Phosphodiesterase inhibition in heart failure |
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Authors: | Matthew Movsesian Josef Stehlik Fabrice Vandeput Michael R Bristow |
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Institution: | (1) Cardiology Section, VA Salt Lake City Health Care System, 500 Foothill Boulevard, Salt Lake City, UT 84148, USA;(2) Department of Internal Medicine (Cardiology), University of Utah, Salt Lake City, UT, USA;(3) Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA;(4) Division of Cardiology, University of Colorado, Denver, CO, USA |
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Abstract: | Drugs that inhibit cyclic nucleotide phosphodiesterase activity act to increase intracellular cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP) content. In total, 11 families of these enzymes—which differ with respect
to affinity for cAMP and cGMP, cellular expression, intracellular localization, and mechanisms of regulation—have been identified.
Inhibitors of enzymes in the PDE3 family of cyclic nucleotide phosphodiesterases raise intracellular cAMP content in cardiac
and vascular smooth muscle, with inotropic and, to a lesser extent, vasodilatory actions. These drugs have been used for many
years in the treatment of patients with heart failure, but their long-term use has generally been shown to increase mortality
through mechanisms that remain unclear. More recently, inhibitors of PDE5 cyclic nucleotide phosphodiesterases have been used
as cGMP-raising agents in vascular smooth muscle. With respect to cardiovascular disease, there is evidence that these drugs
are more efficacious in the pulmonary than in the systemic vasculature, for which reason they are used principally in patients
with pulmonary hypertension. Effects attributable to inhibition of myocardial PDE5 activity are less well characterized. New
information indicating that enzymes from the PDE1 family of cyclic nucleotide phosphodiesterases constitute the majority of
cAMP- and cGMP-hydrolytic activity in human myocardium raises questions as to their role in regulating these signaling pathways
in heart failure. |
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