Role of prostanoid IP and EP receptors in mediating vasorelaxant responses to PGI2 analogues in rat tail artery: Evidence for Gi/o modulation via EP3 receptors

Eur J Pharmacol. 2011 Mar 11;654(3):258-65. doi: 10.1016/j.ejphar.2010.12.005. Epub 2010 Dec 24.


Prostanoid IP receptors coupled to Gs are thought to be the primary target for prostacyclin (PGI(2)) analogues. However, these agents also activate prostanoid EP(1-4) receptor subtypes to varying degrees, which are positively (EP(2/4)) or negatively (EP(3)) coupled to adenylate cyclase through Gs or Gi, respectively. We investigated the role of these receptors in modulating relaxation to PGI(2) analogues cicaprost, iloprost and treprostinil in pre-contracted segments of rat tail artery. Prostanoid IP (RO1138452), EP(4) (GW627368X), EP(3) (L-798106), EP(1-3) (AH6809), and EP(1) (SC-51322) receptor antagonists were used to determine each receptor contribution. The role of G(i/o) was investigated using pertussis toxin (PTX), while dependence on cAMP was determined using adenylate cyclase (2'5'dideoxyadenosine, DDA) and protein kinase A (2'-O-monobutyryladenosine- 3',5'-cyclic monophosphorothioate, Rp- isomer, Rp-2'-O-MB-cAMPS) inhibitors, and by measurement of tissue cAMP. All analogues caused relaxation which was significantly (P<0.01) inhibited by RO1138452; with maximum response to cicaprost, iloprost and treprostinil reduced by 51%, 66% and 37%, respectively. GW627368X had no effect when used alone, but in combination with RO1138452, caused a rightward shift of the curves for cicaprost and iloprost but not treprostinil. PTX treatment potentiated relaxation to all 3 analogues (P<0.01), as did L798106 and AH6809 but not SC-51322. Basal cAMP levels were higher in PTX-treated tissues and DDA- and Rp-2'-O-MB-cAMPs--sensitive responses increased to analogue concentrations <0.1μM. In conclusion, prostanoid EP(3) receptors via G(i/o) negatively modulate prostanoid IP receptor-mediated relaxation to cicaprost, iloprost and treprostinil. However, other pathways contribute to analogue-induced vasorelaxation, the nature of which remains unclear for treprostinil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / drug effects*
  • Arteries / metabolism
  • Arteries / physiology
  • Cyclic AMP / metabolism
  • Epoprostenol / analogs & derivatives
  • Epoprostenol / pharmacology*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • In Vitro Techniques
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin / metabolism*
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism*
  • Tail / blood supply*
  • Vasodilation / drug effects*
  • Vasodilator Agents / chemistry
  • Vasodilator Agents / pharmacology


  • Ptgir protein, rat
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin
  • Receptors, Prostaglandin E, EP3 Subtype
  • Vasodilator Agents
  • Epoprostenol
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go