Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation.

AIMS: To directly compare the differential effects of oxygen, prostacyclin and iloprost (aerosolized and intravenous) in primary pulmonary hypertension. METHODS AND RESULTS: Twenty-one patients with severe primary pulmonary hypertension underwent right heart catheterization following oxygen inhalation, inhalation of aerosolized iloprost, intravenous prostacyclin or intravenous iloprost. The stability of the iloprost solution was tested for up to 4 weeks. Oxygen slightly decreased pulmonary vascular resistance. Intravenous prostacyclin (7.2+/-3.4 ng kg(-1) min(-1)) reduced pulmonary (1772+/-844 vs 1325+/-615 dyn s cm(-5), P<0.001) and systemic vascular resistance, and arterial and right atrial pressure, while cardiac output increased. Iloprost inhalation diminished pulmonary (1813+/-827 vs 1323+/-614 dyn s cm(-5), P<0.001) and systemic vascular resistance, and pulmonary artery (58+/-12 vs 50+/-12 mmHg,P<0.001) and right atrial pressure, while cardiac output increased. With intravenous iloprost (1.2+/-0.5 ng kg(-1) min(-1), n=8) a decrease in pulmonary (2202+/-529 vs 1515+/-356 dyn s cm(-5), P<0.05) and systemic vascular resistance and right a trial pressure occurred while cardiac output increased. Iloprost solution remained stable for 33 days while losing <10% (4 degrees C) of its active drug concentration.Conclusions Intravenous iloprost and prostacyclin have very similar haemodynamic profiles. In contrast, only inhaled iloprost exerted selective pulmonary vasodilation, reducing pulmonary vascular resistance and pulmonary artery pressure without systemic vasodilation. The longer half-life and extended stability despite lower costs render iloprost an attractive alternative to chronic prostacyclin treatment in primary pulmonary hypertension.     

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。     

Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension.

OBJECTIVES: This study investigated the short- and long-term outcome of children with pulmonary arterial hypertension (PAH) treated with inhaled iloprost. BACKGROUND: Inhaled iloprost has been approved for the treatment of adults with PAH, but little is known about the effects in children with PAH. METHODS: We evaluated the acute effects of inhaled iloprost on hemodynamic status and lung function and the response to long-term therapy in 22 children (range 4.5 to 17.7 years) with PAH (idiopathic, n = 12; congenital heart disease, n = 10). Cardiac catheterization, standard lung function testing before and after iloprost inhalation, 6-min walk test, World Health Organization functional class, and hemodynamic parameters were monitored. RESULTS: Acute administration of inhaled iloprost lowered mean pulmonary artery pressure equivalent to the response to inhaled nitric oxide with oxygen. Acute iloprost inhalation reduced forced expiratory volume in 1 s and mid-volume forced expiratory flow by 5% and 10%, respectively, consistent with acute bronchoconstriction. At 6 months, functional class improved in 35%, decreased in 15%, and remained unchanged in 50% of children. Sixty-four percent of patients continued receiving long-term iloprost therapy, 36% stopped iloprost, due to lower airway reactivity, clinical deterioration, or death. In 9 patients on chronic intravenous prostanoids, 8 transitioned from intravenous prostanoids to inhaled iloprost, which continued during follow-up. CONCLUSIONS: Inhaled iloprost caused sustained functional improvement in some children with PAH, although inhaled iloprost occasionally induced bronchoconstriction. Most patients tolerated the transition from intravenous to inhaled prostanoid therapy. Clinical deterioration, side effects, and poor compliance, owing to the frequency of treatments, could limit chronic treatment in children.     

Long-term treatment of pulmonary hypertension with aerosolized iloprost.

