Biology Reference
In-Depth Information
Phosphodiesterase Inhibition in Heart Failure
Matthew A. Movsesian and Rakesh C. Kukreja
Contents
1 PDE3 Cyclic Nucleotide Phosphodiesterases in Human Myocardium .................... 238
2 PDE3 Inhibitors in the Treatment of Heart Failure ........................................ 240
3 Altered PDE4 Activity and Heart Failure ................................................. 242
4 Effects of PDE5 Inhibition in Cardiac Disease . ........................................... 242
5 Possible Involvement of PDE1 Inhibition in the Effects of Sildenafil .................... 243
6 Conclusions ................................................................................. 245
References ....................................................................................... 245
Abstract Compounds that inhibit the catalytic activity of cyclic nucleotide phos-
phodiesterases are used as therapeutic agents to increase intracellular cAMP and/or
cGMP content in cells or tissues of interest. In patients with heart failure, inhibitors
of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases are used to
raise intracellular cAMP content in cardiac muscle, with inotropic actions. These
drugs are effective in acute applications, but their long-term use has been compli-
cated by an increase in cardiovascular mortality in clinical trials. Inhibitors of
enzymes in the PDE5 family have been used to raise cGMP content in cardiac
muscle in animal models of pressure overload, chronic
b
-adrenergic receptor
stimulation, ischemic injury, and doxorubicin toxicity, and have been shown to
have antihypertrophic and cardioprotective actions. Recent experimental results
raise some question as to the likely applicability of these findings to humans, in
whose hearts PDE5 is present at much lower levels than those seen in animal
models, and raise the possibility of PDE1, a dual-specificity phosphodiesterase
M.A. Movsesian (
*
)
Cardiology Section, VA Salt Lake City Health Care System, Departments of Internal Medicine
(Cardiology) and Pharmacology and Toxicology, University of Utah, 500 Foothill Boulevard, Salt
Lake City, UT, USA
e-mail: matthew.movsesian@va.gov
R.C. Kukreja
Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University,
Richmond, VA, USA
