Effect of endotoxemia on hypoxic pulmonary vasoconstriction in unanesthetized sheep

This study examined the effect of acute endotoxemia on hypoxic pulmonary vasoconstriction (HPV) in awake sheep. Thirteen sheep were chronically instrumented with Silastic catheters in the pulmonary artery, left atrium, jugular vein, and carotid artery; with a Swan-Ganz catheter in the main pulmonary artery; with a chronic lung lymph fistula; and with a tracheostomy. Base-line HPV was determined by measuring the change in pulmonary vascular resistance (PVR) while sheep breathed 12% O2 for 7 min. Concentrations of immunoreactive 6-keto-PGF1 alpha and thromboxane B2 (TXB2) were measured in lung lymph during the hypoxic challenge. Escherichia coli endotoxin (0.2-0.5 micrograms/kg) was infused intravenously. Four hours after endotoxemia, HPV was measured. In five sheep, meclofenamate was infused at 4.5 h after endotoxemia and HPV measured again. During the base-line hypoxic challenge, PVR increased by 36 +/- 9% (mean +/- SE). There was no significant change in lung lymph 6-keto-PGF1 alpha or TXB2 levels with hypoxia. Twelve of the 13 sheep showed a decrease in HPV 4 h after endotoxemia; the mean change in PVR with hypoxia was -8 +/- 5%, which was significantly (P less than 0.05) reduced compared with base-line HPV. The infusion of meclofenamate at 4.5 h after endotoxin did not restore HPV.     

Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension

Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs.     

Effects of chronic estrogen-receptor blockade on ovine perinatal pulmonary circulation

Prolonged infusions of 17beta-estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182,780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen (FI(O(2))). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However, treatment with ICI abolished the vasodilator response to ventilation with low FI(O(2)) [change in PVR -30 +/- 6% (CTRL) vs. +10 +/- 13%, (ICI), P < 0.05] without reducing the vasodilator response to ventilation with high FI(O(2)) [change in PVR, -73 +/- 3% (CTRL) vs. -77 +/- 4%, (ICI); P = not significant]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% (P < 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation.     

Developmental changes in synthesis of and responsiveness to prostaglandins I2 and E2 in hypoxic lamb lungs

Previous studies have shown that the attenuated hypoxic pulmonary vasoconstriction (HPV) of young newborn lamb lungs was enhanced by cyclooxygenase inhibition. We sought to determine whether this reflected greater synthesis of and (or) responsiveness to dilator prostaglandins (PG). Protocol 1 measured responses to graded hypoxia and perfusate concentrations of 6-keto-PGF1alpha (the stable metabolite of PGI2) and PGE2 in isolated lungs from 1-day- and 1-month-old lambs. Protocol 2 compared dose responses and segmental vascular resistances during infusion of PGI2 and PGE2 in hypoxic, cyclooxygenase-inhibited, lungs from 1- to 2-day-old and 1- to 3-month-old lambs. Lungs of 1-day-old lambs with attenuated responses to 4% O2 had significantly higher perfusate concentrations of 6-keto-PGF1alpha and PGE2, but responses to both PGE2 and the more potent vasodilator, PGI2 did not differ with age. These data support the hypothesis that attenuated HPV in young newborn lamb lungs is due to increased synthesis of dilator PG, particularly PGI2.     

Rho kinase activation maintains high pulmonary vascular resistance in the ovine fetal lung

Mechanisms that maintain high pulmonary vascular resistance (PVR) in the fetal lung are poorly understood. Activation of the Rho kinase signal transduction pathway, which promotes actin-myosin interaction in vascular smooth muscle cells, is increased in the pulmonary circulation of adult animals with experimental pulmonary hypertension. However, the role of Rho kinase has not been studied in the fetal lung. We hypothesized that activation of Rho kinase contributes to elevated PVR in the fetus. To address this hypothesis, we studied the pulmonary hemodynamic effects of brief (10 min) intrapulmonary infusions of two specific Rho kinase inhibitors, Y-27632 (15-500 microg) and HA-1077 (500 microg), in chronically prepared late-gestation fetal lambs (n = 9). Y-27632 caused potent, dose-dependent pulmonary vasodilation, lowering PVR from 0.67 +/- 0.18 to 0.16 +/- 0.02 mmHg x ml(-1) x min(-1) (P < 0.01) at the highest dose tested without lowering systemic arterial pressure. Despite brief infusions, Y-27632-induced pulmonary vasodilation was sustained for 50 min. HA-1077 caused a similar fall in PVR, from 0.39 +/- 0.03 to 0.19 +/- 0.03 (P < 0.05). To study nitric oxide (NO)-Rho kinase interactions in the fetal lung, we tested the effect of Rho kinase inhibition on pulmonary vasoconstriction caused by inhibition of endogenous NO production with nitro-L-arginine (L-NA; 15-30 mg), a selective NO synthase antagonist. L-NA increased PVR by 127 +/- 73% above baseline under control conditions, but this vasoconstrictor response was completely prevented by treatment with Y-27632 (P < 0.05). We conclude that the Rho kinase signal transduction pathway maintains high PVR in the normal fetal lung and that activation of the Rho kinase pathway mediates pulmonary vasoconstriction after NO synthase inhibition. We speculate that Rho kinase plays an essential role in the normal fetal pulmonary circulation and that Rho kinase inhibitors may provide novel therapy for neonatal pulmonary hypertension.     

