Mechanisms of calcitonin gene-related peptide-induced increases of pulmonary blood flow in fetal sheep.

Fetal pulmonary blood flow is regulated by various vasoactive substances. One, calcitonin gene-related peptide (CGRP), increases pulmonary blood flow. We examined four key physiological mechanisms underlying this response using the blocker drugs CGRP receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor [N(omega)-nitro-L-arginine (L-NNA)], adenosine triphosphate-dependent potassium (K(ATP)) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin) in 17 near-term fetal sheep. Catheters were placed in the left (LPA) and main pulmonary arteries, and an ultrasonic flow transducer was placed around the LPA to measure flow continuously. CGRP was injected directly into the LPA (mean 1.02 microgram/kg) before and after blockade, and responses to CGRP were statistically compared. Before blockade, CGRP increased LPA blood flow from 23 +/- 25 to 145 +/- 77 ml/min (means +/- SD), and these increases were significantly attenuated by CGRP(8-37) (n = 6; 91% inhibition), L-NNA (n = 6; 86% inhibition), and glibenclamide (n = 6; 69% inhibition). No significant changes were found with indomethacin (n = 6; 4% inhibition). Thus, in the fetal pulmonary circulation, CGRP increases pulmonary blood flow not only through its specific receptor but also, in part, through nitric oxide release and K(ATP) channel activation.

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo.

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE(2) and 6ketoPGF(1alpha) production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 +/- 0.6 microg/ml, mean +/- standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE(2) and 6ketoPGF(1alpha). Indomethacin (0.7 +/- 0.2 microg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

Effects of nitroglycerin and indomethacin on fetal-maternal circulation and on fetal cerebral blood flow and metabolism in sheep.

OBJECTIVE: Our purpose was to evaluate the effects of maternal administration of nitroglycerin and indomethacin on maternal and fetal hemodynamics and on fetal cerebral blood flow and metabolism in sheep. STUDY DESIGN: Invasive vascular and fetal carotid flow monitoring was established in 12 gravid ewes. Isotonic sodium chloride solution, nitroglycerin, and indomethacin were infused maternally, and maternal and fetal heart rate, blood pressure, blood gas values, fetal carotid blood flow, and flow variability were measured. Fetal cerebral uptake of oxygen, glucose, and lactate were calculated. RESULTS: Nitroglycerin infusion caused a significant increase in maternal and fetal heart rate and a significant decrease in maternal and fetal mean arterial pressure at a dosage of 10 microram/kg per minute, without a change in blood gas values. Neither drug had any effect on fetal carotid blood flow, flow variability, or cerebral substrate metabolism. CONCLUSION: Maternal administration of nitroglycerin and indomethacin caused no adverse maternal or fetal circulatory changes and did not alter fetal carotid blood flow or substrate metabolism.

Control of the pulmonary circulation in the fetus and during the transitional period to air breathing.

During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.

Mechanisms of adrenomedullin-induced increase of pulmonary blood flow in fetal sheep.

Mechanisms of adrenomedullin-induced increases in fetal pulmonary blood flow were examined in 19 near-term fetal sheep using four key blocker drugs: nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine), calcitonin gene-related peptide (CGRP) receptor blocker, ATP-dependent potassium (K(ATP)) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin). Catheters were inserted into the left pulmonary artery and superior vena cava to administer drugs and into the main pulmonary and carotid arteries to measure pressures and heart rate. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. Adrenomedullin (mean 1.06 microg/kg) was injected into the left pulmonary artery before and after infusion of N(omega)-nitro-L-arginine (mean 96.5 mg/kg, n = 6), glibenclamide (mean 11.8 mg/kg, n = 6), CGRP receptor blocker (mean 312.0 microg/kg, n = 6), and indomethacin (mean 1.7 mg/kg, n = 8). Blockade was confirmed by appropriate agonist injection. The adrenomedullin-induced response in left pulmonary artery blood flow was inhibited by N(omega)-nitro-L-arginine (inhibition rate 99%) and significantly attenuated by glibenclamide (inhibition rate 44%); however, no significant changes were found with CGRP receptor blocker or indomethacin (inhibition rate 0 and 17%, respectively). The responses of the main pulmonary and carotid arterial pressures were similarly affected by those blockers. Our data suggest that in the fetal pulmonary circulation, the adrenomedullin-induced increase in pulmonary blood flow depends largely on nitric oxide release and partly on K(ATP) channel activation, and does not involve the CGRP receptor or a cyclooxygenase-mediated mechanism.

