DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

HMW-Kininogen
927
Angiotensinogen
Renin
Angiotensin I
Angiotensin II
AT 1
Receptor
Vasoconstriction
Aldosterone release
Na + retention
Tissue proliferation
ACE
(Kininase II)
Inactive
products
Bradykinin
Kallidin
B 2
Receptor
Plasma
Kallikrein
Mediator release
(NO, PGs, EDHF)
Vasodilation
Na + excretion
Pain (acute)
Tissue
Kallikrein
CPM/N (Kininase I)
Aminopeptidase
CPM/N (Kininase I)
LMW-Kininogen
des-Arg 9 -Bradykinin
des-Arg 10 -Kallidin
B 1
Receptor
G q/i G q/i G q/i
Mediator release
(NO, PGs)
Vasodilation
Pain (chronic)
Leukocyte recruitment
Figure 32–4. Synthesis and receptor interactions of active peptides generated by the kallikrein-kinin and renin-angiotensin systems.
Bradykinin is generated by the action of plasma kallikrein on high-molecular-weight (HMW) kininogen, whereas kallidin (Lys 1 -
bradykinin) is released by the hydrolysis of low-molecular-weight (LMW) kininogen by tissue kallikrein. Kallidin and bradykinin are
the natural ligands of the B 2
receptor but can be converted to corresponding agonists of the B 1
receptor by removal of the C-terminal
Arg by kininase I–type enzymes: the plasma membrane–bound carboxypeptidase M (CPM) or soluble plasma carboxypeptidase N
(CPN). Kallidin or [des-Arg 10 ]-kallidin can be converted to the active peptides bradykinin or to [des-Arg 9 ]-bradykinin by aminopeptidase
cleavage of the N-terminal Lys residue. In a parallel fashion, the inactive decapeptide angiotensin I is generated by the action
of renin on the plasma substrate angiotensinogen. By removal of the C-terminal His–Leu dipeptide, angiotensin-converting enzyme
(ACE) generates the active peptide angiotensin II (AngII). These two systems have opposing effects. AngII is a potent vasoconstrictor
that also causes aldosterone release and Na + retention via activation of the AT 1
receptor; bradykinin is a vasodilator that stimulates
Na + excretion by activating the B 2
receptor. ACE generates active AngII and, at the same time, inactivates bradykinin and kallidin;
thus, its effects are prohypertensive, and ACE inhibitors are effective antihypertensive agents. The B 2
receptor mediates most of
bradykinin’s effects under normal circumstances, whereas synthesis of the B 1
receptor is induced by inflammatory mediators in
inflammatory conditions. Both B 1
and B 2
receptors couple through G q
to activate PLC and increase intracellular Ca 2+ ; the physiological
response depends on receptor distribution on particular cell types and occupancy by agonist peptides. For instance, on endothelial
cells, activation of B 2
receptors results in Ca 2+ –calmodulin–dependent activation of eNOS and generation of NO, which causes
cyclic GMP accumulation and relaxation in neighboring smooth muscle cells. However, in endothelial cells under inflammatory conditions,
B 1
receptor stimulation results in prolonged NO production via G i
and MAP kinase-dependent activation of iNOS expression.
On smooth muscle cells, activation of kinin receptors coupling through G q
results in an increased [Ca 2+ ] i
and contraction. B 1
and B 2
receptors also can couple through G i
to activate PLA 2
, causing the release of arachidonic acid and the local generation of prostanoids
(PGs) and other metabolites such as endothelium-derived hyperpolarizing factor (EDHF). Kallikrein also plays a role in the intrinsic
blood coagulation pathway (see Chapter 30).
CHAPTER 32
HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS
The Endogenous Kallikrein–
Kininogen–Kinin System
Synthesis of Kinins. Bradykinin is a nonapeptide; kallidin,
a decapeptide containing an additional N-terminal
lysine, is sometimes referred to as lysyl-bradykinin
(Table 32–3). The two peptides are cleaved from α 2
globulins termed kininogens (Figure 32–4). There are
two kininogens: high-molecular-weight (HMW)
kininogen and low-molecular-weight (LMW) kininogen.
A number of serine proteases will generate kinins,
but the highly specific proteases that release bradykinin