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Mechanisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of N-methylsufonyl-12,12-dibromododec-11-enamide (DDMS), a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 +/- 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 +/- 12% vs. 2 +/- 4% change in PVR, L-NA vs. L-NA + DDMS, P < 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension.     

Influence of bronchial arterial PO2 on pulmonary vascular resistance

In six anesthetized and mechanically ventilated adult sheep, the bronchial artery was perfused with blood from an oxygenator-pump circuit. When the lungs were ventilated with 100% O2 and the bronchial O2 tension (PbrO2) was approximately 600 Torr, the mean of the pulmonary vascular resistances (PVR) measured at the beginning (3.32 +/- 0.29 units) and end (3.17 +/- 0.13 units) of the experiment was 3.24 +/- 0.20 units. When the PbrO2 was changed to 58 +/- 1 Torr, the PVR (2.99 +/- 0.14 units) did not change significantly. However, when the lungs were ventilated with air as PbrO2 was decreased to 91 +/- 4, 77 +/- 3, 56 +/- 2, and 42 +/- 1 Torr, the PVR increased to 3.67 +/- 0.18, 4.03 +/- 0.16, 4.79 +/- 0.19, and 4.71 +/- 0.35 units, respectively. However, when the PbrO2 was decreased further to 26 +/- 1 and 13 +/- 1 Torr, the PVR decreased to 3.77 +/- 0.28 and 3.91 +/- 0.30 units, respectively. In contrast, the bronchial vascular resistance decreased monotonically as PbrO2 decreased. The bronchial circulation supplies vasa vasorum to the walls of all but the smallest pulmonary arteries, and it is therefore suggested that the PO2 of the bronchial circulation is responsible for the bimodal response of the pulmonary vasculature, with stimulation of hypoxic pulmonary vasoconstriction at moderate hypoxemia and of hypoxic pulmonary vasodilation at profound hypoxemia. The physiological and pathophysiological significance of the influence of systemic PO2 on pulmonary vascular tone is discussed.     

Pulmonary vascular dysfunction in preterm lambs with chronic lung disease

Chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance (PVR) and leads to structural abnormalities of the lung circulation in newborn sheep. Compared with normal lambs born at term, chronically ventilated preterm lambs have increased pulmonary arterial smooth muscle and elastin, fewer lung microvessels, and reduced abundance of endothelial nitric oxide synthase. These abnormalities may contribute to impaired respiratory gas exchange that often exists in infants with chronic lung disease (CLD). Nitric oxide inhalation (iNO) reduces PVR in human infants and lambs with persistent pulmonary hypertension. We wondered whether iNO might have a similar effect in lambs with CLD. We therefore studied the effect of iNO on PVR in lambs that were delivered prematurely at approximately 125 days of gestation (term = 147 days) and mechanically ventilated for 3 wk. All of the lambs had chronically implanted catheters for measurement of pulmonary vascular pressures and blood flow. During week 2 of mechanical ventilation, iNO at 15 parts/million for 1 h decreased PVR by approximately 20% in 12 lambs with evolving CLD. When the same study was repeated in eight lambs at the end of week 3, iNO had no significant effect on PVR. To see whether this loss of iNO effect on PVR might reflect dysfunction of lung vascular smooth muscle, we infused 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP; 150 microg. kg(-1). min(-1) iv) for 15-30 min in four of these lambs at the end of week 3. PVR consistently decreased by 30-35%. Lung immunohistochemistry and immunoblot analysis of excised pulmonary arteries from lambs with CLD, compared with control term lambs, showed decreased soluble guanylate cyclase (sGC). These results suggest that loss of pulmonary vascular responsiveness to iNO in preterm lambs with CLD results from impaired signaling, possibly related to deficient or defective activation of sGC, the intermediary enzyme through which iNO induces increased vascular smooth muscle cell cGMP and resultant vasodilation.     