Regulation of uterine smooth muscle function during gestation.

The uterus is unique among smooth muscular organs in that, during pregnancy, it undergoes profound, largely reversible, changes orchestrated by the ovarian hormones. These changes facilitate uterine adaptation to the stretch induced by the growing fetus such that a state of myometrial contractile quiescence can be maintained. This quiescent state usually is maintained until fetal development is sufficient for extrauterine life, at which point unknown mechanisms precipitate conversion to a highly contractile state. Throughout pregnancy, signaling mechanisms for myometrial contractility are altered--first to promote quiescence and then again to promote contractions. The mechanisms responsible for these changes are only partially understood. This review attempts to summarize salient features of many of the changes in uterine contractile signaling and the current state of ongoing investigations of their mechanisms. We have also highlighted some newer information and concepts from nonuterine tissues, which we believe may provide insight into the control of uterine smooth muscle function. Some detail has been omitted, and can be found in the many excellent reviews cited. We hope that this discussion may stimulate the interests of other investigators. The diverse areas of inquiry offer hope that this decade will lead to a fuller understanding of myometrial function and the development of vastly improved approaches for the control of preterm labor.

Calcitonin gene-related peptide increases pulmonary blood flow in fetal sheep.

Calcitonin gene-related peptide (CGRP) may play a role in regulation of pulmonary vascular tone in adults. We set out to establish whether or not CGRP has any effect on the fetal pulmonary circulation. Hemodynamic effects of exogenous CGRP were studied in seven near-term fetal sheep. Single CGRP injections into left pulmonary artery (LPA), compared with acetylcholine, and five repeated CGRP injections were studied. Single CGRP injections (1.36 +/- 0.13 micrograms/kg) increased LPA blood flow (transit time ultrasound) significantly, from 26 +/- 22 to 202 +/- 86 ml/min (P < 0.05), and decreased pulmonary and aortic pressures, from 58 +/- 5 to 48 +/- 6 mmHg and from 56 +/- 3 to 46 +/- 5 mmHg, respectively (P < 0.05). LPA resistance decreased from 3.69 to 0.24 mmHg.min.ml-1 (P < 0.05). These changes were similar to those with acetylcholine. Five CGRP injections at 5-min intervals increased LPA flow significantly, in stepwise fashion, and LPA resistance decreased. Heart rate increased stepwise, without changes in pulmonary or carotid arterial pressures. Exogenous CGRP is a potent pulmonary vasodilator in fetal sheep and increases pulmonary flow. CGRP-induced increases in heart rate are not secondary to decreased systemic blood pressure but reflect a positive chronotropic effect. These findings suggest a role for endogenous CGRP in the remarkable decrease in pulmonary vascular resistance during the transition to extrauterine life.

Adrenomedullin increases pulmonary blood flow in fetal sheep.

We studied the effects of exogenously administered adrenomedullin on fetal pulmonary arterial blood flow in near-term fetal sheep. The hemodynamic effects of a single injection of adrenomedullin into the left pulmonary artery were compared with those of acetylcholine; the effects of repeated injections of adrenomedullin were also studied. In seven unanesthetized fetal sheep, catheters were inserted into the left pulmonary artery to administer drugs, and into the main pulmonary and carotid arteries to measure pressures. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. A single 5-microgram injection of adrenomedullin (1.90 +/- 0.35 micrograms/kg of fetal weight) increased pulmonary arterial blood flow significantly, from 17 +/- 10 to 120 +/- 21 mL/min (p < 0.001). Two micrograms of acetylcholine (0.74 +/- 0.14 microgram/kg of fetal weight) also increased left pulmonary arterial blood flow, from 18 +/- 16 to 113 +/- 37 mL/min, but the effect of adrenomedullin on flow was more prolonged than was that of acetylcholine. Additionally, adrenomedullin and acetylcholine similarly decreased mean pulmonary arterial pressure by 11 and 16%, respectively, but adrenomedullin did not decrease mean carotid arterial pressure to the same degree as acetylcholine (2 versus 19%, respectively). Five sequentially repeated injections of adrenomedullin, once every 5 min, increased left pulmonary arterial blood flow significantly in a stepwise manner without significantly changing heart rate or mean pulmonary and carotid arterial pressures. We conclude that exogenously administered adrenomedullin is a pulmonary vasodilator in fetal sheep and has the ability to increase pulmonary blood flow significantly; there is less effect on the systemic circulation. This finding might be important in considering the therapeutic use of this peptide in the management of persistent pulmonary hypertension in the perinatal period.

