Relaxant actions of nonprostanoid prostacyclin mimetics on human pulmonary artery
Publication in refereed journal


摘要The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) similar to 0.6 nM], U-46619 (IC50 similar to 0.9 NM), and K+ (similar to 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-Delta(6,6a)-6a-carba PGI(1) (TEI-9063) greater than or equal to cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-1 6 beta,20-dimethyl-Delta(6,6a)-6a-carba PGI(1) (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been underestimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 similar to 2.5 nM) >> 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.
著者Jones RL, Qian YM, Wise H, Wong HNC, Lam WL, Chan HW, Yim APC, Ho JKS
期刊名稱Journal of Cardiovascular Pharmacology
頁次525 - 535
關鍵詞cicaprost; human pulmonary artery; IP receptors; nonprostanoid prostacyclin mimetics; pulmonary vasodilators; TP receptor antagonists
Web of Science 學科類別Cardiac & Cardiovascular Systems; CARDIAC & CARDIOVASCULAR SYSTEMS; Cardiovascular System & Cardiology; Pharmacology & Pharmacy; PHARMACOLOGY & PHARMACY

上次更新時間 2020-26-10 於 02:21