The patency of the ductus arteriosus in newborn lambs and its physiological consequences

Dawes, G. S.; Mott, Joan C.; Widdicombe, J. G.

doi:10.1113/jphysiol.1955.sp005313

Cited by 62 publications

(23 citation statements)

References 10 publications

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“…The pulmonary artery pressure, though lower than that in the foetus, has not yet fallen to adult levels and hypoxia has an exaggerated pressor effect in the pulmonary circulation which may be due to the persistence of the foetal type of pulmonary arterial media and reactivity to low Po2 (Thomas, 1964). Evidence for this so-called 'transitional' type of circulation in the new-born period has been given by and Adams & Lind (1957) in new-born babies, by Rudolph, Auld, Golinko & Paul (1961) in new-born goats and puppies, by Reeves & Leathers (1964) in new-born calves, and by Dawes, Mott & Widdicombe (1955) in newborn lambs. These authors also noted that the normal direction of flow through the ductus arteriosus was from aorta to pulmonary artery and it is M. J. P UR VES 72 also clear that, making allowances for the variety of methods used to measure this, the ductus is functionally patent for a variable period after birth and that there are species differences.…”

Section: Discussionmentioning

confidence: 96%

The effects of hypoxia in the new‐born lamb before and after denervation of the carotid chemoreceptors*

Purves¹

1966

The Journal of Physiology

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SUMMARY1. Twenty-seven unanaesthetized new-born lambs, 6 hr-10 days old, responded to two levels of inspired oxygen, 125 and 110 mm Hg (alveolar CO2 being controlled) with a sustained increase in minute ventilation (1), a small increase in heart rate and a less consistent rise in systemic blood pressure.2. An increase in v was observed when arterial oxygen tension (Pa, 02) had fallen by 6-15 mm Hg. There appeared to be no fixed threshold of Pa,°a t which ventilation started to increase.3. The increase in ventilation caused by these levels of hypoxia was significantly and directly related to the age of the lamb and to its control alveolar C02.4. More severe hypoxia caused a progressive increase in v until Pa, 02 was about 25 mm Hg when respiration failed. This increase at P., 02 > 25 mm Hg was markedly potentiated when alveolar PCO2 (PA,co2) was increased and abolished after bilateral denervation of the carotid chemoreceptors.5. Significant (> 10%) left-to-right shunts were found in ten out of twelve lambs lightly anaesthetized with pentobarbitone sodium, breathing air. Hypoxia diminished the left-to-right pressure gradient largely by its pressor effect on the pulmonary circulation. When inspired 02 tension (P, 02) was 70 mm Hg, all seven lambs studied showed a reversal of the pressure gradient and evidence of right-to-left shunts (11-42 %) across the ductus arteriosus.6. The implications of these findings have been discussed with reference * This study was supported in part by USPHS grant HE-06285.

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Section: Discussionmentioning

confidence: 96%

The effects of hypoxia in the new‐born lamb before and after denervation of the carotid chemoreceptors*

Purves¹

1966

The Journal of Physiology

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“…The major factor actively stimulating contraction is probably the effect of increasing oxygen tension. After birth, the ductus is exposed to arterial blood because of the reversal of the direction of flow [14], and arterial oxygen tension rises rapidly after delivery [17].There is a large body of evidence obtained from studies on the lamb ductus arteriosus which supports the cytochrome P 450 /endothelin (ET)-1 hypothesis [8]. In this hypothesis, cytochrome P 450 is the oxygen sensor, and its activation promotes contraction.…”

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Effects of TAK-044, a Nonselective Endothelin Receptor Antagonist, on the Spontaneous and Indomethacin- or Methylene Blue-Induced Constriction of the Ductus Arteriosus in Rats.

