title: 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.
abstract: 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.
authors.affiliation: BHF Laboratories, Department of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK. n.orie@ucl.ac.uk
authors.forename: Nelson N
authors.initials: NN
authors.lastname: Orie
authors.forename: Lucie H
authors.initials: LH
authors.lastname: Clapp
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism*; D013623:Tail / Q000098:blood supply*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology
chemical_list: C491909:Ptgir protein, rat; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014665:Vasodilator Agents; D011464:Epoprostenol; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go