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Kinins
- 1. Factor XII PlasmaPrekallikrein 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 www.freelivedoctor.com
- 2. Kinins Pharmacological effectsVasodilation + ↑ capilary permeability Extravascular smooth muscle contraction (bronchioles, GI slow rhythmic contraction) Stimulation of nerve endings – pain Increase in Na excretion in kidney Physiological and Pathophysiological Role Renal and Cardiovascular Regulation Inflammatory Response and Pain ? Role in the effects of ACE Inhibitors www.freelivedoctor.com
- 3. Role in theKidney – Control of Na Excretion BN-Ki BN-Ka BN-Ki BN-Ka www.freelivedoctor.com
- 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 www.freelivedoctor.com
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- 7. Ebelactone B EbelactoneB Systolic Blood Pressure (mmHg) Age (weeks) Age (weeks) BN-Ki BN-Kath Veh EbelB www.freelivedoctor.com
- 8. Kinins ACE DegradationACE 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 www.freelivedoctor.com
- 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 www.freelivedoctor.com
- 10. Saline Losartan Ramipril+ HOE 140 Ramipril www.freelivedoctor.com
- 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 www.freelivedoctor.com
- 12. Effect of varioustreatments 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 www.freelivedoctor.com
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- 15. LVP LV dP/dt HR CF LDH CPK Lactate Lactate Glycogen ATP CP Bradykinin Ramiprilat % Change vs. Control Cardiodynamic Venous Effluent Myocardial tissue www.freelivedoctor.com
- 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 www.freelivedoctor.com
- 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 www.freelivedoctor.com
- 18. Infarct Size Heart:BodyWeight Ratio Moexepril Effect of Chronic Treatment with Moexipril±Icatibant and Losartan on Infarct Size and Cardiac Mass Moexepril +Icatibant Losartan Moexepril Moexepril +Icatibant Losartan www.freelivedoctor.com
- 19. HOE 140 EnalaprilControl Enalapril HOE 140 HOE/Enal mg/day Urinary Albumin Excretion Rate in Diabetic Rats www.freelivedoctor.com
- 20. ACE Inhibitor AIIReceptor 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 www.freelivedoctor.com
- 21. Potential Uses ofKinin Antagonists Asthma and bronchoconstriction Septic Shock Hypotension due to pancreatitis Inflammation and pain Rhinovirus symptoms www.freelivedoctor.com