Effects of Chronic in Utero Hypoxia on the Pulmonary Vasculature of the Newborn Guinea Pig

Abstract

ABSTRACT. This report analyzes the effect on pulmonary vascular structure and function in the newborn guinea pig of chronic fetal hypoxemia, induced by maternal hypobaric hypoxia (380-420 torr) without direct interference with the utero-placental blood flow. Six pregnant guinea pigs were maintained in hypobaric chambers, 10 newborns from their litters being the hypoxic group. Twenty newborns from the litters of 10 pregnant guinea pigs maintained in air were the control group. After spontaneous delivery catheters were placed in the left carotid and the main pulmonary arteries of the newborns. Oxygen consumption was measured, pressures recorded from the pulmonary artery, right ventricle, and right atrium, oxygen saturation and hemoglobin concentration estimated on blood from systemic arteries, pulmonary artery, and right atrium, and cardiac output calculated (Fick principle). All data were normalized per kilogram body weight. Morphometric analysis of the pulmonary vasculature after injection of the pulmonary arteries showed no difference between the groups. Contrary to expectation chronic hypoxemia in utero did not cause pulmonary hypertension or the precocious muscularization of the precapillary unit found in human cases of persistent pulmonary hypertension: it caused growth retardation, a feature not typical of the human syndrome. (Pediatr Res 20: 292-295,1986) Abbreviation v 0 2 , oxygen consumptionAcute alveolar hypoxia in man and experimental animals causes pulmonary hypertension by vasoconstriction that is rapidly reversible on return to air (1-5). Chronic hypoxia causes progressive hypertension and structural changes in the pulmonary vasculature that are only partly reversible (6-8). Morphometric analysis shows that these changes include an increase in the thickness of the arterial medial coat, the appearance of muscle in the smaller more peripheral arteries that are normally not muscular, and a reduction in the density of intraacinar arteries that fill with injection medium (6, 7). In the exteriorized fetal sheep and newborn lamb, numerous studies have demonstrated an increase in pulmonary vascular resistance in response to acute Rcceivcd Junc 13, 1984; accepted November 18, 1985 hypoxia (5, 9, 10). The speculation that chronic fetal hypoxemia causes persistent pulmonary hypertension in the newborn is based on these acute studies in which hypoxemia is caused by a reduction in uterine or placental blood flow. Few investigators have examined the effect of chronic hypoxemia on the intact fetus.Recently we have reported severe structural abnormalities of the microcirculation of the lungs in two series of newborns with fatal persistent pulmonary hypertension (1 1, 12), notably muscularization of the intraacinar pulmonary arteries that normally at this age are free of muscle. Our present study analyzes the effect on the structure and function of the pulmonary vascular bed of the newborn guinea pig after chronic fetal hypoxemia induced by maternal hypoxia without any direct interference with the utero placent...

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

“…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.…”

“…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.…”

Ligating the Ductus Arteriosus before Birth Causes Persistent Pulmonary Hypertension in the Newborn Lamb

“…However, pulmonary arterial pressure averaged less than systemic on room air, pulmonary blood flow was not measured, and hypoxemia was not reported. Chronic intrauterine hypoxia alone did not cause pulmonary hypertension in newborn guinea pigs (24).…”

“…Thus, investigators have placed pregnant animals in environments with low Fi,,, embolized the placenta, or partially occluded the umbilical cord (24)(25)(26). These approaches should divert even more of the right ventricular output away from the lungs in the fetus (7).…”

The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

“…66 Several experimental models have been used to explore the pathogenesis and pathophysiology of PPHN. 63,[67][68][69][70] PH induced experimentally by early closure of the ductus arteriosus in fetal sheep alters lung vascular reactivity and structure, causing the failure of postnatal adaptation at delivery and providing a useful model of PPHN. Studies with this model show that chronic hypertension without high blood flow impairs fetal lung vascular structure and function.…”