Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers.

Richards, A. Mark; Wittert, Gary; Espiner, Eric A.; Yandle, Timothy G.; Ikram, Hamid; Frampton, Chris

doi:10.1161/01.res.71.6.1501

Cited by 81 publications

(52 citation statements)

References 30 publications

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“…The ANP response is consistent with previous reports 16 - 17 and may reflect increases in central blood volume and atrial pressures, decreased blood flow to sites of ANP metabolism, or both, both effects being secondary to the peripheral vasoconstriction induced by angiotensin II. In the case of BNP, the acute significant increase in blood pressure and thus left ventricular load and wall tension may have enhanced BNP secretion, and (as for ANP) vasoconstriction may have impaired delivery of BNP to sites of metabolism.…”

Section: Discussionsupporting

confidence: 90%

Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension.

et al. 1993

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In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angJotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (/*<.O5, both groups) but suppressed plasma brain natriuretic peptide (P<.01, both groups) in association with significant falls in arterial pressure (/*<.O5, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20±5 vs 13±3 pmol/L, P<.05), whereas brain natriuretic peptide was unchanged (7±0J vs 7±0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 ±11 vs 17 ±4 pmol/L, P<.05, and 7.5±0.6 vs 5.5±0.4 pmol/L, / > <.O5, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure. Thus, stimuli that incorporate substantial changes in arterial pressure may induce acute and chronic concordant changes in plasma brain natriuretic peptide, whereas other events that alter central blood volume and atrial stretch without major concomitant changes in arterial pressure will alter plasma atrial natriuretic peptide but not brain natriuretic peptide. (Hypertension 1993,22:231-236) KEY WORDS • natriuretic peptides, brain • hypertension, essential blood pressure • posture • membrane metalloendopeptidase natriuretic peptides, atrial • B rain natriuretic peptide (BNP) is the second member of the family of natriuretic peptides to be discovered and characterized. 1 Originally detected in porcine brain, it is present in greatest concentrations in cardiac tissue. 24 Although small amounts of BNP may be cosecreted with atrial natriuretic peptide (ANP) from specific atrial myocyte granules, 5 the predominant source of circulating BNP appears to be through constitutive secretion from ventricular myocytes. 6 In healthy individuals, circulating plasma concentrations of BNP are lower than concurrent levels of ANP. However, in patients with cardiac impairment levels rise to equal or exceed plasma ANP, and, similar to ANP, increments in BNP are related to the severity of cardiac disease. 67 It remains unclear whether hypertension is associated with any significant consistent disturbance in plasma BNP, but at least some reports indicate BNP is increased in proportion to left ventricular hypertrophy (LVH), left ventricular load, or both.8 BNP and ANP exhibit a similar array o...

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Section: Discussionsupporting

confidence: 90%

Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension.

et al. 1993

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Section: Discussionmentioning

confidence: 62%

“…This compound, and RXP407, are weak inhibitors of NEP, a peptidase that in humans and rats also participates in the metabolism of Ang I and BK. 23,24 Accordingly, the in vivo effects of RXPA380 and RXP407 on the cleavage of Ang I and BK, reported in this study, are not likely to reflect the inhibition of NEP, but more probably the selective inhibition of either the N-or C-domain of ACE.The inhibition profiles of mouse ACE by RXPA380 and RXP407, using Ang I as substrate, are characterized by the presence of two titration domains (Figure 2A), corresponding to the sequential inhibition of the two ACE active sites by these highly selective inhibitors. This interpretation is supported by the monophasic shape of the inhibition profile observed when a mixture of RXPA380 and RXP407 is used to inhibit ACE.…”

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confidence: 99%

Roles of the Two Active Sites of Somatic Angiotensin-Converting Enzyme in the Cleavage of Angiotensin I and Bradykinin

