CONTRACTILE EFFECTS OF PROSTANOIDS ON FETAL RABBIT DUCTUS-ARTERIOSUS

We wished to determine whether any evidence indicates that the ductus arteriosus has prostanoid receptors coupled to contractile pathways an d whether the sensitivity of the ductus to the dilator effect of prost aglandin E(2) (PGE(2)) was inhibited by other prostanoids. Rings of du ctus arteriosus were isolated from fetal New Zealand White rabbits (28 days of gestation) and mounted in vitro. In the presence of 1 mu M in domethacin, the vessel was relaxed with either 300 nM forskolin or 10 nM PGE(2), and cumulative concentration-contraction response curves to several synthetic prostanoids were obtained with or without a recepto r antagonist when available. The vessel was also precontracted with 1 mu M indomethacin and 25 mM K+ in 13-14.5 kPa O-2, and cumulative conc entration-relaxation response curves to PGE(2) were obtained with and without addition of prostanoids. In 300 nM forskolin, both U46619 and sulprostone caused concentration-dependent contractions of the ductus in the nanomolar range (EC(50) values, i.e., the interpolated molar co ncentration of the drug causing 50% of its own eventual maximum respon se of 33 and 42 nM, respectively). Responses to GR63799X and PGF(2 alp ha) were complicated by the fact that these agonists caused relaxation at high concentrations (greater than or equal to 30 nM). The response to U46619 was shifted to the right by the thromboxane receptor antago nist EP 092. In 10 nM PGE(2), U46619, sulprostone, and GR63799X elicit ed similar contractile responses, whereas PGF(2 alpha) had no effect. Incubation in 10 nM U46619 or PGF(2 alpha) had no effect on the sensit ivity of the ductus to the dilator effect of PGE(2), but 10 nM sulpros tone increased the EC(50) to PGE(2) by 119% and 3 mu M sulprostone inc reased it by 157%. The fetal rabbit ductus arteriosus has contractile receptors for thromboxane and for PGE(2). The contractile receptor for PGE, appears to modulate the vessel's sensitivity to the dilator effe ct of PGE(2).