A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group

OBJECTIVE: We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH). BACKGROUND: Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO. METHODS: During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored. RESULTS: Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003). CONCLUSIONS: During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.     

Prolonged nitric oxide inhalation fails to regress hypoxic vascular remodeling in rat lung

STUDY OBJECTIVE: The purpose of present study was to investigate whether long-term nitric oxide (NO) inhalation during the recovery in air might improve the regression of chronic hypoxic pulmonary hypertension (PH) and vascular changes. MATERIALS AND METHODS: The rats were exposed to 10 ppm of NO in air for 10 days (n = 12) and 30 days (n = 4), or 40 ppm of NO in air for 10 days (n = 6) and 30 days (n = 12) following 10 days of hypobaric hypoxia (380 mm Hg, 10% oxygen). For each NO group, air control rats following hypoxic exposure were studied at the same time (n = 13, 11, 9, and 11, respectively). Normal air rats (n = 6) without hypoxic exposure and rats (n = 7) following 10 days of hypoxic exposure were used as normal and chronic hypoxic control groups, respectively. Muscularization of normally nonmuscular peripheral arteries and medial hypertrophy of normally muscular arteries were assessed by light microscopy. An additional 16 rats were used to investigate the recovery of pulmonary artery pressure with (n = 8) and without NO inhalation (n = 8) after 10 days of hypobaric hypoxia. RESULTS: Long-term hypoxia-induced PH, right ventricular hypertrophy (RVH), and hypertensive pulmonary vascular changes, each of which regressed partly after recovery in room air. There were no differences among rats with and without NO during each recovery period in RVH, medial wall thickness of muscular artery, and the percentages of muscularized arteries at the alveolar wall and duct levels. Continuous inhaled 40 ppm NO decreased pulmonary artery pressure from 40.1 +/- 1.1 to 29.9 +/- 3.8 mm Hg (mean +/- SE) [n = 8], which was not different in the rats without NO inhalation (n = 8). Urine nitrate level was higher in rats that had inhaled NO. CONCLUSION: Continuous NO inhalation showed no effect on regression of pulmonary vascular remodeling in chronic hypoxic PH after returning to room air.     

Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension

OBJECTIVES: We sought to investigate the impact of adjunct sildenafil on exercise capacity and hemodynamic parameters in patients with pulmonary arterial hypertension (PAH) who fulfilled predefined criteria of deterioration despite ongoing treatment with inhaled iloprost. BACKGROUND: Inhaled iloprost is an effective therapy in PAH. The phosphodiesterase-5 inhibitor sildenafil exerts pulmonary vasodilation and may amplify prostanoid efficacy. METHODS: Of 73 PAH patients receiving long-term inhaled iloprost treatment, 14 fulfilled criteria of deterioration unresponsive to conventional treatment. These patients received adjunct oral sildenafil over a period of nine to 12 months, leaving the inhalative iloprost regimen unchanged. RESULTS: Before iloprost therapy, the baseline 6-min walking distance was 217 +/- 31 m (mean +/- SEM), with an improvement to 305 +/- 28 m within the first three months of iloprost treatment and a subsequent decline to 256 +/- 30 m after 18 +/- 4 months. Adjunct therapy with sildenafil reversed the deterioration and increased the 6-min walk distance to 346 +/- 26 m (p = 0.002, Wilcoxon test) at three months of combined therapy, with a sustained efficacy up to 12 months (349 +/- 32 m, p = 0.002). The distribution of New York Heart Association functional classes (IV/III/II) improved from September 9, 2000, before sildenafil, to January 8, 2003, after nine to 12 months with sildenafil. All hemodynamic variables changed favorably: pulmonary vascular resistance decreased from 2,494 +/- 256 before sildenafil to 1,950 +/- 128 dynes.s.cm(-5).m(2) after three months of adjunct sildenafil (p = 0.036). Two patients died of severe pneumonia during the period of combined therapy. No further serious adverse events occurred. CONCLUSIONS; In patients with severe PAH deteriorating despite ongoing prostanoid treatment, long-term adjunct oral sildenafil improves exercise capacity and pulmonary hemodynamics. A combination of prostanoids and sildenafil is an appealing concept for future treatment of pulmonary hypertension.     

