Characterization of dilator prostanoid receptors in the fetal rabbit ductus arteriosus.

G C Smith, R A Coleman, J C McGrath

Index: J. Pharmacol. Exp. Ther. 271(1) , 390-6, (1994)

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Abstract

The purpose of this study was to determine which receptors mediate the dilator effects of prostaglandins (PGs) on the ductus arteriosus of the fetal rabbit. Isolated rings of the vessel from fetal New Zealand White rabbits were precontracted with indomethacin (1 microM) and potassium (25 mM) in 100 to 110 mmHg oxygen, and the dilator effects of a range of synthetic prostanoids were quantified by cumulative relaxant concentration-effect curves. The potencies of agonists were quantified with reference to PGE2 by the equieffective molar ratio (EMR): EC50 test agonist/EC50 PGE2. The effects on these responses of available antagonists were also studied. None of a range of synthetic prostanoids with selective agonism of EP1, EP2 or EP3 receptors was as potent as PGE2. The rank order of potency was as follows: PGE2 (EC50 = 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 beta (R*),3 alpha]]-4-(benzoyl-amino)phenyl 7-[3 hydroxy-2(2-hydroxy-3-phenoxypropoxy)-5- oxocyclopentyl]-4-heptenoate, single enantiomer (GR 63799K) (EMR 685, 95% CI 427-944) >> ((+/-)-trans-2-[4[(1-hydroxphenyl) phenyl]-5-oxocylopentaneheptanoic acid (AH13205) (EMR > 100,000) > or = sulprostone (EMR > 10,000) > or = 0. The EP1 antagonists, 6-isopropoxy-9-oxoxanthine-2-carboxylic acid (AH6809) (10 microM) and 8-clorodi-benz[b,f][1,4]oxazepine-10 (11H)-carboxylic acid, 2-acetylhydrazide (SC19220) (30 microM), had no significant effect on the sensitivity of the ductus to PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)