kinins
DESCRIPTION
TRANSCRIPT
Factor XII
PlasmaPrekallikrein
Plasmakallikrein
HMW Kininogen
Bradykinin
Kininases(ACE)
Inactive Fragments
LMW Kininogen
Kallidin
Tissuekallikrein
TissuePrekallikrein
Negatively charged particleglass, LPS, collagen
Clotting/fibrinolysis pathway
Biological effect thruB2 receptor mainly
Plasmin
by liver
by exocrine glands
Factor XIIa
Trypsin
by liver
www.freelivedoctor.com
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
www.freelivedoctor.com
Role in the Kidney – Control of Na Excretion
BN-Ki
BN-Ka
BN-Ki
BN-Ka
www.freelivedoctor.com
○ 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
www.freelivedoctor.com
www.freelivedoctor.com
Ebelactone B Ebelactone B
SystolicBlood Pressure(mmHg)
Age (weeks) Age (weeks)
BN-Ki BN-Kath
Veh
EbelB
www.freelivedoctor.com
Kinins
ACE
Degradation
ACE Inhibitor B2 Icatibant
IP3
↑ Ca++
PLA2
PGI2 L-arginine NO
↑cAMP
ACGC
↑cGMP
RelaxationAnti-ischemic
Anti-proliferativeAnti-atherosclerotic
+
Smooth muscle cell
Endothelial cell
www.freelivedoctor.com
Blo
od P
ress
ure
(m
mH
g)
LV
Wei
ght
(mg/
100g
BW
)
R2R1VC R1+H
R2+H
R2R1VC 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 operationV: control + vehicleR1: ramipril 1 mg/kg
R1+H: Ramipril 1mg + HOE 140R2: ramipril 10 µg/kgR2+H: Ramipril 10µg + HOE 140
www.freelivedoctor.com
Saline Losartan
Ramipril + HOE 140Ramipril
www.freelivedoctor.com
Neo
inti
mal
/Tot
al a
rter
y A
rea
(%)
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
Effect of various treatments on neointima formation in the carotid artery 2 weeks after balloon injury
Saline L-NAME Ramipril Ramipril + L-NAME
Neo
inti
mal
are
a/T
otal
art
ery
area
%
* #
+ #
* P<0.05 vs Saline; +:P<0.05 vs. Ramipril; #: P<0.05 vs. L-NAMEwww.freelivedoctor.com
www.freelivedoctor.com
www.freelivedoctor.com
LV
P
LV
d
P/d
t
HR
CF
LD
H
CP
K
Lac
tate
Lac
tate
Gly
coge
n
AT
P
CP
Bradykinin Ramiprilat
% C
hang
e vs
. Con
trol
Cardiodynamic Venous Effluent Myocardial tissue
www.freelivedoctor.com
LV
P
LV
d
P/d
t
HR
CF
LD
H
CP
K
Lac
tate
Lac
tate
Gly
coge
n
AT
P
CP
Cardiodynamic Venous Effluent Myocardial tissue
Ramipril Ramipril + Icatibant
Reversal by Kinin Antagonist of Cardioprotective Effect of ACE Inhibitor
www.freelivedoctor.com
Control
PC
PC+Icat.
Icat.
BK+Icat.
BK
Role of Bradykinin in the cardioprotective effects ofIschemic 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
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
Losartanwww.freelivedoctor.com
HOE 140
Enalapril
ControlEnalaprilHOE 140HOE/Enal
mg/
day
Urinary Albumin Excretion Rate in Diabetic Rats
www.freelivedoctor.com
ACE Inhibitor AII Receptor Blocker
Blocks formationof AII incompletely
Blocks Kininase II
↑ Kinins↓ AII effects & aldosterone
PROTECTION
Blocks AT-1R
AT-2R Free
More completeInhibition of AII effects
Preserve Anti-proliferativeeffect
www.freelivedoctor.com
Potential Uses of Kinin Antagonists
• Asthma and bronchoconstriction
• Septic Shock
• Hypotension due to pancreatitis
• Inflammation and pain
• Rhinovirus symptoms
www.freelivedoctor.com