Respiratory effects of a patent ductus arteriosus in premature newborn lambs

We examined the respiratory effects of a patent ductus arteriosus in 29 premature lambs (131-135 days gestational age) after infiltrating the ductal wall with formaldehyde solution (Formalin) and placing a snare around the ductus to regulate its patency. The lambs were given sheep surfactant, paralyzed, and mechanically ventilated at birth. We first compared 8 lambs with open ductus and 13 lambs with closed ductus during the 12 h after birth. Although lambs with open ductus had greater pulmonary blood flow (301 +/- 36 vs. 188 +/- 11 ml.min-1.kg-1, mean +/- SE, at 12 h of age) and mean pulmonary arterial (44 +/- 3 vs. 33 +/- 2 mmHg) and left ventricular end-diastolic (6 +/- 0.6 vs 4 +/- 0.7 mmHg) pressures, we found no differences in dynamic respiratory compliance (Cdyn = 0.55 +/- 0.07 vs. 0.55 +/- 0.03 ml.cmH2O-1.kg-1), midtidal volume resistance (62 +/- 5 X 10(-3) vs. 62 +/- 7 X 10(-3) cmH2O.ml-1.s), or functional residual capacity (FRC = 27 +/- 3 vs. 26 +/- 2 ml.kg-1). Alveolar-arterial PO2 difference was lower in the lambs with open ductus (238 +/- 65 vs. 362 +/- 37 Torr). Next, we challenged eight lambs with two separate saline infusions (50 ml.kg-1 over 3 min), each given with the ductus alternately closed or open. When the ductus was closed, FRC was unchanged, but Cdyn increased by 18% immediately after the infusion. When the ductus was open, FRC decreased by 16% and Cdyn decreased by 12%. We conclude that the premature lamb is surprisingly resistant to changes in respiratory function from ductal patency during the immediate neonatal period.     

Hypoxic pulmonary vasoconstriction does not affect hydrostatic pulmonary edema formation

We studied the effects of regional hypoxic pulmonary vasoconstriction (HPV) on lobar flow diversion in the presence of hydrostatic pulmonary edema. Ten anesthetized dogs with the left lower lobe (LLL) suspended in a net for continuous weighing were ventilated with a bronchial divider so the LLL could be ventilated with either 100% O2 or a hypoxic gas mixture (90% N2-5% CO2-5% O2). A balloon was inflated in the left atrium until hydrostatic pulmonary edema occurred, as evidenced by a continuous increase in LLL weight. Left lower lobe flow (QLLL) was measured by electromagnetic flow meter and cardiac output (QT) by thermal dilution. At a left atrial pressure of 30 +/- 5 mmHg, ventilation of the LLL with the hypoxic gas mixture caused QLLL/QT to decrease from 17 +/- 4 to 11 +/- 3% (P less than 0.05), pulmonary arterial pressure to increase from 35 +/- 5 to 37 +/- 6 mmHg (P less than 0.05), and no significant change in rate of LLL weight gain. Gravimetric confirmation of our results was provided by experiments in four animals where the LLL was ventilated with an hypoxic gas mixture for 2 h while the right lung was ventilated with 100% O2. In these animals there was no difference in bloodless lung water between the LLL and right lower lobe. We conclude that in the presence of left atrial pressures high enough to cause hydrostatic pulmonary edema, HPV causes significant flow diversion from an hypoxic lobe but the decrease in flow does not affect edema formation.     

Hypoxic bronchodilation.

Recent advances in computed tomographic imaging provide a unique method to serially and directly visualize acute physiological response in the lung. To directly investigate the airway response to hypoxia, high-resolution computed tomographic scans of the lungs of eight intact anesthetized minipigs were serially repeated before, during, and after ventilation with a hypoxic gas mixture (inspired fraction of O2 congruent to 0.07). This approach demonstrated an acute reversible 56 +/- 8% (SE) dilation in large airways (greater than 2 mm diam) and a 90 +/- 15% dilation in small airways (less than 1.99 mm diam) with decreased inspired O2 tension. Of the airways studied, 70 of 76 dilated. Hypoxic bronchodilation may interact with hypoxic pulmonary vasoconstriction in the fundamental physiological process of ventilation-perfusion matching in the lung.     

