Left Pulmonary Artery Flow Research Articles

Vascular endothelial growth factor causes pulmonary vasodilation through activation of the phosphatidylinositol-3-kinase-nitric oxide pathway in the late-gestation ovine fetus.

Vascular endothelial growth factor (VEGF) causes vasodilation in adult models of peripheral vascular disease and myocardial ischemia through the acute release of nitric oxide (NO). However, the hemodynamic effects of VEGF and its effects on NO production have not been studied in the developing lung circulation. We hypothesized that VEGF causes fetal pulmonary vasodilation, and that its actions are mediated through the release of endogenous NO. We performed surgery in 16 fetal lambs (125-135 d gestation; term = 147 d), and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for local drug infusion. Pulmonary vascular resistance in the left lung was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA flow. Fetal lambs were treated with brief infusions of recombinant human VEGF (dose, 0.5-2.0 micro g) into the LPA. Recombinant human VEGF infusions acutely increased LPA flow by up to 3-fold (p < 0.02) and decreased pulmonary vascular resistance by 65% (p < 0.05) in a dose-related fashion, without affecting aortic pressure or heart rate. To determine the mechanism of VEGF-induced vasodilation, we studied the effects of nitro-L-arginine, an NO synthase inhibitor, and LY294002, a phosphatidylinositol-3-kinase inhibitor, on the response to VEGF. We found that pretreatment with either nitro-L-arginine or LY294002 completely inhibited the vasodilator response to recombinant human VEGF (p < 0.005). These findings suggest that recombinant human VEGF causes fetal pulmonary vasodilation, and that this response is likely mediated by the release of NO through activation of phosphatidylinositol-3-kinase.

Vascular Endothelial Growth Factor Causes Pulmonary Vasodilation through Activation of the Phosphatidylinositol-3-Kinase-Nitric Oxide Pathway in the Late-Gestation Ovine Fetus

Vascular endothelial growth factor (VEGF) causes vasodilation in adult models of peripheral vascular disease and myocardial ischemia through the acute release of nitric oxide (NO). However, the hemodynamic effects of VEGF and its effects on NO production have not been studied in the developing lung circulation. We hypothesized that VEGF causes fetal pulmonary vasodilation, and that its actions are mediated through the release of endogenous NO. We performed surgery in 16 fetal lambs (125–135 d gestation; term = 147 d), and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for local drug infusion. Pulmonary vascular resistance in the left lung was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA flow. Fetal lambs were treated with brief infusions of recombinant human VEGF (dose, 0.5–2.0 μg) into the LPA. Recombinant human VEGF infusions acutely increased LPA flow by up to 3-fold (p < 0.02) and decreased pulmonary vascular resistance by 65% (p < 0.05) in a dose-related fashion, without affecting aortic pressure or heart rate. To determine the mechanism of VEGF-induced vasodilation, we studied the effects of nitro-l-arginine, an NO synthase inhibitor, and LY294002, a phosphatidylinositol-3-kinase inhibitor, on the response to VEGF. We found that pretreatment with either nitro-l-arginine or LY294002 completely inhibited the vasodilator response to recombinant human VEGF (p < 0.005). These findings suggest that recombinant human VEGF causes fetal pulmonary vasodilation, and that this response is likely mediated by the release of NO through activation of phosphatidylinositol-3-kinase.

Nitric oxide decreases lung liquid production via guanosine 3',5'-cyclic monophosphate.

We studied the role of cGMP in nitric oxide (NO)-induced changes in lung liquid production (J(v)) in chronically instrumented fetal sheep. Forty-five studies were done in which J(v) was measured by a tracer dilution technique. Left pulmonary arterial flow (Q(lpa)) was measured by a Doppler flow probe. There were two series of experiments. In the first, we gave 8-bromo-cGMP, a cGMP analog, by either the pulmonary vascular or intraluminal route; in the second, we used agents to inhibit or enhance endogenous cGMP activity. When infused directly into the pulmonary circulation, 8-bromo-cGMP significantly increased Q(lpa) but had no effect on J(v). Conversely, when instilled into the lung liquid, 8-bromo-cGMP had no effect on Q(lpa) but significantly reduced J(v). Inhibition of guanylate cyclase activity with methylene blue totally blocked, whereas phosphodiesterase inhibition with Zaprinast significantly enhanced, the effect of instilled NO on J(v). Thus the reduction in lung liquid caused by NO appears to be mediated by cGMP, perhaps through a direct effect on the pulmonary epithelium.

