Beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors: shifting the focus from inotropy to cyclic adenosine monophosphate

J Am Coll Cardiol. 1999 Aug;34(2):318-24. doi: 10.1016/s0735-1097(99)00220-x.

Abstract

Clinical trials of beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors in heart failure have demonstrated a reduction in survival in treated patients despite initial inotropic responses. These findings have led many to infer that activation of the mechanisms through which contractility is increased has deleterious effects on failing myocardium. It should be remembered, however, that these agents act proximately by raising intracellular cyclic adenosine monophosphate (cAMP) content and stimulating protein phosphorylation by cAMP-dependent protein kinase, and that the proteins whose phosphorylation contributes to the inotropic responses may be different from the proteins whose phosphorylation contributes to the reduction in survival. Evidence in support of the latter interpretation is presented, and potential therapeutic approaches through which the phosphorylation of different proteins might be selectively affected are considered.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Activating Transcription Factor 2
  • Adrenergic beta-Agonists / adverse effects
  • Adrenergic beta-Agonists / pharmacology*
  • Adrenergic beta-Agonists / therapeutic use
  • Animals
  • Cyclic AMP / physiology*
  • Cyclic AMP Response Element-Binding Protein / physiology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Heart Failure / drug therapy
  • Heart Failure / mortality
  • Heart Failure / physiopathology*
  • Hemodynamics / drug effects
  • Hemodynamics / physiology
  • Humans
  • Myocardial Contraction / drug effects*
  • Myocardial Contraction / physiology
  • Myocardium / metabolism
  • Phosphorylation
  • Signal Transduction
  • Transcription Factors / physiology

Substances

  • Activating Transcription Factor 2
  • Adrenergic beta-Agonists
  • Cyclic AMP Response Element-Binding Protein
  • Transcription Factors
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 3