Beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors: shifting the focus from inotropy to cyclic adenosine monophosphate.
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.
Movsesian
M A
MA
Salt Lake City VA Medical Center, University of Utah School of Medicine, USA. matthew.movsesian@hsc.utah.edu
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D051698:Activating Transcription Factor 2; D000318:Adrenergic beta-Agonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006333:Heart Failure / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology
D051698:Activating Transcription Factor 2; D000318:Adrenergic beta-Agonists; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3