Perfusatory recovery of the grafted lung during convalescence from acute rejection.

The aim of this study was to evaluate whether or not perfusatory recovery of the grafted lung occurs is the early stage of convalesce from acute rejection following a single lung transplantation. Eight adult mongrel dogs underwent an allotransplantation of the left lung with treatment of 10 mg/kg cyclosporine and 4 mg/kg azathioprine. Doppler flow probes were placed to the ascending aorta and the left pulmonary artery. Immunosuppressant therapy was discontinued to induce rejection after postoperative day 14. When the left pulmonary artery flow rate (l-PAFR) decreased to less than 20%, methylprednisolone (20 mg/kg) was administered for 3 days along with a resumption of cyclosporine and azathioprine. Pulmonary circulation and chest roentgenograms were evaluated every day through the rejection episode. An open lung biopsy was also performed in each dog to obtain specimens of the grafts and native lungs for histologic examination. When l-PAFR decreased to less than 20%, mild acute rejection was found in all dogs. l-PAFR increased significantly on the third day after methylprednisolone treatment. Thereafter, a histologic examination revealed minimal acute rejection in one dog and no abnormality in seven dogs. The perfusatory recovery of the grafted lung was thought to reflect the histological change in the course of convalescence.

Aerosol delivery of diethylenetriamine/nitric oxide, a nitric oxide adduct, causes selective pulmonary vasodilation in perinatal lambs

Postnatal adaptation of the pulmonary circulation is mediated partly by endothelium-derived nitric oxide (NO). Recent studies have demonstrated that inhaled NO causes selective and sustained vasodilation in infants with persistent pulmonary hypertension of the newborn. Because the short half-life of NO limits its clinical application, we hypothesized that aerosol delivery of an NO-adduct, diethylene-triamine (DETANO), can cause sustained and selective pulmonary vasodilation. To test the acute effects of DETANO, we studied the pulmonary vascular response of late-gestation fetal lambs (n = 8; age = 138 days; term = 147) to aerosolized DETANO in the presence of an endothelium-derived NO inhibitor, nitro-L-arginine. To determine whether DETANO has a sustained effect, fetal lambs were ventilated with FiO2 0.10 before and 15 minutes after they were treated with aerosolized DETANO. Fetal lambs were acutely prepared. Nitro-L-arginine (1 mg/min × 30 minutes) was infused into the left pulmonary artery before ventilation with FiO2 1.00 for 30 minutes, followed by continued ventilation with FiO2 0.10 for 10 minutes. This represented the control period. Ventilation was continued with FiO2 1.00, and aerosolized DETANO was given in doses of 0.1, 0.4, and 1.0 mg. Fifteen minutes after the last dose of DETANO was administered, animals were ventilated with FiO2 0.10. In the control period, during ventilation with FiO2 0.10, left pulmonary artery flow was 122 ± 33 mL/min and decreased to 104 ± 22 mL/min. Aerosol delivery of DETANO increased left pulmonary artery flow to 176 ± 26 mL/min (P < .05) and had no effect on aortic pressure or heart rate. After DETANO was administered, ventilation with FiO2 0.10 did not cause any change in left pulmonary artery flow. We conclude that DETANO can cause selective fetal pulmonary vasodilation. Aerosol delivery of DETANO may increase the clinical applications of NO.

Does ductal occlusion with the Gianturco coil cause left pulmonary artery and/or descending aorta obstruction?

