Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors

Adam, Albert; Cugno, Massimo; Molinaro, Giuseppe A.; Pérez, M. Trujillo; Lepage, Yves; Agostoni, A

doi:10.1016/s0140-6736(02)08914-6

Cited by 167 publications

(103 citation statements)

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“…-BK, correlating with a decreased activity of plasma APP (247,248). This anomaly could also be observed in patients who presented an AR (119) or a SHR (245,249).…”

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The Kallikrein-Kinin System: Current and Future Pharmacological Targets

et al. 2005

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Abstract. The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

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“…-BK, correlating with a decreased activity of plasma APP (247,248). This anomaly could also be observed in patients who presented an AR (119) or a SHR (245,249).…”

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The Kallikrein-Kinin System: Current and Future Pharmacological Targets

et al. 2005

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“…10 Notably, the main adverse effects of ACE inhibition, that is, cough and angioedema, have also been attributed to amplified reactions to BK when its enzymatic degradation is impaired. 11 The cardioprotective effects of ACE inhibition are well recognized, but have been mostly attributed to inhibition of the formation of angiotensin II, whose cardiotoxic (and nephrotoxic) properties were described long ago. The fact that angiotensin AT 1 receptor blockadewhich does not involve alteration in BK metabolism-can similarly prevent or minimize end-organ damage has initially focused attention on the angiotensin-mediated actions of both interventions.…”

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confidence: 99%

Cardioprotective properties of bradykinin: role of the B2 receptor

et al. 2010

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Following the introduction of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and ischemic heart disease, there has been increasing interest in the bradykinin-mediated aspects of ACE inhibition. Several preclinical and clinical studies have been conducted using genetically engineered animals or pharmacological agonists and antagonists of the two receptors of bradykinin, B 1 R and B 2 R. The results have mostly indicated that the B 1 R, whose expression is induced by tissue damage, seem to have mostly noxious effects, whereas the constitutively expressed B 2 R, when activated, exert mostly beneficial actions. Accumulating evidence in the recent literature suggests that the B 2 R have an important role in the process of ischemic post-conditioning that limits the ischemia/reperfusion injury of the myocardium. In this article, we describe a series of experiments conducted on mice submitted to acute myocardial infarct and treated either with ACE inhibition (which produces potentiation of bradykinin resulting in non-selective B 1 R and B 2 R activation) or with a potent and highly selective B 2 R agonist. These data suggest that this latter pharmacological approach offers functional and structural benefits and is therefore a promising cardioprotective therapeutic modality against acute ischemic events. INTRODUCTIONThe possible role of bradykinin (BK) in cardiovascular regulation has intrigued scientists for many years. A member of the kinin system discovered in the late 1920s, BK is a nonapeptide whose existence was first recognized by Roha e Silva et al. 1 from its effects on intestinal smooth muscle. Since then, several other actions of BK were described, including vascular contraction and relaxation, participation in the process of inflammatory reactions, interaction with central and peripheral neural structures, stimulation of synthesis and release of various vasoactive substances, enhanced insulin-dependent glucose transport and utilization, etc.Circulatory homeostasis is the result of a constant equilibrium between vasoconstrictors (e.g., pressor neurohormonal factors like angiotensin II, catecholamines, vasopressin, endothelin) and vasodilators (like kinins, prostaglandins, NO, etc.). Bradykinin, a tissue hormone that regulates the regional blood flows of vital organs, is an important member of the latter group. 2 The role of BK in cardiovascular regulation under physiological and pathological conditions attracted the interest of clinicians with the advent of angiotensinconverting enzyme (ACE) inhibitors, which in the last two decades have become standard therapy for hypertension, ischemic heart disease and heart failure. 3 In recent years the work of many investigators has produced a lot of new information regarding the role of kinins in the pathophysiology of hypertension and the prevention of its end-organ complications.

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“…15 In fact, several studies have demonstrated that the C-2399A SNP in XPNPEP2 is associated with decreased APP activity and angioedema in selected populations. [14][15][16] To date, however, few studies have investigated the role of APP in acute hypotensive transfusion reactions, 9,11 and no studies have determined whether the C-2399A SNP may be a contributing factor to acute hypotensive transfusion reactions in patients not taking ACE-Is.…”

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The Development of a Novel Molecular Assay Examining the Role of Aminopeptidase P Polymorphisms in Acute Hypotensive Transfusion Reactions

Hui

Tormey

2013

Archives of Pathology &Amp; Laboratory Medicine

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N Context.-Acute hypotensive transfusion reactions are potentially harmful adverse effects of transfusion attributable to bradykinin generation. They are most often seen in patients taking angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) because of the role ACE plays in metabolizing bradykinin. However, a number of acute hypotensive transfusion reactions occur in patients not taking ACE-Is. Aminopeptidase P (APP), another important enzyme responsible for bradykinin degradation, is encoded by the polymorphic XPNPEP2 gene. Some polymorphisms in XPNPEP2 have been associated with decreased APP activity. However, the role that APP polymorphisms play in acute hypotensive transfusion reactions has never been investigated.Objective.-To develop a molecular assay to examine for the C-2399A single-nucleotide polymorphism (SNP) in the APP gene, XPNPEP2, in patients experiencing acute hypotensive transfusion reactions unassociated with ACEIs.Design.-We developed an assay using polymerase chain reaction and DNA sequencing with primers targeted at XPNPEP2 (59-GAGTATTATGTGGGGACCATCC-39 and 59-ATGCCTCGCAGAGACAAGAG-39). Polymorphism zygosity was determined by comparing the sense/antisense sequencing results. This assay was then applied to patients with acute hypotensive transfusion reactions not taking ACE-Is (n = 4).Results.-A C-2399A SNP assay was successfully developed and applied to patients with acute hypotensive transfusion reactions. In a pilot study, 2 patients (50%) were found to possess C-2399A polymorphisms. One was found to be homozygous, and the other was heterozygous.Conclusions.-Our C-2399A SNP assay can be used to study acute hypotensive transfusion reactions in patients not taking ACE-Is. Initial data indicate that the C-2399A polymorphism may be a contributing factor in such reactions. However, further studies are necessary to better define the role of APP polymorphisms in relation to acute hypotensive transfusion reactions unassociated with ACEIs.(Arch Pathol Lab Med. 2013;137:96-99; doi: 10.5858/ arpa.2011-0466-OA) A cute hypotensive transfusion reactions are relatively rare, but potentially serious adverse events in which a transfusion recipient manifests a marked decrease in blood pressure with a virtual absence of other signs and symptoms.1,2 Much of the pathophysiology of acute hypotensive transfusion reactions has been linked to bradykinins and their metabolites, mediators that can induce substantial vasodilation and smooth muscle relaxation in vivo, with a resultant decrease in blood pressure.3 Some studies have also shown that bradykinin accumulation and hypotensive episodes may be exacerbated in transfused patients taking angiotensin-converting enzyme (ACE) inhibitors (ACE-Is), because ACE is a key enzyme in the degradation of bradykinin.3-11 However, based on reports of acute hypotensive transfusion reactions occurring in the absence of ACE-I use, 5,12 it is possible that other pathways may contribute to the accumulation of bradykinin and/or their metabolites and result in hypotension in the se...

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Aminopeptidase P in individuals with a history of angio-oedema on ACE inhibitors

Cited by 167 publications

References 4 publications

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

Cardioprotective properties of bradykinin: role of the B2 receptor

The Development of a Novel Molecular Assay Examining the Role of Aminopeptidase P Polymorphisms in Acute Hypotensive Transfusion Reactions

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