Indomethacin prevents ventilation-induced decreases in pulmonary vascular resistance of the middle region in fetal lambs

Previously, we report that the major site of pulmonary vascular resistance in fetal lambs occurred in the middle region defined by vascular occlusion, and that this region exhibited the greatest decrease upon ventilation with O2. To assess the relative individual contributions of ventilation and oxygenation to this decrease, we determined the distribution of pressures across the pulmonary circulation in isolated perfused lungs from 20 fetal lambs (131 - 137 d gestation) by inflow and outflow vascular occlusions. A membrane oxygenator was included in the extracorporeal circuit to control the PO2 at 4 kPa (30 torr) in the unventilated fetal lungs. Half of the fetal lungs were ventilated first without changing the initial gas tensions, and the others were oxygenated first by changing the initial gas tension to a hyperoxic mixture [PO2 = 26.6 kPa (200 torr)] without ventilation. Finally, both groups of lungs were ventilated and oxygenated. In addition, indomethacin was added to the perfusate (0.112 mM, or 40 micrograms/mL) in half of the preparations in each group to determine the effect of prostaglandins on the distribution of pressures during these conditions. The decrease in the total pulmonary vascular resistance with ventilation and/or oxygenation was primarily due to changes in the middle pressure gradient (delta Pm). In fetal lungs without indomethacin, ventilation without oxygenation reduced delta Pm from 6.1 +/- 0.8 to 2.5 +/- 1.0 kPa, or 74% of the total ventilation- and oxygenation-induced decrease in delta Pm (final value = 1.2 +/- 0.6 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)     

Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs

The factors responsible for the high pulmonary vascular resistance in the fetus are not well known. Thromboxane (TX) A2 is a potent pulmonary vasoconstrictor. To determine whether TXA2 may play a role in fetal pulmonary vasoconstriction, we infused the specific TX synthetase inhibitor U63,557A into eight chronically instrumented fetal lambs (134-137 days gestational age, full term 145 days) and measured pulmonary blood flow, pulmonary and systemic arterial pressure, and heart rate. U63,557A (3 mg/kg as a bolus then 3 micrograms/kg/min for 120 min infused in the main pulmonary artery) did not change pulmonary blood flow, pulmonary mean arterial pressure, and pulmonary vascular resistance during the infusion and during 2 h following the end of the infusion. During the infusion, TXB2 arterial plasma concentrations decreased from 106.1 +/- 17.5 to 8.7 +/- 2.9 pg/ml. In three of the fetal lambs, immediately after the 2-h infusion of U63,557A, we infused the leukotriene end-organ antagonist FPL 57231 into the main pulmonary artery (1 mg/kg/min for 60 min). TXA2 synthesis inhibition did not prevent the pulmonary vasodilation induced by FPL 57231. Pulmonary blood flow increased from 64.8 +/- 24.4 to 669.5 +/- 65.6 ml/min/100 g lung tissue during the FPL 57231 infusion. We conclude that TXA2 does not play a role in the maintenance of elevated fetal pulmonary vascular tone, either directly or as a mediator of leukotriene action.     

Leukotriene inhibition prevents and reverses hypoxic pulmonary vasoconstriction in newborn lambs

The effects of the leukotriene antagonist FPL 57231 on the circulation were studied in spontaneously breathing normoxic and hypoxic newborn lambs in order to evaluate the role of leukotrienes in the perinatal control of hypoxic pulmonary vasoconstriction. Hypoxia produced a 58% increase in pulmonary arterial pressure (p less than 0.05) and a 37% increase in pulmonary vascular resistance (p less than 0.05). Hypoxic pulmonary vasoconstriction was abolished by the prior infusion of FPL 57231. Pulmonary arterial pressure increased by only 8% and pulmonary vascular resistance decreased by 10% from normoxia. The infusion of FPL 57231 during hypoxia-induced pulmonary vasoconstriction reversed the increase in pulmonary arterial pressure (p less than 0.05) and pulmonary vascular resistance (p less than 0.05). The hypoxia-induced increase in cardiac output was maintained during the infusion of FPL 57231. Leukotrienes may play a significant role in the mediation of hypoxic pulmonary vasoconstriction. Leukotriene inhibition with FPL 57231 may be useful in the management of infants with persistent pulmonary hypertension syndrome.     

