Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Dec;90(6):2147–2155. doi: 10.1172/JCI116100

Oxygen modulates prostacyclin synthesis in ovine fetal pulmonary arteries by an effect on cyclooxygenase.

P W Shaul 1, W B Campbell 1, M A Farrar 1, R R Magness 1
PMCID: PMC443365  PMID: 1334969

Abstract

Prostacyclin (PGI2) plays an integral role in O2 mediation of pulmonary vasomotor tone in the fetus and newborn. We hypothesized that O2 modulates PGI2 synthesis in vitro in ovine fetal intrapulmonary arteries, with decreasing O2 causing attenuated synthesis. A decline in PO2 from 680 to 40 mmHg caused a 26% fall in basal PGI2 synthesis. PGI2 synthesis maximally stimulated by bradykinin, A23187, and arachidonic acid were also attenuated at low PO2, by 35%, 33%, and 35%, respectively. PGE2 synthesis was equally affected. In contrast, varying O2 did not alter PGI2 synthesis with exogenous PGH2, which is the product of cyclooxygenase and the substrate for prostacyclin synthetase. Prostaglandin-mediated effects of O2 on cAMP production were also examined. Decreasing PO2 to 40 mmHg caused complete inhibition of basal cAMP production, whereas cAMP production stimulated by exogenous PGI2 was not affected. In parallel studies of mesenteric arteries, PGI2 synthesis and cAMP production were enhanced at low O2. Thus, PGI2 synthesis in fetal intrapulmonary arteries is modulated by changes in O2, with decreasing O2 causing attenuated synthesis. This process is due to an effect on cyclooxygenase activity, it causes marked parallel alterations in cAMP production, and it is specific to the pulmonary circulation.

