Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels

Comp Biochem Physiol A Mol Integr Physiol. 2005 Oct;142(2):136-43. doi: 10.1016/j.cbpb.2005.04.012. Epub 2005 May 31.


Biochemical studies have established the presence of a NO pathway in the heart, including sources of NO and various effectors. Several cardiac ion channels have been shown to be modified by NO, such as L-type Ca(2+), ATP-sensitive K(+), and pacemaker f-channels. Some of these effects are mediated by cGMP, through the activity of three main proteins: the cGMP-dependent protein kinase (PKG), the cGMP-stimulated phosphodiesterase (PDE2) and the cGMP-inhibited PDE (PDE3). Other effects appear independent of cGMP, as for instance the NO modulation of the ryanodine receptor-Ca(2+) channel. In the case of the cardiac L-type Ca(2+) channel current (I(Ca,L)), both cGMP-dependent and cGMP-independent effects have been reported, with important tissue and species specificity. For instance, in rabbit sinoatrial myocytes, NO inhibits the beta-adrenergic stimulation of I(Ca,L) through activation of PDE2. In cat and human atrial myocytes, NO potentiates the cAMP-dependent stimulation of I(Ca,L) through inhibition of PDE3. In rabbit atrial myocytes, NO enhances I(Ca,L) in a cAMP-independent manner through the activation of PKG. In ventricular myocytes, NO exerts opposite effects on I(Ca,L): an inhibition mediated by PKG in mammalian myocytes but by PDE2 in frog myocytes; a stimulation attributed to PDE3 inhibition in frog ventricular myocytes but to a direct effect of NO in ferret ventricular myocytes. Finally, NO can also regulate cardiac ion channels by a direct action on G-proteins and adenylyl cyclase.

Publication types

  • Review

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Calcium / chemistry
  • Calcium / metabolism
  • Cats
  • Cyclic AMP / chemistry
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic GMP / metabolism*
  • Cyclic GMP-Dependent Protein Kinases / chemistry
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Heart Diseases / metabolism
  • Heart Ventricles / pathology
  • Humans
  • Hypertrophy
  • Ion Channels* / chemistry
  • Ions / chemistry
  • Muscle Cells / metabolism
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism
  • Nitric Oxide / chemistry
  • Nitric Oxide / metabolism*
  • Potassium / chemistry
  • Rabbits
  • Signal Transduction
  • Tissue Distribution


  • Ion Channels
  • Ions
  • Nitric Oxide
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Adenylyl Cyclases
  • Cyclic GMP
  • Potassium
  • Calcium