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

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Aminopeptidase P
Kininase I
(Carboxypeptidase M, Carboxypeptidase N)
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
Dipeptidyl-peptidase IV
interact on the cell surface to form an efficient signaling complex;
disruption of this interaction decreases the efficiency of generation
and delivery of des-Arg-kinin agonist to the B 1
receptor and reduces
subsequent B 1
signaling (Zhang et al., 2008). B 1
receptors are normally
absent or expressed at low levels in most tissues. B 1
receptor
expression is upregulated by tissue injury and inflammation and by
cytokines, endotoxins, and growth factors (Bhoola et al., 1992; Leeb-
Lundberg et al., 2005). Carboxypeptidase M expression also is
increased by cytokines (Sangsree et al., 2003), to such a degree that
B 1
receptor effects may predominate over B 2
effects.
The B 2
receptor activates PLA 2
and PLC via interaction with
distinct G proteins. Kinin-induced PLC activation through G q
activates
the IP 3
–Ca 2+ pathway, stimulating PKC activity and also
enhancing NO synthesis by eNOS/NOS3. Bradykinin activates the
pro-inflammatory transcription factor NF-κB through Gα q
and βγ
subunits and also activates the MAP kinase pathway. Coupling of
activated B 2
receptors to G i
leads to PLA 2
activation and the liberation
of arachidonate from membrane-bound phospholipids, which is
converted to a variety of derivatives, including inflammatory mediators
and vasodilator epoxyeicosatrienoic acids (EETs) and prostacyclin
(Campbell and Falck, 2007; Leeb-Lundberg et al., 2005)
(Chapter 33).
B 1
receptors also couple through G q
and G i
to activate many
of the same signal transduction pathways as the B 2
receptor (Leeb-
Lundberg et al., 2005). However, B 1
receptor activation enhances
NO production by stimulation of the inducible nitric oxide synthase
(iNOS) rather than eNOS (Zhang et al., 2007). The B 1
and B 2
receptors
also differ in their time courses of downregulation; the B 2
receptor
response is rapidly desensitized, whereas the B 1
response is not. This
likely is due to modification at a Ser/Thr-rich cluster present in
the C-terminal tail of the B 2
receptor that is not conserved in the B 1
receptor sequence (Leeb-Lundberg et al., 2005).
Because B 2
receptors are distributed widely and couple to
several G proteins, receptor agonists are employed frequently as
tools to activate and study signal transduction pathways in a variety
of cells. The antagonist icatibant (HOE-140) is commonly used to
prove that cellular responses are mediated by B 2
receptors.
Kininase II
[Angiotensin-Converting Enzyme,
Neutral Endopeptidase 24.11/(Neprilysin)]
Figure 32–5. Schematic diagram of the degradation of bradykinin. Arrows denote the primary cleavage sites in bradykinin. Bradykinin
and kallidin are inactivated in vivo primarily by kininase II [angiotensin-converting enzyme (ACE)]. Neutral endopeptidase 24.11
(neprilysin), cleaves bradykinin and kallidin at the same Pro–Phe bond as ACE and also is classified as a kininase II–type enzyme. In
addition, aminopeptidase P can inactivate bradykinin by hydrolyzing the N-terminal Arg 1 –Pro 2 bond, leaving bradykinin susceptible
to further degradation by dipeptidyl peptidase IV. Bradykinin and kallidin are converted to their respective des-Arg 9 or des-Arg 10
metabolites by kininase I–type carboxypeptidases M and N. Unlike the parent peptides, these kinin metabolites are potent ligands for
B 1
kinin receptors but not B 2
kinin receptors.
Nevertheless, blocking increased signaling through the B 2
receptor
does not necessarily indicate enhanced kinin generation because
some proteases (e.g., kallikrein) can activate the B 2
receptor directly,
and this also is blocked by HOE-140 (Biyashev et al., 2006).
Activation of the angiotensin AT 2
receptor results in responses
(e.g., vasodilation) that oppose those of the activated angiotensin
AT 1
receptor (e.g., vasoconstriction) (Chapter 26); this can be mediated
in part by cross-talk through activation of B 2
receptors (Widdop
et al., 2003).
Functions and Pharmacology of
Kallikreins and Kinins
The availability of specific kinin-receptor antagonists
and the generation of B 1
and B 2
receptor knockout mice
have advanced our understanding of the roles of the
kinins (Leeb-Lundberg et al., 2005; Pesquero and
Bader, 2006). Antagonists currently are being investigated
in diverse areas such as pain, inflammation,
chronic inflammatory diseases and the cardiovascular
system. That the beneficial effects of ACE inhibitor
therapy rests in part on enhancing bradykinin activity
(e.g., on the heart, kidney, blood pressure; see Chapter 26)
demonstrates the complexities in interpreting bradykinin’s
actions.
Systems Pharmacology of Kinins
Pain. The kinins are powerful algesic agents that cause an
intense burning pain when applied to the exposed base of
a blister. Bradykinin excites primary sensory neurons and
provokes the release of neuropeptides such as substance
P, neurokinin A, and calcitonin gene–related peptide.
Although there is overlap, B 2
receptors generally mediate
acute bradykinin algesia, whereas the pain of chronic