Phosphodiesterase inhibition in heart failure

Matthew Movsesian Josef Stehlik Fabrice Vandeput Michael R. Bristow

US Department of Veterans Affairs 2008

Abstract Drugs that inhibit cyclic nucleotide phospho-

diesterase activity act to increase intracellular cyclic

adenosine monophosphate (cAMP) and cyclic guanosine

monophosphate (cGMP) content. In total, 11 families of

these enzymeswhich differ with respect to affinity for

cAMP and cGMP, cellular expression, intracellular local-

ization, and mechanisms of regulationhave 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 myocar-

dium raises questions as to their role in regulating these

signaling pathways in heart failure.

Keywords Cyclic nucleotide phosphodiesterases cAMP cGMP Inotropic agents Vasodilators Heart failure

Introduction

Cyclic nucleotides are ubiquitous intracellular second

messengers. Hormones whose actions lead to stimulation

of adenylyl cyclase activity increase the conversion of

adenosine triphosphate (ATP) to cyclic adenosine mono-

phosphate (cAMP) through the formation of an

intramolecular phosphodiester. Similarly, hormones whose

actions lead to stimulation of guanylyl cyclase increase the

conversion of guanosine triphosphate (GTP) to cyclic

guanosine monophosphate (cGMP). Other enzymes atten-

uate these signals by hydrolyzing the phosphodiester

bonds, converting cAMP and cGMP to AMP and GMP.

These latter enzymes are referred to as cyclic nucleotide

phosphodiesterases.

Eleven families of cyclic nucleotide phosphodiesterases

have been identified. Individual families may consist of

more than one gene, and individual genes may give rise to

more than one protein through mechanisms that include

transcription from alternative initiation sites, alternative

splicing, and translation from alternative initiation sites.

M. Movsesian (&) J. StehlikCardiology Section, VA Salt Lake City Health Care System,

500 Foothill Boulevard, Salt Lake City, UT 84148, USA

e-mail: matthew.movsesian@va.gov

M. Movsesian J. Stehlik F. VandeputDepartment of Internal Medicine (Cardiology), University

of Utah, Salt Lake City, UT, USA

M. Movsesian F. VandeputDepartment of Pharmacology and Toxicology, University

of Utah, Salt Lake City, UT, USA

M. R. Bristow

Division of Cardiology, University of Colorado, Denver,

CO, USA

123

Heart Fail Rev

DOI 10.1007/s10741-008-9130-x