Cerebral blood flow during treatment for pulmonary hypertension.

AIM: To determine if the haemodynamics of systemic and cerebral circulation are changed during treatment for persistent pulmonary hypertension of the newborn (PPHN). METHODS: Fifteen term newborn piglets with hypoxia induced pulmonary hypertension were randomly assigned either tolazoline infusion (Tz), hyperventilation alkalosis(HAT), and inhaled nitric oxide (iNO). Mean pulmonary arterial pressure (PAP), mean systemic arterial pressure (SAP), and cerebral blood flow volume (CBF) were measured. RESULTS: During hypoxic breathing, PAP increased significantly in all groups. After treatment PAP decreased significantly in all groups, but no significant difference was observed between groups. SAP decreased significantly only in the Tz group, and CBF reduced significantly only in the HAT group. On the other hand, iNO did not change SAP or CBF. CONCLUSION: Inhaled NO might be ideal for the resolution of pulmonary hypertension.     

Effects of magnesium sulphate and nitric oxide in pulmonary hypertension induced by hypoxia in newborn piglets.

AIM--To examine the haemodynamic effects of intravenous magnesium sulphate on an animal model of neonatal pulmonary hypertension induced by hypoxia. METHODS--The cardiac index (Q), pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), and pulmonary (PVRI) and systemic (SVRI) vascular resistance indices were measured in nine newborn piglets (including three controls). Pulmonary hypertension was induced by lowering the FIO2 to 0.12-0.14, after which there was a significant increase in PAP and PVRI (37% and 142%, respectively; p < 0.01) and a significant fall in SAP and Q (30% and 33%, respectively; p < 0.01). RESULTS--Magnesium sulphate was infused intravenously as four doses of 25 mg/kg, 15 minutes apart, which resulted in a significant mean (SD) increase in serum magnesium (0.83 (0.07) mmol/l to 1.82 (0.19) mmol/l; p < 0.01). After the initial dose SAP, SVRI, PAP and PVRI decreased, but not significantly. Each subsequent dose of (50, 75, 100 mg/kg) was accompanied by further significant reductions in these variables from control baseline (p < 0.05). The PVRI:SVRI ratio remained unchanged throughout. Inhaled nitric oxide (NO) 40 ppm was administered after the last dose of magnesium sulphate. The PVRI:SVRI significantly decreased (p < 0.05), indicating that reversible pulmonary hypertension remained after a maximum dose of magnesium sulphate. CONCLUSIONS--Unlike NO, magnesium sulphate is not a selective pulmonary vasodilator and may lead to deleterious effects on systemic pressures in critically ill newborns.     

Contribution of pulmonary surfactant with inhaled nitric oxide for treatment of pulmonary hypertension

BACKGROUND: Combined therapy of inhaled nitric oxide (iNO) with pulmonary surfactant replacement was reported to improve oxygenation in patients or animal models of persistent pulmonary hypertension of the newborn with pulmonary surfactant deficiency lung. To evaluate the potential of iNO for the treatment of persistent pulmonary hypertension of the newborn, pulmonary arterial pressure (PAP) was measured during iNO before and after pulmonary surfactant replacement in an animal model of pulmonary hypertension with surfactant deficiency. METHODS: Seven newborn piglets were injected with L-nitro-arginine-methylester to produce an animal model of pulmonary hypertension. After PAP increased, iNO (30 p.p.m.) was introduced. Then iNO was stopped, and animals were subjected to lung lavage with saline. After recording the effect of iNO, all animals then received exogenous pulmonary surfactant installation. After surfactant treatment, iNO was again introduced. RESULTS: Pulmonary arterial pressure and systemic arterial pressure were increased significantly by >30% after infusion of L-nitro-arginine-methylester. During iNO only PAP was reduced significantly. Respiratory system compliance decreased significantly after lung lavage, and increased significantly after pulmonary surfactant replacement with concomitant increase of PaO2. In contrast, significant reduction of PAP with iNO before and after pulmonary surfactant replacement were also observed. The reduction ratios of PAP under each condition were 75.2 +/- 7.4%, 81.3 +/- 3.1%, and 79.1 +/- 5.3%, respectively (not significant among conditions). CONCLUSION: These results suggest that iNO is still a potent pulmonary arterial vasodilator even under pulmonary surfactant deficiency in an animal model of pulmonary hypertension.     

