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Investigation of the prostacyclin (IP) receptor antagonist RO1138452 on isolated blood vessel and platelet preparations
Author(s) -
Jones R L,
Wise H,
Clark R,
Whiting R L,
Bley K R
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706841
Subject(s) - agonist , prostacyclin , endocrinology , medicine , chemistry , prostanoid , antagonist , receptor , pharmacology
Background and purpose: The current study examined the utility of the recently described prostacyclin (prostanoid IP) receptor antagonist RO1138452 (2‐(4‐(4‐isopropoxybenzyl)‐phenylamino) imidazoline) as a tool for classifying prostanoid receptors. Experimental approach: pA 2 values were determined on isolated smooth muscle and platelet preparations. Key results: RO1138452 antagonized relaxation of human pulmonary artery, guinea‐pig aorta and rabbit mesenteric artery induced by the selective IP agonist cicaprost. Schild plots had slopes close to unity, generating pA 2 values of 8.20, 8.39 and 8.12 respectively. Non‐surmountable antagonism was sometimes found with the higher concentrations of RO1138452, attributable to the EP 3 contractile action of cicaprost. RO1138452 did not block relaxation of guinea‐pig trachea induced by the EP 2 ‐selective agonist butaprost. In contrast, there was a modest inhibition of butaprost‐induced relaxation of human pulmonary artery by RO1138452, implying activation of both EP 2 and IP receptors by butaprost. RO1138452 did not affect relaxation induced by PGE 2 (EP 4 agonist) and substance P (NK 1 /endothelium‐dependent agonist) in rabbit mesenteric artery. In human and rat platelet‐rich plasmas, RO1138452 antagonized cicaprost‐induced inhibition of platelet aggregation in a surmountable manner; pA 2 values may have been affected by binding of RO1138452 to plasma protein. RO1138452 did not affect the inhibitory actions of PGD 2 (DP 1 agonist) and NECA (adenosine A 2A agonist) in human platelets. Conclusions and implications: The data indicate that RO1138452 is a potent and selective IP receptor antagonist. RO1138452 represents an important addition to our armoury of prostanoid receptor antagonists and a potential clinical agent in situations where prostacyclin has a pathophysiological function. British Journal of Pharmacology (2006) 149 , 110–120. doi: 10.1038/sj.bjp.0706841