RELAXANT ACTIONS OF NONPROSTANOID PROSTACYCLIN MIMETICS ON HUMAN PULMONARY-ARTERY

The specific prostacyclin (IP) receptor agonist cicaprost relaxed huma n pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) similar to 0.6 nM], U-46619 (IC50 simi lar to 0.9 NM), and K+ (similar to 40% maximal relaxation); endotheliu m removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-di methyl-Delta(6,6a)-6a-carba PGI(1) (TEI-9063) greater than or equal to cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prost acyclin > 15-deoxy-16 alpha-hydroxy-1 6 beta,20-dimethyl-Delta(6,6a)-6 a-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 prostacyc lin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] ac etic acid (BMY 45778; IC50 similar to 2.5 nM) >> 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 o n human platelet membranes, it is suggested that the slightly shallowe r log concentration-response curves for BMY 45778, BMY 42393, and CU 2 3 may reflect the near-maximal receptor occupancy required for complet e relaxation. A fifth nonprostanoid, CU 602, had much shallower log co ncentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial ag onism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostac yclin analogs on washout of the organ bath; by the inhalation route, t his type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulm onary vasodilators.