Pulmonary arterial hypertension (PAH), defined as elevated pulmonary arterial pressure and pulmonary vascular resistance, is an end-point of a variety of conditions. The only therapy that has been shown to improve both quality of life and survival is intravenous prostacyclin (prostaglandin I2 (PGI2), epoprostenol). The effect of long-term aerosolized iloprost (Ilomedin, Schering, Berlin, Germany and Vienna, Austria), a stable prostacyclin analogue and potent vasodilator, on haemodynamics and functional status was investigated in 12 patients with severe pulmonary hypertension. Haemodynamic measurements and vasodilator testing by right heart catheterization were performed prior to and after long-term iloprost inhalation therapy. Haemodynamic improvement or increased exercise tolerance was not observed in any of the patients. After a mean+/-SD treatment period of 10+/-5 months, mean+/-SD pulmonary vascular resistance had increased from 11+/-3 Wood Units (mmHg.L(-1).min) to 13+/-4 Wood Units, with unchanged arterial oxygen saturation (92+/-4%, versus 91+/-4%). Within the study period, three patients went into right heart failure and had to be placed on intravenous epoprostenol. The authors conclude that inhaled iloprost in addition to conventional therapy in the presently recommended dose of 100 microg.day(-1) delivered in 8-10 2 h portions, is not an efficient vasodilator therapy in severe pulmonary hypertension. It remains to be shown whether dose increases and/or combination protocols will be effective, or whether inhalation of iloprost may be safe for selected cases of pulmonary hypertension.     

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.     

脐血间充质干细胞移植对大鼠肺动脉高压的治疗作用研究

目的:观察脐血间充质干细胞(mesenchymal stem cells,MSCs)移植对SD大鼠肺动脉高压(PAH)的治疗作用。方法:将60只健康雄性SD大鼠随机分为4组,每组15只(n=15),即①正常对照组:不做任何处理;②模型组:以腹主动脉-腔静脉瘘分流术(abdominal aortocaval fistula shuning,A-VF)+单野百合碱(monocrotaline,MCT)注射建立大鼠PAH模型,故也可称为A-VF+MCT组;③干细胞移植组:在建立PAH模型后4周,经尾静脉注射Ho-echst 33342荧光染料标记的脐血MSCs,故此组也可称A-VF+MCT+MSCs组;④培养液对照组:在建立PAH模型后4周,经尾静脉注射培养脐血MSCs的培养液,故此组也可称为A-VF+MCT+培养液组。4周后以右心导管法测定平均肺动脉压(mPAP)、右心室肥厚指数[RVHI=RV/(LV+S)]、肺小动脉中层厚度占血管外径的百分比[MA(%)]和血管壁中层横截面积占血管总横截面积的百分比[MA(%)],观察肺小动脉重构情况。检测血流动力学、肺小动脉重塑及脐血MSCs的定植情况。结果:与正常对照组比较,造模实验证实,4周后A-VF+MCT组大鼠可形成典型的PAH,8周后mPAP明显增高,动脉中膜明显增厚,右心室出现明显肥厚;而A-VF+MCT+MSCs组大鼠mPAP、RV/(LV+S)、MT%和MA%均显著下降(P<0.01)。PAH大鼠死亡率从66.7%下降到13.3%。荧光显微镜观察显示脐血MSCs已成功定植到肺血管内膜。结论:以A-VF+MCT建立的大鼠PAH模型可形成重度PAH。脐血MSCs移植能显著降低肺动脉压力,减轻肺小动脉重构及右心室肥厚,显著降低PAH大鼠的死亡率。     

Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies.

OBJECTIVES: This study sought to investigate the effects of inhaled treprostinil on pulmonary hemodynamics and gas exchange in severe pulmonary hypertension. BACKGROUND: Inhaled iloprost therapy has a proven clinical efficacy in pulmonary arterial hypertension, but this therapy necessitates 6 to 9 inhalation sessions per day. Treprostinil has a longer plasma half-life and might provide favorable properties when applied by inhalation. METHODS: Three different studies were conducted on a total of 123 patients by means of right heart catheterization: 1) a randomized crossover-design study (44 patients), 2) a dose escalation study (31 patients), and 3) a study of reduction of inhalation time while keeping the dose fixed (48 patients). The primary end point was the change in pulmonary vascular resistance (PVR). RESULTS: The mean pulmonary arterial pressure of the enrolled patients was approximately 50 mm Hg in all studies. In study 1, both treprostinil and iloprost at an inhaled dose of 7.5 mug displayed a comparable PVR decrease, with a significantly different time course (p < 0.001), treprostinil showing a more sustained effect on PVR (p < 0.0001) and fewer systemic side effects. In study 2, effects of inhalation were observed for 3 h. A near-maximal acute PVR decrease was observed at 30 mug treprostinil. In study 3, treprostinil was inhaled at increasing concentrations with a pulsed ultrasonic nebulizer, mimicking a metered dose inhaler. A dose of 15 mug treprostinil was inhaled with 18, 9, 3, 2 pulses, or 1 pulse, each mode achieving comparable, sustained pulmonary vasodilation without significant side effects. CONCLUSIONS: Inhaled treprostinil exerts sustained pulmonary vasodilation with excellent tolerability at relatively low doses and may be inhaled in a few breaths.     