The inhibition of the postnatal rise of 2,3-diphosphoglycerate in newborn lambs as a result of glucose perfusion

Due to the abrupt increase in 2,3-diphosphoglycerate (2,3-DPG) concentration in the newborn lamb, which begins soon after birth, this interval in development was considered an excellent period to test the hypothesis that glucose perfusions could inhibit 2,3-DPG synthesis. Ten newborn lambs were divided into two groups and perfused either with glucose (15 mg/kg/min) or physiologic saline (45% NaCl) for 10 days. Blood gases, electrolytes, glycemia, O2 pressure at 50% Hb saturation, and 2,3-DPG levels were compared in the two groups. Glucose levels remained significantly elevated during the first 3 days in the glucose perfused group. The O2 pressure at 50% Hb saturation increased in both groups but was significantly lower in the glucose perfused group when determined on day 5 and 8. The postnatal increase in 2,3-DPG was significantly diminished in the glucose infused lambs, which suggests that glucose perfusion has an inhibiting effect on erythrocyte 2,3-DPG synthesis.     

Renal effects of cyclooxygenase-2 inhibition in fetal lambs

We used late gestation fetal lambs to examine the effects of a selective COX-2 inhibitor (celecoxib) on fetal renal function. After a 2-hour baseline period, each fetus was exposed to either saline (control, n = 10), 'low-dose' celecoxib (plasma concentration 0.47 microg/ml, n = 4), or 'high-dose' celecoxib (1.4 microg/ml, n = 8) during a 5-hour study period. High-dose celecoxib (but not low-dose celecoxib) caused a significant decrease in urine volume, free water clearance, arterial pH, and an increase in blood lactate compared with the control group. There were no significant differences in creatinine clearance, fractional excretion of sodium and potassium, or in renal blood flow between the 3 groups. These effects are similar to those reported for the nonselective COX-1/-2 inhibitor, indomethacin. COX-2 appears to play an important role in promoting free water excretion in the fetal lamb.     

Role of ATP-dependent potassium channels in pulmonary vascular tone of fetal lambs with congenital diaphragmatic hernia

High mortality in newborn babies with congenital diaphragmatic hernia (CDH) is principally due to persistent pulmonary hypertension. ATP-dependent potassium (K(ATP)) channels might modulate pulmonary vascular tone. We have assessed the effects of Pinacidil, a K(ATP) channel opener, and glibenclamide (GLI), a K(ATP) channel blocker, in near full-term lambs with and without CDH. In vivo, pulmonary hemodynamics were assessed by means of pressure and blood flow catheters. In vitro, we used isolated pulmonary vessels and immunohistochemistry to detect the presence of K(ATP) channels in pulmonary tissue. In vivo, pinacidil (2 mg) significantly reduced pulmonary vascular resistance (PVR) in both controls and CDH animals. GLI (30 mg) significantly increased pulmonary arterial pressure (PAP) and PVR in control animals only. In vitro, pinacidil (10 microM) relaxed, precontracted arteries from lambs with and without CDH. GLI (10(-5) microM) did not raise the basal tone of vessels. We conclude that activation of K(ATP) channels could be of interest to reduce pulmonary vascular tone in fetal lambs with CDH, a condition often associated with persistent pulmonary hypertension of the newborn.     

Air trapping causes a Ca2(+)-channel-mediated increase in pulmonary vascular resistance in neonatal lambs.

Air trapping and alveolar hyperinflation may occur during mechanical ventilation in the presence of severe airway obstruction, during fast ventilator rates, and when expiratory time is compromised. Inadvertent positive end-expiratory pressure may occur with air trapping and increased mean airway pressure. The pulmonary artery pressure response to air trapping, produced during volume-regulated time-cycled ventilation, was studied in neonatal lamb lungs, isolated in situ, and perfused at a constant flow rate (50-75 ml.kg-1.min-1), both before and after Ca2(+)-channel blockade with verapamil (5 mg). The hub of the endotracheal tube was narrowed to a 1.5-mm orifice to produce fixed proximal airway obstruction. Air trapping was then produced by lengthening inspiratory time from 25 to 80%, at zero end-expiratory pressure. The magnitude of inadvertent positive end-expiratory pressure due to air trapping was estimated by end-expiratory occlusion pressure. End-expiratory occlusion pressure was 0.20 +/- 0.03 kPa (1.7 +/- 0.2 mm Hg) and 1.60 +/- 0.01 kPa (11.8 +/- 1.0 mm Hg), at 25 and 80% inspiratory times, respectively. On lengthening inspiratory time, mean pulmonary artery pressure (mPpa) increased briskly within 30 s followed by a gradual increase over the next 4 min. Verapamil blunted both the brisk and the gradual increase in mPpa on lengthening inspiratory time. Lengthening inspiratory time increased the mPpa by 2.0 +/- 0.1 kPa (14.7 +/- 0.8 mm Hg) from baseline, and verapamil reduced this increase to 1.3 +/- 0.1 kPa (10.1 +/- 0.6 mm Hg; p less than 0.05 by analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)     

Piriprost: a putative leukotriene synthesis inhibitor increases pulmonary blood flow in fetal lambs

