Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin‐mediated angioedema

Fryer, Ryan M.; Segreti, Jason A.; Banfor, Patricia N.; Widomski, D. L.; Backes, Bradley J.; Lin, C W; Ballaron, Stephen J.; Cox, Bryan F.; Trevillyan, James M.; Reinhart, Glenn A.; Geldern, Thomas W von

doi:10.1038/sj.bjp.0707641

Cited by 116 publications

(105 citation statements)

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“…50 As both ACE and neprilysin are key enzymes in the metabolism of bradykinin, it is hypothesized that dual inhibition of ACE and neprilysin by omapatrilat and other vasopeptidase inhibitors results in a significantly greater elevation of bradykinin levels relative to ACE inhibition alone, which in a subset of patients can lead to excessive vascular leakage, fluid extravasation and angioedema, explaining the unfavorable tolerability issues observed for omapatrilat. 51 The objective of two current drug research and development programs conducted by Theravance (South San Francisco, CA, USA) and Novartis is the discovery of compounds that replicate the superior efficacy of omapatrilat through dual inhibition of the RAS and neprilysin, but without elevation of bradykinin levels and associated high risk for angioedema. This is achieved through inhibition of the RAS at the level of the AT 1 receptor rather than at the level of the converting enzyme, which is the rate-limiting enzyme in bradykinin metabolism.…”

Section: Next Generation Arbs That Inhibit Neprilysin Activitymentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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Angiotensin receptor blockers (ARBs) are well-tolerated drugs that are known to be useful for inhibiting activity of the reninangiotensin (RAS) system, treating hypertension and reducing the risk for cardiovascular disease. However, inhibition of the RAS does not control all pathophysiological mechanisms of hypertension or cardiovascular risk and many patients continue to suffer from cardiovascular events and metabolic disturbances despite being treated with an ARB, an angiotensin-converting enzyme inhibitor or both, in addition to other standard therapies for cardiovascular disease. Recently, it has become apparent that bifunctional molecules can be designed that do more than just block AT 1 receptors and that can target additional mechanisms of hypertension, cardiovascular disease and diabetes besides just increased activity of the renin-angiotensin system. Specifically, next generation ARBs are becoming available that are intended to not only antagonize AT 1 receptors, but also block endothelin receptors, function as nitric oxide donors, inhibit neprilysin activity and increase natriuretic peptide levels, or stimulate the peroxisome proliferator-activated receptor c (PPARc). In this review, we: (1) discuss the potential importance of multifunctional ARBs that can reduce cardiovascular and metabolic risk through multiple mechanisms that go beyond just inhibition of the renin-angiotensin system and (2) describe specific examples of next generation ARBs in development that are intended to do more than simply block AT 1 receptors.

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Section: Next Generation Arbs That Inhibit Neprilysin Activitymentioning

confidence: 99%

Next generation multifunctional angiotensin receptor blockers

Kurtz

Klein

2009

Hypertens Res

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“…59 Subsequent rodent studies suggested that omapatrilat also inhibits the bradykinin-metabolizing enzyme aminopeptidase P (APP) 60 and that the combined inhibition of neprilysin, ACE, and APP may be the mechanism causing elevated levels of bradykinin leading to angioedema. 61 Thus, while there appear to be clinical benefits, the inherent risks of angioedema led to the United States Food and Drug Administration (FDA) to reject the New Drug Application for omapatrilat in 2002. 62 …”

Section: Omapatrilatmentioning

confidence: 99%

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Buggey

Mentz

DeVore

et al. 2015

Journal of Cardiac Failure

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Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future. (J Cardiac Fail 2015;21:741e750)

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“…Inhibition of bradykinin-metabolizing enzymes can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, vasopeptidase inhibitor, omapatrilat [13]. Vasopeptidase inhibitors simultaneously inhibit both ACE and neutral endopeptidase (NEP).…”

mentioning

confidence: 99%

“…However, the relative contribution of specific bradykininmetabolizing enzymes to this effect is unclear and confounded by the lack of a predictive preclinical model of angioedema. Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min, and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk [13]. In the presence of omapatrilat, bradykinin produced dose-dependent hypotension, an effect abolished by B2 receptor blockade.…”

mentioning

confidence: 99%

Aneurysm formation and bradykinin

Luft¹

2009

J Mol Med

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In this issue, Merino et al. publish a provocative paper on accelerated aortic aneurysm formation in mice lacking both apolipoprotein E (APOE) and the bradykinin[1] (B1) receptor [1]. Their disease model is the APOE genedeleted (−/−) mouse that I admittedly love. These are indeed the mice that "keep on giving" [2]. APOE−/− mice not only are cooperative in terms of developing atherosclerosis but also develop aortic aneurysms when infused with angiotensin (Ang) II, making them an ideal model for studying this serious clinical disease [3]. APOE−/− mice are not unique in this regard; low-density lipoprotein receptor −/− mice work equally as well. The role of Ang II is interesting and is independent of the blood pressure increase [4]. Norepinephrine, on the other hand, is much less prone to provoke aneurysm formation.Merino et al.[1] fed APOE gene-deficient mice and APOE-deficient mice that had been crossed into a B1 receptor −/− model namely, an APOE−/− and B1−/− "double-knockout" model, a high-fat diet. The cholesterol elevations of both groups were the same. However, the absent B1 receptors made the atherosclerosis and aneurysm formation worse. The expressions of cyclic guanylyl monophosphate (cGMP)-dependent kinase I, CD-11, F4/ 80, monocyte colony-stimulating factor (mCSF), and tumor necrosis factor (TNF)-α were also increased in the aortas of the double knockout, compared to APOE−/− mice. Peroxisome proliferator-activated receptor γ (PPARγ) protein and the matrix metalloproteinase-9 (MMP9) activity, on the other hand, were decreased in the aortas of the doubleknockout mice. Remarkably, Ang II was not required for aneurysm formation, although Ang II infusion experiments in the mice were conducted. Again, aneurysm formation in the double-knockout mice was worse than in other groups.What is it about the bradykinin B1 receptor? The B1 receptor plays an important role in mediating the inflammatory effects of the kallikrein-kinin pathway. The B1 receptor −/− mice have revealed that the receptor plays a pivotal role in the cellular, particularly neutrophil, recruitment associated with acute inflammatory responses. Neutrophil recruitment has been implicated in the early stages of atherosclerosis. The B1 receptor plays a major role in chemokine (CXCL5 and CCL2) expression. Thus, we might have speculated that absence of the B1 receptor would protect from atherosclerosis and aneurysm formation, rather than the other way around. The authors argue that upregulation of cGMP-dependent kinase I could have facilitated the atherosclerosis. Indeed, a proatherosclerotic role for cGMP-dependent protein kinase I has been described in vascular smooth muscle cells [5]. The cGMP-dependent protein kinase I is a potential mediator of nitric oxide (NO) signaling in vascular smooth muscle cells. Postnatal ablation of cGMP-dependent protein kinase I selectively in the vascular smooth muscle cells of mice reduced atherosclerotic lesion area, demonstrating that smooth muscle cGMP-dependent protein kinase I promotes atherogenesis. Cell fate ma...

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Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin‐mediated angioedema

Cited by 116 publications

References 56 publications

Next generation multifunctional angiotensin receptor blockers

Next generation multifunctional angiotensin receptor blockers

Angiotensin Receptor Neprilysin Inhibition in Heart Failure: Mechanistic Action and Clinical Impact

Aneurysm formation and bradykinin

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