Negatively charged particle glass, LPS, collagen Clotting/fibrinolysis pathway
Factor XII
Factor XIIa
Plasmin Trypsin
Plasma Prekallikrein
Plasma kallikrein
Tissue Prekallikrein
Tissue kallikrein
by exocrine glands
by liver
HMW Kininogen by liver
Bradykinin
Kallidin
LMW Kininogen
Kininases (ACE)
Inactive Fragments
Biological effect thru B2 receptor mainly
Kinins • •
• •
Pharmacological effects Vasodilation + ↑ 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
Role in the Kidney – Control of Na Excretion
BN-Ki
BN-Ki
BN-Ka
BN-Ka
Influence of NaCl load on systolic BP in 2 strains of rats Influence of various Na diets at week 7
○ BN-Kitasoco
Influence of 2% NaCl diet from 7-11 weeks
● BN-Katholiek
BN-Ki
BN-Kath
Ebelactone B
Systolic Blood Pressure (mmHg)
Ebelactone B
Veh
EbelB
Age (weeks)
Age (weeks)
Kinins
Degradation ACE Inhibitor
ACE
Icatibant
B2
Endothelial cell
PLA2 IP3
↑ Ca++
PGI2
L-arginine +
NO
AC
↑cAMP
Relaxation Anti-ischemic Anti-proliferative Anti-atherosclerotic
Smooth muscle cell
GC
↑cGMP
Blood Pressure (mmHg)
LV Weight (mg/100gBW)
Effect of orally administered ramipril and coadministration of HOE 140 (BK antagonist) on mean BP and LVW in rats with aortic banding
C
V
R1 R1 R2 R2 +H +H
C: sham operation V: control + vehicle R1: ramipril 1 mg/kg
C
V
R1 R1 R2 R2 +H +H
R1+H: Ramipril 1mg + HOE 140 R2: ramipril 10 Âľg/kg R2+H: Ramipril 10Âľg + HOE 140
Saline
Losartan
Ramipril
Ramipril + HOE 140
Neointimal/Total artery Area (%)
Effect of various treatments on neointima formation in the carotid artery 2 weeks after balloon injury
Saline
Losartan
HOE 140
Ramipril
Ramipril + HOE 140
Neointimal area/Total artery area %
+ # * #
Saline
L-NAME
Ramipril
Ramipril + L-NAME
Effect of various treatments on neointima formation in the carotid artery 2 weeks after balloon injury * P<0.05 vs Saline; +:P<0.05 vs. Ramipril; #: P<0.05 vs. L-NAME
Bradykinin Ramiprilat
CP
ATP
Glycogen
Venous Effluent
Lactate
Lactate
CPK
LDH
CF
HR
LV dP/dt
LVP
% Change vs. Control
Cardiodynamic Myocardial tissue
Reversal by Kinin Antagonist of Cardioprotective Effect of ACE Inhibitor
Ramipril
CP
ATP
Glycogen
Myocardial tissue
Lactate
Lactate
CPK
Venous Effluent
LDH
CF
HR
LV dP/dt
LVP
Cardiodynamic
Ramipril + Icatibant
Role of Bradykinin in the cardioprotective effects of Ischemic preconditioning on myocardial infarct size in the rabbit.
Control PC PC+Icat. Icat. BK BK+Icat.
Infarct Size PC: 5 min occlusion followed by 10 min reperfusion followed by 30 min occlusion. Similar protection achieved with exogenous BK.
Effect of Chronic Treatment with MoexiprilÂąIcatibant and Losartan on Infarct Size and Cardiac Mass Infarct Size
Moexepril
Moexepril +Icatibant
Heart:Body Weight Ratio
Losartan
Moexepril
Moexepril +Icatibant
Losartan
Urinary Albumin Excretion Rate in Diabetic Rats
Enalapril
mg/day
Control Enalapril HOE 140 HOE/Enal HOE 140
AII Receptor Blocker
ACE Inhibitor
Blocks formation Blocks Kininase II of AII incompletely
↓ AII effects & aldosterone
Blocks AT-1R
AT-2R Free
↑ Kinins More complete Preserve Inhibition of AII effects
PROTECTION
Antiproliferative effect
Potential Uses of Kinin Antagonists • • • • •
Asthma and bronchoconstriction Septic Shock Hypotension due to pancreatitis Inflammation and pain Rhinovirus symptoms