Thirty-two patients (median age 4.5 years) underwent transcatheter Gianturco coil occlusion of a patent ductus arteriosus. Transthoracic echocardiography was performed the day after coil placement and at intermediate follow-up (median 8.6 months). Echocardiographic results were compared with angiographic and hemodynamic data obtained during catheterization. Two-dimensional (2D) echocardiography performed the day after ductal occlusion displayed evidence of coil protrusion into the left pulmonary artery in 28 of 31 patients (90%) and into the descending aorta in 17 of 29 (59%). However, pulsed Doppler analysis demonstrated normal left pulmonary arterial flow velocities in 28 of 29 patients (97%) and normal descending aortic flow velocities in 26 of 27 (96%). Pulse Doppler results were corroborated by angiographic and hemodynamic catheterization data, which showed no evidence of adjacent vessel obstruction. Peak Doppler velocities among patients with and without 2D echocardiographic left pulmonary artery or descending aorta coil impingement did not differ significantly. The discrepancy between 2D and pulse Doppler findings did not change significantly at intermediate follow-up. Thus, transcatheter occlusion of the patent ductus arteriosus with properly implanted Gianturco coils does not cause significant obstruction to flow in the left pulmonary artery or descending aorta despite frequently misleading 2D echocardiographic images of coil impingement on these vessels.

K+-channel blockade inhibits shear stress-induced pulmonary vasodilation in the ovine fetus.

To determine whether K+-channel activation mediates shear stress-induced pulmonary vasodilation in the fetus, we studied the hemodynamic effects of K+-channel blockers on basal pulmonary vascular resistance and on the pulmonary vascular response to partial compression of the ductus arteriosus (DA) in chronically prepared late-gestation fetal lambs (128-132 days gestation). Study drugs included tetraethylammonium (TEA; Ca2+-dependent K+-channel blocker), glibenclamide (Glib; ATP-dependent K+-channel blocker), charybdotoxin (CTX; preferential high-conductance Ca2+-dependent K+-channel blocker), apamin (Apa; low-conductance Ca2+-dependent K+-channel blocker), and 4-aminopyridine (4-AP; voltage-dependent K+-channel blocker). Catheters were inserted in the left pulmonary artery (LPA) for selective drug infusion and in the main pulmonary artery, aorta, and left atrium to measure pressure. An inflatable vascular occluder was placed around the DA. LPA flow was measured with an ultrasonic flow transducer. Animals were treated with saline, high- or low-dose TEA, Glib, Apa, CTX, CTX plus Apa, or 4-AP injected into the LPA. DA compression caused a time-related decrease in pulmonary vascular resistance in the control, Glib, Apa, CTX, CTX plus Apa, and low-dose TEA groups but not in the high-dose TEA and 4-AP groups. These data suggest that pharmacological blockade of Ca2+- and voltage-dependent K+-channel activity but not of low-conductance Ca2+- and ATP-dependent K+-channel activity attenuates shear stress-induced fetal pulmonary vasodilation.

Pulmonary and caval flow dynamics after total cavopulmonary connection

ObjectiveTo assess flow dynamics after total cavopulmonary connection (TCPC).DesignCross-sectional study.SettingAarhus University Hospital.PatientsSeven patients (mean age 9 (4–18) years) who had previously undergone a lateral tunnel TCPC mean 2 (0.3–5) years...

Pulmonary circulatory parameters as indices for the early detection of acute rejection after single lung transplantation.

We investigated the relationship between the changes in the pulmonary blood flow and histology during acute rejection following single lung transplantation. In single lung transplantation using adult mongrel dogs, immunosuppression with cyclosporine and azathioprine was discontinued after postoperative day 14 to induce rejection. Doppler flow probes were placed adjacent to the ascending aorta and the left pulmonary artery to measure the blood flow on a daily basis. In addition, chest roentgenograms were also examined daily. The pulmonary pressure was measured using a Swan-Ganz catheter prior to and following the induction of rejection. Open lung biopsies were performed when the left pulmonary artery flow decreased to half of the prerejection value. The pulmonary artery flow decreased to 14.3% of the aortic flow 5 days after the discontinuation of immunosuppression. The graft pulmonary vascular resistance increased significantly compared to the prerejection values (P < 0.001). This was not accompanied by any abnormalities on chest roentgenography. The histology was consistent, with marked perivascular lymphocytic infiltration with little alveolar or interstitial changes. During rejection, the increased pulmonary vascular resistance in the graft was probably the result of perivascular inflammatory cell infiltration, which was seen prior to changes on chest roentgenography. Changes in the left pulmonary artery flow and histology thus appear to be closely correlated in the early stages of acute rejection.

