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Bradykinin and kinin physiology and pharmacology

see also autacoids


  • IV injection of urine produced hypotension which lead to the discovery of kallikrein (“pancreas”) 1937 & that this generated an active substance kallidin in 1948 which was shown to be a decapeptide (1961? - bradykinin with added lysine) cleaved from a plasma alpha2 globulin kallidinogen in 1970 later known as LMW kininogen as another plasma alpha2 globulin HMW kininogen is cleaved by kallikrein (& some serine proteases) to form bradykinin;
  • Trypsin & some snake venoms acting on plasma globulin formed a substance that decr. BP & slowly developing contraction GIT - bradykinin in 1949 which was isolated in 1960 & shown to be a nonapeptide.
  • In mid-1980's, peptide antagonists of bradykinin developed;

Endogenous Kallikrein-Kininogen-Kinin System:

2 distinct systems:

I. Plasma kallikrein converts HMW kininogen to bradykinin:
  • anomalous -ve charged surfaces, collagen, glass, etc.
  • ⇒ activate Hageman factor
    • ⇒ activates clotting pathway;
    • ⇒ activates plasminogen fibrinolysis system;
    • ⇒ fluid-phase activ. of complement;
    • ⇒ forms fragments (esp. if kallikrein, HMW kininogen present)
    • ⇒ converts prekallikrein to kallikrein
    • ⇒ +ve feedback on activ. Hageman factor & frag.formn
    • ⇒ converts HMW kininogen to bradykinin
  • Inhib. processes:
    • Inhibitors of kallikrein cleavage of HMW kininogen:
      • C1 esterase inhibitor;
      • alpha2 macroglobulin;
      • alpha1 antitrypsin (mainly tissue kallikrein though);
    • kinase I & II (ACE) cleave bradykinin to inactive frag. T½ 15sec;
II. Tissue or glandular kallikrein (MW 29,000) => LMW kininogen=>kallidin:
  • Ag-Ab complement activation ⇒ cell lysis ⇒ kininogenase release
    • ⇒ direct cleavage LMW kininogen ⇒ kallidin;
  • unidentified protease cleaves tissue prekallikrein ⇒ tiss-kallikrein
    • ⇒ cleavage of HMW or LMW kininogen ⇒ kallidin;
  • Inhib. processes:
    • Inhibitors of tissue kallikrein cleavage of kininogen:
      • alpha1 antitrypsin most important;
      • Kinase I & II (ACE) cleave kallidin to inactive fragments T½ 15s;
  • Tissue prekallikrein:
    • synthesis incr. by:
      • aldosterone in kidney & saliv.gland;
      • androgens in certain other glands;
    • secretion incr. by: vagal stimulation of pancreas;

Physiological Functions of bradykinin/kallidin:


  • B2 receptors in NS localised to sites involving nociception such as superf.layers spinal cord, thin unmyelinated fibres, & cells in sensory ganglia where stimulation elicits pain;

Renal Fn:

  • ? renal kallikrein involved in local regulation renal function;
  • incr. electrogenic transport of Cl in collecting duct via stimulation of

receptors on basolat. surface of tubule cell;


  • ? role in regulation BP as kininase II same as ACE;
  • ? kinins may blunt effect of pressor agents;


  • kinins mimic manifestations of inflammation:
  • inhaled Ag or rhinoviral rhinitis;
  • hereditary angioedema (HAE) (defect in C1 esterase inhib)
  • ? role in inflamm. response in gout, endotoxic shock, DIC

Pharmacologic properties of bradykinin/kallidin:

  • NB. kallidin & bradykinin equipotent & similar responses as H1 agonists;
  • Normal tissue responses seem to be via B2 receptors but tissue damage induces B1 receptor production;

B1 receptor:

  • sensitive also to kininase I metabolites of bradykinin/kallidin;
  • synth. receptors induced by trauma or path. insults;
  • vasoconstriction of arteries & veins;
  • closure ductus arteriosis, constriction umbil. vessels (?B1)
B1 antagonists:
  • current B2 antagonists also inhib. B1;
  • pure B1: des-Arg[Leu]bradykinin & des-Arg[Leu]kallidin;

B2 receptor:

  • similar mechanism as for H1 (ie. via Plipase C);
  • potent vasodilatation via EDRF incr. arterioles, venules with receptors on endothelial cells (as for H1 but 10 more potent);
  • dilatation fetal pulm. A. (?B2);
  • incr. capillary permeab. via separation endo.cells of small venules;
  • bronchoconstriction; uterotonic in rats; GIT contraction pigs;
  • intense burning pain if applied to base of blister;
  • throbbing, burning pain in hand if inject into brachial A;
  • NB. no itch!!?
B2 antagonists:
  • non-selective: D-Arg[4-OH-Pro-D-Phe]bradykinin but v.short T½;
    • ⇒ symptom relief from URTI rhinitis;
    • ⇒ decr. pain from burns;
    • ⇒ decr. allergic asthma;

Kallikrein inhibitors:

  • Aprotinin (Trasylol)
    • used to Rx ac.pancreatitis & carcinoid synd. ?unsuccessful;
bradykinin.txt · Last modified: 2010/08/17 04:35 by

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