Deficient production of cyclic AMP: Pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure

M. D. Feldman, L. Copelas, J. K. Gwathmey, P. Phillips, S. E. Warren, F. J. Schoen, W. Grossman, J. P. Morgan

Research output: Contribution to journalArticlepeer-review

406 Scopus citations

Abstract

We studied the effects of different classes of inotropic drugs on human working myocardium in vitro that was isolated from the hearts of patients with end-stage heart failure, and compared the responses to these drugs with those noted in muscles from nonfailing control hearts. Although peak isometric force generated in response to increased extracellular calcium reached control levels in the muscles from patients with heart failure, the time course of contraction and rate of relaxation were greatly prolonged. The inotropic effectiveness of the β-adrenergic agonist isoproterenol and the phosphodiesterase inhibitors milrinone, caffeine, and isobutylmethylxanthine was markedly reduced in muscles from the patients with heart failure. In contrast, the effectiveness of inotropic stimulation with acetylstrophanthidin and the adenylate cyclase activator forskolin was preserved. After a minimally effective dose of forskolin was given to elevate intracellular cyclic AMP levels, the inotropic responses of muscles from the failing hearts to phosphodiesterase inhibitors were markedly potentiated. These data indicate that an abnormality in cyclic AMP production may be a fundamental defect present in patients with end-stage heart failure that can markedly diminish the effectiveness of agents that depend on generation of this nucleotide for production of a positive inotropic effect.

Original languageEnglish (US)
Pages (from-to)331-339
Number of pages9
JournalCirculation
Volume75
Issue number2
DOIs
StatePublished - 1987

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Deficient production of cyclic AMP: Pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure'. Together they form a unique fingerprint.

Cite this