Doppler echocardiographic assessment of pulmonary blood flow in healthy newborns.

The aim of this study was to determine interobserver variation in Doppler assessment of mean left pulmonary arterial flow velocity, and its normal values during the first 24h of life. The interobserver variation was determined by a Bland and Altman analysis of the values of mean velocity measured in 21 newborns by 2 observers. Then, normal values of mean velocity were measured in 15 newborns at 5, 10 and 15 min of life in the delivery room, and in 14 other newborns at 1, 2, 6, 12 and 24h of life in the nursery unit. The interobserver variation was found to be acceptable. Mean velocity had a few variations within the first 24 h, but remained consistently above 20 cm s(-1). In conclusion, mean velocity values below 20 cm(-1) suggest low pulmonary blood flow.

Complement-mediated pulmonary xenograft injury: studies in swine-to-primate orthotopic single lung transplant models.

The pathogenesis of acute pulmonary xenograft injury has not yet been determined. The present study evaluates the role of complement in mediating pulmonary xenograft dysfunction by using cobra venom factor (CVF) to deplete recipient complement and transgenic swine, which express human regulators of complement activation (human decay-accelerating factor [hDAF] and hCD59). Fifteen orthotopic lung transplants were performed as follows: group I, swine-to-swine (n=5); group II, unmodified swine-to-baboon (n=3); group III, unmodified swine-to-(CVF treated) baboon (n=3); and group IV, hCD59/hDAF swine-to-baboon (n=4). Left pulmonary artery flow and pulmonary vascular resistance were measured at 30-min intervals. Serial lung biopsies were examined by light microscopy and immunofluorescence. The activation of complement was quantified by measurement of baboon plasma CH50 and C4 functional activity. Group II xenotransplants ceased functioning within 30 min of reperfusion. Histopathologic ab normalities included erythrocyte/platelet aggregates and hemorrhagic pulmonary edema. Groups I and IV showed excellent function throughout. hDAF/hCD59 lungs (group IV) showed trace venular fibrin plugs and moderate loss of alveolar architecture. Pretreatment with CVF (group III) was ineffective in preventing xenograft injury. These results characterize the fundamental features of discordant pulmonary xenotransplantation. Correction of the known defects in the regulation of heterologous complement activation was partially effective in preventing pulmonary xenograft dysfunction, suggesting that complement mediates, in part, some of the features of acute lung injury after discordant lung xenotransplantation.

Doppler echocardiographic assessment of pulmonary blood flow in healthy newborns

The aim of this study was to determine interobserver variation in Doppler assessment of mean left pulmonary arterial flow velocity, and its normal values during the first 24 h of life. The interobserver variation was determined by a Bland and Altman analysis of the values of mean velocity measured in 21 newborns by 2 observers. Then, normal values of mean velocity were measured in 15 newborns at 5,10 and 15 min of life in the delivery room, and in 14 other newborns at 1, 2, 6, 12 and 24 h of life in the nursery unit. The interobserver variation was found to be acceptable. Mean velocity had a few variations within the first 24 h, but remained consistently above 20 cm s‐1. In conclusion, mean velocity values below 20 cm‐1 suggest low pulmonary blood flow.

