Effects of Uk 69 578: A Novel Atriopeptidase Inhibitor

Northridge, D B; Alabaster, Colin; Connell, JohnM.C.; Dilly, StephenG.; Lever, A.F.; Jardine, AlanG.; Barclay, Paul L.; Dargie, H. J.; Findlay, Ian; Samuels, GillianM.R.

doi:10.1016/s0140-6736(89)90714-9

Cited by 179 publications

(107 citation statements)

References 17 publications

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“…Candoxatril does not affect the activity of carboxypeptidase A, leucine aminopeptidase (aminopeptidase M) or angiotensin-converting enzyme, which belong to the same zinc metalloprotease superfamily as NEP-24.11 [20], or that of the more closely NEP-related enzyme, endothelin-converting enzyme-1 [31]. Following oral administration, candoxatril is rapidly absorbed and converted to the active drug by plasma esterases [21,34].…”

Section: Discussionmentioning

confidence: 99%

“…1). Then, candoxatril (5 mg/ kg, dissolved in 0.9% NaCl), a selective NEP-24.11 inhibitor [20,21] (kindly provided by Dr Jane Lundbeck, Novo Nordisk, Måløv, Denmark) was given as a bolus i.v. injection via the ear vein catheter over 2 min.…”

Section: Methodsmentioning

confidence: 99%

“…This study investigated the physiological relevance of NEP-24.11 in GLP-1 metabolism, using candoxatril (a selective NEP-24.11 inhibitor [20,21]) and a previous protocol that revealed the physiological role of DPP-IV in GLP-1 and GIP metabolism [9,22] and of NEP-24.11 in glucagon degradation [23]. The influence of candoxatril on the metabolic stability and antihyperglycaemic/insulinotropic effects of GLP-1 was examined in anaesthetised pigs.…”

Section: Introductionmentioning

confidence: 99%

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Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

et al. 2005

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Aims/hypothesis: The incretin hormone glucagon-like peptide 1 (GLP-1) has antihyperglycaemic effects, but its therapeutic usefulness is limited by its metabolic instability. Dipeptidyl peptidase IV (DPP-IV) is established as the primary inactivating enzyme, but the roles of other enzymes remain unclear. Methods: The effect of candoxatril, a selective inhibitor of neutral endopeptidase (NEP) 24.11, on GLP-1 pharmacokinetics/pharmacodynamics with or without DPP-IV inhibition was examined in anaesthetised pigs. Results: During GLP-1 infusion, candoxatril doubled C-terminal immunoreactivity, improving the pharmacokinetics (t ½ 2.3±0.1 to 8.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

et al. 2005

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“…3,4 In humans, the administration of exogenous ANP and the inhibition of natriuretic peptide degradation by use of neutral endopeptidase inhibitors have been found to increase sodium and water excretion and to lower blood pressure. [5][6][7][8] Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that possess the ability to inhibit the membrane-bound zinc metalloproteases ACE EC 2.4.15.1 and the neutral endopeptidase EC 3.4.24.11 (NEP). 9 Thus, omapatrilat simultaneously decreases angiotensin II generation by inhibiting ACE activity and reduces the metabolic degradation of natriuretic peptides by inhibiting NEP.…”

mentioning

confidence: 99%

Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

et al. 2002

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Abstract-This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (PϽ0.001 versus placebo; PϽ0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (PϽ0.01). These hormonal effects were associated with a significant fall in blood pressure (PϽ0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (PϽ0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (PϽ0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (PϽ0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (PϭNS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy. Key Words: hemodynamics, renal Ⅲ sodium Ⅲ angiotensin-converting enzyme Ⅲ neutral endopeptidase Ⅲ omapatrilat Ⅲ vasopeptidase Ⅲ human A ngiotensin II is an important physiological modulator of renal function through its hemodynamic, glomerular, and tubular effects. 1 Hence, under most circumstances, interruption of the renin-angiotensin cascade with ACE inhibitors or angiotensin II type 1 receptor antagonists in humans promotes sodium excretion and increases renal blood flow without affecting glomerular filtration rate (GFR). As a result, filtration fraction decreases. 2 Atrial natriuretic peptide (ANP), the brain natriuretic peptide, and the C-type natriuretic peptide represent another family of peptides that have an important impact on renal function. 3,4 Indeed, in addition to a peripheral vasodilation, these peptides elicit diuresis and natriuresis, an attenuation of the release of renin and aldosterone and of the sympathetic nervous activity. 3 High plasma ANP and brain natriuretic peptide levels have been measured under several clinical conditions in which sodium and water retention occur, such as congestive heart failure or chronic renal failure. 3,4 In humans, the administration of exogenous ANP and the inhibition of natriuretic peptide...

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“…10,17 However, a reduction in blood pressure has not been clearly demonstrated in normotensive subjects, 10,18,20,21 and two studies have even reported an increase in blood pressure 22,23 despite the potent vasodilator actions of the natriuretic peptides. 12,13,16 Also, several studies on hypertensive patients 19,[32][33][34][35] have not demonstrated a reduction in blood pressure.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1998

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Background-Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone. Methods and Results-Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12Ϯ2%; Pϭ0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (Pϭ0.6) after pretreatment with both placebo (13Ϯ1%, Pϭ0.006) and enalapril (17Ϯ6%, Pϭ0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ET A antagonist BQ-123 (100 nmol/min), and both combined.

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Effects of Uk 69 578: A Novel Atriopeptidase Inhibitor

Cited by 179 publications

References 17 publications

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig

Renal Hemodynamic and Natriuretic Effects of Concomitant Angiotensin-Converting Enzyme and Neutral Endopeptidase Inhibition in Men

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

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