The peptidic urotensin-II receptor ligand GSK248451 possesses less intrinsic activity than the low-efficacy partial agonists SB-710411 and urantide in native mammalian tissues and recombinant cell systems.
Several peptidic urotensin-II (UT) receptor antagonists exert 'paradoxical' agonist activity in recombinant cell- and tissue-based bioassay systems, likely the result of differential urotensin-II receptor (UT receptor) signal transduction/coupling efficiency between assays. The present study has examined this phenomenon in mammalian arteries and recombinant UT-HEK (human embryonic kidney) cells.BacMam-mediated recombinant UT receptor upregulation in HEK cells augmented agonist activity for all four peptidic UT ligands studied. The nominal rank order of relative intrinsic efficacy was U-II>urantide ([Pen(5)-DTrp(7)-Orn(8)]hU-II(4-11))>SB-710411 (Cpa-c[DCys-Pal-DTrp-Lys-Val-Cys]-Cpa-amide)>>GSK248451 (Cin-c[DCys-Pal-DTrp-Orn-Val-Cys]-His-amide) (the relative coupling efficiency of recombinant HEK cells was cat>human>>rat UT receptor). The present study further demonstrated that the use of high signal transduction/coupling efficiency isolated blood vessel assays (primate>cat arteries) is required in order to characterize UT receptor antagonism thoroughly. This cannot be attained simply by using the rat isolated aorta, an artery with low signal transduction/coupling efficiency in which low-efficacy agonists appear to function as antagonists. In contrast to the 'low-efficacy agonists' urantide and SB-710411, GSK248451 functioned as a potent UT receptor antagonist in all native isolated tissues studied (UT receptor selectivity was confirmed in the rat aorta). Further, GSK248451 exhibited an extremely low level of relative intrinsic activity in recombinant HEK cells (4-5-fold less than seen with urantide). Since GSK248451 (1 mg kg(-1), i.v.) blocked the systemic pressor actions of exogenous U-II in the anaesthetized cat, it represents a suitable peptidic tool antagonist for delineating the role of U-II in the aetiology of mammalian cardiometabolic diseases.
Behm
David J
DJ
Department of Vascular Biology and Thrombosis, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. david.j.behm@gsk.com
Stankus
Gerald
G
Doe
Christopher P A
CP
Willette
Robert N
RN
Sarau
Henry M
HM
Foley
James J
JJ
Schmidt
Dulcie B
DB
Nuthulaganti
Parvathi
P
Fornwald
James A
JA
Ames
Robert S
RS
Lambert
David G
DG
Calo'
Girolamo
G
Camarda
Valeria
V
Aiyar
Nambi V
NV
Douglas
Stephen A
SA
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002415:Cats; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014579:Urotensins / Q000378:metabolism / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C503137:GSK248451; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; C473646:SB-710411; C121697:UTS2R protein, human; D014579:Urotensins; D014662:Vasoconstrictor Agents; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; C029677:urotensin II; D002118:Calcium