Nitric oxide decreases lung liquid production in fetal lambs

To examine the effect of nitric oxide on fetal lung liquid production, I measured lung liquid production in fetal sheep at 130 +/- 5 days gestation (range 122-137 days) before and after intrapulmonary instillation of nitric oxide. Thirty-one studies were done in which net lung luminal liquid production (JV) was measured by plotting the change in lung luminal liquid concentration of radiolabeled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. To see whether changes in JV might be associated with changes in pulmonary hemodynamics, pulmonary and systemic pressures were measured and left pulmonary arterial flow was measured by an ultrasonic Doppler flow probe. Variables were measured during a 1- to 2-h control period and for 4 h after a small bolus of isotonic saline saturated with nitric oxide gas (10 or 100%) was instilled into the lung liquid. Control (saline) instillations (n = 6) caused no change in any variable over 6 h. Nitric oxide instillation significantly decreased JV and increased pulmonary blood flow; these effects were sustained for 1-2 h. There was also a significant but transient decrease in pulmonary arterial pressure. Thus intrapulmonary nitric oxide causes a significant decrease in lung liquid and is associated with a decrease in pulmonary vascular resistance. In a separate series of experiments either amiloride or benzamil, which blocks Na+ transport, was mixed into the lung liquid before nitric oxide instillation; still, there was a similar reduction in lung liquid production. Thus the reduction in lung liquid secretion caused by nitric oxide does not appear to depend on apical Na+ efflux.

Purine nucleotides contribute to pulmonary vasodilation caused by birth-related stimuli in the ovine fetus.

We investigated the hypothesis that the purine nucleotides ATP and adenosine mediate the pulmonary vasodilation that occurs at birth in fetal lambs. We instrumented 44 fetal lambs to measure left pulmonary arterial pressure and flow. In control studies, we investigated the effects of sequential ventilation with 10, 50, and 100% O2 on fetal pulmonary arterial pressure and flow and pulmonary vascular resistance (PVR). We also measured the blood and plasma ATP levels in the pulmonary artery and left atrium in the control studies. In three separate groups of studies, we investigated the effects of 8-phenyltheophylline, an adenosine-receptor antagonist, and cibacron blue, an inhibitor of ATP-sensitive P2y receptors, given alone or in combination, on the response of PVR to sequential ventilation. Fetal arterial PO2 increased during ventilation with 50 and 100% O2 but not with 10% O2. Ventilation with 10% O2 caused a 4-fold increase in pulmonary blood flow and a 10-fold decrease in PVR. Ventilation with 50 and 100% O2 caused a 7-fold increase in pulmonary blood flow and a 20-fold decrease in PVR. Blood and plasma ATP levels in the pulmonary artery and blood ATP levels in the left atrium increased significantly during ventilation with 50 and 100% O2 but not with 10% O2. Pretreatment of animals with 8-phenyltheophylline attenuated the increase in pulmonary flow and decrease in PVR caused by ventilation at all fractions of inspired O2 (FIO2 levels). Pretreatment of animals with cibacron blue attenuated pulmonary vasodilation at 50 and 100% FIO2. Combined treatment with 8-phenyltheophylline and cibacron blue caused complete inhibition of the decrease in PVR in response to ventilation at the three FIO2 levels. Incubation of fetal red blood cells in vitro with 100% O2 caused an increase in ATP production. An increase in arterial PO2 in the fetus causes an increase in blood ATP levels, and an inhibition of ATP receptors attenuates the O2-induced decrease in PVR. Adenosine-receptor inhibition attenuates both ventilation- and O2-induced changes in PVR. Increased synthesis and release of ATP plays a major role in causing pulmonary vasodilation in response to birth-related stimuli in the ovine fetus.

INTRAUTERINE TREATMENT WITH ESTRADIOL IMPROVES HEMODYNAMICS AND VASCULAR REMODELING IN AN OVINE MODEL OF PULMONARY HYPERTENSION. † 1567