Hemodynamic effects of levcromakalim in neonatal porcine pulmonary hypertension

Levcromakalim (LKM; a K(ATP) channel opener) reverses hypoxic pulmonary vasoconstriction in isolated pulmonary arteries and perfused lungs. This vasorelaxation is blocked by glibenclamide (GLB; a K(ATP) channel blocker). We evaluated the hemodynamic effect of LKM followed by GLB in a chronically instrumented neonatal porcine model of pulmonary hypertension, created by exposing piglets to hypoxia (n = 7) or heat-killed group B streptococci (GBS) (n = 6). Hypoxia increased pulmonary arterial pressure (PAP), which LKM decreased, and GLB subsequently increased in a dose-dependent manner. Systemic arterial pressure (SAP) did not change with hypoxia but was also decreased by LKM and increased by GLB. GBS also led to increased PAP, but LKM significantly reduced only SAP, which was then increased by GLB. We conclude LKM is capable of reversing hypoxic, but not GBS-induced, pulmonary hypertension but lacks specificity for the neonatal pulmonary vasculature.     

Endothelin-A receptor blockade in porcine pulmonary hypertension

Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET(A)) receptor activation. We hypothesized that ET(A) blockers (EMD 122946 and BQ 610) would reduce hypoxia-induced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n = 12) or heat-killed GBS (n = 11). ET(A) blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET(A) blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (>100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (<25%) changes in SAP or SVRI. Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO(2) did not change with GBS but decreased with BQ 610. ET(A) receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET(A) blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infection-associated), and the specific ET(A) antagonist used.     

吸入一氧化氮逆转幼猪急性缺氧性肺动脉高压

目的 观察吸入不同浓度一氧化氮（ＮＯ）是否可逆转幼猪急性缺氧性肺动脉高压。方法 选用１０头上海种白猪。利用低氧建立急性缺氧性肺动脉高压模型。吸入不同浓度ＮＯ（０,１０,２０,４０,８０,１２０ｐｐｍ）。在各时相分别进行血液动力学指标、二氧化氮和高铁血红蛋白浓度监测。结果 吸入不同浓度ＮＯ可明显降低肺动脉平均压（ＭＰＡＰ）、肺循环阻力指数（ＰＶＲＩ）、跨肺压（ＴＰＧ）、体肺动脉压之比（Ｐｐ／Ｐｓ）、     

Intravenous dipyridamole enhances the effects of inhaled nitric oxide and prevents rebound pulmonary hypertension in piglets

Inhaled nitric oxide (NO) is increasingly used in the treatment of pulmonary hypertension, despite its potential toxicity and the risk of life-threatening rebound pulmonary hypertension upon its discontinuation. We investigated whether i.v. dipyridamole, a cGMP phosphodiesterase inhibitor, increased the effects of inhaled NO and prevented rebound pulmonary hypertension. In 14 anesthetized and mechanically ventilated piglets, pulmonary hypertension was induced with U-46619, a thromboxane A(2) analogue. Response to NO and rebound pulmonary hypertension were evaluated without and with i.v. dipyridamole. Low-dose dipyridamole (10 micro g/kg/min) increased cardiac output and augmented the effects of inhaled NO on pulmonary vascular resistance, with marginal additive effect on mean pulmonary artery pressure. Pulmonary vascular resistance decreased from 904 to 511 (20 parts per million NO) (p < 0.0005) and 358 dyne s cm(-5) (20 parts per million NO + dipyridamole) (p < 0.001 versus NO alone), and mean pulmonary artery pressure decreased from 29.0 to 20.5 (p < 0.0001) and 19.3 mm Hg (NS versus NO), respectively. Mean arterial pressure decreased from 85 to 74 mm Hg (dipyridamole + NO) (p < 0.01). High-dose dipyridamole (100 micro g/kg/min) with inhaled NO reduced pulmonary vascular resistance to 334 dyne s cm(-5) but also decreased mean arterial pressure to 57 mm Hg. Eight piglets developed rebound pulmonary hypertension. Two died of acute right ventricular failure and, in five, rebound pulmonary hypertension was prevented by low-dose dipyridamole. In conclusion, low-dose i.v. dipyridamole augments the effects of inhaled NO on right ventricular afterload with moderate changes in systemic hemodynamics, and can prevent rebound pulmonary hypertension.     

