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. 1989 Jun;83(6):1849–1858. doi: 10.1172/JCI114091

Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs.

S H Abman 1, P F Shanley 1, F J Accurso 1
PMCID: PMC303905  PMID: 2723062

Abstract

To determine the effects of chronic intrauterine pulmonary hypertension on the perinatal pulmonary circulation, we induced chronic elevations of pulmonary artery pressure in 24 late-gestation fetal lambs by maintaining partial compression of the ductus arteriosus with an inflatable vascular occluder. Pulmonary artery pressure was increased from 44 +/- 1 to 62 +/- 3 mmHg for 3-14 d. Although left pulmonary artery blood flow initially increased during acute partial ductus compression, the increase in flow was not sustained during chronic ductus compression despite persistent elevations of pulmonary artery pressure (P less than 0.01). Chronic hypertension decreased the slope of the pressure-flow relationship from 3.4 +/- 0.3 (initial) to 0.9 +/- 0.1 ml/min per mmHg, and blunted the fetal pulmonary vascular response to small increases in PO2 (P less than 0.0001). Pulmonary hypertension for greater than 8 d increased the wall thickness of small pulmonary arteries (P less than 0.001). Compared with controls, hypertensive animals had higher pulmonary artery pressure, lower pulmonary blood flow, and predominant right-to-left ductus shunting after cesarean-section delivery (P less than 0.0001). We conclude that chronic pulmonary hypertension in utero, in the absence of hypoxemia or sustained increases in blood flow, causes abnormal fetal pulmonary vasoreactivity, structural remodeling, and the failure to achieve the normal decline in pulmonary resistance at birth.

