Abstract | 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: CONCLUSIONS AND IMPLICATIONS: We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP 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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Authors | R M Fryer, J Segreti, P N Banfor, D L Widomski, B J Backes, C W Lin, S J Ballaron, B F Cox, J M Trevillyan, G A Reinhart, T W von Geldern |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 153
Issue 5
Pg. 947-55
(Mar 2008)
ISSN: 0007-1188 [Print] England |
PMID | 18084312
(Publication Type: Journal Article)
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Chemical References |
- Angiotensin-Converting Enzyme Inhibitors
- Enzyme Inhibitors
- Indans
- Peptides
- Propionates
- Pyridines
- Thiazepines
- omapatrilat
- candoxatril
- Lisinopril
- Aminopeptidases
- X-Pro aminopeptidase
- Neprilysin
- apstatin
- Bradykinin
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Topics |
- Aminopeptidases
(antagonists & inhibitors)
- Angioedema
(etiology)
- Angiotensin-Converting Enzyme Inhibitors
(administration & dosage, pharmacology)
- Animals
- Bradykinin
(drug effects, metabolism)
- Dose-Response Relationship, Drug
- Drug Evaluation, Preclinical
(methods)
- Enzyme Inhibitors
(pharmacology)
- Hypotension
(etiology)
- Indans
(pharmacology)
- Lisinopril
(pharmacology)
- Male
- Neprilysin
(antagonists & inhibitors)
- Peptides
(pharmacology)
- Propionates
(pharmacology)
- Pyridines
(administration & dosage, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Thiazepines
(administration & dosage, pharmacology)
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