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;

• 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;

• 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;

• 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 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

• 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;

• 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)

• current B2 antagonists also inhib. B1;
• pure B1: des-Arg[Leu]bradykinin & des-Arg[Leu]kallidin;

• 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!!?

• 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;

• Aprotinin (Trasylol)
  • used to Rx ac.pancreatitis & carcinoid synd. ?unsuccessful;