Decreased endothelial nitric oxide synthase (eNOS) may contribute to the high pulmonary vascular resistance (PVR) which characterizes persistent pulmonary hypertension of the newborn (PPHN). In experimental PPHN produced by ductus arteriosus (DA) ligation in fetal lambs, eNOS mRNA, protein, and activity are reduced. Because E2 upregulates eNOS in several experimental settings, we hypothesized that estradiol treatment would attenuate the hemodynamic and histologic changes of pulmonary hypertension (PH), and that this effect may be mediated by upregulation of eNOS. We studied the effects of chronic E2 treatment of late gestation (126-128 d; term=147 d) fetal lambs. Immediately following DA ligation and placement of catheters in the main pulmonary artery (MPA) and aorta, fetal lambs were treated with daily infusion of E2 (10 mcg; n=6) or saline (ctrl; n=5) in the MPA. Eight days after the initial surgery, a left pulmonary artery (LPA) flow transducer was placed and lambs were then delivered and mechanically ventilated with FiO2=1.0. Mean pulmonary artery pressure inutero was not different between groups(73±7 vs. 79±3 mm Hg, day 8; E2 vs. ctrl). At delivery, E2 animals had lower PVR, better oxygenation, and higher LPA flow(table; *=p<0.05, E2 vs. ctrl).

Endothelin A Receptor Blockade Decreases Pulmonary Vascular Resistance in Severe Experimental Hyaline Membrane Disease † 112

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide which modulates basal pulmonary vascular resistance (PVR) in the normal ovine fetus and contributes to high PVR after chronic intrauterine pulmonary hypertension. Pulmonary hypertension complicates the course of the premature lamb with severe hyaline membrane disease (HMD); however, whether ET-1 plays a role in the pathophysiology of HMD is unknown. To test the hypothesis that ET-1 activity contributes to high PVR in the premature fetal lung with severe HMD, we studied the hemodynamic effects of a selective ET A receptor antagonist, BQ 123, in 7 fetal lambs (gestational age 125 days; 147 days = term). We placed catheters in the main pulmonary artery (PAP), aorta (AoP), and left atrium(LAP) to measure pressure and an ultrasonic flow transducer on the left pulmonary artery (LPA) to measure blood flow. After baseline measurements, animals were intubated, treated with surfactant (Infasurf), and mechanically ventilated (FiO2, 1.00). Animals were treated with either BQ 123 (1 mg/hour, n= 4) or saline (control; n = 3) in the MPA. One animal in the control group died at 4 hours. In comparison with controls, BQ 123 treated animals had lower PVR and improved LPA flow at 8 hours. (* = p<0.05 between groups)Table We conclude that selective ET A receptor blockade lowers PVR in experimental HMD. We speculate that ET-1 contributes to pulmonary hypertension in an ovine model of severe HMD.

Ventilation-induced pulmonary vasodilation at birth is modulated by potassium channel activity.

At birth, pulmonary blood flow rapidly increases 8- to 10-fold, and pulmonary arterial pressure falls by 50% within 24 h. The postnatal adaptation of the pulmonary circulation is mediated, in part, by endothelium-derived nitric oxide (EDNO). Recent studies suggest that EDNO may reduce vascular resistance, in part, by activating K+ channels. We hypothesized that K+ channels modulate the changes in pulmonary hemodynamics associated with birth. To test this hypothesis, we studied the effect of K+ channel inhibition on two separate, but interdependent stimuli: 1) mechanical ventilation with low inspired O2 concentrations (designed to maintain normal fetal blood gas tensions) and 2) mechanical ventilation with high inspired O2 concentrations. Tetraethyl-ammonium (TEA, 1 mg/min for 100 min; n = 5), a nonspecific K+ channel blocker, glibenclamide (Gli, 1 mg/min for 30 min; n = 6), an ATP-sensitive K+ channel blocker, or saline (n = 7) was infused into the left pulmonary artery (LPA) of acutely instrumented fetal lambs. The umbilical-placental circulation remained intact, and lambs were ventilated with 0.10 inspired O2 concentration (FIO2) for 60 min, followed by 1.0 FIO2 for 20 min. Neither TEA nor Gli had an effect on basal pulmonary tone. TEA attenuated the increase in LPA flow and decrease in pulmonary vascular resistance in response to mechanical ventilation with 0.10 and 1.0 FIO2; Gli had no effect. These results support the hypothesis that non-ATP-sensitive K+ channels modulate the transition from fetal to neonatal pulmonary circulation.