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Selected References

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  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. Abman S. H., Wilkening R. B., Ward R. M., Accurso F. J. Adaptation of fetal pulmonary blood flow to local infusion of tolazoline. Pediatr Res. 1986 Nov;20(11):1131–1135. doi: 10.1203/00006450-198611000-00013. [DOI] [PubMed] [Google Scholar]
  3. Accurso F. J., Alpert B., Wilkening R. B., Petersen R. G., Meschia G. Time-dependent response of fetal pulmonary blood flow to an increase in fetal oxygen tension. Respir Physiol. 1986 Jan;63(1):43–52. doi: 10.1016/0034-5687(86)90029-0. [DOI] [PubMed] [Google Scholar]
  4. Allen K. M., Haworth S. G. Impaired adaptation of pulmonary circulation to extrauterine life in newborn pigs exposed to hypoxia: an ultrastructural study. J Pathol. 1986 Nov;150(3):205–212. doi: 10.1002/path.1711500309. [DOI] [PubMed] [Google Scholar]
  5. Anderson D. F., Bissonnette J. M., Faber J. J., Thornburg K. L. Central shunt flows and pressures in the mature fetal lamb. Am J Physiol. 1981 Jul;241(1):H60–H66. doi: 10.1152/ajpheart.1981.241.1.H60. [DOI] [PubMed] [Google Scholar]
  6. CASSIN S., DAWES G. S., MOTT J. C., ROSS B. B., STRANG L. B. THE VASCULAR RESISTANCE OF THE FOETAL AND NEWLY VENTILATED LUNG OF THE LAMB. J Physiol. 1964 May;171:61–79. doi: 10.1113/jphysiol.1964.sp007361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DAWES G. S., MOTT J. C., WIDDICOMBE J. G., WYATT D. G. Changes in the lungs of the new-born lamb. J Physiol. 1953 Jul;121(1):141–162. doi: 10.1113/jphysiol.1953.sp004936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Demello D. E., Murphy J. D., Aronovitz M. J., Davies P., Reid L. M. Effects of indomethacin in utero on the pulmonary vasculature of the newborn guinea pig. Pediatr Res. 1987 Dec;22(6):693–697. doi: 10.1203/00006450-198712000-00016. [DOI] [PubMed] [Google Scholar]
  9. Dreyfuss D., Basset G., Soler P., Saumon G. Intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats. Am Rev Respir Dis. 1985 Oct;132(4):880–884. doi: 10.1164/arrd.1985.132.4.880. [DOI] [PubMed] [Google Scholar]
  10. Drummond W. H., Bissonnette J. M. Persistent pulmonary hypertension in the neonate: development of an animal model. Am J Obstet Gynecol. 1978 Aug 1;131(7):761–763. doi: 10.1016/0002-9378(78)90242-9. [DOI] [PubMed] [Google Scholar]
  11. FULTON R. M., HUTCHINSON E. C., JONES A. M. Ventricular weight in cardiac hypertrophy. Br Heart J. 1952 Jul;14(3):413–420. doi: 10.1136/hrt.14.3.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Geggel R. L., Aronovitz M. J., Reid L. M. Effects of chronic in utero hypoxemia on rat neonatal pulmonary arterial structure. J Pediatr. 1986 May;108(5 Pt 1):756–759. doi: 10.1016/s0022-3476(86)81060-5. [DOI] [PubMed] [Google Scholar]
  13. Goldberg S. J., Levy R. A., Siassi B., Betten J. The effects of maternal hypoxia and hyperoxia upon the neonatal pulmonary vasculature. Pediatrics. 1971 Oct;48(4):528–533. [PubMed] [Google Scholar]
  14. Hall S. M., Haworth S. G. Normal adaptation of pulmonary arterial intima to extrauterine life in the pig: ultrastructural studies. J Pathol. 1986 May;149(1):55–66. doi: 10.1002/path.1711490111. [DOI] [PubMed] [Google Scholar]
  15. Harker L. C., Kirkpatrick S. E., Friedman W. F., Bloor C. M. Effects of indomethacin on fetal rat lungs: a possible cause of persistent fetal circulation (PFC). Pediatr Res. 1981 Feb;15(2):147–151. doi: 10.1203/00006450-198102000-00013. [DOI] [PubMed] [Google Scholar]
  16. Haworth S. G. Pulmonary vascular remodeling in neonatal pulmonary hypertension. State of the art. Chest. 1988 Mar;93(3 Suppl):133S–138S. [PubMed] [Google Scholar]
  17. Haworth S. G., Reid L. Persistent fetal circulation: Newly recognized structural features. J Pediatr. 1976 Apr;88(4 Pt 1):614–620. doi: 10.1016/s0022-3476(76)80021-2. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Levin D. L., Fixler D. E., Morriss F. C., Tyson J. Morphologic analysis of the pulmonary vascular bed in infants exposed in utero to prostaglandin synthetase inhibitors. J Pediatr. 1978 Mar;92(3):478–483. doi: 10.1016/s0022-3476(78)80453-3. [DOI] [PubMed] [Google Scholar]
  20. Levin D. L., Heymann M. A., Kitterman J. A., Gregory G. A., Phibbs R. H., Rudolph A. M. Persistent pulmonary hypertension of the newborn infant. J Pediatr. 1976 Oct;89(4):626–630. doi: 10.1016/s0022-3476(76)80405-2. [DOI] [PubMed] [Google Scholar]
  21. Levin D. L., Hyman A. I., Heymann M. A., Rudolph A. M. Fetal hypertension and the development of increased pulmonary vascular smooth muscle: a possible mechanism for persistent pulmonary hypertension of the newborn infant. J Pediatr. 1978 Feb;92(2):265–269. doi: 10.1016/s0022-3476(78)80022-5. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Lock J. E., Hamilton F., Luide H., Coceani F., Olley P. M. Direct pulmonary vascular responses in the conscious newborn lamb. J Appl Physiol Respir Environ Exerc Physiol. 1980 Jan;48(1):188–196. doi: 10.1152/jappl.1980.48.1.188. [DOI] [PubMed] [Google Scholar]
  24. Mecham R. P., Whitehouse L. A., Wrenn D. S., Parks W. C., Griffin G. L., Senior R. M., Crouch E. C., Stenmark K. R., Voelkel N. F. Smooth muscle-mediated connective tissue remodeling in pulmonary hypertension. Science. 1987 Jul 24;237(4813):423–426. doi: 10.1126/science.3603030. [DOI] [PubMed] [Google Scholar]
  25. Meyrick B., Reid L. Normal postnatal development of the media of the rat hilar pulmonary artery and its remodeling by chronic hypoxia. Lab Invest. 1982 May;46(5):505–514. [PubMed] [Google Scholar]
  26. Murphy J. D., Aronovitz M. J., Reid L. M. Effects of chronic in utero hypoxia on the pulmonary vasculature of the newborn guinea pig. Pediatr Res. 1986 Apr;20(4):292–295. doi: 10.1203/00006450-198604000-00003. [DOI] [PubMed] [Google Scholar]
  27. Murphy J. D., Rabinovitch M., Goldstein J. D., Reid L. M. The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr. 1981 Jun;98(6):962–967. doi: 10.1016/s0022-3476(81)80605-1. [DOI] [PubMed] [Google Scholar]
  28. Padbury J., Agata Y., Ludlow J., Ikegami M., Baylen B., Humme J. Effect of fetal adrenalectomy on catecholamine release and physiologic adaptation at birth in sheep. J Clin Invest. 1987 Oct;80(4):1096–1103. doi: 10.1172/JCI113166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rudolph A. M. High pulmonary vascular resistance after birth: I. Pathophysiologic considerations and etiologic classification. Clin Pediatr (Phila) 1980 Sep;19(9):585–590. doi: 10.1177/000992288001900902. [DOI] [PubMed] [Google Scholar]
  30. Ruiz U., Piasecki G. J., Balogh K., Polansky B. J., Jackson B. T. An experimental model for fetal pulmonary hypertension. A preliminary report. Am J Surg. 1972 Apr;123(4):468–471. doi: 10.1016/0002-9610(72)90201-2. [DOI] [PubMed] [Google Scholar]
  31. Sheldon R. E., Peeters L. L., Jones M. D., Jr, Makowski E. L., Meschia G. Redistribution of cardiac output and oxygen delivery in the hypoxemic fetal lamb. Am J Obstet Gynecol. 1979 Dec 15;135(8):1071–1078. doi: 10.1016/0002-9378(79)90739-7. [DOI] [PubMed] [Google Scholar]
  32. Siassi B., Goldberg S. J., Emmanouilides G. C., Higashino S. M., Lewis E. Persistent pulmonary vascular obstruction in newborn infants. J Pediatr. 1971 Apr;78(4):610–615. doi: 10.1016/s0022-3476(71)80462-6. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Teitel D. F., Iwamoto H. S., Rudolph A. M. Effects of birth-related events on central blood flow patterns. Pediatr Res. 1987 Nov;22(5):557–566. doi: 10.1203/00006450-198711000-00017. [DOI] [PubMed] [Google Scholar]

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