The effect of a nebulized NO donor, DPTA/NO, on acute hypoxic pulmonary hypertension in newborn piglets

NONOates, novel NO donors, are complexes of NO with nucleophiles which spontaneously and nonenzymatically release NO in aqueous solution. This study sought to determine the cardiopulmonary effects of the nebulized NONOate dipropylenetriamine (DPTA)/NO in newborn piglets with acute hypoxia-induced pulmonary hypertension. Twenty sedated and mechanically ventilated piglets (4-10 days old) exposed to hypoxia (Fi(O2) = 0.14) were randomly assigned to receive nebulized saline as placebo (PL) or DPTA/NO (75 mg) after 30 min of hypoxia. Pulmonary artery (P(pa)) and wedge pressures, systemic (P(sa)) and right atrial pressures, cardiac output (CO) and arterial blood gas were measured at baseline and every 15 min for 2 h. Methemoglobin levels were measured at baseline and 1 h after drug nebulization. Data (means +/- SD) were analyzed by repeated-measures analysis of variance. Acute hypoxia resulted in an increase in P(pa) and pulmonary vascular resistance (PVR), which was significantly attenuated by DPTA/NO nebulization as compared to the PL group (p < 0.0001). Changes in P(sa), CO, systemic vascular resistance (SVR), arterial blood gas and methemoglobin levels were not different between groups. In contrast to the increase in PVR/SVR observed during hypoxia in the PL group, there was a significant decrease in this ratio after NONOate administration (p < 0.0001). These data show that acute hypoxic pulmonary hypertension in newborn piglets is markedly attenuated by NONOate nebulization. This response is predominantly in the pulmonary vasculature as the PVR/SVR was significantly lower in the treated group. We speculate that NONOates may have clinical application in the treatment of persistent pulmonary hypertension of the newborn.     

Porcine pulmonary artery and bronchial responses to endothelin-1 and norepinephrine on recovery from hypoxic pulmonary hypertension

Many infants recovering from acute lung disease and pulmonary hypertension still have evidence of reactive airways disease at one year of age, suggesting longer-term airway effects. We hypothesized that parallel changes in smooth muscle would occur in airways and pulmonary arteries from animals with pulmonary hypertension and during normoxic recovery. Thus, two-hour-old piglets were subjected to 3 d chronic hypobaric hypoxia and 3-d-old piglets were subjected to 11 d hypoxia. Some animals were allowed to recover in room air for 3 or 6 d. The amount of smooth muscle and responses of isolated paired bronchial and pulmonary artery rings to endothelin-1 (ET-1) and norepinephrine were studied at the end of hypoxic exposure, on recovery and in age-matched control animals. In all hypoxia induced pulmonary hypertensive animals, smooth muscle area and ET-1 contractile response was increased in the pulmonary arteries and bronchi. Norepinephrine-induced relaxant response was impaired significantly in both bronchi and pulmonary arteries. After 3 d recovery, pulmonary arterial smooth muscle area decreased by 65%, and ET-1-induced contractile responses were normal for age. In the airways, ET-1 contractile response only normalized after six days and bronchial smooth muscle was still increased. After 6 d recovery pulmonary arterial norepinephrine-induced relaxant response had returned to normal, but bronchial response remained impaired. Thus during pulmonary hypertension, both bronchial and pulmonary arterial smooth muscle area and contractile responses are increased. On recovery, regression of bronchial structural and functional abnormalities is slower than in pulmonary arteries.     

