Key result
Tissue kallikrein may initiate ACE inhibitor-induced angioedema, highlighting KLK-1 inhibitors as potential therapies.
Why the study?
Angioedema is a rare side effect of ACE inhibitors proposed to result from bradykinin, but its precise pathophysiological mechanisms and optimal therapeutic targets remain debated.
Highlights the potential role of tissue kallikrein and kinin receptors in the pathophysiology of ACE inhibitor-induced angioedema, identifying new potential therapeutic targets.
Answers are grounded in this paper and cite their sources.
B2 antagonists may prove inadequate for ACEi-AE; challenges BK-B2 paradigm and extends targets to KLK-1 inhibition plus dual receptor blockade.
Angiotensin-converting enzyme (ACE) inhibitors (ACEis) are one of the most successful drug classes for the treatment of hypertension and the prevention of its cardiovascular complications. ACE activates the pressor hormone angiotensin but also inactivates the vasodilator peptide bradykinin (BK). A rare side effect of ACEis, angioedema (AE), has been proposed to result from pro-inflammatory effects of BK. Novel considerations are offered in this debate: (1) the bradykinin B2 receptor antagonist icatibant has had an inconsistent effect on ACEi-associated AE, but its potency and duration of action are much inferior to those of a novel nonpeptide antagonist of this receptor, deucrictibant. (2) Tissue kallikrein (KLK-1) is an effective kininogenase, particularly abundant in the salivary glands, possibly related to orofacial presentation of ACEi-induced AE. (3) The strongly regulated human kinin B1 receptor, optimally responsive to Lys-des-Arg9-BK, is functionally compartmentalized with KLK-1 which produces Lys-BK from kininogens. Chronic treatment with ACEi drugs in laboratory animals induces the expression of vascular B1R that mediates vasodilation. Therefore, ACEi-AE may be largely or completely initiated by KLK-1. Inhibitors of this protease or combined antagonists of both kinin receptor subtypes may be useful for the management of this condition.
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François Marceau (2026) conducted a review in ACE inhibitor-associated angioedema. ACE inhibitors was evaluated. ACE inhibitor-induced angioedema may be largely initiated by tissue kallikrein (KLK-1), suggesting that inhibitors of this protease or combined kinin receptor antagonists may be useful for management.
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