Fetal and maternal hemodynamic and metabolic effects of maternal nitroglycerin infusions in sheep.

OBJECTIVES: We previously demonstrated effective tocolysis with nitroglycerin in laboring sheep. In this study we evaluated maternal and fetal circulatory effects of nitroglycerin. STUDY DESIGN: Vascular catheters and an umbilical Doppler flow transducer were placed in eight ewes. Nitroglycerin was infused maternally over 30 minutes at 1.5, 2.5, 5.0, and 10 microg x kg maternal weight(-1) x min(-1). We recorded maternal and fetal variables before, at the end of each 30-minute infusion period, and 30 minutes later. Fetal regional flow distribution was measured with microspheres. Fetal oxygen, glucose, and lactate uptake were calculated. Data were analyzed by analysis of variance. RESULTS: There were no changes in fetal blood gas values, oxygen or substrate uptake, umbilical flow, output distribution, pressures, or heart rate. Maternal mean pressure fell and heart rate increased concomitantly. Maternal blood gases were unchanged. CONCLUSION: Nitroglycerin at tocolytic and greater doses had no adverse effects on fetal circulatory function during a 2-hour infusion.

Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group.

BACKGROUND: Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. METHODS: In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. RESULTS: Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. CONCLUSIONS: Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Endothelium-derived relaxing factor as a mediator of bradykinin-induced perinatal pulmonary vasodilatation in fetal sheep.

Studies in vivo in fetal sheep have shown that bradykinin is released following oxygenation of the lungs and is at least partly responsible for normal pulmonary vasodilatation in the transition from fetal to extrauterine life. Part of this action involves secondary release of prostaglandin I2 (PGI2). In various adult vessels, bradykinin also stimulates the release of a powerful endothelium-derived relaxing factor (EDRF). Studies in vitro were designed (using a modification of the bioassay cascade superfusion technique) to determine whether non-PGI2-related perinatal pulmonary vasodilatation is mediated by an EDRF. Superfused, precontracted, endothelium-denuded strips of fetal sheep thoracic aorta and the maternal sheep main pulmonary artery served as detectors of an EDRF released from isolated, perfused fetal sheep pulmonary arteries. Bradykinin, in the presence of indomethacin to block PGI2 synthesis, caused perfused fetal pulmonary arteries to release an EDRF, which generated a dose-dependent relaxation (24% for 1.0 microM, 16.8% for 0.1 microM, and 10% for 0.01 microM bradykinin). Thus, bradykinin can produce perinatal pulmonary vasodilatation via a mechanism involving the endothelium-dependent synthesis of an EDRF.

Magnesium sulfate therapy during asphyxia in near-term fetal lambs does not compromise the fetus but does not reduce cerebral injury.

OBJECTIVE: Our purpose was to investigate (1) the safety of fetal magnesium sulfate treatment and (2) possible beneficial effects on the brain during perinatal asphyxia. STUDY DESIGN: In 20 chronically instrumented fetal lambs (gestational age 125.8 +/- 3.5 days) four total umbilical cord occlusions for 5 minutes were repeated at 30-minute intervals. Fetuses received either saline solution (n = 11) or magnesium sulfate (n = 9) as a bolus of 300 mg intravenously 2 hours before occlusions, followed by an infusion of 100 mg/hr until 1 hour after occlusions. RESULTS: In the treated fetuses plasma magnesium levels rose from 0.85 +/- 0.20 to 2.23 +/- 0.40 mmol/ L. Occlusions induced asphyxia, associated with mortality; 4 of 11 fetuses in the control group versus 1 of 9 in the magnesium-treated group died (not significant). Fetal electroencephalographic activity decreased and cerebral impedance increased during occlusions. Maximum spike and seizure activity occurred 5 to 10 hours after asphyxia. Neuronal loss was primarily localized in the corpus striatum. Magnesium caused no alterations in blood pressure, heart rate, or cerebral and peripheral blood flow, nor did it influence electrophysiologic responses or neuronal loss. CONCLUSIONS: Administration of magnesium sulfate was safe but did not offer significant cerebral protection from asphyxia in the near-term fetal lamb.

