Factor XII

1
Negatively charged particle glass, LPS, collagen
Clotting/fibrinolysis pathway
Factor XII
Factor XIIa
Plasmin
Trypsin
Plasma kallikrein
Plasma Prekallikrein
Tissue Prekallikrein
Tissue kallikrein
by exocrine glands
by liver
LMW Kininogen
HMW Kininogen
Bradykinin
Kallidin
by liver
Kininases (ACE)
Biological effect thru B2 receptor mainly
Inactive Fragments
2
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

3
Role in the Kidney Control of Na Excretion
BN-Ki
BN-Ki
BN-Ka
BN-Ka
4
Influence of NaCl load on systolic BP in 2
strains of rats
Influence of 2 NaCl diet from 7-11 weeks
Influence of various Na diets at week 7
? BN-Kitasoco
? BN-Katholiek
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7
BN-Ki
BN-Kath
Ebelactone B
Ebelactone B
Systolic Blood Pressure (mmHg)
Veh
EbelB
Age (weeks)
Age (weeks)
8
Kinins
Degradation
Icatibant
ACE Inhibitor
ACE
B2
Endothelial cell
PLA2
IP3
? Ca
PGI2
NO

L-arginine
AC
GC
Relaxation Anti-ischemic Anti-proliferative Anti-a
therosclerotic
?cGMP
?cAMP
Smooth muscle cell
9
Effect of orally administered ramipril and
coadministration of HOE 140 (BK antagonist) on
mean BP and LVW in rats with aortic banding
Blood Pressure (mmHg)
LV Weight (mg/100gBW)
R1 H
R2
R1
V
C
R2 H
R2 H
R1 H
R2
R1
V
C
C sham operation V control vehicle R1
ramipril 1 mg/kg
R1H Ramipril 1mg HOE 140 R2 ramipril 10
µg/kg R2H Ramipril 10µg HOE 140
10
Saline
Losartan
Ramipril HOE 140
Ramipril
11
Effect of various treatments on neointima
formation in the carotid artery 2 weeks after
balloon injury
Neointimal/Total artery Area ()
Saline Losartan HOE 140
Ramipril Ramipril
HOE 140
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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
Plt0.05 vs Saline Plt0.05 vs. Ramipril
Plt0.05 vs. L-NAME
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Myocardial tissue
Cardiodynamic
Venous Effluent
Change vs. Control
LV dP/dt
Glycogen
Lactate
Lactate
LDH
CPK
ATP
LVP
HR
CF
CP
Bradykinin
Ramiprilat
16
Reversal by Kinin Antagonist of Cardioprotective
Effect of ACE Inhibitor
Cardiodynamic
Venous Effluent
Myocardial tissue
LV dP/dt
Glycogen
Lactate
LDH
CPK
LVP
Lactate
ATP
HR
CF
CP
Ramipril
Ramipril Icatibant
17
Role of Bradykinin in the cardioprotective
effects of Ischemic preconditioning on myocardial
infarct size in the rabbit.
Control
PC
PCIcat.
Icat.
BK
BKIcat.
Infarct Size
PC 5 min occlusion followed by 10 min
reperfusion followed by 30 min occlusion. Similar
protection achieved with exogenous BK.
18
Effect of Chronic Treatment with
MoexiprilIcatibant and Losartan on Infarct Size
and Cardiac Mass
Infarct Size
HeartBody Weight Ratio
Moexepril Icatibant
Moexepril Icatibant
Moexepril
Losartan
Moexepril
Losartan
19
Urinary Albumin Excretion Rate in Diabetic Rats
Enalapril
Control Enalapril HOE 140 HOE/Enal
mg/day
HOE 140
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AII Receptor Blocker
ACE Inhibitor
Blocks AT-1R
AT-2R Free
Blocks formation of AII incompletely
Blocks Kininase II
Preserve Anti- proliferative effect
More complete Inhibition of AII effects
? Kinins
? AII effects aldosterone
PROTECTION
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Potential Uses of Kinin Antagonists

• Asthma and bronchoconstriction
• Septic Shock
• Hypotension due to pancreatitis
• Inflammation and pain
• Rhinovirus symptoms