Kinins

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

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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-Ka

BN-Ki

BN-Ka


○ 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




Ebelactone B Ebelactone B

SystolicBlood Pressure(mmHg)

Age (weeks) Age (weeks)

BN-Ki BN-Kath

Veh

EbelB


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


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


Saline Losartan

Ramipril + HOE 140Ramipril


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


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



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


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


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


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


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


Potential Uses of Kinin Antagonists

• Asthma and bronchoconstriction

• Septic Shock

• Hypotension due to pancreatitis

• Inflammation and pain

• Rhinovirus symptoms


Documents

Kinins