Exogenous endothelin-1 causes renal vasodilation in the fetal lamb.

PURPOSE: Endothelin-1 is known to be a potent vasoconstrictor. We investigated the effects and mechanisms of action of endothelin-1 and its receptors in regulating renal vascular tone in the fetal lamb. MATERIALS AND METHODS: We observed the in vivo effects of endothelin-1, an endothelin-b receptor agonist (4-alanine-endothelin-1), endothelin-a receptor antagonists (BQ-610 and BQ-123), and the inhibition of prostaglandin and nitric oxide synthesis on the response of the renal circulation to endothelin-1 in a chronic preparation in third trimester fetal lambs. RESULTS: After injection of 250 ng./kg. endothelin-1 into the descending aorta proximal to the renal arteries in 8 fetal animals, renal blood flow increased (4.4 +/- 0.7 ml. per minute per kg., p < 0.001 versus vehicle), as did mean arterial blood pressure (3.0 +/- 0.3 mm. Hg,p < 0.001 versus vehicle). Calculated renal vascular resistance decreased (-1.1 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001 versus vehicle). After injection of 1,725 ng./kg. 4-alanine-endothelin-1 in 5 animals renal blood flow increased (3.8 +/- 0.4 ml. per minute per kg., p < 0.05 versus vehicle) and mean arterial blood pressure was unchanged (1.6 +/- 1.7 mm. Hg). Calculated renal vascular resistance decreased (-0.8 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.05 versus vehicle). After injection of 0.5 mg./kg. BQ-610 in 6 animals renal blood flow increased (2.3 +/- 0.7 ml. per minute per kg., p < 0.05) and mean arterial blood pressure decreased (-2.7 +/- 0.3 mm. Hg, p < 0.05 versus vehicle). Calculated renal vascular resistance decreased but this difference was not statistically significant (-0.7 +/- 0.3 mm. Hg per minute per kg./ml., p < 0.07). A dose of 1 mg./kg. BQ-123 in 2 animals decreased renal vascular resistance markedly. Infusion of a prostaglandin synthesis inhibitor (1 mg./kg. per minute meclofenamic acid) did not alter the decrease in renal vascular resistance after endothelin-1 (-0.7 +/- 0.4 mm. Hg per minute per kg./ml). In contrast, during infusion of a nitric oxide synthesis inhibitor (1.5 mg./kg. per minute N-omega-nitro-L-arginine) endothelin-1 increased renal vascular resistance (1.2 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001). CONCLUSIONS: Endothelin-1 is a vasodilator in the fetal renal circulation, which acts primarily via endothelin-b receptors. Ongoing activity of endothelin-a receptors contributes to renal vascular tone in fetal lambs. The vasodilatory effects of endothelin-1 in the fetal lamb renal circulation are mediated via the nitric oxide system and not via prostanoids.

Endothelin receptor blockade does not alter the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs with oxygen. Both mechanical and humoral factors are involved, including the release of vasoactive substances such as prostacyclin and endothelium-derived nitric oxide (EDNO). However, the exact mechanisms remain unclear. Because endothelin-1 (ET-1) produces potent pulmonary vasodilation in the fetus via EDNO release and ET-1 concentrations are increased at birth, we considered that ET-1 activity may participate in the pulmonary vasodilation that occurs with O2 ventilation. Therefore, we studied and compared the changes in pulmonary hemodynamics associated with in utero O2 ventilation with and without ET-1 receptor blockade induced by an infusion of Ro 47-0203 (Bosentan, a nonselective ET receptor antagonist), in 13 late-gestation fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by an infusion of meclofenamate, and ductus arteriosus constriction was prevented by prior formalin infiltration. The infusion of Ro 47-0203 blocked the decrease in pulmonary vascular resistance induced by injections of either ET-1 (-0.985 versus +0.012 mm Hg/mL/min/100 g of lung, p < 0.05) or 4-Ala-ET-1 (an ETb receptor agonist) (-0.717 versus -0.052 mm Hg/mL/min/100 g of lung, p < 0.05). However, ET receptor blockade did not change the increase in pulmonary blood flow or decrease in pulmonary vascular resistance associated with in utero O2 ventilation. This study suggests that endogenous ET-1 activity does not play an important role in the vasodilatory response to ventilation with O2 in utero.

