Cyclic AMP relaxation of rat aortic smooth muscle is mediated in part by decrease of depletion of intracellular Ca(2+) stores and inhibition of capacitative calcium entry

Vascul Pharmacol. 2013 Jan;58(1-2):98-104. doi: 10.1016/j.vph.2012.08.007. Epub 2012 Aug 31.


Despite a large number of studies, the mechanism by which 3',5'-cyclic monophosphate (cAMP) induces vasorelaxation is not fully understood. The comparison between results obtained in different vessels or species has often been the source of conflicting reports. In order to shed more light onto this mechanism, we studied the effects of forskolin in phenylephrine-pre-contracted endothelium-denuded rat aorta and measured cAMP levels in rat aortic myocytes by enzyme-immunoassay. Nanomolar forskolin relaxed phenylephrine-induced contractions. This effect was mimicked by dibutyryl-cAMP and was potentiated by rolipram or a p38-mitogen-activated protein kinase (p38-MAPK) inhibitor (SB-203580). Nifedipine and verapamil partially relaxed phenylephrine-induced contractions, while further application of cAMP-elevating agents fully relaxed these contractions. In Ca(2+)-free extracellular solution, forskolin reduced phenylephrine-induced transient contractions and reduced the Ca(2+)-induced contraction after depletion of intracellular stores. Nanomolar concentrations of forskolin increased basal cAMP levels only in the presence of rolipram or phenylephrine, which did not modify intracellular levels of cAMP by themselves. In conclusion, relaxation by cAMP is mediated in part by decrease of depletion of intracellular Ca(2+) stores and inhibition of capacitative calcium entry. This study provides the first evidence that inhibition of PDE4 or p38-MAPK potentiates the vasodilator effect of cAMP-elevating agents in rat aortic myocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / cytology
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / metabolism*
  • Calcium / metabolism*
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism*
  • Imidazoles / pharmacology
  • Male
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Nifedipine / pharmacology
  • Phenylephrine / pharmacology
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Inbred WKY
  • Rolipram / pharmacology
  • Vasodilation / drug effects
  • Vasodilator Agents / pharmacology
  • Verapamil / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors


  • Imidazoles
  • Phosphodiesterase 4 Inhibitors
  • Pyridines
  • Vasodilator Agents
  • Colforsin
  • Phenylephrine
  • Verapamil
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases
  • Nifedipine
  • Rolipram
  • SB 203580
  • Calcium