Differential agonistic and antagonistic effects of the urotensin-II ligand SB-710411 at rodent and primate UT receptors.
SB-710411 (Cpa-c[d-Cys-Pal-d-Trp-Lys-Val-Cys]-Cpa-amide) inhibited [(125)I]urotensin-II rat and monkey UT receptor binding (pK(i)s 7.50+/-0.07 and 6.82+/-0.06). However, whereas SB-710411 antagonized urotensin-II-induced inositol phosphate formation at the rat UT receptor (pK(b) 6.54+/-0.05), this ligand functioned as an agonist at the monkey UT receptor (pEC(50) 6.56+/-0.35, E(max) 5.27+/-0.65-fold over basal). Indeed, in contrast to the rat UT receptor (and rat isolated arteries), SB-710411 exhibited intrinsic activity in monkey arteries acting as an efficacious vasoconstrictor (pEC(50)s 5.03+/-0.18 to 5.71+/-0.21, E(max)s 101+/-4 to 218+/-58% KCl). These data demonstrate that caution must be taken when extrapolating the pharmacology of a specific ligand(s) between the rodent and primate UT receptors.
Behm
David J
DJ
Vascular Biology, Cardiovascular and Urogenital CEDD, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. david_j_behm@gsk.com
Herold
Christopher L
CL
Camarda
Valeria
V
Aiyar
Nambi V
NV
Douglas
Stephen A
SA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008024:Ligands; D008252:Macaca fascicularis; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013045:Species Specificity; D014579:Urotensins / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D007295:Inositol Phosphates; D008024:Ligands; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; C473646:SB-710411; D014579:Urotensins; C473142:Uts2r protein, rat; D014662:Vasoconstrictor Agents; C029677:urotensin II