ATP RELEASE MEDIATES OXYGEN INDUCED PULMONARY VASODILATION IN FETAL LAMBS.† 2031

The pulmonary vascular resistance (PVR) undergoes a dramatic decrease at birth to facilitate gas exchange by the lung in postnatal life. Oxygen is the most important stimulus that causes this pulmonary vasodilation. We proposed the hypothesis that exposure to O2 causes an increase in oxidative phosphorylation and ATP synthesis in pulmonary vascular endothelial cells and/or red cells. Increased release of this ATP into plasma then mediates the pulmonary vasodilation caused by O2. We previously reported that ATP causes pulmonary vasodilation in fetal lambs by stimulating the P2y purinergic receptor on the endothelial cells. The objectives of this study were to investigate the effects of 2,4 dinitrophenol (DNP), an uncoupler of oxidative phosphorylation, on (1) plasma ATP levels in pulmonary artery during O2 exposure and (2) changes in PVR caused by O2 exposure. We studied three fetal lambs that had catheters inserted in left pulmonary artery(LPA), aorta and right and left atria and a flow transducer around the LPA. Control studies were done by giving the pregnant ewe 100% O2 resulting in a 6±3 torr increase in fetal PaO2. Exposure to O2 was repeated after giving 1 mg of DNP, into the LPA over ten min. Data are shown as mean±SD. * P<0.05 from baseline (BL), # from control and $ from 10 min O2. PAP & SAP = pulmonary and systemic pressures. The increase in plasma ATP levels and LPA flow and decrease in PVR caused by O2 was attenuated by DNP. These preliminary data indicate that release of ATP mediates O2 induced pulmonary vasodilation in fetal lamb.Table

Pulmonary vasodilator drugs decrease lung liquid production in fetal sheep.

To examine a potential relationship between pulmonary vasodilatation and fetal lung liquid production, I measured lung liquid production in 20 fetal sheep at 130 +/- 4 days gestation while using several agents known to increase pulmonary blood flow. Thirty-two studies were done in which left pulmonary arterial flow (Qlpa) was measured by an ultrasonic Doppler flow probe and net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of radiolabeled albumin, an impermeant tracer that was mixed into the lung liquid at the start of each study. Qlpa and Jv were measured during a 1- to 2-h baseline period and then during a 1- to 2-h infusion period in which the fetuses received either an intravenous infusion of acetylcholine (n = 8), prostaglandin D2 (n = 10), or the leukotriene blocker FPL-55712 (n = 7). These vasodilators work by different mechanisms, each mechanism having been implicated in the decrease in pulmonary vascular resistance seen at birth. Control (saline) infusions (n = 7) caused no change in either Qlpa or Jv over 4 h. All vasodilator agents significantly increased pulmonary blood flow and decreased Jv. Pulmonary arterial pressure did not change significantly in either the control, acetylcholine, prostaglandin, or leukotriene-blocker studies, indicating that pulmonary vascular resistance decreased. Thus agents that increase pulmonary blood flow by mechanisms that occur at birth also decrease lung liquid production in fetal lambs.

Pulmonary haemodynamics after surfactant replacement in severe neonatal respiratory distress syndrome.

Aortopulmonary pressure difference and pulmonary blood flow velocity were studied during the first 48 hours of life in 12 premature neonates with severe respiratory distress syndrome (RDS), treated by natural surfactant, and in 25 premature neonates with mild RDS. A non-invasive Doppler ultrasound method was used to estimate aortopulmonary pressure difference and pulmonary blood flow velocity from the left pulmonary artery. Aortopulmonary pressure difference was significantly lower at 6 hours of age in the infants with severe RDS and was not increased one hour after surfactant therapy. Aortopulmonary gradient started to rise at 24 hours of age and was equal to that of neonates with mild RDS at 48 hours. Pulmonary blood flow velocity was significantly lower, initially in the severe RDS group, and was not increased one hour after surfactant therapy. Left pulmonary artery flow velocity began to rise after 24 hours and reached the values of the mild RDS group at 48 hours. These data indicate that aortopulmonary pressure difference and pulmonary blood flow are low in the acute phase of RDS and that surfactant treatment does not seem to affect these values.