B-Type Natriuretic Peptide Levels

McCord

Mundy²,

Hudson³

et al. 2004

Arch Intern Med

150

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“…ANP and ET-1 were extracted from the plasma using Sep-Pak C18 cartridges (Waters of Millipore, Milford, MA) that had been preconditioned with methanol followed by 0.2 mol/L sodium phosphate-citric acid and were passed through the equilibrate cartridge. After washing with water, the cartridges were eluted with methanol-water (90:10, v/v), then ANP and ET-1 concentrations determined by the sandwich-enzyme immuno-assay method [Maki et al, 2001].…”

Section: Biochemical Parameters Of Acute and Chronic Heart Failurementioning

confidence: 99%

Therapeutic effects of CPU 86017 on acute and chronic congestive cardiac failure mediated by reducing ET‐1?NOS and oxidative stress in rats

Wang

Shi

Dai

2004

Drug Development Research

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CPU 86017, a derivative of berberine, was administered to rats in which acute and chronic heart failure was induced by left coronary artery ligation for 3 h and 8 weeks, respectively. The rats were divided into the following groups: sham operation, coronary artery ligation (CAL), CALþ CPU 86017 (80, 40 and 20 mg/kg, ig) and CALþ captopril (60 mg/kg, ig). In the acute model, the systolic parameters of LVSP and LVþdp/dtmax as well as the diastolic parameters of LVEDP and LV-dp/dtmin improved significantly on pretreatment of CPU 86017 (80 mg/kg). Reductions in elevated serum CPK, LDH, MDA, GOT, GPT, infarcted area and blood viscosity were also significant (P o 0.01). In the chronic model, CPU 86017 (80 mg/kg) preserved the systolic parameters of LVSP and LVþdp/dtmax and the diastolic function of the LVEDP and LV-dp/dtmin. CPU 86017 completely suppressed elevated plasma ANP and ET-1, serum and tissue iNOS, NO and MDA, whereas the decreased SOD was improved. CPU 86017 and captopril improved cardiac failure performance and regressed cardiac remodeling in CHF by reducing tissue weight index: lung weight/body weight (BW), right ventricular weight/BW, and left ventricular weight/BW. CPU 86017 exerted beneficial actions in cardiac performance in models of both acute and chronic heart failure, mainly by suppressing ET-1, iNOS, and oxidative stress in infarcted tissue.

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Long-term treatment with neutral endopeptidase inhibitor improves cardiac function and reduces natriuretic peptides in rats with chronic heart failure

Abstract: The results suggest that chronic treatment with NEP inhibitor improves depressed cardiac function in rats with CHF. ONO-9902 may offer a new and possible therapeutic approach in patients with CHF.

Cited by 25 publications

References 25 publications

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

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

Relationship Between Obesity and B-Type Natriuretic Peptide Levels

Therapeutic effects of CPU 86017 on acute and chronic congestive cardiac failure mediated by reducing ET‐1?NOS and oxidative stress in rats

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