Effects of Indomethacin in Utero on the Pulmonary Vasculature of the Newborn Guinea Pig

De, Demello; Jd, Murphy; Mj, Aronovitz; Davies, Paul; Lm, Reid

doi:10.1203/00006450-198712000-00016

Cited by 13 publications

(9 citation statements)

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“…However, the density of the fullymuscularized arteries within the intraacinar area (EDT 10 pm) was similar in treated and non-treated lambs, indicating that intrauterine exposure to indomethacin did not cause the abnormal muscularization that has been observed in fatal cases of PPHN (Ohara and Ogata 1988). Another recent study (Demello et al 1987) has shown similar findings to our present results Demello's group reported that treating pregnant Guinea pigs with indomethacin did not cause the intraacinar structural changes of PPHN. However, Wild et al (1989) reported that pulmonary hypertension due to mechanical ligation of the ductus arteriosus in fetal lambs in utero caused partial muscularization of the intraacinar pulmonary arteries, and Levin et al (1978a) reported similar results.…”

Section: Discussionsupporting

confidence: 92%

Effects of Indomethacin in Utero on the Pulmonary Vasculature of the Newborn Lambs.

Ohara

Ogata

Tezuka

1991

Tohoku J. Exp. Med.

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Section: Discussionsupporting

confidence: 92%

Effects of Indomethacin in Utero on the Pulmonary Vasculature of the Newborn Lambs.

Ohara

Ogata

Tezuka

1991

Tohoku J. Exp. Med.

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“…This work establishes a link between intrauterine events and the failure of postnatal adaptation of the pulmonary circulation at birth, and demonstrates histologic features and pathophysiologic abnormalities characteristic of human persistent pulmonary hypertension of the newborn (6,7,10,14,15). Although previous studies have suggested that fetal events may alter either vascular reactivity (31,32) or structure (1 1-13, 16,17), more recent studies have failed to confirm these observations (18)(19)(20) (16). Similarly, partial ductus closure secondary to cyclooxygenase inhibition (15) or ligation (16,17,33) leads to similar structural lesions of small pulmonary arteries.…”

Section: Discussionmentioning

confidence: 58%

“…Similarly, partial ductus closure secondary to cyclooxygenase inhibition (15) or ligation (16,17,33) leads to similar structural lesions of small pulmonary arteries. However, recent attempts to induce these proliferative pulmonary vascular lesions in newborn rats and guinea pigs after maternal exposure to hypoxia, or chronic maternal administration ofindomethacin to guinea pigs, failed to result in similar lesions (18,19,20). Although species differences may potentially explain some differences between studies, these latter studies lacked intrauterine measurements to confirm successful closure of the ductus, or the development of significant pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 85%

“…Finally, data from animal studies suggest that chronic fetal hypertension or hypoxia may cause structural lesions similar to those found in humans with PPHN (1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. However, recent attempts to demonstrate physiologic or histologic abnormalities after chronic intrauterine hypoxia or indomethacin treatment have not supported this hypothesis, and mechanisms contributing to the initiation and progression of the pulmonary vascular abnormalities of PPHN are unknown (18)(19)(20). In addition, no study has actually linked intrauterine events with altered perinatal pulmonary vasoreactivity, the inability to achieve or sustain a drop in pulmonary vascular resistance at birth, and structural vascular changes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Abman¹,

Shanley²,

Accurso³

1989

J. Clin. Invest.

170

163

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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 < 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 < 0.0001). Pulmonary hypertension for > 8 d increased the wall thickness of small pulmonary arteries (P < 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 < 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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“…However, in that study, indomethacin also induced a significant decrease in the ED of pulmonary vessels, thus vasoconstriction may have accounted for the change in medial width to ED ratio. Administration of indomethacin to guinea pigs during fetal development did not produce pulmonary artery hypertension or the characteristic vascular changes of PPHN (22). A previous study without injection of the pulmonary vasculature or quantitative analysis found that fetal sheep exposed to 1-2 wk of surgical ligation of the ductus arteriosus developed right ventricular hypertrophy and adventitial fibrosis of small pulmonary arteries (23).…”

Section: Resultsmentioning

confidence: 99%

Ligating the Ductus Arteriosus before birth Remodels the Pulmonary Vasculature of the Lamb

Wild¹,

Nickerson²,

Morin

1989

Pediatr Res

110

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ABSTRACT. The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in thc proportion of partially and fully muscularized pulmonary arteries a t the level of the terminal bronchiole and within the acinus (p < 0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion. Prenatal closure of the ductus arteriosus for 6 to 17 d in fetal lambs produces anatomic changes in small pulmonary arteries of the newborn lamb. These anatomic changes are similar to pathologic alterations reported in human neonates dying with idiopathic persistent pulmonary hypertension of the newborn. The clinical syndrome of idiopathic PPHN is characterized morphologically by the abnormal presence of muscle in the walls of the smallest pulmonary artery branches (1). The etiology of PPHN occurring in the absence of primary cardiac, pulmonary,

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Effects of Indomethacin in Utero on the Pulmonary Vasculature of the Newborn Guinea Pig

Cited by 13 publications

References 0 publications

Effects of Indomethacin in Utero on the Pulmonary Vasculature of the Newborn Lambs.

Effects of Indomethacin in Utero on the Pulmonary Vasculature of the Newborn Lambs.

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

Ligating the Ductus Arteriosus before birth Remodels the Pulmonary Vasculature of the Lamb

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