Bradykinin-2 (Kallidin / Lys-Bradykinin)

Overview

Bradykinin-2, more commonly known as kallidin or Lys-bradykinin ([Lys⁰]-bradykinin), is a decapeptide of the kallikrein-kinin system (KKS). It is the tissue-derived counterpart to plasma-derived bradykinin: while bradykinin is a nonapeptide released from high-molecular-weight kininogen by plasma kallikrein, kallidin is a decapeptide released from low-molecular-weight kininogen by tissue kallikrein. The two peptides share the C-terminal nonapeptide core and consequently exhibit very similar pharmacology, but differ by an N-terminal lysine in kallidin.

The "bradykinin-2" designation reflects historical nomenclature in which plasma-derived bradykinin was considered the prototype and the tissue-derived form was numbered sequentially. Kallidin (the preferred modern term) was identified shortly after bradykinin in the late 1950s and early 1960s as a similar kinin released by a distinct enzymatic route.

Kallidin is rapidly converted to bradykinin by plasma aminopeptidase activity that removes the N-terminal lysine, meaning that most circulating kinin activity ultimately converges on bradykinin acting at the B2 receptor. However, kallidin itself is biologically active and may act locally before conversion, particularly at sites of tissue kallikrein release (glandular secretions, inflammation). Both peptides serve as precursors for des-Arg metabolites that activate the inducible B1 receptor.

Structure/Sequence

Kallidin (Bradykinin-2): Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (KRPPGFSPFR)

• Length: 10 amino acids (decapeptide)
• Molecular weight: ~1,189 g/mol
• Relationship to bradykinin: Bradykinin (RPPGFSPFR, 9 aa) = kallidin minus N-terminal Lys
• Precursor: Low-molecular-weight kininogen (LMW-K)
• Generating enzyme: Tissue kallikrein (KLK1)

Sequence Features

• Highly proline-rich (3 prolines in 10 residues) — imparts conformational constraint
• Basic residues: N-terminal Lys, internal Arg, C-terminal Arg
• Serine at position 7: Contributes to kallikrein cleavage specificity
• C-terminal arginine: Required for B2 receptor binding

Related Metabolites

• des-Arg¹⁰-kallidin (Lys-des-Arg-BK): N-terminal lysine form of des-Arg-BK; selective B1 receptor agonist
• des-Arg⁹-bradykinin: The B1 receptor endogenous agonist derived from bradykinin
• [Hyp³]-bradykinin: Hydroxyproline-3 form found in some species

Mechanism of Action

B2 Receptor (Constitutive)

Kallidin binds and activates the B2 bradykinin receptor:

• Gq/11 coupling: Activates phospholipase C → IP3/DAG → calcium release and PKC
• Gi/o coupling: Some tissues
• Phospholipase A2 activation: Arachidonic acid release, prostaglandin and leukotriene generation
• NO synthesis: eNOS activation → endothelial vasodilation
• Widely expressed: Endothelium, vascular smooth muscle, nerve endings, immune cells

B1 Receptor (Inducible)

Kallidin itself has low affinity for B1; the des-Arg metabolite Lys-des-Arg-BK is a potent B1 agonist:

• Inducible expression: B1 receptors are not constitutively expressed but are upregulated by inflammation (IL-1, LPS, injury)
• Gq and Gi coupling similar to B2
• Roles: Chronic inflammation, hyperalgesia, tissue remodeling

Tissue Kallikrein Generation

Tissue kallikrein (KLK1) is released at sites of:

• Glandular secretion (salivary, pancreatic, prostatic)
• Inflammation
• Vascular injury
• Renal tubular activity

Kallidin generation thus occurs locally, in contrast to plasma kallikrein-driven bradykinin release during contact activation.

Rapid Conversion to Bradykinin

Plasma aminopeptidase M (APN / CD13) rapidly cleaves the N-terminal lysine from kallidin, yielding bradykinin:

• Conversion half-life: seconds
• Most circulating kinin activity mediated via bradykinin

ACE-Mediated Inactivation

Both kallidin and bradykinin are rapidly inactivated by ACE (kininase II) removing the C-terminal dipeptide. ACE inhibitors increase kinin availability, contributing to their pharmacological effects and also to adverse effects like cough and angioedema.

Physiological Effects

• Vasodilation (particularly arteriolar)
• Increased vascular permeability
• Stimulation of sensory nerve endings → pain signaling
• Smooth muscle contraction (bronchial, uterine, GI)
• Diuresis and natriuresis
• Mediation of inflammatory responses

Research Summary

Common Discussion Topics

1. Plasma vs tissue kinin systems — The distinction between plasma-derived bradykinin (from HMW-K by plasma kallikrein) and tissue-derived kallidin (from LMW-K by tissue kallikrein) reflects two parallel kinin-generating systems. Plasma kallikrein activates during contact system cascade (factor XII, etc.), while tissue kallikrein operates in exocrine and local contexts.

2. Convergence on bradykinin — Because plasma aminopeptidase rapidly converts kallidin to bradykinin, much of the circulating kinin activity ultimately flows through bradykinin. However, kallidin's local actions before conversion remain functionally significant, particularly in tissues with high tissue kallikrein expression.

3. B1 vs B2 receptor system — The B2 receptor is constitutive and mediates most acute kinin effects. B1 is inducible and emerges during chronic inflammation and tissue injury. Kallidin supplies B1 after N-terminal modification (Lys-des-Arg-BK). This inducible arm is analogous to other upregulated-on-injury receptor systems.

4. ACE inhibitor cough and angioedema — Because ACE inactivates kinins, ACE inhibitors raise bradykinin and kallidin levels, contributing to cough in ~10% and to rare angioedema. The kinin connection explains why angiotensin receptor blockers (ARBs) do not share these side effects.

5. Hereditary angioedema — HAE involves unregulated bradykinin/kallidin generation due to C1-esterase-inhibitor deficiency. Therapeutic approaches targeting the kallikrein-kinin system (e.g., icatibant as B2 antagonist) exemplify clinical exploitation of kinin pharmacology.

Related Compounds

• Bradykinin — plasma-derived nonapeptide from the same kinin system
• Angiotensin-(1-7) — cross-talking RAS peptide that potentiates bradykinin B2 signaling
• Substance P — related pro-inflammatory sensory neuropeptide
• Icatibant — selective B2 receptor antagonist