Umbilical cord compression produces pulmonary hypertension in newborn lambs: a model to study the pathophysiology of persistent pulmonary hypertension in the newborn

We investigated the effects of chronic intrauterine hypoxaemia produced by prolonged partial umbilical cord compression on the circulation shortly after birth in lambs. Vascular catheters were inserted in 10 fetal sheep at 120 to 130 days gestation to measure descending aortic blood gases, arterial pH, and arterial O2 saturation. An inflatable silicone rubber balloon cuff was also placed around the umbilical cord. After recovery and the return of descending aortic blood gases to the normal range, the balloon was gradually inflated, decreasing the PaO2 from 21.2 +/- 3.6 to 17.5 +/- 1.3 mm Hg and the arterial O2 saturation from 57.1 +/- 9.2% to 37.2% +/- 5.2. After 14.3 +/- 3.7 days of partial umbilical cord compression, the lambs were delivered by Caesarean section, instrumented to measure systemic and pulmonary arterial, right atrial and pulmonary arterial wedge pressures, pulmonary and systemic blood flows, and mechanically ventilated. Five normal lambs were also studied. From 60 to 120 min after delivery, when compared to normal lambs, the umbilical compression lambs had an increased pulmonary arterial pressure (P less than 0.05) pulmonary vascular resistance (P less than 0.05), and right atrial pressure (P less than 0.05) with similar arterial blood gases. In both groups, hypoxic ventilation produced an increase in pulmonary arterial pressure (P less than 0.05) which on return to room air ventilation decreased to baseline in the normal lambs but not in the umbilical cord compression lambs (P less than 0.05). Prolonged partial umbilical cord compression produces chronic fetal hypoxaemia and pulmonary arterial hypertension after birth. This may represent a model to study the pathophysiology of persistent pulmonary hypertension syndrome.     

Pulmonary hemodynamics and vascular reactivity in asphyxiated term lambs resuscitated with 21 and 100% oxygen

An increase in oxygen tension is an important factor in decreasing pulmonary vascular resistance (PVR) at birth. Birth asphyxia results in acidosis and increased PVR. We determined the effect of resuscitation with 21 vs. 100% O(2) on pulmonary hemodynamics, pulmonary arterial (PA) reactivity, and oxidant stress in a lamb model of in utero asphyxia. Term fetal lambs were acutely asphyxiated by intrauterine umbilical cord occlusion for 10 min resulting in acidosis (pH 6.96 ± 0.05 and Pco(2) 103 ± 5 Torr), bradycardia, systemic hypotension, and increased PVR. Lambs were treated with 30 min of resuscitation with 21% or 100% O(2) (n = 6 each). Pa(O(2)) was significantly elevated with 100% O(2) resuscitation compared with 21% O(2) (430 ± 38 vs. 64 ± 8 Torr), but changes in pH and Pa(CO(2)) were similar. The 100% O(2) induced greater increase in pulmonary blood flow and decrease in PVR at 1 min of life, but subsequent values were similar to 21% O(2) group between 2 and 30 min of life. Oxygen uptake from the lung and systemic oxygen extraction was similar between the two groups. Pulmonary arteries showed increased staining for superoxide anions and increased contractility to norepinephrine following resuscitation with 100% O(2). The increased PA contractility induced by 100% O(2) was reversed by scavenging superoxide anions with superoxide dismutase and catalase. We conclude that resuscitation of asphyxiated lambs with 100% O(2) increases Pa(O(2)) but does not improve lung oxygen uptake, decrease PVR at 30 min, or increase systemic oxygen extraction ratios. Furthermore, 100% O(2) also induces oxidative stress and increases PA contractility. These findings support the new neonatal resuscitation guidelines recommending 21% O(2) for initial resuscitation of asphyxiated neonates.     

