CHARACTERIZATION OF THE EFFECT OF OXYGEN-TENSION ON RESPONSE OF FETALRABBIT DUCTUS-ARTERIOSUS TO VASODILATORS

Objective: The aims of the study were (1) to elucidate the effects of raised oxygen tension on the response of the ductus arteriosus to a ra nge of vasodilators; and (2) to establish the effect, if any, of cyclo -oxygenase inhibition on the interaction between oxygen and prostaglan din (PG)E(2). Methods: Rings of ductus arteriosus were isolated from f etal New Zealand White rabbits at 28 d gestation (term = 31) and preco ntracted with 10 mu M noradrenaline in the presence of the cyclo-oxyge nase inhibitor indomethacin (1 mu M). Cumulative relaxation response c urves were obtained from a range of vasodilators and their pEC(50) (-l og(10) of the interpolated molar concentration causing 50% of the maxi mum response) and maximum relaxant response (MRR) were determined in 1 5% oxygen (neonatal oxygen tension, 13-14.3 kPa) and 2% oxygen (fetal oxygen tension, 2.5-3.0 kPa). In addition, the effects of (1) omitting indomethacin and (2) its substitution by 1 mu M flubriprofen were stu died on the interaction between oxygen and PGE(2). Results: In 1 mu M indomethacin, nifedipine and atrial natriuretic peptide had no effect on ductal tone in either oxygen tension. In 15% oxygen, the rank order of MRR was forskolin>cicaprost>PGE(2) much greater than cromakalim mu ch greater than sodium nitroprusside approximate to adenosine approxim ate to 0. The MRR of all agonists was increased in 2% oxygen except fo rskolin which caused complete relaxation in 15% oxygen. In 15% oxygen, the rank order of pEC(50) was PGE(2) much greater than cicaprost appr oximate to cromakalim approximate to forskolin. PGE(2) was 70.8 times more potent than cicaprost. The pEC(50) of all four agonists was incre ased in 2% oxygen. The increase in pEC(50) could not be explained by a decreased extent of precontraction. The MRR to PGE(2) in 15% oxygen a nd the magnitude of the increase in pEC(50) to PGE(2) going from 15% t o 2% oxygen were the same in 1 mu M flubriprofen, 1 mu M indomethacin, or in the absence of these drugs. However, in 2% oxygen, the MRR to P GE(2) was increased in 1 mu M indomethacin or 1 mu M flubriprofen comp ared with control. Conclusions: (1) Increasing oxygen tension from fet al to neonatal levels desensitises the ductus arteriosus to a range of vasodilators. (2) There is evidence that prostacyclin has a physiolog ical role in the control of the rabbit ductus arteriosus. (3) The effe ct of oxygen on the potency of PGE(2) is independent of cyclo-oxygenas e products, whereas its effect on the efficacy of PGE(2) is modulated by an endogenous cyclo-oxygenase product.