Biology Reference
In-Depth Information
caused by the exposure of collagen, the most thrombogenic constituent of the
subendothelial matrix. The interaction of platelet glycoprotein GPIb-V-IX receptor
complex via von Willebrand factor with exposed collagen initiates reversible
recruitment of platelets to the injured site. Subsequently, binding of platelet glyco-
protein (GP) VI and the inside-out activation of integrins, such as GPIa/IIa and
GPIIb/IIIa, results in the firm adhesion of platelets to the injured vessel wall.
Thereafter, a platelet plug is formed by the recruitment of additional platelets
from the circulation, by linking through GPIIb/IIIa and the release of the secondary
mediators, adenosine diphosphate (ADP) and thromboxane A
2
(TXA
2
). These
agonists, together with locally produced thrombin, contribute to platelet activation
by stimulating receptors that couple to heterotrimeric G proteins (Gq and Gi). The
end result is the elevation of intracellular calcium, leading to platelet shape change
and to a further increase and production of local mediators that foster activation.
This, in turn, serves as a positive-feedback mechanism to amplify the initial signals,
ensuring the rapid activation and recruitment of platelets in the growing thrombus
(Jackson et al.
2009
; Nieswandt and Watson
2003
).
Many platelet antagonists that are currently in clinical use block only one
activation pathway: for example, ADP-receptor antagonists inhibit the ADP-
mediated pathway, while aspirin blocks the formation and secretion of TXA
2
.
However, elevation of intracellular cyclic nucleotides interferes with all known
platelet activation pathways, including adhesion, degranulation, aggregation, and
even downregulation of proinflammatory platelet surface molecules, an effect very
important for the prevention and development of atherosclerotic lesions (Schwarz
et al.
2001
), making cyclic nucleotides attractive targets for inhibiting platelet
activation.
In platelets, three types of PDEs (PDE2, 3, and 5) have been detected. Among
these, inhibitors of PDE3 have been shown to be the most potent in inhibiting
platelet activation. These inhibitors include milrinone, cilostamide, enoxamide,
cilostazol, and NT-702 (Ishiwata et al.
2007
). Thus, there has been much interest
in PDE3 inhibitors for blocking platelet activation. There are two subtypes of
PDE3, PDE3A, and 3B, with 3A being the predominant subtype in platelets
(Sun et al.
2007
). Current PDE3 inhibitors inhibit both PDE3A and 3B. The effects
of cilostazol on platelets are discussed in more detail in Sect.
4.1
. PDE2 inhibitors
have been reported to have no effect on platelet activation (Dunkern and Hatzelmann
2005
; Zhang and Colman
2007
). Although PDE5 inhibitors are able to potentiate
nitric oxide donor-mediated inhibition of platelet activation (Gudmundsdottir et al.
2005
; Schmidt et al.
2001
; Wilson et al.
2008
), contradictory findings have been
reported on the effect of PDE5 inhibitors alone, with some studies reporting
inhibition (Chiu et al.
1997
; Gudmundsdottir et al.
2005
) and others reporting a
lack of inhibition of platelet activation (Dunkel et al.
2007
; Schmidt et al.
2001
;
Wilson et al.
2008
). However, in those studies that demonstrating a PDE5 inhibitor-
mediated suppression of platelet activation, it is not clear whether this effect is
due directly to cGMP-dependent protein phosphorylation or to an indirect effect
involving cGMP-mediated inhibition of PDE3 via cGMP's competition for cAMP
hydrolysis at the active site of PDE3 (Maurice
2005
; Zaccolo and Movsesian
2007
).