先天性心脏病并重度肺动脉高压患者雾化吸入伊诺前列素的即刻效应

目的 评价雾化吸入伊洛前列素对重度成人先天性心脏病相关性肺动脉高压血液动力学的影响.方法 对165例经超声心动图诊断先天性心脏病合并重度肺动脉高压患者进行左右心导管检查获得基线血液动力学参数后雾化吸入伊洛前列素20 μg,10 min时再记录相关血液动力学资料,对比吸入伊诺前列素前后血液动力学的变化.结果 伊洛前列素吸入结束后即刻和吸入前比较,患者主动脉和肺动脉的压力略有下降(P＜0.05),但心率、主动脉平均压、肺动脉收缩压与主动脉收缩压的比值(Pp/Ps)差异均无统计学意义(P＞0.05).肺循环血量(Qp)明显增加[(7.2±4.8)L/min比(9.9±7.2)L/min,P＜0.01],肺血管阻力(PVR)明显下降[(13.4±8.7)Wood单位比(9.5±6.6)Wood单位,P＜0.01],左向右分流量明显增加[(3.2±4.4)L/min比(5.5±7.0)L/min,P＜0.01]及右向左分流量明显减少[(1.0±1. 0)L/min比(0.7±0.7)L/min,P＜0.01].亚组分析结果提示,不是所有先天性心脏病合并重度肺动脉高压患者血液动力学均呈相同的变换趋势,存在动脉导管未闭和(或)心室间隔缺损患者的肺动脉压力明显高于继发于心房间隔缺损患者,而且更易出现艾森曼格综合征(P＜0.05).结论 伊洛前列素雾化吸入可快速降低先天性心脏病相关性肺动脉高压的压力、肺血管阻力,明显增加右心排血量,对体循环压力及心率影响较小,可以作为评估急性肺血管反应的肺血管扩张剂.

Abstract：

Objective To investigate the immediately effects of inhaled aerosolized iloprost in adult patients with severe pulmonary arterial hypertension(PAH)secondary to congenital heart diseases(CHD).Methods Adult patients with severe PAH secondary to CHD(n = 165)were included in this study. Right heart catheterization was performed, Pulmonary and systemic blood flow, the oxygen consumption VO2(ml/min)were calculated using Fick's principle. Pulmonary vascular resistances(PVR)were calculated with standard formulas and indexed to body surface area. Hemodynamic parameters were measured before and after iloprost inhalation(20 μg). Results Post iloprost inhalation, heart rate, mean aortic pressure, pulmonary systolic pressure to aortic systolic pressure ratio all remained unchanged(P ＞ 0. 05), while pulmonary artery pressure(PAP)were significantly reduced and Qp significantly increased from(7. 2 ±4. 8)L/min to(9. 9 ±7.2)L/min(P＜0.01), PVR was also significantly reduced from(13.4 ±8.7)Wood units to(9.5 ±6. 6)Wood units(P ＜0. 01),and left-to-right shunt volume increased from(3.2 ±4. 4)L/min to(5. 5 ±7.0)L/min(P ＜ 0. 01)and right -to-left shunt volume decreased from(1.0 ± 1.0)L/min to(0. 7 ± 0. 7)L/min(P ＜ 0. 01). Subgroup analysis showed that adult patients with patent ductus arteriosus and/or ventricular septal defects are more likely to develop severe pulmonary arterial hypertension or Eisenmenger syndrome than patients with atrial septal defects. Conclusions Inhaled Aerosolised iloprost use is effective and safe for adult patients with severe pulmonary arterial hypertension secondary to congenital heart diseases.     