Leukotrienes may control fetal pulmonary vascular tone since infusions of putative leukotriene receptor antagonists markedly increase pulmonary blood flow and decrease pulmonary vascular resistance in fetal lambs. This hypothesis would be strengthened if inhibition of leukotriene synthesis also produced similar hemodynamic changes. We therefore studied the effects of piriprost (U 60257), a putative leukotriene synthesis inhibitor, on thirteen fetal lambs at 137 to 140 days gestation. In preliminary studies in four fetal lambs, doses of U 60257 greater than 20 mg/kg increased pulmonary blood flow. In the nine other fetal lambs, U 60257 (31.7 +/- 4.1 mg/kg) increased pulmonary blood flow by 502% (p less than 0.05) and decreased pulmonary vascular resistance by 87% (p less than 0.05). Pulmonary arterial and left atrial pressures were unchanged. Descending aortic pressure was increased (p less than 0.05) and heart rate was decreased (p less than 0.05). The abilities of both putative leukotriene synthesis inhibitors and leukotriene receptor antagonists to similarly increase fetal pulmonary blood flow and decrease pulmonary vascular resistance are consistent with the hypothesis that leukotrienes play a role in regulating fetal pulmonary vascular tone.     

Cromolyn sodium decreases the pulmonary vascular response to alveolar hypoxia in lambs

We investigated the effect of cromolyn sodium, a mast cell stabilizing agent, on the pulmonary vascular response to alveolar hypoxia in six chronically instrumented lambs aged 9 to 11 days. Each lamb was instrumented on day 6 or 7 for measurements of systemic arterial, pulmonary arterial and left atrial pressures, and pulmonary blood flow. The animals were allowed to recover from surgery at least 3 days before they were studied. Each animal was studied twice, once with a cromolyn sodium infusion and once with a normal saline infusion (placebo). These paired experiments were separated by 24 h. Physiologic measurements were made during a 1-min predose control period, after an 8-min drug or placebo infusion, and after a 15-min period of alveolar hypoxia. Cromolyn sodium infusion alone did not affect baseline cardiovascular variables. Alveolar hypoxia following placebo infusion produced an increase in pulmonary arterial pressure and pulmonary vascular resistance; these responses were blocked in the animals given cromolyn sodium prior to induction of hypoxia. These results show that cromolyn sodium blocks the pulmonary vascular response to hypoxia and provide indirect evidence that mast cell degranulation, with subsequent release of vasoactive agents, mediates the pulmonary vascular response to hypoxia in newborn lambs.     

Low-intensity fetal lungs on MRI may suggest the diagnosis of pulmonary hypoplasia

Background: Pulmonary hypoplasia is a common cause of neonatal death. Despite the recent advances in prenatal diagnosis with US, the diagnosis of pulmonary hypoplasia is difficult. The recent application of fast MR imaging may provide additional valuable information. Objective: To evaluate pulmonary hypoplasia in the fetus with MRI. Materials and methods: The subjects comprised 23 fetuses (18–40 weeks' gestation), including major anomalies diagnosed on fetal ultrasonography (n = 20), maternal abnormality (n = 2) and one normal twin. MRI was performed with a 1.5-T magnet and half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences. MR images were interpreted by three radiologists with special attention to the intensity of the lungs. The lung-to-liver intensity ratio was calculated by means of region-of-interest (ROI) analysis. The diagnosis of pulmonary hypoplasia depended on clinical, surgical and autopsy findings. Results: All fetuses with normal pulmonary development showed high intensity in the lung except for one fetus at 24 weeks' gestational age. All fetuses with pulmonary hypoplasia showed lung of low intensity. Conclusions: Low-intensity fetal lung on MRI imaging indicates pulmonary hypoplasia after 26 weeks' gestation. Received: 10 January 2000 Revised: 28 June 2000 Accepted: 6 March 2001     

内皮素与胎肺发育及新生儿持续性肺动脉高压

内皮素 (ｅｎｄｏｔｈｅｌｉｎ ,ＥＴ)是迄今所发现的作用最强的内源性血管收缩肽 ,在心血管、肺、肾、肝、脑等脏器的疾病发生中 ,组织或血浆ＥＴ浓度有不同程度升高 ,ＥＴ在许多疾病发生中的作用日渐受到重视。肺是内皮素含量最丰富的器官 ,也是内皮素合成、代谢的主要场所。ＥＴ对气道平滑肌细胞、上皮细胞、肺血管平滑肌细胞、肺泡上皮细胞、成纤维细胞的功能活动均有调控作用。本文对ＥＴ 1在胎肺发育及新生儿持续性肺动脉高压 (ＰＰＨＮ)中的作用作一综述。1　内皮素及其受体在肺内分布　　ＥＴ由Ｙａｎａｇｉｓａｗａ在 1988年分离、…     

Influence of increased pulmonary vascular pressures on the closure of the ductus arteriosus in newborn lambs

