Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema

Blais, Charles; Rouleau, Jean‐Lucien; Brown, Nancy J.; Lepage, Yves; Spence, J. David; Munoz, Claudio; Friborg, Jacques; Geadah, David; Gervais, Nicole; Adam, Albert

doi:10.1016/s0162-3109(99)00133-2

Cited by 70 publications

(51 citation statements)

References 23 publications

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“…The mechanism remains unclear, but bradykinin and its metabolite des-arg 9 -bradykinin have been implicated in ACE-induced angioedema. 48 Plasma bradykinin concentrations can rise Ͼ10-fold during acute attacks of angioedema associated with ACE inhibitor therapy. 49 Recently, an enzyme defect involved in the des-arg 9 -bradykinin metabolism, aminopeptidase P, leading to bradykinin and to an even greater extent to des-arg 9 -bradykinin accumulation, has been reported.…”

Section: Vasopeptidase Inhibition and Angioedemamentioning

confidence: 99%

“…49 Recently, an enzyme defect involved in the des-arg 9 -bradykinin metabolism, aminopeptidase P, leading to bradykinin and to an even greater extent to des-arg 9 -bradykinin accumulation, has been reported. 48 Vasopeptidase inhibitors acting simultaneously on 2 enzymes that inactivate bradykinin, ie, ACE and NEP, may increase the risk of angioedema. Company statements refer to a rate of angioedema associated with omapatrilat similar to that reported for ACE inhibitors.…”

Section: Vasopeptidase Inhibition and Angioedemamentioning

confidence: 99%

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Vasopeptidase Inhibitors

et al. 2001

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Abstract-The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/ water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow.Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure. Key Words: hypertension Ⅲ heart failure Ⅲ treatment S tructural, humoral, and neuronal factors are involved in cardiovascular regulation, among them the sympathetic and parasympathetic nervous systems and renin-angiotensinaldosterone system (RAAS). The endothelium is a source of paracrine mediators such as nitric oxide (NO), endotheliumderived hyperpolarizing factor (EDHF), and endothelin (Figure 1). Circulating and local regulatory mediators exhibit complex synergisms and interactions; the sympathetic nervous system stimulates secretion of renin and angiotensin (Ang) II, which centrally and at the presynaptic level increase sympathetic nerve activity and enhance endothelin and vasopressin production. The natriuretic peptide system, consisting of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), of myocardial origin, and C-type natriuretic peptide (CNP), of endothelial origin, on the other hand, counteracts the RAAS and endothelin. Endothelial substances act primarily locally and exhibit vasoconstrictor, vasodilating, and mitogenic effects. Some endothelial substances stimulate the production of cytokines and growth factors, leading to vascular smooth muscle ...

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Section: Vasopeptidase Inhibition and Angioedemamentioning

confidence: 99%

Section: Vasopeptidase Inhibition and Angioedemamentioning

confidence: 99%

Vasopeptidase Inhibitors

et al. 2001

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“…14,15 Thus, APP inhibition potentiates the effect of bradykinin in an ACEI-treated rat model. 16 Blais et al 17 previously studied the metabolism of bradykinin in the sera of patients with a history of ACEI-associated angioedema. During ACE inhibition, the relative contribution of kininase I to the degradation of bradykinin is increased in these patients compared with controls.…”

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confidence: 99%

Dipeptidyl Peptidase IV Activity in Patients With ACE-Inhibitor-Associated Angioedema

et al. 2002

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Abstract-Bradykinin and substance P have been implicated as mediators in angiotensin-converting enzyme inhibitor (ACEI)-associated angioedema. Studies investigating the metabolism of bradykinin in sera from patients with a history of ACEI-associated angioedema and controls suggest that there is a defect in a non-ACE, non-kininase I pathway of bradykinin degradation, such as the aminopeptidase P (APP)/dipeptidyl peptidase IV (DPPIV) pathway. This study tested the hypothesis that serum APP or DPPIV activity is decreased in patients with ACEI-associated angioedema. APP and DPPIV activity were measured in sera collected from patients during ACEI-associated angioedema, from patients with a remote history of ACEI-associated angioedema, and from normotensive and untreated hypertensive controls. The effects of acute and chronic ACEI and corticosteroid treatment on serum DPPIV activity were also assessed. DPPIV activity was similar in normotensive volunteers (37.8Ϯ6.3 nmol/mL per min), in untreated hypertensive subjects who had been exposed previously to ACEI without angioedema (36.2Ϯ4.3 nmol/mL per min), in hypertensive patients with a remote history of angioedema (35.1Ϯ8.5 nmol/mL per min), and in chronically ACEI-treated hypertensive subjects (36.1Ϯ5.6 nmol/mL per min). DPPIV activity decreased with increasing age (R 2 ϭ0.10, Pϭ0.016). Subject group significantly affected DPPIV activity (Fϭ6.208, Pϭ0.016) such that DPPIV activity was significantly lower in patients with ACEI-associated angioedema (26.9Ϯ4.1 nmol/mL per min) than in normotensive controls, in previously ACEI-exposed untreated hypertensive volunteers, or in ACEI-treated hypertensive volunteers, even after controlling for age. There was no effect of acute ACE inhibition or corticosteroids on DPPIV activity. With respect to APP activity, there was no difference between groups. These results suggest that DPPIV activity is depressed in individuals with hypertension during acute ACEI-associated angioedema. Key Words: edema Ⅲ angiotensin-converting enzyme inhibitors Ⅲ peptides Ⅲ bradykinin A ngioedema is a rare but potentially life-threatening side effect of angiotensin-converting enzyme inhibitors (ACEI) characterized by swelling of the lips, tongue, mouth, throat, other parts of the face, or, rarely, the hands, feet, or abdominal viscera. 1,2 Whereas the risk of ACEI-associated angioedema has been reported to be 0.1 to 0.4% in predominantly white populations, the risk is increased 4-to 5-fold in black populations, suggesting that genetic or environmental factors modulate the risk of angioedema. 3,4 The risk of angioedema secondary to vasopeptidase inhibitors, which block both ACE and neutral endopeptidase (NEP), may be higher than that associated with ACE inhibition alone. 5 Although the exact mechanism of ACEI-associated angioedema is not known, both bradykinin and substance P, substrates of ACE and NEP, have been implicated in the pathogenesis of angioedema. 6 -9 For example, activation of the kallikrein-kinin system has been demonstrated in hereditary angi...

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“…15 Although AEs related to angioedema were not observed in the present study, this study was small (n ¼ 123) and of short duration (20 days in total). Accumulation of bradykinin or one of its metabolites (BK1-8) is believed to be involved in the occurrence of angioedema, 25,26 and omapatrilat protects bradykinin from degradation and increases the production of BK1-8 by two-to threefold over GW660511X. 27 Consequently, the risk of angioedema may be less for GW660511X than for omapatrilat.…”

Section: Discussionmentioning

confidence: 99%

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

Pearce²,

Danoff

2006

J Hum Hypertens

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This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensinconverting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), X90 and p109 mm Hg; systolic blood pressure (SBP), X150 and p180 mm Hg). After a single-blind 2-to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n ¼ 62) or to active treatment (n ¼ 61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (À8.00 mm Hg, P ¼ 0.002) and DBP (À5.38 mm Hg, P ¼ 0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (Po0.001) reductions in serum ACE activity and significant (Po0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P ¼ 0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.

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Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema

Cited by 70 publications

References 23 publications

Vasopeptidase Inhibitors

Vasopeptidase Inhibitors

Dipeptidyl Peptidase IV Activity in Patients With ACE-Inhibitor-Associated Angioedema

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

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