Inhibition of type 5 phosphodiesterase counteracts β2-adrenergic signalling in beating cardiomyocytes

Cardiovasc Res. 2015 Jun 1;106(3):408-20. doi: 10.1093/cvr/cvv123. Epub 2015 Apr 7.

Abstract

Aims: Compartmentalization of cAMP and PKA activity in cardiac muscle cells plays a key role in maintaining basal and enhanced contractility stimulated by sympathetic nerve activity. In cardiomyocytes, activation of adrenergic receptor increases cAMP production, which is countered by the hydrolytic activity of selective phosphodiesterases (PDEs). The intracellular regional dynamics of cAMP production and hydrolysis modulate downstream signals resulting in different biological responses. The interplay between beta receptors (βARs) signalling and phosphodiesterase 5 (PDE5) activity remains to be addressed.

Methods and results: Using combined strategies with pharmacological inhibitors and genetic deletion of PDEs and βAR isoforms, we revealed a specific pool of cAMP that is under dual regulation by PDE2 and, indirectly, PDE5 activity. Inhibition of PDE5 with sildenafil produces a cGMP-dependent activation of PDE2 that attenuates cAMP generation induced by βAR agonists, with concomitant modulation of stimulated contraction rate and calcium transients. PDE2 haploinsufficiency abolished the effects of sildenafil. The negative chronotropic effect of PDE5 inhibition through PDE2 activation was also observed in sinoatrial node tissue from adult mice. PDE5 inhibition selectively lowered contraction rate stimulated by β2AR, but not β1AR activation, supporting a compartmentalization of the cGMP-modulated pool of cAMP.

Conclusion: These data identify a new effect of PDE5 inhibitors on the modulation of cardiomyocyte response to adrenergic stimulation via PDE5-PDE2-mediated cross-talk.

Keywords: Chronotropy; PDE2; PDE5; Sildenafil; βARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Animals
  • Animals, Newborn
  • Calcium Signaling / drug effects
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / deficiency
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / genetics
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
  • Heart Rate / drug effects*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Contraction / drug effects*
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-1 / metabolism
  • Receptors, Adrenergic, beta-2 / deficiency
  • Receptors, Adrenergic, beta-2 / drug effects*
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism
  • Signal Transduction / drug effects*
  • Time Factors

Substances

  • Adrb1 protein, mouse
  • Adrenergic beta-2 Receptor Agonists
  • Phosphodiesterase 5 Inhibitors
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, mouse
  • Cyclic GMP