AC-NP改善大鼠低氧性肺动脉高压

目的 明确 AC-NP（一种新型的钠尿肽分子）对于低氧性肺动脉高压的在体效应。方法 采用间断性减压低氧的方法复制低氧性肺动脉高压(HPH)大鼠模型,以AC-NP〔50 μg/(kg·d)〕治疗HPH大鼠1周。检测分析血流动力学指标,以及右心室和肺动脉的重构情况。结果 低氧可致大鼠肺动脉压异常升高。AC-NP治疗1周显著降低HPH大鼠的肺动脉压、肺血管阻力、右心室肥厚和肺动脉的肌化,同时肺血流量显著增加。另外,静脉急性给予AC-NP可以显著改善HPH大鼠的血流动力学指标。结论 AC-NP对HPH具有一定的治疗作用。     

Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide

STUDY OBJECTIVES: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH. DESIGN: Single center, case series, pharmacohemodynamic study. SETTING: Cardiac catheterization laboratory of a tertiary care academic teaching hospital. PATIENTS: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH. INTERVENTIONS: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization. MEASUREMENTS AND RESULTS: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function. CONCLUSIONS: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.     

Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension

BACKGROUND: Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension. METHODS AND PATIENTS: Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15mug; n=25 or 30mug; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5). RESULTS: Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed. CONCLUSION: The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.     

Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension

STUDY OBJECTIVES: Different vasodilators and different routes of application are used for the treatment of primary pulmonary hypertension (PPH). Recently, sildenafil, a phosphodiesterase-V inhibitor, has been shown to have beneficial hemodynamic effects in PPH. However, the hemodynamic effects of sildenafil have not been characterized and compared to other vasodilators such as inhaled nitric oxide (iNO) or iloprost in PPH in the same group of patients. STUDY DESIGN: We investigated prospectively 10 consecutive patients with PPH using iNO, iloprost aerosol, and oral sildenafil to test acute hemodynamic response during right-heart catheterization. RESULTS: iNO, iloprost aerosol, and sildenafil caused a significant fall of mean pulmonary artery pressure and pulmonary vascular resistance (PVR) [p < 0.05]. Correspondingly, cardiac output and mixed venous saturation increased slightly in all groups. Systemic arterial pressure and vascular resistance were mainly unaltered. Using a PVR reduction of > or =20% to define a significant response, 7 of 10 patients were responders to iloprost aerosol, whereas 4 of 10 patients responded to iNO and oral sildenafil. Improvement of oxygenation as indicated by an increase of arterial oxygen tension was observed with iloprost aerosol (p < 0.01). CONCLUSION: All of the three substances, iNO, iloprost aerosol, and oral sildenafil, significantly improved pulmonary hemodynamics in patients with PPH. The most prominent hemodynamic effects and improvement of oxygenation were observed with iloprost aerosol.     

吡那地尔防治大鼠低氧性肺动脉高压肺血管重建的实验研究

目的研究钾通道开放剂吡那地尔对低氧性肺动脉高压（ＨＰＨ）及其肺血管重建的影响。方法Ｗｉｓｔｅｒ大鼠４６只,随机分为３组：对照组１５只;低氧组１６只;治疗组（低氧＋吡那地尔）１５只。低氧组及治疗组建立低氧性肺动脉高压动物模型,治疗组于每天缺氧前腹腔注射吡那地尔３ｍｇ／ｋｇ。 ４周后测定各组平均肺动脉压（ｍＰＡＰ）、右心室（ＲＶ）／左心室＋室间隔（ＬＶ＋ Ｓ）比值和肺小动脉病理及其形态计量学。结果（１）低氧组ｍＰＡＰ、ＲＶ／（ＬＶ＋Ｓ）分别为（２８．４ ± ２．８）ｍｍＨｇ和（０．３０±０．０３）,明显高于对照组（１６．２±１．８）ｍｍ Ｈｇ和（０．２２±０．０３）（Ｐ＜０．０１）,管壁厚度与血管外径比值（ＭＴ％）、管壁面积与血管总面积比值（ＭＡ％）分别为（２５．７±２．６）％和（７５．３±５．６）％,亦明显高于对照组（１８．５±２．９）％和（５９．９±６．６）％（Ｐ＜０．０１）,管腔面积与血管总面积比值（ＶＡ％）为（２４．３±５．６）％,明显低于对照组（４０．７±８．１）％（Ｐ＜０．０１）。提示慢性缺氧导致大鼠发生明显肺动脉高压及右心室肥厚和肺小动脉管壁增厚、管腔狭窄等肺血管重建等改变。（２）治疗组ｍＰＡＰ、ＲＶ／     

Inhaled iloprost is a potent acute pulmonary vasodilator in HIV-related severe pulmonary hypertension.