Full text

PDF
2147

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abman S. H., Accurso F. J., Wilkening R. B., Meschia G. Persistent fetal pulmonary hypoperfusion after acute hypoxia. Am J Physiol. 1987 Oct;253(4 Pt 2):H941–H948. doi: 10.1152/ajpheart.1987.253.4.H941. [DOI] [PubMed] [Google Scholar]
  2. Badesch D. B., Orton E. C., Zapp L. M., Westcott J. Y., Hester J., Voelkel N. F., Stenmark K. R. Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. Am J Respir Cell Mol Biol. 1989 Dec;1(6):489–498. doi: 10.1165/ajrcmb/1.6.489. [DOI] [PubMed] [Google Scholar]
  3. Busse R., Förstermann U., Matsuda H., Pohl U. The role of prostaglandins in the endothelium-mediated vasodilatory response to hypoxia. Pflugers Arch. 1984 May;401(1):77–83. doi: 10.1007/BF00581536. [DOI] [PubMed] [Google Scholar]
  4. Campbell A. G., Cockburn F., Dawes G. S., Milligan J. E. Pulmonary vasoconstriction in asphyxia during cross-circulation between twin foetal lambs. J Physiol. 1967 Sep;192(1):111–121. doi: 10.1113/jphysiol.1967.sp008291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Davidson D. Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs. J Appl Physiol (1985) 1988 Apr;64(4):1676–1682. doi: 10.1152/jappl.1988.64.4.1676. [DOI] [PubMed] [Google Scholar]
  6. Dembinska-Kiec A., Rücker W., Schönhöfer P. S. Effects of PGI2 and PGI analogues on cAMP levels in cultured endothelial and smooth muscle cells derived from bovine arteries. Naunyn Schmiedebergs Arch Pharmacol. 1980 Feb;311(1):67–70. doi: 10.1007/BF00500304. [DOI] [PubMed] [Google Scholar]
  7. Dworetz A. R., Moya F. R., Sabo B., Gladstone I., Gross I. Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation. Pediatrics. 1989 Jul;84(1):1–6. [PubMed] [Google Scholar]
  8. Fagan J. M., Goldberg A. L. Inhibitors of protein and RNA synthesis cause a rapid block in prostaglandin production at the prostaglandin synthase step. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2771–2775. doi: 10.1073/pnas.83.8.2771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fox W. W., Gewitz M. H., Dinwiddie R., Drummond W. H., Peckham G. J. Pulmonary hypertension in the perinatal aspiration syndromes. Pediatrics. 1977 Feb;59(2):205–211. [PubMed] [Google Scholar]
  10. Green R., Rojas J., Sundell H. Pulmonary vascular response to prostacyclin in fetal lambs. Prostaglandins. 1979 Dec;18(6):927–934. doi: 10.1016/0090-6980(79)90129-1. [DOI] [PubMed] [Google Scholar]
  11. Gryglewski R. J., Korbut R., Ocetkiewicz A. Generation of prostacyclin by lungs in vivo and its release into the arterial circulation. Nature. 1978 Jun 29;273(5665):765–767. doi: 10.1038/273765a0. [DOI] [PubMed] [Google Scholar]
  12. Harper J. F., Brooker G. Femtomole sensitive radioimmunoassay for cyclic AMP and cyclic GMP after 2'0 acetylation by acetic anhydride in aqueous solution. J Cyclic Nucleotide Res. 1975;1(4):207–218. [PubMed] [Google Scholar]
  13. Kulmacz R. J., Lands W. E. Characteristics of prostaglandin H synthase. Adv Prostaglandin Thromboxane Leukot Res. 1983;11:93–97. [PubMed] [Google Scholar]
  14. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  15. Leffler C. W., Hessler J. R., Green R. S. The onset of breathing at birth stimulates pulmonary vascular prostacyclin synthesis. Pediatr Res. 1984 Oct;18(10):938–942. doi: 10.1203/00006450-198410000-00006. [DOI] [PubMed] [Google Scholar]
  16. Leffler C. W., Hessler J. R. Perinatal pulmonary prostaglandin production. Am J Physiol. 1981 Nov;241(5):H756–H759. doi: 10.1152/ajpheart.1981.241.5.H756. [DOI] [PubMed] [Google Scholar]
  17. Leffler C. W., Tyler T. L., Cassin S. Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats. Am J Physiol. 1978 Apr;234(4):H346–H351. doi: 10.1152/ajpheart.1978.234.4.H346. [DOI] [PubMed] [Google Scholar]
  18. Levin D. L., Rudolph A. M., Heymann M. A., Phibbs R. H. Morphological development of the pulmonary vascular bed in fetal lambs. Circulation. 1976 Jan;53(1):144–151. doi: 10.1161/01.cir.53.1.144. [DOI] [PubMed] [Google Scholar]
  19. Lewis A. B., Heymann M. A., Rudolph A. M. Gestational changes in pulmonary vascular responses in fetal lambs in utero. Circ Res. 1976 Oct;39(4):536–541. doi: 10.1161/01.res.39.4.536. [DOI] [PubMed] [Google Scholar]
  20. Lock J. E., Olley P. M., Coceani F. Direct pulmonary vascular responses to prostaglandins in the conscious newborn lamb. Am J Physiol. 1980 May;238(5):H631–H638. doi: 10.1152/ajpheart.1980.238.5.H631. [DOI] [PubMed] [Google Scholar]
  21. Lyrene R. K., Welch K. A., Godoy G., Philips J. B., 3rd Alkalosis attenuates hypoxic pulmonary vasoconstriction in neonatal lambs. Pediatr Res. 1985 Dec;19(12):1268–1271. doi: 10.1203/00006450-198512000-00009. [DOI] [PubMed] [Google Scholar]
  22. Madden M. C., Vender R. L., Friedman M. Effect of hypoxia on prostacyclin production in cultured pulmonary artery endothelium. Prostaglandins. 1986 Jun;31(6):1049–1062. doi: 10.1016/0090-6980(86)90208-x. [DOI] [PubMed] [Google Scholar]
