Phosphodiesterase Inhibition in Heart Failure - Phosphodiesterases as Drug Targets - page 242

3 Altered PDE4 Activity and Heart Failure
While the focus of this chapter is on phosphodiesterase inhibition and heart failure,
it is worth noting the possible involvement of another phosphodiesterase in this
disease. A leak of sarcoplasmic reticulum-sequestered Ca 2+ through ryanodine-
sensitive Ca 2+ channels has been identified as a possible pathogenetic mechanism
in heart failure in humans, and this leak has been associated with hyperphosphory-
lation of these channels (Nimer et al. 1995 ; Reiken et al. 2003 ; Marx et al. 2000 ).
PDE4D3, a cAMP-specific phosphodiesterase present at relatively low levels
in human myocardium, co-immunoprecipitates with ryanodine-sensitive Ca 2+
channels, and the activity of ryanodine-sensitive Ca 2+ channel-bound PDE4D3 is
significantly decreased in patients with heart failure (Lehnart et al. 2005 ). This
decrease in associated PDE4D3 activity might explain the hyperphosphorylation
of the ryanodine-sensitive Ca 2+ channels. These findings are evidence of a potential
adverse effect of PDE4 inhibition in heart failure. The consideration at this point is
hypothetical, as PDE4 inhibitors are not used in the treatment of cardiovascular
disease.
4 Effects of PDE5 Inhibition in Cardiac Disease
Enzymes in the PDE5 family are characterized by their high selectivity and
moderately high affinity for cGMP ( K M ~ 2.0 m M) and by their importance in the
regulation of vascular smooth muscle contraction. One gene, PDE5A, gives rise to
three isoforms, of which two, PDE5A1 and PDE5A2, are expressed in heart (Lin
et al. 2002 ). PDE5 inhibitors such as sildenafil increase intracellular cGMP content
in vascular smooth muscle cells, and the resulting potentiation of cGMP-mediated
vasodilatory responses is the basis for their use in the treatment of erectile dysfunc-
tion and pulmonary hypertension (Francis and Corbin 2005 ; Kass et al. 2007 ;
Movsesian et al. 2009 ). These subjects are covered elsewhere in this volume.
More recently, investigators have been studying effects that are more likely
attributable to the inhibition of PDE5 activity in cardiac muscle itself (as opposed
to effects that can be attributed to the vasodilating effects of PDE5 inhibition).
Sildenafil blocks the development of isoproterenol-induced cardiac hypertrophy in
rats, an effect that is accompanied by an increase in survival (Hassan and Ketat 2005 ).
Similar observations have been made in mice, where sildenafil blocks and reverses
the development of hypertrophy following aortic constriction (Takimoto et al. 2005 ;
Nagayama et al. 2009 ). Other benefits have been demonstrated in models of myo-
cardial infarction, and sildenafil has been shown to reduce infarct size following
ischemic injury in rabbit and mouse models (Ockaili et al. 2002 ; Salloum et al. 2003 ).
Sildenafil protects against the apoptotic consequences of hypoxia in isolated mouse
ventricular myocytes (Das et al. 2005 ), and antiapoptotic and survival benefits of
sildenafil have been demonstrated in mice whose left anterior descending coronary
arteries were ligated (Salloum et al. 2008 ). Finally, sildenafil has been shown to have