As antiretroviral therapy has improved life expectancy in human immunodeficiency virus (HIV) infection, the life-limiting complication of HIV-related pulmonary hypertension has come into focus. Inhalation of the stable prostacyclin analogue iloprost is an effective treatment for various forms of precapillary pulmonary hypertension. The main objective of the present study was to evaluate the safety and efficacy of inhaled iloprost in HIV-related pulmonary hypertension. In eight patients with severe pulmonary hypertension related to HIV infection, right heart and femoral artery catheterisation were performed. The acute effect of oxygen, inhaled nitric oxide and aerosolised iloprost was investigated. Four patients underwent long-term treatment with inhaled iloprost. The rank order of pulmonary vasodilatory potency was iloprost>NO>O2, with a maximum reduction (mean +/- SEM) in pulmonary vascular resistance of 30.6 +/- 3.1% (p < 0.001), 5.9 +/- 3.9% and -0.6 +/- 3.9%, respectively. Concomitantly, inhaled iloprost significantly increased the cardiac index and central venous oxygen saturation. Chronic treatment with inhaled iloprost tended to improve the 6 min walking distance and decreased pulmonary vascular resistance in all patients (although not significantly). No serious adverse events and no major interactions with the ongoing antiretroviral therapy were noted. In conclusion, inhaled iloprost is a potent pulmonary vasodilator in human immune deficiency virus-related pulmonary hypertension. Future studies are warranted to confirm the encouraging long-term beneficial results observed in the present limited number of patients.     

Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.     

Effect of inhaled iloprost during off-medication time in patients with pulmonary arterial hypertension

BACKGROUND: Iloprost is a stable prostacyclin analogue that is associated with a longer duration of vasodilatation and has been approved for inhalative use with 6 or 9 inhalations during the daytime and a night pause. It is not known if during the night pause rebound pulmonary hypertension occurs. The aim of this study was to assess the hemodynamics in iloprost-treated patients during the daytime and at night. METHODS: We enrolled 5 adult patients (aged 45 +/- 10 years) with idiopathic pulmonary arterial hypertension (IPAH) and chronic inhaled iloprost therapy for at least 12 months. Further medication remained unchanged during the study period. Hemodynamics were monitored by right heart catheterization. RESULTS: After 30-60 min of nebulized iloprost, mean pulmonary arterial pressures (PAP) decreased from 68 +/- 15 to 51 +/- 18 mm Hg (p = 0.004). After 6 h off-medication sleeping time, mean PAP initially increased until 2 a.m. and decreased subsequently until wake-up time at 6 a.m. Mean PAP, cardiac index and pulmonary vascular resistance at night were not significantly different from the values during the day. CONCLUSIONS: In this study, patients with IPAH and chronic nebulized iloprost therapy did not reveal a rebound pulmonary hypertension during off-medication sleeping time.     

Inhaled iloprost reverses vascular remodeling in chronic experimental pulmonary hypertension

RATIONALE: Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH. OBJECTIVES: The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats. Methods: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline. RESULTS: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed. CONCLUSIONS: We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.     

Cardio-vascular effects of sildenafil: new data

Sildenafil is an inhibitor of phosphodiesterase 5, which has important vasodilatory properties. Though sildenafil provokes a decrease in systemic arterial pressure, its safety has been confirmed in large series of patients on several kinds of anti-hypertensive therapy. Likewise, post-marketing surveys, in the US or United Kingdom, have recorded a number of cardio-vascular deaths following sildenafil administration which was lower than expected, provided the contra-indication with the concomitant use of nitrates is observed. In patients with known or suspected coronary artery disease, sildenafil does not modify the tolerance or results of echocardiographic exercise testing. However, sildenafil does increase coronary flow reserve, both in narrowed or normal coronary arteries, with no sign of a "steal" phenomenon. Because of its capacity to retard the degradation of cGMP, by the inhibition of phosphodiesterase 5, the effect of sildenafil in primary pulmonary hypertension has been evaluated in several studies: acutely, sildenafil decreases pulmonary artery pressure, either alone or in combination with inhaled iloprost or NO. On the same line, sildenafil decreases hypoxia-induced pulmonary hypertension in normal volunteers. These findings, together with reports of long-term improvement in symptoms and levels of pulmonary artery pressure in patients with primary pulmonary hypertension, will warrant further trials to document its potential role in this otherwise severe disease.     

左旋精氨酸对吸入一氧化氮降低肺动脉高压的延长作用

目的观察一氧化氮底物左旋精氨酸（Ｌａｒｇ）延长吸入一氧化氮（ＮＯ）选择性降低肺动脉高压过程中的作用。方法８只猪麻醉后制成急性缺氧性肺动脉高压模型，在ＳｗａｎＧａｎｚ导管和动脉导管监测下吸入ＮＯ（１２～１５ｐｐｍ）的过程中静脉注入Ｌａｒｇ（共１０ｇ），观察停用ＮＯ后体循环和肺循环血流动力学的变化情况。结果单纯吸入ＮＯ能选择性降低急性缺氧性肺动脉高压，肺动脉压力从４２±０４ｋＰａ降至２５±０５ｋＰａ（１ｋＰａ＝７．５ｍｍＨｇ，Ｐ＜０．０１），肺血管阻力从５６±２５ｋＰａ·ｓ·Ｌ１降至３１±１３ｋＰａ·ｓ·Ｌ－１（Ｐ＜０．０１），但持续时间短；ＮＯ吸入加静脉注射Ｌａｒｇ没有使肺动脉压进一步下降，但能显著延长吸入ＮＯ对肺动脉压的降压时间（２０倍），对体循环血压则无影响。结论提供内源性ＮＯ的底物Ｌａｒｇ能延长ＮＯ的降压作用，提示急性缺氧时ＮＯ的生成可能有相对不足。     

Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to pulmonary fibrosis

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mmHg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn.s.cm-5 (p < 0.005, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left-shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn.s.cm-5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.     

Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium

We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca(2+)-dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter <80 microm) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia.     

吸入伊洛前列腺素在先天性心脏病伴发肺动脉高压患者中的急性血管反应试验

目的:观察吸入伊洛前列腺素对先天性心脏病伴发肺动脉高压者的急性血管反应。方法:予15例患者(室间隔缺损10例,房间隔缺损3例,动脉导管未闭及心内膜垫缺损各1例)吸入氧气15min,而后吸入20μg伊洛前列腺素,测量吸氧前后、吸药后即刻、15min及30min的肺动脉和股动脉压并取各部位血测值。结果:吸药后即刻肺动脉平均压及全肺阻力较吸氧前明显降低(P<0.001),而左心排血指数未见明显变化(P=0.244),试验过程中患者未出现不良反应。结论:在急性血管反应试验中,使用雾化吸入的伊洛前列腺素可以安全、有效的在短时间内选择性扩张肺血管、降低肺动脉压力及肺循环阻力,而对体循环影响较小。     

Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia

Pulmonary hypertension contributes significantly to morbidity and mortality in bronchopulmonary dysplasia (BPD), but little is known about the relative contribution of arterial tone, structural remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, we studied the acute effects of oxygen tension, inhaled nitric oxide (iNO), and calcium channel blockers (CCB) in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure (PAP) and pulmonary to systemic vascular resistance ratio (PVR/SVR) were 34 +/- 3 mm Hg and 0.42 +/- 0.07, respectively. In response to hypoxia, PAP and PVR/SVR increased by 50 +/- 8% and 82 +/- 14%, respectively (p < 0.01). Hyperoxia decreased PVR/SVR by 28 +/- 9% (p = 0.05). The addition of iNO treatment (20-40 ppm) to hyperoxia decreased PAP and PVR/SVR by 29 +/- 5% (p < 0.01) and 45 +/- 6% (p < 0.05) from baseline values, respectively, achieving near normal values. CCB did not alter PAP or PVR/SVR from baseline values. We conclude that hyperoxia plus iNO causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD.     

Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis.

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation-perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I(2) caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 +/- 4.2 to 31.6 +/- 3.1 mm Hg, and pulmonary vascular resistance (RL) from 810 +/- 226 to 386 +/- 69 dyn. s. cm(-)(5) (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with RL decreasing from 726 +/- 217 to 458 +/- 81 dyn. s. cm(-)(5). In contrast, both intravenous PGI(2) and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI(2) infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI(2) analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI(2) or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.     

伊洛前列素在小儿先天性心脏病肺动脉高压术后的应用研究

目的:探究伊洛前列素治疗小儿先天性心脏病(CHD)术后肺动脉高压(PAH)的安全性及有效性。方法:选择合并PAH的CHD体外循环下行双心室矫治术患儿50例,年龄6个月～18岁,中位数年龄4.5(2.78,8.0)岁,分为吸入伊洛前列素组(组Ⅰ)、静注前列腺素E1(PGE1)组(组Ⅱ)。所有患儿均于术前放置PICCO及Swan-Ganz导管。通过术后测定、FICK法计算2组患儿用药前后血流动力学指标,包括体循环阻力指数、肺血管阻力指数。在相同通气条件下,比较2组患儿用药前后血流动力学指标在用药后48 h内的变化趋势。结果:伊洛前列素组肺体血管压力比(Pp/Ps):用药后即刻、用药后30 min较用药前差异有统计学意义(P<0.001);肺体循环阻力比(Rp/Rs):用药后即刻较用药前差异有统计学意义(P<0.05),用药后30 min较用药前差异有统计学意义(P<0.001);心排指数(CI):用药后即刻及用药后30 min差异有统计学意义(P<0.05)。结论:吸入性伊洛前列素是高效的选择性肺血管扩张剂,可以显著降低合并PAH的CHD术后患儿的肺动脉压力(PAP)和肺血管阻力(PVR)。应用吸入性伊洛前列素可以提高CHD术后患儿的CI。伊洛前列素用于治疗CHD术后PAH是有效安全的。