Acute adverse reactions associated with angiotensin-converting enzyme inhibitors: genetic factors and therapeutic implications

Nikpoor, Borzoo; Duan, Qing; Rouleau, Guy A.

doi:10.1517/14656566.6.11.1851

Cited by 25 publications

(12 citation statements)

References 19 publications

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“…Previous studies have demonstrated that APP contributes to the regulation of BK metabolism and that depressor responses to apstatin are exacerbated in the presence of ACE inhibition, an effect correlated with increases in measured concentrations of BK in the plasma ( Kitamura et al , 1999 ). In the present study, we clearly demonstrated the importance of APP in the in vivo degradation of BK, second only to ACE in potency, and furthermore suggest that concomitant inhibition of both enzymes by omapatrilat is probably the primary mechanism responsible for the large depressor response in rats (and subsequent angioedema in patients); a finding consistent with increased susceptibility to angioedema in patients with low APP activity on ACE inhibitor therapy ( Adam et al , 2002 ; Duan et al , 2005 ; Nikpoor et al , 2005 ). Thus, there is a need to develop novel BME inhibitors with better selectivity (for example, no APP inhibitory activity) to ensure patient safety from adverse events mediated by APP inhibition ( Jandeleit‐Dahm, 2006 ).…”

Section: Discussionsupporting

confidence: 76%

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

Fryer

Segreti

Banfor

et al. 2008

British J Pharmacology

118

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Background and purpose: Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema. Experimental approach: 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. Key results: In the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B 2 blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril þ A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone. Conclusions and implications:We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE4APPcNEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/ NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease.

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Section: Discussionsupporting

confidence: 76%

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

Fryer

Segreti

Banfor

et al. 2008

British J Pharmacology

118

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“…The study of the inter‐relationship between changes in levels of different autocrine modulators, which can occur independently of changes in plasma concentrations ( Slight et al ., 1999 ), may have important clinical implications. These relate to adverse side effects of commonly used drugs such as ACE inhibitors ( Mann et al ., 2005 ; Nikpoor et al ., 2005 ). Thus, understanding the function and interdependence of autocrine modulators will enable a rational design of treatment strategies for correcting or preventing diabetic complications.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone and the autocrine modulation of potassium currents and oxidative stress in the diabetic rat heart

Shimoni

Chen

Emmett

et al. 2008

British J Pharmacology

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Background and purpose: Aldosterone plays a major role in cardiac pathology. This study was designed to investigate the role of cardiac aldosterone in modulating K þ currents and oxidative stress in the streptozotocin-induced diabetic rat heart. Experimental approach: Transient and sustained K þ currents were measured in ventricular myocytes by voltage clamp. Plasma and cellular aldosterone were measured by ELISA. Fluorescent dihydroethidium (DHE) was used to assess superoxide ions as markers of oxidative stress. Key results: The mineralocorticoid antagonist spironolactone (1 mM, 5-9 h) significantly augmented both K þ currents in diabetic males, with a concomitant shortening of the action potential but had no effect in myocytes from control males or from diabetic females. Effects of spironolactone were restored in ovariectomized diabetic females and abolished in orchidectomized diabetic males. The aldosterone synthase inhibitor FAD286 (1 mM, 5-9 h) significantly augmented K þ currents in cells from diabetic males, but not females. Spironolactone and FAD286 significantly reduced oxidative stress in cells from diabetic males. Plasma aldosterone content was elevated in diabetic males (relative to control), but not in females. Cellular aldosterone was also elevated, but not significantly. The elevation in aldosterone was only partly dependent on a concomitant increase in cellular angiotensin II. Conclusions and implications: A gender-related, sex-hormone-dependent elevation in plasma and cardiac cell aldosterone contributed to oxidative stress and to attenuation of K þ currents in diabetic male rats. Aldosterone may thus contribute to diabetes-associated cardiac arrhythmias. Aldosterone elevation was partly related to levels of angiotensin II, but residual, angiotensin II-independent, aldosterone maintains functional relevance.

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“…A more likely explanation is that cases with asthma and ACE‐I‐induced cough, one or more cofactors may have increased risk. Potential cofactors include CHF, bradykinin receptor gene polymorphism, ACE insertion/deletion polymorphism, bradykinin‐induced increase in the sensitivity of the sensorial nerve fibers of the airways, defects of the APP enzyme for the degradation of bradykinin and increased cough reflex sensitivity …”

Section: Discussionmentioning

confidence: 99%

The presence of underlying asthma should be investigated in patients diagnosed with ACE inhibitor induced cough

Yılmaz

Türk

Ketencioğlu

et al. 2020

Clinical Respiratory J

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Introduction Why do only some of patients who are prescribed angiotensin converting enzyme inhibitors (ACE‐I) develop cough? The pathogenesis of ACE‐I‐induced cough remains controversial and requires further studies. Objective We aim to investigate whether asthma is a contributing cause of ACE‐I‐induced cough. Methods Patients attending a cardiology clinic between March 2016 and March 2017 who were diagnosed with ACE‐I induced cough were included in this study. ACE‐I‐induced cough was defined as cough which developed within 4 weeks after initiation of ACE‐I therapy and which improved within 4 weeks after discontinuation of the ACE‐I. Patients who had received ACE‐I treatment for at least 6 months without side effects were included in the study as a control group. Face‐to‐face questionnaires, pulmonary function tests (PFT) and skin prick tests were applied to all the patients. If there was discordance between asthma history and PFT results, a methacholine bronchial provocation test (BPT) was performed. Results A total of 43 patients with ACE‐I induce cough were compared with 50 controls. Bronchial hyperreactivity (BHR), rhinitis, atopy and family history of asthma were more frequent in patients with ACE‐I induced cough (P < .001). Patients with ACE‐I‐induced cough had significantly higher incidence of diagnosed asthma [OR = 8.28 (95%CI: 3.26‐21.03) P < .001]. Conclusions Asthma and an atopic background constitute a substantial risk factor for ACE‐I induced cough. The presence of underlying asthma should be investigated in patients diagnosed with ACE inhibitor induced cough. However, the fact that most asthma patients tolerate ACE‐I therapy, indicates that other cofactors are likely involved.

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Acute adverse reactions associated with angiotensin-converting enzyme inhibitors: genetic factors and therapeutic implications

Cited by 25 publications

References 19 publications

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

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

Aldosterone and the autocrine modulation of potassium currents and oxidative stress in the diabetic rat heart

The presence of underlying asthma should be investigated in patients diagnosed with ACE inhibitor induced cough

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