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  1. 1. Factor XII Plasma Prekallikrein Plasma kallikrein HMW Kininogen Bradykinin Kininases (ACE) Inactive Fragments LMW Kininogen Kallidin Tissue kallikrein Tissue Prekallikrein Negatively charged particle glass, LPS, collagen Clotting/fibrinolysis pathway Biological effect thru B2 receptor mainly Plasmin by liver by exocrine glands Factor XIIa Trypsin by liver
  2. 2. Kinins <ul><li>Pharmacological effects </li></ul><ul><li>Vasodilation + ↑ capilary permeability </li></ul><ul><li>Extravascular smooth muscle contraction (bronchioles, GI slow rhythmic contraction) </li></ul><ul><li>Stimulation of nerve endings – pain </li></ul><ul><li>Increase in Na excretion in kidney </li></ul><ul><li>Physiological and Pathophysiological Role </li></ul><ul><li>Renal and Cardiovascular Regulation </li></ul><ul><li>Inflammatory Response and Pain </li></ul><ul><li>? Role in the effects of ACE Inhibitors </li></ul>
  3. 3. Role in the Kidney – Control of Na Excretion BN-Ki BN-Ka BN-Ki BN-Ka
  4. 4. ○ BN-Kitasoco ● BN-Katholiek Influence of NaCl load on systolic BP in 2 strains of rats Influence of various Na diets at week 7 Influence of 2% NaCl diet from 7-11 weeks
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  7. 7. Ebelactone B Ebelactone B Systolic Blood Pressure (mmHg) Age (weeks) Age (weeks) BN-Ki BN-Kath Veh EbelB
  8. 8. Kinins ACE Degradation ACE Inhibitor B2 Icatibant IP 3 ↑ Ca ++ PLA 2 PGI 2 L-arginine NO ↑ cAMP AC GC ↑ cGMP Relaxation Anti-ischemic Anti-proliferative Anti-atherosclerotic + Smooth muscle cell Endothelial cell
  9. 9. Blood Pressure (mmHg) LV Weight (mg/100gBW) R2 R1 V C R1 +H R2 +H R2 R1 V C R1 +H R2 +H Effect of orally administered ramipril and coadministration of HOE 140 (BK antagonist) on mean BP and LVW in rats with aortic banding C: sham operation V: control + vehicle R1: ramipril 1 mg/kg R1+H: Ramipril 1mg + HOE 140 R2: ramipril 10 µg/kg R2+H: Ramipril 10µg + HOE 140
  10. 10. Saline Losartan Ramipril + HOE 140 Ramipril
  11. 11. Neointimal/Total artery Area (%) Saline Losartan HOE 140 Ramipril Ramipril + HOE 140 Effect of various treatments on neointima formation in the carotid artery 2 weeks after balloon injury
  12. 12. Effect of various treatments on neointima formation in the carotid artery 2 weeks after balloon injury Saline L-NAME Ramipril Ramipril + L-NAME Neointimal area/Total artery area % * # + # * P<0.05 vs Saline; +:P<0.05 vs. Ramipril; #: P<0.05 vs. L-NAME
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  15. 15. LVP LV dP/dt HR CF LDH CPK Lactate Lactate Glycogen ATP CP Bradykinin Ramiprilat % Change vs. Control Cardiodynamic Venous Effluent Myocardial tissue
  16. 16. LVP LV dP/dt HR CF LDH CPK Lactate Lactate Glycogen ATP CP Cardiodynamic Venous Effluent Myocardial tissue Ramipril Ramipril + Icatibant Reversal by Kinin Antagonist of Cardioprotective Effect of ACE Inhibitor
  17. 17. Control PC PC+Icat. Icat. BK+Icat. BK Role of Bradykinin in the cardioprotective effects of Ischemic preconditioning on myocardial infarct size in the rabbit. PC: 5 min occlusion followed by 10 min reperfusion followed by 30 min occlusion. Similar protection achieved with exogenous BK. Infarct Size
  18. 18. Infarct Size Heart:Body Weight Ratio Moexepril Effect of Chronic Treatment with Moexipril±Icatibant and Losartan on Infarct Size and Cardiac Mass Moexepril +Icatibant Losartan Moexepril Moexepril +Icatibant Losartan
  19. 19. HOE 140 Enalapril Control Enalapril HOE 140 HOE/Enal mg/day Urinary Albumin Excretion Rate in Diabetic Rats
  20. 20. ACE Inhibitor AII Receptor Blocker Blocks formation of AII incompletely Blocks Kininase II ↑ Kinins ↓ AII effects & aldosterone PROTECTION Blocks AT-1R AT-2R Free More complete Inhibition of AII effects Preserve Anti- proliferative effect
  21. 21. Potential Uses of Kinin Antagonists <ul><li>Asthma and bronchoconstriction </li></ul><ul><li>Septic Shock </li></ul><ul><li>Hypotension due to pancreatitis </li></ul><ul><li>Inflammation and pain </li></ul><ul><li>Rhinovirus symptoms </li></ul>