Angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril) are zinc metallopeptidases. The zinc ion is coordinated by two histidines and a glutamate in the active site and activates a water molecule for nucleophilic attack. Lisinopril competitively inhibits ACE with a Ki of approximately 0.27 nM. ACE normally cleaves the C-terminal dipeptide from angiotensin I to form angiotensin II. ACE ALSO inactivates bradykinin. Which clinical consequence results SPECIFICALLY from impaired bradykinin degradation?

• A Hyperkalemia due to reduced aldosterone
• B Renal afferent arteriolar dilation causing AKI in bilateral renal artery stenosis
• C First-dose hypotension in volume-depleted patients
• D Dry persistent cough and angioedema ✓

Explanation

ACE (kininase II) degrades bradykinin and substance P. When ACE is inhibited by ACE inhibitors, bradykinin accumulates. Bradykinin stimulates B2 receptors on bronchial epithelium and vascular endothelium, triggering prostaglandin and nitric oxide release. Persistent dry cough (via bradykinin-mediated sensitization of sensory C-fibers) occurs in 10-20% of patients, especially in Asian populations. Angioedema (potentially life-threatening, involving pharyngeal edema) is a rare but serious bradykinin-mediated effect. Hyperkalemia occurs due to reduced aldosterone (from decreased angiotensin II) — a renin-angiotensin mechanism, not bradykinin. AKI in renal artery stenosis and first-dose hypotension are also angiotensin II-related, not bradykinin-related effects.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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