Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts

Int J Mol Sci. 2022 Feb 15;23(4):2145. doi: 10.3390/ijms23042145.


Cardiac contractility is regulated by several neural, hormonal, paracrine, and autocrine factors. Amongst these, signaling through β-adrenergic and serotonin receptors generates the second messenger cyclic AMP (cAMP), whereas activation of natriuretic peptide receptors and soluble guanylyl cyclases generates cyclic GMP (cGMP). Both cyclic nucleotides regulate cardiac contractility through several mechanisms. Phosphodiesterases (PDEs) are enzymes that degrade cAMP and cGMP and therefore determine the dynamics of their downstream effects. In addition, the intracellular localization of the different PDEs may contribute to regulation of compartmented signaling of cAMP and cGMP. In this review, we will focus on the role of PDEs in regulating contractility and evaluate changes in heart failure.

Keywords: 5-HT4; ANP; BNP; CNP; GC-A; GC-B; beta-adrenergic receptor; cardiomyocyte; inotropic response; lusitropic response.

Publication types

  • Review

MeSH terms

  • Animals
  • Cyclic AMP / metabolism*
  • Cyclic GMP / metabolism*
  • Heart Failure / metabolism*
  • Humans
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / metabolism
  • Phosphoric Diester Hydrolases / metabolism
  • Second Messenger Systems / physiology
  • Signal Transduction / physiology*


  • Cyclic AMP
  • Phosphoric Diester Hydrolases
  • Cyclic GMP