Takizawa

Horikoshi

Shen

et al. 2000

The Journal of Veterinary Medical Science

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ABSTRACT. We studied the effects of TAK-044, a nonselective endothelin (ET) receptor antagonist, on the indomethacin-or methylene blue-induced constriction of the ductus arteriosus (DA) in rats and compared them with the effects on spontaneous DA constriction. Injection of TAK-044 into 21-day-old fetuses in utero was performed through the uterine wall of laparotomized mother rats under light ether anesthesia. The fetuses were autopsied 3 hr after treatment with TAK-044 (10 mg/kg) in utero and simultaneous administration to the laparotomized mother rats of indomethacin (3 mg/kg, po) or methylene blue (100 mg/kg, ip). In the second experiment, pregnant rats were decapitated on day 21 of gestation to obtain newborn rats by cesarean delivery. Newborn rats which were given TAK-044 (2, 10 mg/kg) immediately after or 1 hr before cesarean delivery were autopsied at various times after birth. In both experiments, pups were rapidly frozen in an acetone-dry ice mixture at autopsy to evaluate the DA constriction by the whole-body freezing and shaving method. TAK-044 injection into the fetus 3 hr before autopsy completely inhibited the DA constriction induced by maternal treatment with indomethacin or methylene blue. TAK-044 caused dose-dependent inhibition of the spontaneous closure of the DA after birth. The inhibitory effect was more pronounced in pups which were given TAK-044 in utero 1 hr before birth; however, the inhibitory effect was incomplete in newborn pups. These results, together with the previous finding that BQ-123, an ET A -specific receptor antagonist, inhibits the ductal constriction induced by oxygen in vitro [Coceani et al., 1992], indicate that the ET A receptor plays a significant role in the indomethacin-or methylene blue-induced DA constriction as well as in the spontaneous DA constriction after birth, and also indicate that the inhibition of ET A receptor by TAK-044 was more easily achieved in fetuses than in neonates.-KEY WORDS: ductus arteriosus, endothelin receptor, indomethacin, methylene blue, TAK-044.The ductus arteriosus (DA) connects the main pulmonary artery and the descending aorta during the fetal period, allowing blood to flow from the right ventricle to bypass the lungs. Ductal patency in utero is an active state principally maintained by the potent dilator effect of prostaglandins, particularly PGE 2 [9], and the nitric oxidecGMP system [15,30]. Closure at birth occurs because of contraction of the smooth muscle of the DA. The major factor actively stimulating contraction is probably the effect of increasing oxygen tension. After birth, the ductus is exposed to arterial blood because of the reversal of the direction of flow [14], and arterial oxygen tension rises rapidly after delivery [17].There is a large body of evidence obtained from studies on the lamb ductus arteriosus which supports the cytochrome P 450 /endothelin (ET)-1 hypothesis [8]. In this hypothesis, cytochrome P 450 is the oxygen sensor, and its activation promotes contraction. The effect of oxygen on the enzyme is propos...

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“…The isolated lungs of foetal lambs were perfused with warm maternal or foetal heparinized blood as described by Dawes, Mott & Widdicombe (1955a) and were ventilated with positive pressure by a Starling Ideal pump. The lungs were not removed from the body, but were perfused in situ from the pulmonary trunk after tying the ductus arteriosus; the venous effluent was collected from the left atrium, and the great veins were ligated in order to prevent loss of blood through the foramen ovale.…”

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The viability of premature lambs

Born¹,

Dawes²,

Mott³

1955

The Journal of Physiology

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In mature newborn lambs the pulmonary arterial blood pressure falls, and the direction of blood flow through the ductus arteriosus is reversed soon after ventilation of the lungs. This is caused by the large increase in pulmonary vascular conductance which results from expansion of the lungs; indeed this increase in pulmonary vascular conductance is one of the principal factors on which the metamorphosis of the foetal into the adult circulation depends (Born, Dawes, Mott & Widdicombe, 1955). In a previous paper (Dawes, Mott, Widdicombe & Wyatt, 1953), it was noticed that when the lungs of two young lambs (111 and 121 days gestation; full term 147 days) were ventilated with oxygen, the arterial oxygen saturation fell to very low levels on tying the umbilical cord. It was suggested that this might be related to the failure of pulmonary blood flow to increase substantially on ventilation in premature lambs. The present paper describes the effect on the arterial oxygen saturation and on the lungs of ventilating lambs delivered by caesarian section, ranging in gestation age from 89 days upwards. Many of these lambs had twin siblings; the change in the pulmonary vascular bed on ventilation was also examined by perfusion of the isolated lungs of the twins. METHODSClun-Hampshire or Suffolk ewes were delivered under Dial-urethane (5:5-diallylbarbituric acid 0-g, urethane 0-4 g/ml.) or sodium pentobarbitone anaesthesia as described previously (Dawes, Mott, Widdicombe & Wyatt, 1953). The systemic arterial blood pressure of the foetuses, of from 89 to 139 days gestation age, was measured by a condenser manometer (frequency response >150 c/s, including gauge-head and catheter) from the femoral artery. Heart rate was calculated from records of the pulse wave, displayed on an oscilloscope and photographed at intervals of 1-2 min throughout the experiment. Carotid arterial blood samples (0-5-1.0 ml.) were withdrawn into syringes for analysis of their oxygen content; they were mixed with a trace of heparin (20%) and sodium fluoride (4%), and placed in an ice-water mixture in a vacuum flask until estimated. In a few lambs the chest was opened up the midline in order to measure blood flow through the left pulmonary artery with a density flowmeter (Dawes, Mott & Vane, 1953) as described previously (Dawes, Mott, Widdicombe & Wyatt, 1953). In some other lambs the chest was opened to the left of the midline, with removal of one or more ribs in order to give access to the ductus arteriosus, whose external diameter was measured directly with a pair of calipers. Pulmonary arterial

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The patency of the ductus arteriosus in newborn lambs and its physiological consequences

Cited by 62 publications

References 10 publications

The effects of hypoxia in the new‐born lamb before and after denervation of the carotid chemoreceptors*

The effects of hypoxia in the new‐born lamb before and after denervation of the carotid chemoreceptors*

Effects of TAK-044, a Nonselective Endothelin Receptor Antagonist, on the Spontaneous and Indomethacin- or Methylene Blue-Induced Constriction of the Ductus Arteriosus in Rats.

The viability of premature lambs

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