Kinin (Bradykinin)
- Kinin is a
polypeptides local hormones, such as Bradykinin and Kallidin.
- Kinins are
potent vasodilator peptides, they are formed enzymatically for protein
substrates called Kininogen.
- Kinin is a
component of the Kinin-Kallikrein System. The kinin-kallikrein system or simply
kinin system is a poorly understood hormonal system with limited available
research.
Bio synthesis
-
Kallikreins are present in plasma and in several
tissues.
-
Plasma prekallikrein can be activated to plasma
kallikrein by hageman factor, trypsin and possibly kallikrein itself.
-
Tissue kallikrein are different from those of plasma
kallikrein.
-
Kininogen is the precursors of kinins and substrates
of kallikreins.
-
Two types of Kininogens: low-molecular weight
(LMW-kininogen) and high- molecular weight (HMW-kininogen).
-
HMW-kininogen is converted to bradykinin by plasma
kallikrein.
-
LMW-kininogen is converted to kallidin by tissue
kallikrein.
* Three kinins have been identified in mammals:
1) Bradykinin; is the predominant kinin in plasma.
2) Lysyl-bradykinin (Kallidin), is the major urinary form.
3) Methionyl-lysyl-bradykinin.
- Kinins are metabolized rapidly (half-life < 15 seconds) by two
plasma kininase I and kininase II.
Pharmacodynamics
- Kinins on arteriesà
marked arteriolar dilatation. Approximately 10 times more vasodilator than
histamine.
- The vasodilatation may result from;
- Direct
inhibitory effect on arteriolar smooth muscle.
- Release
of nitric oxide (NO).
- Release
of vasodilator prostaglandins.
- Kinins on veins Contraction, may result from:
- Direct
stimulatory effect on venous smooth muscle.
- Release
of vasoconstrictor prostaglandins.
- Kallikreins may
play a role in the physiological activation of various prohormones, including Proinsulin
and prorenin.
- Bradykinin role in inflammation and pain has long been
known to produce;
four classic symptoms of inflammation;
1) Redness
2) Local heat
3) Swelling
4) Pain
- Intradermal injection of kinins cause → potent pain
producing substances.
- Bradykinin may play beneficial, protective role in
certain CV diseases and ischemic stroke-induced brain injury, on other hand it
is implicated in cancer and some CNS diseases.
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Drugs Affecting The Kinin-Kallikrein System |
|
- The action of
kinins can be enhanced with ACE inhibitors. - The synthesis of
kinins can be inhibited with the kallikrein inhibitors. - Kinin receptors
antagonists. |
|
Kallikrein Inhibitors |
|
Aprotinin (Trasylol) |
|
- Aprotinin also
known as bovine pancreatic trypsin inhibitor (BPTI). - Act by inhibits
several serine proteases, specifically trypsin, chymotrypsin, plasmin and
kallikrein; leads to inhibition of fibrinolysis. - Used to reduce
bleeding during complex surgery (e.g. cardiopulmonary bypass). - Warning;
Aprotinin may cause severe and sometimes fatal allergic reactions
(anaphylaxis). |
|
Ecallantide (Kalbitor) |
|
- Ecallantide is a
plasma kallikrein inhibitor. - Act by blocking
substances (e.g. bradykinin) that cause swelling, inflammation, and pain
associated with hereditary angioedema (HAE). - Uses; Treatment
of acute attacks of hereditary angioedema (HAE). - Warning;
Ecallantide may cause severe and sometimes fatal allergic reactions (anaphylaxis). |
|
Kinin Receptors Antagonists |
|
Icatibant (Firazyr) |
|
- Icatibant is a
bradykinin B; receptor blocker. - Uses; Treatment
of acute attacks of hereditary angioedema (HAE). - Common side
effects; pain and redness at the injection site. |
Vasopressin or Arginine
vasopressin (AVP)
or Antidiuretic hormone
(ADH)
- It is regulate the body retention of water (it is
released when the body is dehydrated).
- It is responsible for increasing water reabsorption in
the collecting ducts of the kidney à
reducing urine volume à
Increase blood volumeà
Increase blood pressure.
Natriuretic Peptides
(NP)
- Natriuretic peptides is a peptides refers to induces
natriuresis (process of excretion of sodium in the urine).
- Natriuretic peptides possess potent natriuretic,
diuretic, and vasodilating activities and control body fluid homeostasis and
control blood pressure.
- Most Common Natriuretic peptides; 1) Atrial Natriuretic
Peptide (ANP).
2) Brain Natriuretic Peptide (BNP).
3) C-type Natriuretic Peptide (CNP).
- Atrial Natriuretic Peptide (ANP) is synthesized,
stored, and released by atrial myocytes in response to atrial distension,
angiotensin II, endothelin (potent vasoconstrictor), and sympathetic
stimulation.
- ANP binds to a specific receptors (ANP receptors) cause
a reduction in blood volume (decrease sodium reabsorption) à reduction in cardiac output
and systemic blood pressure.
- Brain Natriuretic Peptide (BNP) is synthesized largely
by the ventricles (as well as in the brain where it was first identified), BNP
is released by the same mechanisms that release ANP, and it has similar
physiological actions.
C-type Natriuretic Peptide (CNP) is located predominantly
in the CNS but is also present in several tissues, CNP has a less natriuretic
and diuretic activity than ANP and BNP.
- N.B: Vasopeptidase inhibitors (e.g. Omapatrilat,
Sampatrilat and Fasidotrilat) are a new class of cardiovascular agents capable
of inhibiting neutral endopeptidase and angiotensin- converting enzymes, which
leads to potentiation of natriuretic peptide actions and suppression of the
renin-angiotensin system.
Vasoactive Intestinal
Polypeptide (VIP)
- Vasoactive intestinal peptide (VIP) is produced in many
tissues includes; gut, pancreas and brain.
- VIP stimulates contractility in the heart, causes
vasodilation, increases glycogenolysis, lowers arterial blood pressure and
relaxes the smooth muscle of trachea, stomach and gall bladder.
Substance P (SP)
- Substance P (SP) is a neuropeptide, acting as a
neurotransmitter and as a neuromodulator.
- SP is an important element in pain perception
(transmission of pain information into the CNS).
- SP has been associated with the regulation of mood
disorders, anxiety, stress, nausea and emesis.
- SP causes contraction of venous, intestinal and
bronchial smooth muscle.
Calcitonin Gene Related
Peptide (CGRP)
- Calcitonin gene related peptide (CGRP) is produced in
both peripheral and central neurons.
- It is a potent peptide vasodilator and can function in
the transmission of pain.
- Increased levels of CGRP have been reported in
migraine.
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