INTERACTIONS BETWEEN INDOMETHACIN, NORADRENALINE AND VASODILATORS IN THE FETAL RABBIT DUCTUS-ARTERIOSUS

1 Interactions between indomethacin, noradrenaline and vasodilators we re studied in rings of ductus arteriosus isolated from fetal rabbits. The effect of incubation with prostaglandin E2 (PGE2) on the noradrena line concentration-contraction response curve was studied in the prese nce and absence of indomethacin. Also, the ductus was pre-contracted w ith 10 muM noradrenaline and concentration-relaxation response curves (CRRC) to PGE2, cicaprost, cromakalim and forskolin were obtained in t he presence and absence of indomethacin. 2 In the absence of indometha cin, PGE2 (from 1 nM to 100 nM) decreased the pEC50 to noradrenaline t o a maximum of 0.4 to 0.5 log units (i.e. an approximately three fold increase in EC50 [M]). In the presence of 1 muM indomethacin, PGE2 (0. 1 nM to 100 nM) decreased the pEC50 to noradrenaline by 2.39 log units (i.e. a 245 fold increase in EC50). By comparing the control pEC50 to noradrenaline with the relationship between the pEC50 to noradrenalin e and [PGE2] in 1 muM indomethacin, the effect of endogenous PGE2 synt hesized in the vessel wall was estimated as being equivalent to a bath concentration. of approximately 1 nM exogenous PGE2. 3 When the vesse l was pre-contracted with 10 muM noradrenaline, indomethacin had no ef fect on the CRRC to PGE2 but did alter the CRRC to other vasodilators. The sensitivity of the vessel to cicaprost, cromakalim and forskolin was decreased in 1 muM indomethacin compared with control. Forskolin c aused complete relaxation in the presence and absence of indomethacin. Indomethacin decreased the maximum response to cromakalim but increas ed the maximum response to cicaprost. PGE2, 0.3 nM, partially reversed the effect of indomethacin on the sensitivity of the vessel to forsko lin. 4 We conclude that under varying experimental conditions, indomet hacin increased the sensitivity of the ductus to the effects of PGE2 b ut decreased its sensitivity to other vasodilators. Both effects can b e explained by elimination of endogenous PGE2. However, indomethacin i ncreased the maximum response to cicaprost, which cannot be explained by elimination of endogenous PGE2 but may be due to elimination of end ogenous prostacyclin.