钙通道在肺动脉高压发病机制中的研究进展

肺动脉高压是一类严重的进展性疾病,最终导致患者右心衰竭,甚至死亡。肺血管收缩、肺血管重构、血栓形成和血管硬化等诸多原因导致肺动脉高压的发生。众多研究表明,Ca~(2+)信号在维持血管张力和调控血管平滑肌细胞增殖、凋亡等过程中发挥了重要作用,而这一信号转导机制主要由钙通道来调节操纵。文章综述钙通道在肺动脉高压发病机制中的研究进展。     

Vascular potassium channels mediate oxygen-induced pulmonary vasodilation in fetal lambs

The pulmonary vascular resistance decreases at birth secondary to release of endothelium-derived nitric oxide (EDNO). EDNO release is a calcium-dependent process, and endothelial potassium (K+) channels regulate intracellular calcium flux. We investigated the hypothesis that potassium channels mediate oxygen-induced pulmonary vasodilation and EDNO release in fetal lambs. We instrumented 18 near-term fetal lambs at 122-126 days of gestation to measure pulmonary pressures, flow, and resistance. We studied hemodynamic effects of (1) 100% oxygen; (2) pinacidil, an ATP-sensitive K+ (KATP) channel agonist, and (3) S-nitroso-N-acetylpenicillamine (SNAP), a NO donor. We studied the effects of glybenclamide, a K(ATP) channel antagonist, tetraethylammonium chloride (TEA), a preferential KCa channel antagonist, and nitro-L-arginine (NLA), an NO synthase inhibitor, on the response to some of the above agents. Oxygen-induced pulmonary vasodilation was inhibited by both glybenclamide and TEA, indicating that K(ATP) and K(Ca) channels mediate pulmonary vasodilator response to oxygen. Blocking NO synthesis with NLA inhibited pinacidil-mediated pulmonary vasodilation, indicating that K(ATP) channel activation stimulates NO release. SNAP-mediated pulmonary vasodilation was inhibited by TEA, but not glybenclamide, indicating that K(Ca) channels, but not K(ATP) channels, mediate effects of NO on vascular smooth muscle relaxation. In conclusion, K+ channels mediate oxygen-induced pulmonary vasodilation in fetal lambs. K(ATP) channels appear to mediate EDNO release, while K(Ca) channels probably mediate NO effects on vascular smooth muscle.     

Nitric oxide inhalation and nitric oxide synthase inhibitor supplement for endotoxin-induced hypotension

BACKGROUND: This study was performed to determine whether a combined therapy of nitric oxide (NO) inhalation and nitric oxide synthase (NOS) inhibitor is effective in experimental animals with endotoxin-induced refractive hypotension accompanied by pulmonary hypertension. METHODS: Escherichia coli lipopolysaccharide (1 mg/kg) was administered to 10 newborn piglets to induce endotoxemia. The experiment then began 60 min later, when the systemic arterial pressure dropped. The inhalation of 20 p.p.m. NO at 60 and 120 min of endotoxemia created a control group. Another group was also administered N w-nitro-L-arginine (L-NNA; 5 mg) after the first NO inhalation at 60 min of endotoxemia (the L-NNA group). Pulmonary arterial pressure, systemic arterial pressure and cardiac output were measured and compared among the groups. RESULTS: Three of the 5 piglets in the control group died of hypotensive shock, while in the L-NNA group the systemic arterial pressure recovered to pre-endotoxin administration levels. The L-NNA group produced a further increase in pulmonary arterial pressure against which NO inhalation was effective. CONCLUSION: Nitric oxide inhalation alone carries a potential risk of further lowering systemic arterial pressure in a piglet with hypotension induced by endotoxin, whereas the combined therapy resulted in the recovery of the blood pressure to pre-endotoxin levels. The combined therapy was simultaneously effective against pulmonary hypertension.     

Pulmonary arterial responses to reactive oxygen species are altered in newborn piglets with chronic hypoxia-induced pulmonary hypertension

Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. ROS might mediate vascular responses, at least in part, by stimulating prostanoid production. Our goals were to determine whether the effect of ROS on vascular tone is altered in resistance pulmonary arteries (PRAs) of newborn piglets with chronic hypoxia-induced pulmonary hypertension and the role, if any, of prostanoids in ROS-mediated responses. In cannulated, pressurized PRA, ROS generated by xanthine (X) plus xanthine oxidase (XO) had minimal effect on vascular tone in control piglets but caused significant vasoconstriction in hypoxic piglets. Both cyclooxygenase inhibition with indomethacin and thromboxane synthase inhibition with dazoxiben significantly blunted constriction to X+XO in hypoxic PRA. X+XO increased prostacyclin production (70 ± 8%) by a greater degree than thromboxane production (50 ± 6%) in control PRA; this was not the case in hypoxic PRA where the increases in prostacyclin and thromboxane production were not statistically different (78 ± 13% versus 216 ± 93%, respectively). Thromboxane synthase expression was increased in PRA from hypoxic piglets, whereas prostacyclin synthase expression was similar in PRA from hypoxic and control piglets. Under conditions of chronic hypoxia, altered vascular responses to ROS may contribute to pulmonary hypertension by a mechanism that involves the prostanoid vasoconstrictor, thromboxane.     

