Phosphodiesterase Inhibition in Heart Failure - Phosphodiesterases as Drug Targets - page 244

Fig. 4 Signaling pathways
of PKG-dependent
cardioprotection in
myocardial ischemia-
reperfusion injury

PDE5 inhibition

cGMP ↑

PKG

ERK

GSK3ß

Bcl-2

mitoK ATP

MPT

↓ Ca 2+ influx

ATP

↑

Cardioprotection

myocardium, PDE5 seemed to be present at low levels compared to other cGMP-
hydrolytic activities, though other reports indicated that PDE5 expression increased
in pathologic human myocardium (Hambleton et al. 2005 ; Vandeput et al. 2007 ;
Nagendran et al. 2007 ; Pokreisz et al. 2009 ). Recently, the contribution of PDE5 to
cGMP-hydrolytic activity in the left ventricles of mice with normal hearts and mice
with heart failure as a result of myocardial infarction was compared to its contribu-
tion to cGMP-hydrolytic activity in normal and failing human left ventricles. In
normal mice, PDE5 comprised ~ 22% of the Ca 2+ /calmodulin-independent cGMP-
hydrolytic activity of the left ventricles; the percentage was ~ 43% in failing mouse
hearts. In left ventricular myocardium from normal and failing human hearts, in
contrast, PDE5 comprised 5% of the Ca 2+ /calmodulin-independent cGMP-

hydrolytic activity (Vandeput et al. 2009 ). This large difference in the relative levels
of PDE5 in mouse and human myocardium raises some doubt as to whether PDE5
inhibition is as likely to be as beneficial in humans as in mouse models.
At the same time, while sildenafil is generally regarded as PDE5-selective, its
potency as an inhibitor of PDE5 is only ~30-fold higher than its potency as an
inhibitor of PDE1 (Vandeput et al. 2009 ). Enzymes in the latter family are character-
ized by their activation by Ca 2+ and calmodulin and their moderately high affinity for
cGMP and, for some isoforms, cAMP (Bender 2007 ). PDE1 is present in high
abundance in human left ventricular myocardium (Fig. 1 ) and in mouse left ventricu-
lar myocardium. In several of the studies showing cardioprotective effects in mouse
hearts, sildenafil was used at concentrations 1.0 m M(Nagendranetal. 2007 ;Das

et al. 2005 ;Fisheretal. 2005 ; Pokreisz et al. 2009 ;Takimotoetal. 2007 ), and at this
concentration its inhibition of cGMP-hydrolytic activity in mouse left ventricles is