Neonatal conditions associated with increased pulmonary artery pressure have an increased incidence of patent ductus arteriosus. We operated on 15 near term fetal lambs and placed mechanical occluders into or around both branch pulmonary arteries so that main pulmonary artery blood pressure could be controlled. The lambs were delivered and ventilated for 4 h. In seven lambs, the branch vessels were obstructed so that pulmonary artery pressure increased to equal aortic pressure; in eight lambs (control), the branch vessels were not obstructed. There were no significant differences between the two groups in circulating prostaglandin E2 or 6 keto F1 alpha concentrations, PaO2, pH, or PaCO2. Despite these similarities, ductus resistance in the lambs with elevated pulmonary pressure was significantly less than that in the control lambs. After the 4 h measurements, we studied the ductus in vitro. We have previously found that ductus arteriosus constriction produces ischemia of its muscle wall that limits its ability to dilate or constrict any further. Ductus from lambs with elevated pulmonary pressure had a significantly increased ability to respond to oxygen, prostaglandin E2, and indomethacin compared with ductus from control lambs; these findings are consistent with less ductus constriction in vivo. Thus, the high incidence of patent ductus arteriosus in neonates with elevated pulmonary vascular resistance may be due in part to the increased pulmonary vascular pressure, which opposes ductus constriction and preserves ductus responsiveness. Conversely, the normal drop in pulmonary pressure that occurs in full term infants may facilitate the closure of the ductus after delivery.     

The effect of alpha-adrenergic blockade on the pulmonary vascular response to dopamine in neonatal lambs

The effect of alpha-adrenergic blockade by phentolamine on the pulmonary vascular response to dopamine was studied in chronically prepared newborn lambs. Dopamine was administered at doses of 2.7 micrograms . kg-1 . min-1, 27 micrograms . kg-1 . min-1 and 270 micrograms . kg-1 . min-1 with and without alpha-adrenergic blockade. Dopamine infusion at 270 micrograms . kg-1 . min-1 caused a rise in the mean pulmonary artery pressure from 22 +/- 3.2 mmHg (mean +/- S.E.) at baseline to 36 +/- 4.1 mmHg (P less than 0.001). This rise was unaffected by alpha-adrenergic blockade. Dopamine infusion alone did not change pulmonary blood flow, but, in the presence of alpha-adrenergic blockade, pulmonary blood flow rose from 190 +/- 12 ml . min-1 . kg-1 at baseline to 280 +/- 13 ml . min-1 . kg-1 at the maximum dopamine infusion rate (P less than 0.001). Pulmonary vascular resistance was the same before and after alpha-adrenergic blockade and did not change from the baseline value during dopamine infusion.     

Epithelial squames in fetal lungs as an index of respiratory insufficiency

Summary In a series of 260 perinatal autopsies, 30% showed epithelial squames in fetal alveoli. No correlation could be obtained to implicate the presence of alveolar squames as a pathogenic lesion in respiratory insufficiency of the new born. From the Department of Pathology, JIPMER, Pondicherry 6.     

Adenosine triphosphate and adenosine increase the pulmonary blood flow to postnatal levels in fetal lambs.

We investigated the hypothesis that purine nucleotides may mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We studied nine fetal lambs 3 d after placement of intravascular catheters, a flow transducer around the left pulmonary artery, and an inflatable vascular occluder around the ductus arteriosus. The pressure-flow relationship of left lung during a brief occlusion of the ductus arteriosus was studied as an index of pulmonary vascular resistance. We investigated the pulmonary vascular effects of adenosine, ATP, or saline (control) in doses of 0.01-2.50 mumol/kg/min infused into the right atrial line, and measured blood adenosine and ATP levels in samples from the pulmonary artery and left atrium. We also investigated the mechanism of pulmonary vascular effects of adenosine and ATP. Adenosine and ATP caused significant decreases in pulmonary vascular resistance and increases in pulmonary blood flow in doses of 0.08-2.5 mumol/kg/min. The pulmonary blood flow increased to levels seen in postnatal lambs at doses of 1.2 and 2.5 mumol/kg/min of adenosine and ATP. The baseline blood adenosine and ATP levels in fetus were 8 and 70% of levels in postnatal lambs. ATP concentrations increased to postnatal levels and adenosine levels increased to 20% of postnatal levels at infusion rates of 1.2 and 2.5 mumol/kg/min. The pulmonary vasodilation caused by adenosine and ATP was attenuated by 8-phenyltheophylline and cibacron blue, respectively, but not by indomethacin. We conclude that adenosine and ATP are pulmonary vasodilators and increase the fetal pulmonary flow to postnatal levels in doses that increase their blood concentrations to less than or equal to postnatal levels.(ABSTRACT TRUNCATED AT 250 WORDS)