Protective Effects of CGS 30440, a Combined Angiotensin-Converting Enzyme Inhibitor and Neutral Endopeptidase Inhibitor, in a Model of Chronic Renal Failure

Cohen, David S.; Mathis, J.; Dotson, Ronald; Graybill, S C; Wosu, N.

doi:10.1097/00005344-199807000-00014

Cited by 29 publications

(20 citation statements)

References 34 publications

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“…In addition, omapatrilat reversed the decrease in glomerular filtration rates and reduced elevated plasma creatinine levels. These findings extend the results of previous work showing beneficial effects of the vasopeptidase inhibitor CGS 30440 in alleviating renal injury [16]. They suggest that vasopeptidase inhibition may be a therapeutic approach for retarding progression of renal injury, a condition in which reductions in both blood pressure and proteinuria are considered important targets.…”

Section: Vasopeptidase Inhibitors and Renal Diseasesupporting

confidence: 87%

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease

Kubota

Dean

Balding

et al. 2001

Current Science Inc

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In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.

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Section: Vasopeptidase Inhibitors and Renal Diseasesupporting

confidence: 87%

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease

Kubota

Dean

Balding

et al. 2001

Current Science Inc

View full text Add to dashboard Cite

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“…Such a possibility is suggested by the reduction in renal ACE activity with omapatrilat being associated with a greater increase in the plasma renin activity than seen with perindopril treatment. In some of the previous studies comparing ACE/NEP inhibition to ACE inhibition, there was a significant difference in blood pressure between the two groups and therefore it was not possible to determine blood pressure-independent effects of agents such as omapatrilat [13,17].…”

Section: Discussionmentioning

confidence: 99%

“…Previous research using the first of the VPIs, omapatrilat, has examined the beneficial effects on ameliorating developing clinical and experimental hypertension [14,15,16]. In addition, an increasing number of studies have explored these agents in models of non-diabetic renal disease [13,17,18]. In a study comparing both selective ACE and NEP inhibitors and another less potent dual ACE/NEP inhibitor mixanpril, albuminuria was partially prevented in a 4 week study in diabetic SHR [19].…”

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confidence: 99%

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

et al. 2003

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Aims. Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Methods. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg −1 · day −1 ) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg −1 ·day −1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor β, β-inducible geneh3 and nephrin were also quantitated.Results. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFβ and βig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. Conclusion/Interpretation. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease. [Diabetologia (2003) 46:961-971]

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“…19,41,42 These studies concluded that vasopeptidase inhibitors conferred greater renal protection than did ACE inhibitors. The major quantitative effect of omapatrilat overwhelming that of enalapril affected proteinuria, as reported by Taal et al 21 in a protocol characterized by delayed treatment with both drugs until 4 weeks after the onset of hypertension.…”

Section: Figurementioning

confidence: 99%

Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide–Deficient Rats

et al. 2003

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Abstract-Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received N G -nitro-L-arginine methyl ester (L-NAME, 20 mg · kg Ϫ1 · d Ϫ1 ) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg · kg) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was Ϸ90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet. Key Words: hypertension, renal Ⅲ kidney failure Ⅲ angiotensin-converting enzyme Ⅲ peptides Ⅲ nitric oxide Ⅲ sodium, dietary V asopeptidase inhibitors are novel molecules that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). 1 The emergence of this new class of drugs followed the demonstration that ACE and NEP are 2 key enzymes that play a major role in regulating cardiovascular and renal functions. The simultaneous inhibition of these 2 enzymes can reduce the vasopressive, hypertrophic, and antinatriuretic activities of the renin-angiotensin system and potentiate the vasodilatory, natriuretic, and antiproliferative effects of bradykinin and natriuretic peptides. 2 As a component of the circulating and local renin-angiotensin system, ACE catalyzes the conversion of angiotensin I (Ang I) to Ang II, a vasoconstrictor agent playing a central role in the pathogenesis of hypertension. In addition to its direct actions, Ang II increases the production of endothelin-1 (ET-1), and plasminogen activator inhibitor-1, both of which promote vasoconstriction, thrombosis, and fibrosis. 3,4 ACE inhibition is a well-established and effective treatment for hypertension. Nevertheless, it has been recently proposed that, in addition to ACE inhibition, inhibition of NEP, which augments the effects of natriuretic peptides, including atrial, B-type, and C-type natriuretic p...

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Protective Effects of CGS 30440, a Combined Angiotensin-Converting Enzyme Inhibitor and Neutral Endopeptidase Inhibitor, in a Model of Chronic Renal Failure

Cited by 29 publications

References 34 publications

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease

Evidence for cardioprotective, renoprotective, and vasculoprotective effects of vasopeptidase inhibitors in disease

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

Renal Effects of Omapatrilat and Captopril in Salt-Loaded, Nitric Oxide–Deficient Rats

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