  23. Magness R. R., Osei-Boaten K., Mitchell M. D., Rosenfeld C. R. In vitro prostacyclin production by ovine uterine and systemic arteries. Effects of angiotensin II. J Clin Invest. 1985 Dec;76(6):2206–2212. doi: 10.1172/JCI112229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Marshall P. J., Kulmacz R. J., Lands W. E. Constraints on prostaglandin biosynthesis in tissues. J Biol Chem. 1987 Mar 15;262(8):3510–3517. [PubMed] [Google Scholar]
  25. McIntyre T. M., Zimmerman G. A., Satoh K., Prescott S. M. Cultured endothelial cells synthesize both platelet-activating factor and prostacyclin in response to histamine, bradykinin, and adenosine triphosphate. J Clin Invest. 1985 Jul;76(1):271–280. doi: 10.1172/JCI111957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Meyrick B., Niedermeyer M. E., Ogletree M. L., Brigham K. L. Pulmonary hypertension and increased vasoreactivity caused by repeated indomethacin in sheep. J Appl Physiol (1985) 1985 Aug;59(2):443–452. doi: 10.1152/jappl.1985.59.2.443. [DOI] [PubMed] [Google Scholar]
  27. Morin F. C., 3rd, Egan E. A., Ferguson W., Lundgren C. E. Development of pulmonary vascular response to oxygen. Am J Physiol. 1988 Mar;254(3 Pt 2):H542–H546. doi: 10.1152/ajpheart.1988.254.3.H542. [DOI] [PubMed] [Google Scholar]
  28. Ohki S., Ogino N., Yamamoto S., Hayaishi O. Prostaglandin hydroperoxidase, an integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J Biol Chem. 1979 Feb 10;254(3):829–836. [PubMed] [Google Scholar]
  29. Rabinovitch M., Boudreau N., Vella G., Coceani F., Olley P. M. Oxygen-related prostaglandin synthesis in ductus arteriosus and other vascular cells. Pediatr Res. 1989 Oct;26(4):330–335. doi: 10.1203/00006450-198910000-00009. [DOI] [PubMed] [Google Scholar]
  30. Rabinovitch M., Gamble W., Nadas A. S., Miettinen O. S., Reid L. Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. Am J Physiol. 1979 Jun;236(6):H818–H827. doi: 10.1152/ajpheart.1979.236.6.H818. [DOI] [PubMed] [Google Scholar]
  31. Rabinovitch M., Konstam M. A., Gamble W. J., Papanicolaou N., Aronovitz M. J., Treves S., Reid L. Changes in pulmonary blood flow affect vascular response to chronic hypoxia in rats. Circ Res. 1983 Apr;52(4):432–441. doi: 10.1161/01.res.52.4.432. [DOI] [PubMed] [Google Scholar]
  32. Rabinovitch M., Mullen M., Rosenberg H. C., Maruyama K., O'Brodovich H., Olley P. M. Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat. Am J Physiol. 1988 Mar;254(3 Pt 2):H500–H508. doi: 10.1152/ajpheart.1988.254.3.H500. [DOI] [PubMed] [Google Scholar]
  33. Rudolph A. M. Fetal and neonatal pulmonary circulation. Annu Rev Physiol. 1979;41:383–395. doi: 10.1146/annurev.ph.41.030179.002123. [DOI] [PubMed] [Google Scholar]
  34. Rudolph A. M., Heymann M. A. Hemodynamic changes induced by blockers of prostaglandin synthesis in the fetal lamb in utero. Adv Prostaglandin Thromboxane Res. 1978;4:231–237. [PubMed] [Google Scholar]
  35. Shaul P. W., Farrar M. A., Buja L. M. Ontogeny of beta-adrenergic regulation of adenylate cyclase in intrapulmonary arteries from fetal and postnatal lambs. Pediatr Res. 1991 Dec;30(6):610–615. doi: 10.1203/00006450-199112000-00025. [DOI] [PubMed] [Google Scholar]
  36. Shaul P. W., Farrar M. A., Zellers T. M. Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries. Am J Physiol. 1992 Feb;262(2 Pt 2):H355–H364. doi: 10.1152/ajpheart.1992.262.2.H355. [DOI] [PubMed] [Google Scholar]
  37. Shaul P. W., Kinane B., Farrar M. A., Buja L. M., Magness R. R. Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat. J Clin Invest. 1991 Aug;88(2):447–455. doi: 10.1172/JCI115324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Smith W. L. Prostaglandin biosynthesis and its compartmentation in vascular smooth muscle and endothelial cells. Annu Rev Physiol. 1986;48:251–262. doi: 10.1146/annurev.ph.48.030186.001343. [DOI] [PubMed] [Google Scholar]
  39. Soifer S. J., Kaslow D., Roman C., Heymann M. A. Umbilical cord compression produces pulmonary hypertension in newborn lambs: a model to study the pathophysiology of persistent pulmonary hypertension in the newborn. J Dev Physiol. 1987 Jun;9(3):239–252. [PubMed] [Google Scholar]
  40. Tripp M. E., Heymann M. A., Rudolph A. M. Hemodynamic effects of prostaglandin E1 on lambs in utero. Adv Prostaglandin Thromboxane Res. 1978;4:221–229. [PubMed] [Google Scholar]
  41. Van der Ouderaa F. J., Buytenhek M., Nugteren D. H., Van Dorp D. A. Purification and characterisation of prostaglandin endoperoxide synthetase from sheep vesicular glands. Biochim Biophys Acta. 1977 May 25;487(2):315–331. doi: 10.1016/0005-2760(77)90008-x. [DOI] [PubMed] [Google Scholar]
  42. Wu K. K., Hatzakis H., Lo S. S., Seong D. C., Sanduja S. K., Tai H. H. Stimulation of de novo synthesis of prostaglandin G/H synthase in human endothelial cells by phorbol ester. J Biol Chem. 1988 Dec 15;263(35):19043–19047. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES