Cardiovascular Drugs and Therapy

, Volume 21, Issue 3, pp 171–194

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Review

Abstract

Phosphodiesterase (PDE) inhibitors are potent cardiotonic agents used for parenteral inotropic support in heart failure. Contractile effects of these agents are mediated through cAMP-protein kinase A-induced stimulation of ICa2+ which ultimately results in increased Ca2+-induced sarcoplasmic reticulum Ca2+ release. A number of additional effects such as increases in sarcoplasmic reticulum Ca2+ stores, stimulation of reverse mode Na+–Ca2+ exchange, direct or cAMP-mediated effects on sarcoplasmic reticulum ryanodine receptor, stimulation of the voltage-sensitive sarcoplasmic reticulum Ca2+ release mechanism, as well as A1 adenosine receptor blockade could contribute to positive inotropic responses to PDE inhibitors. Moreover, some PDE inhibitors exhibit Ca2+ sensitizer properties as they could increase the affinity of troponin C Ca2+-binding sites as well as reduce Ca2+ threshold for thin myofilament sliding and facilitate cross-bridge cycling. Inotropic responses to PDE inhibitors are significantly reduced in cardiac disease, an effect largely attributed to downregulation of cAMP-mediated signalling due to sustained sympathetic activation. Four PDE isoenzymes (PDE1, PDE2, PDE3 and PDE4) are present in myocardial tissue of various mammalian species, of which PDE3 and PDE4 are particularly involved in regulation of cardiac myocyte contraction. PDE cAMP-hydrolysing activity is preserved in compensated cardiac hypertrophy but significantly reduced in animal models of heart failure. However, clinical studies have not revealed any changes in distribution profile as well as kinetic and regulatory properties of myocardial PDEs in failing human hearts. A reduction of PDE inhibitors-induced contractile responses in heart failure has therefore been ascribed to reduced cAMP synthesis due to uncoupling of adenylyl cyclase from β-adrenoreceptor. In cardiac myocytes, PDEs are targeted to distinct subcellular compartments by scaffolding proteins such as myomegalin, mAKAP and β-arrestins. Over subcellular microdomains, cAMP hydrolysis by PDE3 and PDE4 allows to control the activity of local pools of protein kinase A and therefore the extent of protein kinase A-mediated phosphorylation of cellular proteins.

Key words

phosphodiesterase myocardial contractility heart failure cAMP compartmentalized signalling 

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Cardiology Group, School of Clinical Sciences, University Clinical DepartmentsUniversity of LiverpoolLiverpoolUK

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