Biology Reference
In-Depth Information
attributable to inhibition of both PDE5 and PDE1 (Vandeput et al.
2009
). This finding
would suggest that inhibition of PDE1 may have contributed to sildenafil's potentia-
tion of cGMP-mediated signaling and its consequent cardioprotective actions in
animal models. A recent study in mouse models has, in fact, shown that PDE1
inhibition was effective in blocking phenylephrine-induced hypertrophy of cardiac
myocytes in vitro and isoproterenol-induced hypertrophy in vivo (Miller et al.
2009
).
These effects were additive with those of sildenafil, raising the possibility that the
antihypertrophic effects of PDE5 inhibition and of PDE1 inhibition involve different
mechanisms.
6 Conclusions
The role for phosphodiesterase inhibitors in the treatment of cardiac muscle disease
is unclear. The use of PDE3 inhibition to raise intracellular cAMP content is a
widely accepted approach to acute decompensation in patients with heart failure,
but its usefulness as an option for long-term therapy is controversial. The large
number of studies whose results, taken together, show an increase in sudden death
in patients treated with PDE3 inhibitors have led most clinicians to try to avoid the
chronic use of these agents and most pharmaceutical companies to “pass” on
investing in new approaches to PDE3 inhibition.
At this time, there is probably much more interest in the cardioprotective actions
of inhibiting cGMP-hydrolytic activity in cardiac myocytes. The benefits seen with
sildenafil in animal models of cardiac disease are very impressive, and there is
growing insight into the downstream mechanisms that are involved. The low
abundance of PDE5 in human myocardium relative to the animal models is a
cause for some concern regarding the therapeutic potential of PDE5 inhibition in
cardiac muscle disease, at least with regard to direct myocardial actions. The results
of ongoing clinical trials of sildenafil in humans with heart failure are likely to
provide greater insight. The possibility that the benefits of potentiating cGMP-
mediated signaling demonstrated in these animal models might alternatively be
achieved through inhibition of other cGMP-hydrolytic enzymes, especially PDE1,
is a very new concept that warrants further investigation.
References
Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P (2005) Phosphodiesterase III inhibitors
for heart failure. Cochrane Database Syst Rev 25:CD002230
Baim DS, McDowell AV, Cherniles J et al (1983) Evaluation of a new bipyridine inotropic agent -
milrinone -in patients with severe congestive heart failure. N Engl J Med 309:748-756
Bender AT (2007) Calmodulin-stimulated cyclic nucleotide phosphodiesterases. In: Beavo JA,
Francis SH, Houslay MD (eds) Cyclic nucleotide phosphodiesterases in health and disease.
CRC Press, Boca Raton, FL, pp 35-54
