Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

Ferro, Charles J.; Spratt, James C.; Haynes, William G.; Webb, David J.

doi:10.1161/01.cir.97.23.2323

Cited by 157 publications

(108 citation statements)

References 68 publications

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“…NEP is involved in the metabolism of other vasoactive peptides, such as bradykinin (39,40) and adrenomedullin (41), which were not investigated; therefore, accumulation of these peptides in the plasma or tissues may play a role in the decrease in BP. The in vivo modulation of endothelin metabolism by NEP (42,43) cannot explain the difference in BP-lowering efficacy between omapatrilat and fosinopril, according to our measurements of plasma endothelins. Omapatrilat slightly and transiently increased plasma Big-ET1 concentrations and had no effect on plasma ET1 concentrations.…”

Section: Effects Of Sodium Balance On Omapatrilat-induced Changes In mentioning

confidence: 62%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodiumdepleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.Omapatrilat is a vasopeptidase inhibitor that has a similar nanomolar inhibitory constant for both neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE) in vitro (1). This drug is designed to treat hypertension (2) and congestive heart failure (3,4). In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5-8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure. However, the beneficial effect of omapatrilat on cardiovascular morbidity compared with lisinopril in patients with congestive heart failure suggested by the IMPRESS study (4) has not been confirmed by the results of the OVERTURE study (12), in which no significant difference in terms of cardiovascular morbidity or mortality between 40 mg of omapatrilat daily and 10 mg of enalapril twice daily was reported.We have previously reported the BP and hormonal effects of a single oral dose of 10 mg of omapatrilat in sodium-depleted normotensive subjects (13). Omapatrilat (10 mg) had a shorter BP-lowering effect than a single oral dose of 20 mg of fosinopril, despite the fact that, at the dose used, both drugs appeared to have a similar potency in inhibiting ACE, whereas omapatrilat, by inhibiting NEP, increased urinary atrial natriuretic peptide (ANP) and blunted the decrease in plasma ANP due to ACE inhibition (13).The doses of omapatrilat subsequently used in the clinical development program were high...

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Section: Effects Of Sodium Balance On Omapatrilat-induced Changes In mentioning

confidence: 62%

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Azizi

Lamarre-Cliché²,

Labatide-Alanore³

et al. 2002

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

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“…Concurrent inhibition of neutral endopeptidase-mediated ET-1 hydrolysis could oppose the benefits of augmented natriuretic peptide levels. Thus, infused ANP lowers systemic blood pressure in humans, while the neutral endopeptidase inhibitor candoxatril exerts a hypertensive effect (34) attributable to increased ET-1 activity (35). Moreover, combined inhibition of neutral endopeptidase/ ACE or neutral endopeptidase/endothelin-converting enzyme lowers blood pressure more effectively than either inhibitor alone in diabetes with concomitant hypertension (31), suggesting that dual inhibitors are a better therapeutic strategy particularly in diabetes.…”

Section: Discussionmentioning

confidence: 99%

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

et al. 2003

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Stimulation of cardiomyocyte guanosine 3,5-cyclic monophosphate (cyclic GMP) via endothelial-derived nitric oxide (NO) is an important mechanism by which bradykinin and ACE inhibitors prevent hypertrophy. Endothelial NO dysfunction and cardiac hypertrophy are morbid features of diabetes not entirely prevented by ACE inhibitors. In cardiomyocyte/endothelial cell cocultures, bradykinin efficacy is abolished by highglucose-induced endothelial NO dysfunction. We now demonstrate that antihypertrophic actions of natriuretic peptides, which stimulate cyclic GMP independently of NO, are preserved in cardiomyocytes despite high-glucose-induced endothelial dysfunction. Further, streptozotocin-induced diabetes significantly impairs the effectiveness of acute antihypertrophic strategies in isolated rat hearts. In hearts from citrate-treated control rats, angiotensin II-stimulated [ 3 H]phenylalanine incorporation and atrial natriuretic peptide and ␤-myosin heavy chain mRNA expression were prevented by B-type natriuretic peptide (BNP), bradykinin, the ACE inhibitor ramiprilat, and the neutral endopeptidase inhibitor candoxatrilat. These antihypertrophic effects were accompanied by increased left ventricular cyclic GMP. In age-matched diabetic hearts, the antihypertrophic and cyclic GMP stimulatory actions of bradykinin, ramiprilat, and candoxatrilat were absent. However, the blunting of hypertrophic markers and accompanying increases in cyclic GMP stimulated by BNP were preserved in diabetes. Thus BNP, which increases cyclic GMP independently of NO, is an important approach to prevent growth in the diabetic myocardium, where endothelium-dependent mechanisms are compromised.

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“…30 Another key component of the NP system is neprilysin (neutral endopeptidase 24.11), which catalyses the degradation of ANP, BNP and CNP as well as the degradation of bradykinin, adrenomedullin, endothelin-1, substance P and angiotensin II (see Figure 1). 31 Neprilysin is a potentially useful therapeutic target in HF.…”

Section: Role Of Natriuretic Peptides In Heart Failurementioning

confidence: 99%

The Mechanism of Action of LCZ696

Menéndez

2016

Cardiac Failure Review

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Heart failure (HF) represents a growing financial burden on healthcare systems and despite therapeutic advances, mortality remains high. Current treatments focus on blocking neurohormonal pathways, such as the renin-angiotensin aldosterone system (RAAS). Recent research has focused on the natriuretic peptide system, which confers beneficial effects in HF, whereas activation of the RAAS and of the sympathetic nervous system has detrimental effects. LCZ696 (sacubutril/valsartan), a first-in-class angiotensin II AT1receptor neprilysin inhibitor, has a unique mode of action that targets both pathways. Clinical studies to date indicate that LCZ696 is effective and safe in mild to moderate arterial hypertension and in HF patients with preserved ejection fraction, and has been shown to be superior to enalapril in patients with moderate to severe HF due to reduced left ventricular ejection fraction.

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Inhibition of Neutral Endopeptidase Causes Vasoconstriction of Human Resistance Vessels In Vivo

Cited by 157 publications

References 68 publications

Physiologic Consequences of Vasopeptidase Inhibition in Humans

Physiologic Consequences of Vasopeptidase Inhibition in Humans

B-Type Natriuretic Peptide Prevents Acute Hypertrophic Responses in the Diabetic Rat Heart

The Mechanism of Action of LCZ696

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