Effects of methylprednisolone on lung oxygen toxicity in awake sheep

The purpose of this study was to measure the effects of high doses of corticosteroids on the response to breathing 100% O2 in sheep. Sheep were prepared for chronic measurement of vascular pressures, cardiac output, gas exchange, and for collection of lung lymph. Tracheostomies were made for accurate delivery of gas mixtures. Eight sheep received methylprednisolone 30 mg/kg body wt every 6 h for eight doses, four for the first 48 h, and four for the final 24-48 h of 100% O2 breathing. Eight control sheep breathed 100% O2 without methylprednisolone, four sheep breathed compressed air without methylprednisolone, and two breathed compressed air and received methylprednisolone. Sheep had daily measurements of hypoxic vasoconstriction (fractional concentration of O2 in inspired gas = 0.12), gas exchange, lymph flow, and lymph and plasma protein concentration. Polymorphonuclear leukocyte (granulocyte) function in experimental and control sheep was assessed ex vivo by tests of chemotaxis, aggregation, and superoxide production. The number of granulocytes in peripheral lung was measured in biopsy tissue taken at the time of original surgery and postmortem. Methylprednisolone did not affect the time course nor magnitude of gas exchange abnormality, lymph flow and composition, loss of hypoxic vasoconstriction, lung granulocyte accumulation, nor postmortem lung water caused by 100% O2 breathing. Sheep receiving methylprednisolone had a shorter survival by several h, independent of the timing of the drug. Granulocytes from methylprednisolone-treated sheep showed normal function ex vivo by all three assays. We conclude that high doses of methylprednisolone unfavorably affect the rate and progression of lung injury in sheep breathing 100% O2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus

Maternal use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) is associated with an increased risk for persistent pulmonary hypertension of the newborn (PPHN), but little is known about 5-HT signaling in the developing lung. We hypothesize that 5-HT plays a key role in maintaining high pulmonary vascular resistance (PVR) in the fetus and that fetal exposure to SSRIs increases 5-HT activity and causes pulmonary hypertension. We studied the hemodynamic effects of 5-HT, 5-HT receptor antagonists, and SSRIs in chronically prepared fetal sheep. Brief infusions of 5-HT (3-20 μg) increased PVR in a dose-related fashion. Ketanserin, a 5-HT 2A receptor antagonist, caused pulmonary vasodilation and inhibited 5-HT-induced pulmonary vasoconstriction. In contrast, intrapulmonary infusions of GR127945 and SB206553, 5-HT 1B and 5-HT 2B receptor antagonists, respectively, had no effect on basal PVR or 5-HT-induced vasoconstriction. Pretreatment with fasudil, a Rho kinase inhibitor, blunted the effects of 5-HT infusion. Brief infusions of the SSRIs, sertraline and fluoxetine, caused potent and sustained elevations of PVR, which was sustained for over 60 min after the infusion. SSRI-induced pulmonary vasoconstriction was reversed by infusion of ketanserin and did not affect the acute vasodilator effects of acetylcholine. We conclude that 5-HT causes pulmonary vasoconstriction, contributes to maintenance of high PVR in the normal fetus through stimulation of 5-HT 2A receptors and Rho kinase activation, and mediates the hypertensive effects of SSRIs. We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation.     

Hypercapnia and response of cerebral blood flow to hypoxia in newborn lambs

Individual effects of hypoxic hypoxia and hypercapnia on the cerebral circulation are well described, but data on their combined effects are conflicting. We measured the effect of hypoxic hypoxia on cerebral blood flow (CBF) and cerebral O2 consumption during normocapnia (arterial PCO2 = 33 +/- 2 Torr) and during hypercapnia (60 +/- 2 Torr) in seven pentobarbital-anesthetized lambs. Analysis of variance showed that neither the magnitude of the hypoxic CBF response nor cerebral O2 consumption was significantly related to the level of arterial PCO2. To determine whether hypoxic cerebral vasodilation during hypercapnia was restricted by reflex sympathetic stimulation we studied an additional six hypercapnic anesthetized lambs before and after bilateral removal of the superior cervical ganglion. Sympathectomy had no effect on base-line CBF during hypercapnia or on the CBF response to hypoxic hypoxia. We conclude that the effects of hypoxic hypoxia on CBF and cerebral O2 consumption are not significantly altered by moderate hypercapnia in the anesthetized lamb. Furthermore, we found no evidence that hypercapnia results in a reflex increase in sympathetic tone that interferes with the ability of cerebral vessels to dilate during hypoxic hypoxia.     

Pulmonary venous pressure increases during alveolar hypoxia in isolated lungs of newborn pigs.

The purpose of this study was to determine whether pulmonary venous pressure increases during alveolar hypoxia in lungs of newborn pigs. We isolated and perfused with blood the lungs from seven newborn pigs, 6-7 days old. We maintained blood flow constant at 50 ml.min-1.kg-1 and continuously monitored pulmonary arterial and left atrial pressures. Using the micropuncture technique, we measured pressures in 10 to 60-microns-diam venules during inflation with normoxic (21% O2-69-74% N2-5-10% CO2) and hypoxic (90-95% N2-5-10% CO2) gas mixtures. PO2 was 142 +/- 21 Torr during normoxia and 20 +/- 4 Torr during hypoxia. During micropuncture we inflated the lungs to a constant airway pressure of 5 cmH2O and kept left atrial pressure greater than airway pressure (zone 3). During hypoxia, pulmonary arterial pressure increased by 69 +/- 24% and pressure in small venules increased by 40 +/- 23%. These results are similar to those obtained with newborn lambs and ferrets but differ from results with newborn rabbits. The site of hypoxic vasoconstriction in newborn lungs is species dependent.     

