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

and kallidin from the kininogens are termed kallikreins
(see “Kallikreins”).
Kallikreins. Bradykinin and kallidin are cleaved from HMW or
LMW kininogens by plasma or tissue kallikrein, respectively (Figure
32–4). Plasma kallikrein and tissue kallikrein are distinct enzymes
that are activated by different mechanisms (Bhoola et al., 1992).
Plasma prekallikrein is an inactive protein of ~88,000 Da that
complexes with its substrate, HMW kininogen (Mandle et al., 1976).
The ensuing proteolytic cascade is restrained by the protease
inhibitors present in plasma. Among the most important of these are
the inhibitor of the activated first component of complement (C1-
INH) and α 2
macroglobulin. Under experimental conditions, the
kallikrein–kinin system is activated by the binding of factor XII, also
known as Hageman factor, to negatively charged surfaces.
Factor XII, a protease that is common to both the kinin and the
intrinsic coagulation cascades (Chapter 30), undergoes autoactivation
(Silverberg et al., 1980) and, in turn, activates prekallikrein.
Importantly, kallikrein further activates factor XII, thereby exerting
a positive feedback on the system. In vivo, factor XII may not
undergo autoactivation on binding to endothelial cells. Instead, the
binding of the HMW kininogen–prekallikrein heterodimer to a multiprotein-receptor
complex on endothelial cells leads to activation of
the prekallikrein-HMW kininogen complex (but not free
prekallikrein) by heat shock protein 90 (Joseph et al., 2002) and by
a lysosomal enzyme designated prolylcarboxypeptidase, which also
is present on endothelial cell membranes (Schmaier, 2008).
Kallikrein activates factor XII, cleaves HMW kininogen, and activates
prourokinase (Schmaier, 2008; Kaplan et al., 2002; Colman,
1999). Human tissue kallikrein is a member of a large multigene
family of 15 members with high sequence identity that are clustered
at chromosome 19q13.4 (Emami and Diamandis, 2007). Only the
classical (or “true”) tissue kallikrein, hK1, generates kinins from
kininogen. Another member, hK3, better known as the prostatespecific
antigen (PSA), is an important marker in diagnosing prostate
cancer, and several other family members are promising tumor biomarkers
(Emami and Diamandis, 2007).
Compared with plasma kallikrein, tissue kallikrein is a smaller
protein (29,000 Da). It is synthesized as a preproprotein in the epithelial
cells or secretory cells in several tissues, including salivary glands,
pancreas, prostate, and distal nephron. Tissue kallikrein also is
expressed in human neutrophils. It acts locally near its sites of origin.
The synthesis of tissue prokallikrein is controlled by a number of
factors, including aldosterone in the kidney and salivary gland and
androgens in certain other glands. The secretion of the tissue
prokallikrein also may be regulated; for example, its secretion from
the pancreas is enhanced by stimulation of the vagus nerve. The activation
of tissue prokallikrein to kallikrein requires proteolytic cleavage
to remove a 7–amino acid propeptide (Takada et al., 1985).
Kininogens. The two substrates for the kallikreins, HMW kininogen
and LMW kininogen, are derived from a single gene by alternative
splicing. The HMW kininogen contains 626 amino acid residues:
The N-terminal “heavy chain” sequence (362 amino acids) consists
of domains 1-3, followed by 9 residue bradykinin sequence (domain 4),
connected to a C-terminal “light chain” sequence (255 amino
acids) containing domains D5 and D6. LMW kininogen is identical
to domains 1-4 of HMW kininogen but is distinguished by its
short C-terminal light chain (Takagaki et al., 1985). HMW kininogen
is cleaved by plasma and tissue kallikrein to yield bradykinin and
kallidin, respectively. LMW kininogen is a substrate only of tissue
kallikrein, and the product is kallidin. The kininogens also inhibit
cysteine proteinases and thrombin binding and have anti-adhesive
and profibrinolytic properties.
Metabolism of Kinins. The decapeptide kallidin is about
as active as the nonapeptide bradykinin, even without
conversion to bradykinin, which occurs when the
N-terminal lysine residue is removed by an aminopeptidase
(Skidgel and Erdös, 1998) (Figure 32–4). The nonapeptide
has the minimal effective structure for standard
responses on B 2
receptors (Figure 32–4 and Table 32–3).
The kinins have an evanescent existence—their t 1/2
in plasma
is only ~15 seconds, and some 80-90% of the kinins may be
destroyed in a single passage through the pulmonary vascular bed.
Plasma concentrations of bradykinin are difficult to measure because
inadequate inhibition of kininogenases or kininases in the blood can
lead to artifactual formation or degradation of bradykinin during
blood collection. When care is taken to inhibit these processes, the
reported physiological concentrations of bradykinin in blood are in
the picomolar range.
The principal catabolizing enzyme in the lung and other vascular
beds is kininase II, or ACE (Figure 32–4) (Chapter 26). Removal
of the C-terminal dipeptide by ACE or neutral endopeptidase 24.11
(neprilysin) inactivates kinins (Skidgel and Erdös, 1998) (Figure 32–5).
A slower-acting enzyme, carboxypeptidase N (lysine carboxypeptidase,
kininase I), releases the C-terminal arginine residue, producing
[desArg 9 ]-bradykinin or [des-Arg 10 ]-kallidin (Table 32–3 and Figures
32–4 and 32–5), which are potent B 1
receptor agonists that no longer
bind B 2
receptors (Bhoola et al., 1992; Skidgel and Erdös, 1998).
Carboxypeptidase N is expressed constitutively in blood plasma,
where its level is ~10 –7 M (Skidgel and Erdös, 1998; Skidgel and
Erdös, 2007). Carboxypeptidase M, which also cleaves basic C-terminal
amino acids, is a widely distributed plasma membrane–bound enzyme
(Skidgel and Erdös, 1998). The recently established crystal structures
of the active subunit of carboxypeptidases N and M revealed an overall
similarity with unique features consistent with their different localizations
and functions (Skidgel and Erdös, 2007). A familial
carboxypeptidase N deficiency, due to mutations in the active subunit,
causes low plasma levels of this enzyme and is associated with
angioedema or urticaria (Skidgel and Erdös, 2007; Matthews et al.,
2004). Finally, aminopeptidase P can cleave the N-terminal arginine,
rendering bradykinin inactive and susceptible to cleavage by dipeptidyl
peptidase IV (Figure 32–5).
Kinin Receptors. The B 1
and B 2
kinin receptors are both
GPCRs, sharing 36% amino acid sequence identity
(Hess, 1997; Leeb-Lundberg et al., 2005).
The classical bradykinin B 2
receptor is constitutively
expressed in most normal tissues, where it selectively binds intact
bradykinin and kallidin (Table 32–3 and Figure 32–4) and mediates
the majority of their effects. The B 1
receptor is activated by the
des-Arg metabolites of bradykinin and kallidin produced by the
actions of carboxypeptidases N and M (Table 32–3 and Figures 32–4
and 32–5). Interestingly, carboxypeptidase M and the B 1
receptor
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CHAPTER 32
HISTAMINE, BRADYKININ, AND THEIR ANTAGONISTS