CHARACTERIZATION OF DILATOR PROSTANOID RECEPTORS IN THE FETAL RABBIT DUCTUS-ARTERIOSUS

The purpose of this study was to determine which receptors mediate the dilator effects of prostaglandins (PGs) on the ductus arteriosus of t he fetal rabbit. Isolated rings of the vessel from fetal New Zealand W hite rabbits were precontracted with indomethacin (1 mu M) and potassi um (25 mM) in 100 to 110 mmHg oxygen, and the dilator effects of a ran ge of synthetic prostanoids were quantified by cumulative relaxant con centration-effect curves. The potencies of agonists were quantified wi th reference to PGE(2) by the equieffective molar ratio (EMR): EC(50) test agonist/EC(50) PGE(2). The effects on these responses of availabl e antagonists were also studied. None of a range of synthetic prostano ids with selective agonism of EP(1), EP(2) or EP(3) receptors was as p otent as PGE(2). The rank order of potency was as follows: PGE(2) (EC( 50) = 0.36 nM [95% confidence intervals [CI] = 0.32-0.41, n = 44], EMR = unity) >> misoprostol (EMR 145, 95% CI 73-217) > [1R-[1 alpha(Z)2 b eta(R)3 alpha]]-4-(benzoyl amino)phenyl 7-[3 3-phenoxypropoxy)-5-oxoc yclopentyl]-4-hepten-oate, single enantiomer (GR63799K) (EMR 685, 95% CI 427-944) >> [(1-hydroxphenyl)phenyl-5-oxocyclopentaneheptanoic acid (AH13205) (EMR > 100,000) greater than or equal to sulprostone (EMR > 10,000) greater than or equal to 0. The EP(1) antagonists, 6-isopropr oxy-9-oxoxanthine-2-carboxylic acid (AH6809) (10 mu M) and 8-clorodi-b enz[b,f][1,4]oxazepine-10 (11H)-carboxylic acid, 2-acetylhydrazide (SC 19220) (30 mu M), had no significant effect on the sensitivity of the ductus to PGE(2). The EP(4) antagonist (1 alpha(Z)2 beta 5 alpha]-7-[5 -[[(1,1'-biphenyl)-4-yl]me- thoxy]-2-(4-morpholinyl)-3-oxocyclopentyl] -4 heptenoic acid (AH23848B) caused concentration-related shifts to th e right of the PGE, concentration-effect curve, yielding a pA(2), of 4 .91 [95% CI 4.36-5.51] but with a Schild plot slope of greater than 1. 0. The EP(2) agonist AH13205, although it caused only a very small rel axation, acted as a weak competitive antagonist of PGE(2) with a pA(2) of 4.85 (95% CI 3.98-5.96). Cicaprost (a selective IP agonist) and -c arbohexyl)-1-(3-cyclohexyl-3-hydroxypropylamino) hydantoin, one racemi c diastereomer (BW245C, a selective DP agonist) both relaxed the ductu s but were less potent than PGE(2) (EMRs: 110, 95% CI 80-140; and 875, 95% CI 677-1074; respectively). AH23848B and AH13205 (both 30 mu M) i nhibited the sensitivity of the ductus to BW245C to a similar extent a s it inhibited that to PGE(2) but had little or no effect on its sensi tivity to cicaprost. The selective DP receptor-blocking drug 6-carbohe xyl)-1-(2-cyclohexyl-2-hydroxyethylamino) hydantoin (BW868C) (10 mu M) caused no significant decrease in sensitivity to BW245C. We conclude that there are two types of dilator prostanoid receptors present in th e fetal rabbit ductus arteriosus: a new EP receptor, probably the rece ntly described EP(4) receptor, and an IP receptor.