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Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice
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β2-adrenergic receptor-coupled phosphoinositide 3-kinase constrains cAMP-dependent increases in cardiac inotropy

Christopher J Gregg1, Jochen Steppan, Daniel R Gonzalez

  • 1Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.

Anesthesia and Analgesia
|August 14, 2010
PubMed
Abstract

Insights

Phosphoinositide 3-kinase (PI3K) regulates cardiac contractility by inhibiting phosphodiesterase 4 (PDE4) activity. This mechanism, involving the beta-2 adrenergic receptor (AR), controls cyclic adenosine monophosphate (cAMP) levels in heart cells.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Emerging evidence suggests phosphoinositide 3-kinase (PI3K) influences cardiac contractility, but the mechanism is unclear.
  • This study investigates the hypothesis that PI3K, coupled with the beta-2 adrenergic receptor (AR), restrains cardiac inotropy via cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) activation.

Purpose of the Study:

  • To elucidate the mechanism by which PI3K modulates cardiac inotropy.
  • To determine the role of cAMP-dependent PDE activation in PI3K-mediated regulation of contractility.

Main Methods:

  • Isolated murine cardiac myocytes were used to assess myocardial contractility, including sarcomere shortening and intracellular calcium transients.
  • The effects of PI3K and PDE4 inhibition on physiological functions, cAMP levels, and PDE activity were measured.

Main Results:

  • PI3K inhibition significantly increased cardiac contractility, indicated by enhanced sarcomere shortening and Ca(2+) handling.
  • This effect was dependent on G(iα) protein activity and involved a concentration-dependent decrease in PDE4 activity.
  • PI3K(γ) was found to co-immunoprecipitate with PDE4D, and beta-2 AR inverse agonist abolished the observed increases in contractility.

Conclusions:

  • PI3K modulates myocardial contractility through a cAMP-dependent mechanism by regulating PDE4 catalytic activity.
  • Basal beta-2 AR activity, PI3K, and PDE4 interaction represent integrative cellular signaling controlling cardiac myocyte contractility.
  • These findings explain how PDE inhibitors like milrinone increase myocardial contractility with or without beta-adrenergic stimulation.

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