Bradykinin

Bradykinin is a 9-amino acid (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) vasoactive kinins peptide generated from kininogen precursors by kallikrein serine proteases. High-molecular-weight kininogen (HMWK) → bradykinin via plasma kallikrein; low-molecular-weight kininogen (LMWK) → kallidin (bradykinin extended by an N-terminal Lys) via tissue kallikrein.

**Key physiological and pharmacological roles:**

1. **Vasodilation and blood pressure**: B2R activation on endothelial cells → eNOS activation → NO production → smooth muscle relaxation. This is why ACE inhibitors lower blood pressure: ACE normally degrades bradykinin, so ACE inhibition leads to bradykinin accumulation → enhanced vasodilation.

2. **ACE inhibitor pharmacology**: The cardiovascular benefit of ACE inhibitors extends beyond Ang II suppression — studies show that B2R blockade abolishes approximately 30-50% of ACE inhibitor's antihypertensive effect. Bradykinin-dependent mechanisms also contribute to ACE inhibitor-mediated cardioprotection in post-MI patients (CONSENSUS, GISSI-3 trials context).

3. **Hereditary Angioedema (HAE)**: HAE type 1 and 2 are caused by deficiency or dysfunction of C1-esterase inhibitor, leading to unregulated plasma kallikrein activity → massive bradykinin production → severe subcutaneous and submucosal edema. The standard of care for HAE attacks now includes icatibant (selective B2R antagonist), ecallantide (kallikrein inhibitor), and lanadelumab (prophylactic kallikrein antibody).

4. **Pain**: Bradykinin is one of the most potent endogenous pain-producing compounds. B1R and B2R activation sensitizes peripheral nociceptors via PLC → IP3 → Ca2+ release → TRPV1 sensitization. This peripheral sensitization contributes to inflammatory hyperalgesia.

5. **Ischemic preconditioning**: Brief ischemia → bradykinin release → B2R → PKC activation → protective cardioprotective signaling (similar to opioid preconditioning).