Influence of an antagonist of slow-reacting substance of anaphylaxis on the cardiovascular manifestations of hypoxia in piglets

Leukotrienes have been implicated in the pathogenesis of hypoxic pulmonary hypertension in adult animals and in persistent pulmonary hypertension with accompanying hypoxemia in the neonate. In order to elucidate the role of leukotrienes in hypoxic pulmonary hypertension in a young animal model, the effects of a leukotriene antagonist, FPL 57231, were evaluated in anesthetized piglets. Cardiac output and vascular pressures were measured and pulmonary and systemic vascular resistances calculated prior to and during hypoxia. These measurements were compared during continued hypoxia between a control and treatment group which received FPL 57231. FPL 57231 infusion resulted in significant decreases in mean pulmonary artery pressure (p less than 0.04), pulmonary vascular resistance (p less than 0.01) and the ratio of pulmonary/systemic vascular resistance (p less than 0.01). Systemic vascular resistance fell approximately 25% from hypoxic baseline (p less than 0.01) while PVR decreased 54%. There were no differences between groups in mean systemic arterial pressure, cardiac output, pH, or PaCO2. In addition, pretreatment with FPL 57231 attenuated the hemodynamic response to hypoxia. These data suggest that leukotrienes may, in part, mediate hypoxic pulmonary vasoconstriction in piglets.     

A novel inhaled organic nitrate that affects pulmonary vascular tone in a piglet model of hypoxia-induced pulmonary hypertension

Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure-function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO2)], tested it in vitro, and administered it to hypoxic piglets. ENO2 lowered pulmonary artery pressure and raised the Po2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO2 is less potent than inhaled NO on a dose-equivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency). These results suggest that ENO2 may hold promise as a safe alternative to NO, particularly in hypoxemic conditions characterized by thiol depletion.     

Pulmonary vascular responses during acute and sustained respiratory alkalosis or acidosis in intact newborn piglets

Acute alkalosis-induced pulmonary vasodilation and acidosis-induced pulmonary vasoconstriction have been well described, but responses were generally measured within 5-30 min of changing pH. In contrast, several in vitro studies have found that relatively brief periods of sustained alkalosis can enhance, and sustained acidosis can decrease, vascular reactivity. In this study of intact newborn piglets, effects of acute (20 min) and sustained (60-80 min) alkalosis or acidosis on baseline (35% O2) and hypoxic (12% O2) pulmonary vascular resistance (PVR) were compared with control piglets exposed only to eucapnia. Acute alkalosis decreased hypoxic PVR, but sustained alkalosis failed to attenuate either baseline PVR or the subsequent hypoxic response. Acute acidosis did not significantly increase hypoxic PVR, but sustained acidosis markedly increased both baseline PVR and the subsequent hypoxic response. Baseline PVR was similar in all piglets after resumption of eucapnic ventilation, but the final hypoxic response was greater in piglets previously exposed to alkalosis than in controls. Thus, hypoxic pulmonary vasoconstriction was not attenuated during sustained alkalosis, but was accentuated during sustained acidosis and after the resumption of eucapnia in alkalosis-treated piglets. Although extrapolation of data from normal piglets to infants and children with pulmonary hypertension must be done with caution, this study suggests that sustained alkalosis may be of limited efficacy in treating acute hypoxia-induced pulmonary hypertension and the risks of pulmonary hypertension must be considered when using ventilator strategies resulting in permissive hypercapnic acidosis.     

