Inhibitory effects of putative peptidic urotensin-II receptor antagonists on urotensin-II-induced contraction of cat isolated respiratory smooth muscle.
Urotensin-II is purported to influence pulmonary function by modulating smooth muscle tone/growth. In the present study, Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analysis indicated the presence of UT receptor mRNA in cat trachea, bronchi and lung parenchyma. Urotensin-II contracted cat isolated trachea and bronchi with similar potencies (pEC(50)s 8.61+/-0.07-8.81+/-0.10). Contractile efficacies ranged from 19+/-9% to 63+/-11% KCl in the primary and secondary bronchi. The peptidic UT receptor antagonists BIM-23127, SB-710411 and GSK248451 (7.18+/-0.12, 7.52+/-0.08 and 9.05+/-0.16 cat recombinant UT pK(i)s) inhibited urotensin-II-induced contraction of cat isolated trachea with pK(b)s 6.36+/-0.11, 6.74+/-0.07 and 9.27+/-0.12, respectively. As such, feline lung contains significant amounts of UT mRNA and this receptor appears to be functionally coupled to bronchoconstriction (the peptidic tool compound GSK248451 representing a sub-nanomolar inhibitor of such effects). These findings suggest that the cat represents a suitable species for future studies designed to assess the effects of the urotensin-II receptor on pulmonary (patho)physiology.
Department of Vascular Biology (UW2510), Cardiovascular and Urogenital Center of Excellence for Drug Discovery, GlaxoSmithKline, P.O. Box 1539, 709 Swedeland Road, King of Prussia, PA 19406-0939, USA. David_J_Behm@gsk.com
David J
DJ
Behm
Zhaohui
Z
Ao
Valeria
V
Camarda
Nambi V
NV
Aiyar
Douglas G
DG
Johns
Stephen A
SA
Douglas
D000818:Animals; D001667:Binding, Competitive; D015152:Blotting, Northern; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002415:Cats; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014579:Urotensins / Q000378:metabolism / Q000494:pharmacology*
C092829:BIM 23127; C503137:GSK248451; D007457:Iodine Radioisotopes; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C473646:SB-710411; D014579:Urotensins; D011189:Potassium Chloride; C029677:urotensin II