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Sarcoplasmic reticulum-associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing

M A Movsesian1, C J Smith, J Krall

  • 1Cardiology Division, University of Utah Medical Center, Salt Lake City 84132.

The Journal of Clinical Investigation
|July 1, 1991
PubMed

Insights

Sarcoplasmic reticulum-associated phosphodiesterase activity is similar in failing and non-failing human hearts. This suggests that reduced effectiveness of phosphodiesterase inhibitors in heart failure is not due to changes in this enzyme.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphodiesterase (PDE) inhibitors are investigated for treating heart failure.
  • Their diminished inotropic efficacy in failing human hearts is not fully understood.
  • Sarcoplasmic reticulum (SR)-associated PDE activity is a potential target.

Purpose of the Study:

  • To investigate sarcoplasmic reticulum-associated cAMP phosphodiesterase activity in failing and non-failing human hearts.
  • To determine if altered PDE activity or sensitivity contributes to reduced drug efficacy in heart failure.

Main Methods:

  • Microsomes from failing (dilated cardiomyopathy) and non-failing human hearts were analyzed.
  • cAMP phosphodiesterase activity was measured and characterized.
  • Kinetic properties (Vmax, Km) and inhibition by cGMP, OPC 3911, and rolipram were assessed.
  • PDE activity was compared to ATP-dependent Ca2+ accumulation.

Main Results:

  • Sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was functionally homogeneous at low cAMP concentrations.
  • PDE activity showed competitive inhibition by cGMP and OPC 3911, but not rolipram.
  • Kinetic properties (Vmax, Km) and sensitivity to OPC 3911 were similar in failing and non-failing hearts.
  • The ratio of PDE activity to Ca2+ accumulation was also comparable.

Conclusions:

  • Diminished inotropic efficacy of PDE inhibitors in failing human hearts is not explained by changes in SR-associated cAMP phosphodiesterase.
  • The level, kinetic properties, or pharmacologic sensitivity of this specific PDE activity remains unchanged in end-stage heart failure.

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