Georgiadis

Beau

Czarny

et al. 2003

Circulation Research

148

152

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Abstract-Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK. Key Words: angiotensin-converting enzyme Ⅲ angiotensin Ⅲ bradykinin Ⅲ phosphinic peptide inhibitors S omatic angiotensin-converting enzyme in vertebrates (ACE, EC 3.4.15.1) is a zinc metallopeptidase involved in the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK), two peptide hormones that play a key role in the regulation of blood pressure, renal and cardiovascular functions. [1][2][3][4][5] These peptides are end products of two highly regulated systems, respectively, the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS). It has been suggested that the plasma KKS could be the physiological counterbalance to the RAS. 6 As ACE is strategically poised between the RAS and KKS systems, the question may arise as to whether the ACE activity is controlled to regulate the balance between the RAS and KKS systems and, if so, by which mechanism.Somatic ACE is a two-domain protein resulting from a tandem gene duplication, with each domain possessing a functional active site. 7,8 Since the discovery that ACE has two active sites, there has been much speculation about the functional significance of the presence of two active sites in the same enzyme. Although the two domains of ACE display in vitro a relatively broad substrate specificity, such as the ability to cleave Ang I and BK, there are some biochemical features that differentiate between the two active sites. 9 -13 For example, the hematoregulatory peptide, Ac-S-D-K-P, was proved in vitro to be specifically cleaved by the N-domain of ACE. 14 The N-domain and C-domain have different in vitro patterns of chloride activation 10 and can be differentiated by the relative potencies of some inhibitors. 12,15 Among these, RXP407, a phosphinic peptide...

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“…This is made complex because NEP is a ubiquitous ecto-enzyme present not only in the kidney but also in the lung, brain, intestine, spleen, endothelial cells, and neutrophils, 39,40 and has multiple substrates. As well as its involvement in the degradation of the natriuretic peptides and bradykinin, 40 NEP also degrades Ang I and II 41,42 and endothelin, 43 whereas NEP inhibition can modulate endothelin-converting enzyme. 44 A word of caution is needed in interpreting data from studies of NEP and vasopeptidase inhibitors because increasing evidence suggests that data obtained with one NEP inhibitor cannot be extrapolated to another.…”

Section: Burrell Et Al Vasopeptidase Inhibition With S21402mentioning

confidence: 99%

Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

et al. 2000

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Abstract-S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensinconverting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction-induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg ⅐ kg), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (PϽ0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (PϽ0.01). Both S21402 and captopril increased plasma renin activity (PϽ0.01), all treatment lowered plasma aldosterone (PϽ0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (PϽ0.01), SCH42495 inhibited NEP (PϽ0.01), and captopril inhibited ACE (PϽ0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (PϽ0.01), SCH42495 reduced right ventricular mass (PϽ0.01), and S21402 decreased left (PϽ0.05) and right ventricular mass (PϽ0.01), atrial mass (PϽ0.05), and lung mass (PϽ0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure. Key Words: vasopeptidase inhibitors Ⅲ neutral endopeptidase Ⅲ heart failure Ⅲ myocardial infarction Ⅲ natriuretic peptides Ⅲ cardiac remodeling C ongestive heart failure (CHF) is a progressive disease characterized by neurohormonal activation, salt and water retention, and cardiac remodeling. Inhibitors of angiotensin converting-enzyme (ACE), which prevent the formation of the constrictor, antinatriuretic, and trophic hormone angiotensin (Ang) II, attenuate ventricular remodeling, improve cardiac function and survival, and are standard treatment for CHF. 1 Atrial natriuretic peptide (ANP) is elevated in proportion to the degree of left ventricular dysfunction 2 and acts as an endogenous antagonist of the renin-angiotensin system (RAS) to cause natriuresis and diuresis, and vasodilation and suppression of the sympathetic nervous system. 3 An increase in endogenous levels of ANP by inhibition of its enzymatic degradation by neutral endopeptidase 24.11 (NEP) is a potential therapeutic strategy in heart failure. 4 Selective NEP inhibition has met with limited success as hyporesponsiveness to the biological actions of ANP occurs with increasing severity of heart failure, whereas the addition of an ACE inhibitor restores some benefits of NEP inhibition, including natriuresis. 5,6 Several compounds that simultaneously inhibit NEP and ACE, or vasopeptidase inhibitor...

show abstract

Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers.

Cited by 81 publications

References 30 publications

Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension.

Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension.

Roles of the Two Active Sites of Somatic Angiotensin-Converting Enzyme in the Cleavage of Angiotensin I and Bradykinin

Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure

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