Effects of maturation and aging on collateral ventilation in sheep

We studied collateral ventilation as a function of age by measuring the resistance (Rcoll) and time constant (Tcoll) of collateral airflow in young (2-10 mo), mature (16-24 mo), and old sheep (6-13 yr). Rcoll was 0.50 +/- 0.11 cmH2O X ml-1 X min (SE) in young sheep and decreased significantly to 0.05 +/- 0.02 and 0.02 +/- 0.01 cmH2O X ml-1 X min in mature and old sheep, respectively. Tcoll was 34.4 +/- 7.9 (SE) s in young sheep and decreased to 5.7 +/- 0.9 and 10.2 +/- 3.1 s in mature and old sheep, respectively. We conclude that a marked decrease in Rcoll and Tcoll occurs between birth and maturity but changes little with further aging. In the young an increased resistance and time constant of collateral airflow may accentuate ventilation perfusion imbalance and impair the removal of secretions in disease states.     

Simultaneous measurement of O2 radicals and pulmonary vascular reactivity in rat lung

The role of endogenous radicals in the regulation of pulmonary vascular tone was evaluated by simultaneous measurement of pulmonary artery pressure and lung radical levels during exposure of isolated rat lungs to varying inspired O2 concentrations (0-95%) and angiotensin II. Lung radical levels, measured "on-line" using luminol and lucigenin-enhanced chemiluminescence, decreased in proportion to the degree of alveolar hypoxia. Radical levels fell during hypoxia before the onset of pulmonary vasoconstriction and promptly returned to basal levels with restoration of normoxic ventilation. Mild alveolar hypoxia (10% O2), which failed to decrease chemiluminescence, did not trigger pulmonary vasoconstriction. Although chemiluminescence tended to decrease more as the hypoxic response strengthened, there was not a simple correlation between the magnitude of the change in chemiluminescence induced by hypoxia and the strength of the hypoxic pressor response. Normoxic chemiluminescence was largely inhibited by superoxide dismutase but not catalase. Superoxide dismutase also increased normoxic pulmonary vascular tone and the strength of the pressor response to hypoxia and angiotensin II. Thus the predominant activated O2 species in the lung, during normoxia, was the superoxide anion or a closely related substance. Alteration of endogenous radical levels can result in changes in vascular tone. It remains uncertain whether the decrease in lung radical production during hypoxia caused pulmonary vasoconstriction or was merely associated with hypoxic ventilation.     

Relationship of leukotriene C4 and D4 to hypoxic pulmonary vasoconstriction in dogs

Leukotrienes C4 and D4 have been implicated as possible mediators of hypoxic pulmonary vasoconstriction. To test this hypothesis, the relationship between pulmonary leukotriene (LT) synthesis in response to hypoxia and alterations in pulmonary hemodynamics was evaluated in pentobarbital sodium-anesthetized, neuromuscular-blocked, male, mongrel dogs. A reduction in the fraction of inspired O2 (FIO2) in vehicle-treated animals (n = 12) from 0.21 to 0.10 was associated with increases in LTC4 and LTD4 in bronchoalveolar lavage fluid (BALF). After 30 min of continuous hypoxia, LTC4 and LTD4 increased from control values of 59.4 +/- 10.4 and 91.7 +/- 18.1 ng/lavage to 142.7 +/- 31.8 (P less than 0.05) and 156.3 +/- 25.3 (P less than 0.01) ng/lavage, respectively. Concomitantly, mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (PVR) were increased over control by 67 +/- 7 (P less than 0.001) and 62 +/- 7% (P less than 0.001), respectively. In contrast, in animals treated with diethylcarbamazine (n = 5), a leukotriene A4 synthase inhibitor, identical reductions in FIO2 were not associated with increases in LTC4 and LTD4 in BALF, although at the same time period, Ppa and PVR were increased over control by 60 +/- 13 (P less than 0.05) and 112 +/- 31% (P less than 0.05), respectively. These results, therefore, do not support the contention that leukotrienes mediate hypoxic pulmonary vasoconstriction in dogs.