title: Characterisation of the effect of oxygen tension on response of fetal rabbit ductus arteriosus to vasodilators.
abstract: 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 range of vasodilators; and (2) to establish the effect, if any, of cyclo-oxygenase inhibition on the interaction between oxygen and prostaglandin (PG)E2.
  
  
  METHODS
  Rings of ductus arteriosus were isolated from fetal New Zealand White rabbits at 28 d gestation (term = 31) and precontracted with 10 microM noradrenaline in the presence of the cyclo-oxygenase inhibitor indomethacin (1 microM). Cumulative relaxation response curves were obtained from a range of vasodilators and their pEC50 (-log10 of the interpolated molar concentration causing 50% of the maximum response) and maximum relaxant response (MRR) were determined in 15% 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 microM flubriprofen were studied on the interaction between oxygen and PGE2.
  
  
  RESULTS
  In 1 microM 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 > PGE2 >> cromakalim >> sodium nitroprusside approximately adenosine approximately 0. The MRR of all agonists was increased in 2% oxygen except forskolin which caused complete relaxation in 15% oxygen. In 15% oxygen, the rank order of pEC50 was PGE2 >> cicaprost approximately cromakalim approximately forskolin. PGE2 was 70.8 times more potent than cicaprost. The pEC50 of all four agonists was increased in 2% oxygen. The increase in pEC50 could not be explained by a decreased extent of precontraction. The MRR to PGE2 in 15% oxygen and the magnitude of the increase in pEC50 to PGE2 going from 15% to 2% oxygen were the same in 1 microM flubriprofen, 1 microM indomethacin, or in the absence of these drugs. However, in 2% oxygen, the MRR to PGE2 was increased in 1 microM indomethacin or 1 microM flubriprofen compared with control.
  
  
  CONCLUSIONS
  (1) Increasing oxygen tension from fetal to neonatal levels desensitises the ductus arteriosus to a range of vasodilators. (2) There is evidence that prostacyclin has a physiological role in the control of the rabbit ductus arteriosus. (3) The effect of oxygen on the potency of PGE2 is independent of cyclo-oxygenase products, whereas its effect on the efficacy of PGE2 is modulated by an endogenous cyclo-oxygenase product.
authors.affiliation: Institute of Physiology, University of Glasgow, United Kingdom.
authors.forename: G C
authors.initials: GC
authors.lastname: Smith
authors.forename: J C
authors.initials: JC
authors.lastname: McGrath
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D019806:Cromakalim; D046508:Culture Techniques; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005480:Flurbiprofen; D007213:Indomethacin / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D016861:Cyclooxygenase Inhibitors; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009599:Nitroprusside; D005576:Colforsin; D005480:Flurbiprofen; D009320:Atrial Natriuretic Factor; D011464:Epoprostenol; D009543:Nifedipine; D000241:Adenosine; D015232:Dinoprostone; C043867:cicaprost; D010100:Oxygen; D009638:Norepinephrine; D007213:Indomethacin