Bradykinin receptor blockade does not affect oxygen-mediated pulmonary vasodilation in fetal lambs.

Both oxygenation and rhythmic stretching of the lungs are factors known to be responsible for pulmonary vasodilation at birth. Based on our previous studies, we proposed that the pulmonary vasodilation caused by oxygen could be mediated, at least in part, through bradykinin release. To test this hypothesis, we evaluated the cardiovascular responses to in utero ventilation during infusion of a B2-subtype bradykinin receptor antagonist (BKA), [N-adamantaneacetyl-D-Arg0,Hyp3,Thi5,8,D-Phe7]bradykinin, at 15-20 micrograms.kg-1.min-1 in eight near-term fetal lambs and during drug vehicle infusion in five control fetal lambs. Prostacyclin synthesis was inhibited by meclofenamate infusion (1.5 mg.kg-1.h-1). Surgical placement of vascular catheters, a flow transducer around the left pulmonary artery, and a tracheostomy tube and formalin infiltration of the ductus arteriosus to maintain its patency in the presence of meclofenamate were performed 72 h before the study. Hemodynamic variables and pulmonary blood flow were measured and pulmonary vascular resistance was calculated before and after in utero ventilation with 100% oxygen. Despite complete blockade by BKA of the pulmonary vasodilation produced by exogenous bradykinin, ventilation with oxygen significantly increased pulmonary blood flow by 676% over baseline state (157.8 +/- 66 to 1224 +/- 265 mL.min-1.100 g-1, p < 0.01) and decreased the pulmonary vascular resistance by 89% from baseline state (0.44 +/- 0.16 to 0.048 +/- 0.01 torr.mL-1.min.100 g, p < 0.01). Such responses to ventilation with oxygen were comparable to those noted in the control animals, in whom bradykinin receptors had not been blocked.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of ATP-MgCl2 in the evaluation and treatment of children with pulmonary hypertension secondary to congenital heart defects.

BACKGROUND: Pulmonary hypertension results in increased morbidity and mortality in children after surgical repair of congenital heart defects. Various vasodilators have been unsuccessful in providing preferential pulmonary vasodilation in these patients. Identification of a more preferential pulmonary vasodilator would improve the assessment, management, and outcome of these children. To determine whether ATP-MgCl2 is a preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects, ATP-MgCl2 was administered during routine cardiac catheterization, and the effects were compared with tolazoline. In addition, ATP-MgCl2 was infused intravenously during episodes of postoperative pulmonary hypertension. METHODS AND RESULTS: During cardiac catheterization in 28 children, the effect of ATP-MgCl2 on the pulmonary artery pressure (PAP) and pulmonary vascular resistance index (Rp) was compared with tolazoline. ATP-MgCl2 (0.1 mg of ATP per kilogram per minute) decreased mean PAP by 24% (P < .05) and Rp by 47% (P < .05) without changing mean systemic arterial pressure or systemic vascular resistance. These effects were comparable to those of tolazoline (1 mg/kg). ATP-MgCl2 produced no significant side effects; tolazoline caused tachycardia, nausea, and vomiting. After cardiac surgery in 7 patients, ATP-MgCl2 decreased PAP by 14% (P < .05) and systemic arterial pressure by 6% (P < .05) and eliminated pulmonary hypertensive crises in 3 of 3 patients. CONCLUSIONS: ATP-MgCl2 is a safe, effective, and preferential pulmonary vasodilator in children with pulmonary hypertension secondary to congenital heart defects. It is useful for evaluating pulmonary vasoreactivity during cardiac catheterization and for treating pulmonary hypertension after cardiac surgery.

The role of endothelin and endothelin receptor subtypes in regulation of fetal pulmonary vascular tone.

