Plasma kinins are polypeptides split off from a plasma globulin Kininogen by the action of specific enzymes Kallikreins. The two important plasma kinins, Kallidin (decapeptide) and Bradykinin (nonapeptide) were discovered around 1950 by two independent lines of investigation into the hypotensive activity of urine and certain snake venoms.
PLASMA KININS
(Bradykinin and Kallidin)
Plasma kinins are
polypeptides split off from a plasma globulin Kininogen by the action of specific enzymes Kallikreins. The two important plasma kinins, Kallidin (decapeptide) and Bradykinin
(nonapeptide) were discovered around 1950 by two independent lines of investigation
into the hypotensive activity of urine and certain snake venoms. These and
other biological fluids were found to act indirectly: they contained enzymes
which generated active substances in the plasma.
Kininogens are α2 globulins present in plasma
which also contains inactive kininogenase prekallikrein.
Prekallikrein is
activated by Hageman factor (factor XII) which itself is activated by tissue
injury and contact with surfaces having negative charge, e.g. collagen, basement
membrane, bacterial liposaccharides, urate crystals, etc. Plasmin facilitates contact activation of Hageman factor. Kinins
are also generated by trypsin, proteolytic enzymes in snake and wasp venoms and
by kallikrein present in kidney, pancreas and other tissues. Bradykinin is
generated from high molecular weight (HMW) kininogen by the action of plasma
kallikrein, because HMW-kininogen does not cross the capillaries. On the other
hand, kallidin can be produced from both low molecular weight (LMW) kininogen
as well as HMW-kininogen by the action of tissue kallikreins. Bradykinin can
also be generated from kallidin on the removal of lysine residue by an aminopeptidase.
Plasma and tissues
also contain kininogenase inhibitory factors of which complement (C1) esterase inhibitor is the most important. Moreover,
kallikreins are normally present in their inactive forms. Thus, physiologically
only small amounts of kinins are generated in plasma and tissues.
Kinins are very
rapidly degraded, primarily in lungs, but also in other tissues and have a t½
of < 1 min. The principal degrading enzyme is Kininase II, also known as ‘angiotensinII converting enzyme’ (ACE)
which splits off 2 amino acids from the carboxyterminal of the peptide chain.
Another carboxypeptidase Kininase I
removes only one amino acid (arginine) producing selective B1 receptor agonistic
metabolites (desArg bradykinin and desArg kallidin) which are further degraded
by other peptidases.
Actions
Bradykinin and
kallidin have similar actions.
CVS
Kinins are more potent
vasodilators than ACh and
histamine. The dilatation is mediated through endothelial NO and PGI2
generation, and involves mainly the arterioles. Larger arteries, most veins and
vessels with damaged endothelium are constricted through direct action on the
smooth muscle. In addition, they can release histamine and other mediators from
mast cells. Injected i.v. kinins cause flushing, throbbing headache and fall in
BP. They markedly increase capillary permeability due to separation of endothelial
cells → exudation and inflammation
occurs if they are injected in a tissue. Intradermal injection produces wheal
and flare (similar to histamine).
Kinins have no direct
action on heart; reflex stimulation occurs due to fall in BP.
Smooth Muscle
Kinin induced
contraction of intestine is slow (bradys—slow, kinein—to move). They cause marked bronchoconstriction in
guineapigs and in asthmatic patients. Action on other smooth muscles
is not prominent, some may be relaxed also.
Neurones
Kinins strongly stimulate nerve endings that transmit
pain and produce a burning sensation. Applied to blister base/injected intraperitoneally
or in the brachial artery, bradykinin produces intense, transient pain and has
been used in analgesic testing.
Kinins release CAs from adrenal medulla. Injected directly in
brain they produce a variety of effects including enhanced sympathetic
discharge. They increase permeability of the blood-brain barrier.
Kidney
Kinins increase renal blood flow as well as facilitate
salt and water excretion by action on tubules. The diuretic effect of
furosemide is reduced by kinin B2 receptor antagonists, indicating
participation of locally generated kinins in this response.
Kinin receptors Existance of two types
of kinin receptors (B1, B2) has been
established. Most kinin actions in noninflamed tissues are mediated by B2
receptors which are constitutively present on:
Visceral smooth muscle—contraction of intestine, uterus, airway.
Vascular endothelium—NO release, vasodilatation,
increased permeability.
Sensory nerves—acute pain.
The B2 receptor is a G-protein
coupled receptor which utilizes the phospholipase-C—IP3/DAG—intracellular Ca2+
mobilization transducer mechanism. Certain responses to kinins, e.g.
bronchoconstriction and renal vasodilatation are attenuated by pretreatment
with PG synthesis inhibitors (aspirin). Aspirin injected i.p. before bradykinin
through the same cannula blocks its algesic action. These responses are mediated
by phospholipase A activation—release of arachidonic acid and generation of
PGs.
The B1 receptor is
located on the smooth muscle of large arteries and veins—mediates contraction
of these vessels, but is expressed minimally in normal tissues. Inflammation
induces synthesis of B1 receptors, so that they might play a major role at
inflamed sites.
Bradykinin has higher
affinity for B2 than for B1 receptors, while Kallidin is equipotent on both.
The des-Arg metabolites of bradykinin and kallidin are the natural selective
agonists of B1 receptor.
Pathophysiological Roles
1. Mediation Of Inflammation Kinins produce all
the signs of inflammation—redness, exudation, pain and leukocyte mobilization.
Tissue injury can cause local kinin production which then sets in motion the
above defensive and reparative processes. Activation of B1 receptors on
macrophages induces production of IL1, TNFα and other
inflammatory mediators.
2. Mediation Of Pain By directly stimulating
nerve endings and by increasing PG production kinins appear to serve as
mediators of pain. The B2 antagonists block acute pain produced by bradykinin,
but induced B1 receptors appear to mediate pain of chronic inflammation.
3. Functional Hyperemia (In Glands During
Secretion) And Regulation Of
Microcirculation—especially in kidney may be occurring through
local kinin production.
4. Production of
kinins is integrated with clotting,
fibrinolysin and complement systems.
Kallikreins may have roles in these
systems which are independent of kinin production.
5. Kinins appear to
play no significant role in regulation of normal BP. However, they may serve to
oppose overactive RAS and exert antiproliferative influence on vascular smooth
muscle in hypertensive states.
6. Kinins cause closure
of ductus arteriosus, dilatation of foetal pulmonary artery and constriction of
umbilical vessels—they may be involved in adjusting from foetal to neonatal
circulation.
7. Kinins play a major
role in the development of angioedema. They also appear to be involved in shock, rhinitis, asthma, ACE inhibitor induced cough, carcinoid,
postgastrectomy dumping syndrome, fluid secretion in diarrhoea, acute pancreatitis and certain immunological reactions.
Because of evanescent
and unpleasant actions, kinins have no clinical use.
After characterization
of B1 and B2 kinin receptors, several peptide and
nonpeptide kinin antagonists have been produced. The synthetic peptide HOE 140
is a selective B2 antagonist resistant to kinin degrading enzymes
and having longer t½, while Icatibant, FR
173657 and some others are orally active
nonpeptide B2 antagonists that have helped in defining the
pathophysiological roles of kinins and have undergone limited trials as
analgesic, anti-inflammatory drugs and in pancreatitis, head injury, etc.
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