Inhaled nitric oxide treatment of children with pulmonary hypertension after cardiac surgery

The presence of pulmonary hypertension in children with a congenital heart defect carries the risk of considerable problems of management immediately after corrective surgery. To evaluate whether inhaled nitric oxide (NO) complements other routine therapeutic measures to lower pulmonary artery pressure, 28 infants and children (ages, 0.85±0.19 years) with this condition were studied within the first few days after surgery. Hemodynamics and/or oxygen saturations were significantly improved by NO inhalation (initial concentration, 15±1.8 ppm) in 27 patients (96%). Mean pulmonary arterial pressure (PAP) declined significantly from 45±5.8 to 27±3.1 mmHg, whereas there were significant increases in mean systemic arterial pressure (55±1.9 to 59±1.8 mmHg) and arterial oxygen saturation (Sao₂, 90±1.9 to 97±1.1%). The changes in PAP (ED₅₀: 0.29±0.07 ppm NO) and Sao₂ (ED₅₀: 0.21±0.04 ppm NO) were dose-dependent with no significant difference in ED₅₀ values. The NO-induced pulmonary vasodilation was independent of the concomitant reduction in arterial carbon dioxide tension. In a case-control study of a subgroup of 18 patients and 35 matched controls, inhaled NO significantly reduced the frequency of pulmonary hypertensive crises by 83% and lowered the mortality rate from 14.2% to zero. During low-dose NO inhalation there was no detectable formation of methemoglobin or significant production of nitric dioxide (NO₂), and no disturbance of platelet aggregation or leukocyte adhesion. It is concluded that in children undergoing cardiac bypass surgery, low-dose inhaled NO improves hemodynamics and oxygenation, and reduces the frequency, severity, and mortality of pulmonary hypertensive crises during perioperative intensive care. We recommend a dose range of 1–10 ppm NO for routine use, and an absolute upper dose limit of 40 ppm NO to avoid potential adverse side effects.     

Effects of a nebulized NONOate, DPTA/NO, on group B streptococcus-induced pulmonary hypertension in newborn piglets

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4-10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 x 10(8) CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p <0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p <0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates.     

Sodium nitroprusside prevents oxygen-free-radical-induced pulmonary vasoconstriction in newborn piglets

The aim of the present study was to test whether hypoxanthine-xanthine oxidase (XO) induced a pulmonary vasoconstriction in newborn piglets, and whether this vasoconstriction could be attenuated or abolished by pretreatment of nitric oxide (NO) donor sodium nitroprusside (SNP). Twenty-five anesthetized newborn piglets (1-3 days old) were randomly assigned to the following four groups: the control group received saline intravenously only; the XO group received 0.1 mmol/kg of hypoxanthine subsequent with XO (1.5 U/kg); the SNP group received the same dosages of hypoxanthine/ XO together with SNP intravenously, allopurinol (ALP) group received ALP intravenously prior to hypoxanthine and XO injection. After giving XO, the pulmonary arterial pressure (PAP) and vascular resistance (PVR) increased, while the cardiac index decreased significantly in the XO group. By contrast, these variables were not significantly modified by XO injection in the SNP and ALP groups. The data suggest that oxygen free radicals induce a pulmonary vasoconstriction in newborn piglets, and this vasoconstriction can be prevented by infusion of the NO donor SNP.     

The Tei index permits evaluation of cardiopulmonary function during inhaled nitric oxide therapy in the hypoxic newborn piglet

The purpose of this study was to test the effectiveness of a new Doppler index combining systolic and diastolic time intervals (the Tei index) in the prospective assessment of ventricular function and pulmonary circulation in a newborn piglet model with hypoxic pulmonary hypertension during inhaled nitric oxide (NO). Piglets were prepared for the experiments under normal air, hypoxia, and hypoxia-with-inhaled-NO conditions. Complete two-dimensional Doppler echocardiographic examinations were performed in each condition. The right-ventricle (RV) Tei index increased with hypoxia and decreased following the inhalation of NO. Furthermore, there was a direct correlation between the individual changes in the RV Tei index and individual changes in mean pulmonary arterial pressure in each condition. We conclude that the Tei index is useful for assessing cardiac function and pulmonary circulation in hypoxic pulmonary hypertension during inhaled NO. These results suggest that the Tei index provides an objective assessment of persistent pulmonary hypertension of the newborn.