The physiologic role of endothelin-1 (ET-1) and its receptors in regulating fetal pulmonary vascular tone is unknown. We therefore investigated the role of ET-1 and its receptors in the regulation of fetal pulmonary vascular tone using BQ 123 (an ETa receptor antagonist) and 4 Ala ET-1 (an ETb receptor agonist). In six fetal sheep in utero, we found that injections of ET-1 (250 ng/kg fetal weight) into the left pulmonary artery increased left pulmonary blood flow (21.0 +/- 17.5 to 74.7 +/- 32.9 mL/kg/min, p < 0.05) and decreased left pulmonary vascular resistance (6.02 +/- 7.00 to 0.84 +/- 0.48 mm Hg/kg/min/mL, p < 0.05). BQ 123 (5 mg) increased pulmonary blood flow (24.6 +/- 28.7 to 47.7 +/- 27.4 mL/kg/min, p < 0.05) and decreased pulmonary vascular resistance (8.84 +/- 10.32 to 1.43 +/- 0.80 mm Hg/kg/min/mL, p < 0.05); 4 Ala ET-1 (1725 ng/kg) markedly increased pulmonary blood flow (8.6 +/- 6.8 to 69.4 +/- 23.1 mL/kg/min, p < 0.05) and decreased pulmonary vascular resistance (12.02 +/- 10.2 to 0.78 +/- 0.44 mm Hg/kg/min/mL, p < 0.05). The absolute increase in pulmonary blood flow produced by ET-1 was attenuated by glibenclamide (an ATP-dependent potassium channel blocker) (flow increase of 73.4 +/- 34.1 versus 49.3 +/- 16.8 mL/kg/min, p < 0.05). This study demonstrates that ETa receptor activation has a small role in maintaining basal fetal pulmonary vascular tone, and that specific ETb receptor activation produces marked pulmonary vasodilation. The increase in pulmonary flow produced by ET-1 in fetuses is partly mediated by ATP-dependent potassium channels.

Fetal lamb pulmonary hypoplasia: pulmonary vascular and myocardial abnormalities.

Neonatal pulmonary hypoplasia resulting from a congenital diaphragmatic hernia (CDH) produces hemodynamic changes and morphologic abnormalities of the pulmonary vasculature. To characterize the myocardial and pulmonary vascular status of the fetus with pulmonary hypoplasia, we studied four chronically instrumented, near-term fetal lambs with pulmonary hypoplasia, induced by producing a diaphragmatic hernia. We found an elevation in the pulmonary arterial pressure (control, 43.8 +/- 5.9 mmHg; CDH, 58.8 +/- 9.1 mmHg; p < 0.05), an elevation in the systemic arterial pressure (control, 43.8 +/- 0.48 mmHg; CDH, 58.6 +/- 6.7 mmHg; p < 0.05), and an elevation in the pulmonary vascular resistance (control, 0.47 +/- 0.11; CDH, 3.87 +/- 1.9; p < 0.05). In addition, though the total pulmonary blood flow was reduced (control, 83.5 +/- 32.9 mL/min; CDH, 22.2 +/- 17.6 mL/min; p < 0.05), the blood flow reduction was proportional to the reduction in the lung mass (control, 79.8 +/- 28.1 [in flow per 100-g lung weight]; CDH, 85.4 +/- 71.7). The increase in the pulmonary vascular resistance in relation to the unit lung mass (control, 0.55 +/- 0.33; CDH, 0.99 +/- 0.5) was not as pronounced as its increase in relation to the total pulmonary blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs. We studied the responses to N omega-nitro-L-arginine, a competitive inhibitor of EDRF synthesis, in nine near-term fetal lambs and to drug vehicle in six of these lambs and the subsequent responses to in utero ventilation with 95% O2 in these fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by meclofenamate. N omega-nitro-L-arginine increased pulmonary and systemic arterial pressures by 28% (P < 0.05) and 31% (P < 0.05), respectively, and decreased pulmonary blood flow by 83% (P < 0.05). In the controls, ventilation with 95% O2 increased pulmonary blood flow by 1,050% (P = 0.05) without changing pressures, thereby decreasing pulmonary vascular resistance by 88% (P = 0.05). During N omega-nitro-L-arginine infusion, ventilation with 95% O2 increased pulmonary blood flow by 162% (P = 0.05) and decreased pulmonary vascular resistance by 74% (P = 0.05). This suggests that EDRF may play an important role in modulating resting pulmonary vascular tone in fetal lambs and in the vasodilatory response to ventilation with O2 in utero.