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.     

改良心导管测定大鼠肺血管阻力的方法

目的 建立一种简单、可重复性强的测定正常及肺动脉高压大鼠肺血管阻力的方法.方法 雄性Sprague-Dawley( 180 ～ 200 g)大鼠45只,随机分为3组:正常对照组、低剂量野百合碱组(50 mg/kg)和高剂量野百合碱组(60 mg/kg).给予大鼠颈背部皮下一次性注射野百合碱建立肺动脉高压大鼠模型.大鼠肺动脉压力采用自制改良的末端呈圆弧形的PE- 50导管行右心导管法测定.心输出量利用热稀释法原理检测.肺血管阻力由平均肺动脉压力除心输出量得出.结果 三组大鼠肺动脉压力、心输出量及肺血管阻力的检测总成功率均分别为98％、100％和96％,组间差异无统计学意义.注射野百合碱21 d后,低、高剂量野百合碱组大鼠的平均肺动脉压均显著高于对照组[(43.1±0.8)mm Hg(1 mm Hg=0.133 kPa)、(54.8±2.2) mm Hg比(17.4±1.0) mm Hg,P均＜0.001],且高剂量组明显高于低剂量组(P＜0.001).低、高剂量野百合碱组大鼠心输出量均明显低于对照组[(77.5±6.9) ml/min、(71.0+6.7)ml/min比(126.8±3.9) ml/min,P均＜0.001],低、高剂量组间差异无统计学意义.低、高剂量野百合碱组大鼠肺血管阻力均显著高于对照组[(0.56±0.06) mm Hg·min-1·ml-1、(0.76±0.08)mm Hg·min-1·ml-1比(0.13±0.01)mm Hg- min-1·ml-1,P均＜0.001],且高剂量组明显高于低剂量组(P=0.01).结论 采用此方法检测大鼠肺血管阻力准确、可靠、操作性强,具有推广价值.     

Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension

BACKGROUND: Inhalation of iloprost, a stable prostacyclin analog, is an effective therapy for pulmonary hypertension with few side effects. This approach may, however, be handicapped by limitations of currently available nebulization devices. We assessed whether the physical characterization of a device is sufficient to predict drug deposition and pharmacologic effects. METHODS: We investigated the effects of a standardized iloprost aerosol dose (5 micro g; inhaled within approximately 10 min) in 12 patients with severe pulmonary hypertension in a crossover design employing three well-characterized nebulizers. The nebulizers use different techniques to increase efficiency and alveolar targeting (Ilo-Neb/Aerotrap [Nebu-Tec; Elsenfeld, Germany], Ventstream [MedicAid; Bognor Regis, UK], and HaloLite [Profile Therapeutics; Bognor Regis, UK]). Measurements were performed using a Swan-Ganz catheter and determination of arterial iloprost plasma levels. RESULTS: During inhalation of iloprost, the pulmonary vascular resistance decreased substantially (baseline, approximately 1,250 dyne.s.cm(-5); decrease, - 35.5 to - 38.0%) and pulmonary artery pressure decreased substantially (baseline, approximately 58 mm Hg; decline, - 18.4 to -21.8%), whereas the systemic arterial pressure was largely unaffected. Cardiac output and mixed venous and arterial oxygen saturation displayed a marked increase. The pharmacodynamic profiles with the three devices were superimposable. Moreover, rapid entry of iloprost into the systemic circulation was noted, peaking immediately after termination of the inhalation maneuver, with very similar maximum serum concentrations (158 pg/mL, 155 pg/mL, and 157 pg/mL), and half-lives of serum levels (6.5 min, 9.4 min, and 7.7 min) for the three nebulizers, respectively. Interestingly, the "half-life" of the pharmacodynamic effects in the pulmonary vasculature (eg, decrease in pulmonary vascular resistance, ranging between 21 and 25 min) clearly outlasted this serum level-based pharmacokinetic half-life. CONCLUSIONS: A standardized dose of aerosolized iloprost delivered by different nebulizer types induces comparable pharmacodynamic and pharmacokinetic responses. Pulmonary vasodilation, persisting after disappearance of the drug from the systemic circulation, supports the hypothesis that local drug deposition largely contributes to the preferential pulmonary vasodilation in response to inhaled iloprost.     

Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats

Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist, on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT(4w) model group (MCT + saline × 3 wks from the 8th day of MCT injection) and urantide early treatment group (MCT + urantide 10 μg/kg/d × 3 wks, 1 week after MCT injection once). For late treatment experiment, rats were divided as controls, MCT(6w) model group (MCT + saline × 2 wks, 4 weeks after MCT injection once) and urantide late treatment group (MCT + urantide 10 μg/kg/d × 2 wks, 4 weeks after MCT injection once). At the end of experiments, mean pulmonary arterial pressures (mPAP) and mean blood pressure (MBP) of rats in each group were measured by catheterization. Right ventricular weight ratio was also weighed. Relaxation effects of urantide on intralobar pulmonary arterial rings of normal control and MCT(4w) model rats were investigated. Pulmonary artery remodeling was detected by hematoxylin and eosin (HE) staining and immunohistochemistry analysis. Serum nitric oxide (NO) levels in all six groups were assayed by ELISA kits. Urantide markedly reduced the mPAP levels of MCT induced PAH in both early and late treatment groups. It didn't change the MBP. Urantide dose-dependently relaxed the pulmonary arterial rings of normal control and MCT(4w) model rats. Moreover, N(G)-Nitro-l-arginine Methyl Ester (l-NAME) blocked the dilation response induced by urantide. In addition, urantide inhibited the pulmonary vascular remodeling remarkably. Serum NO level elevated in both early and late treatment rats with urantide infusion. These results suggest that urantide effectively alleviated MCT induced rats PAH may through relaxing pulmonary arteries and inhibiting pulmonary vascular remodeling. NO pathway might be one of the mechanisms in urantide induced pulmonary artery dilation. Thus, it is expected that urantide may be a novel therapy for PAH.     

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.     

Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension

RATIONALE: Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH. METHODS: In a randomized, multicenter, double-blind trial, inhaled iloprost (5 mug) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening. MEASUREMENTS AND MAIN RESULTS: A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mm Hg; p < 0.001) and pulmonary vascular resistance (-254 dyn x s x cm(-5); p < 0.001). Combination therapy was well tolerated. CONCLUSIONS: Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.     

Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats

Vascular remodeling, rather than vasoconstriction, is believed to account for high vascular resistance in severe pulmonary arterial hypertension (PAH). We have found previously that acute Rho kinase inhibition nearly normalizes PAH in chronically hypoxic rats that have no occlusive neointimal lesions. Here we examined whether Rho kinase-mediated vasoconstriction was also important in a rat model of severe occlusive PAH. Adult rats were exposed to chronic hypoxia ( approximately 10% O(2)) after subcutaneous injection of the vascular endothelial growth factor receptor inhibitor SUGEN 5416. Hemodynamic measurements were made in anesthetized rats after 2 weeks of hypoxia (early group) and 3 weeks of hypoxia plus 2 weeks of normoxia (late group). Both groups developed PAH, with greater severity in the late group. In the early group, intravenous fasudil was more effective than intravenous bradykinin, inhaled NO, or intravenous iloprost in reducing right ventricular systolic pressure. Despite more occlusive vascular lesions, fasudil also markedly reduced right ventricular systolic pressure in late-stage rats. Blood-perfused lungs from late-stage rats showed spontaneous vasoconstriction, which was reversed partially by the endothelin A receptor blocker BQ123 and completely by fasudil or Y-27632. Phosphorylation of MYPT1, a downstream target of Rho kinase, was increased in lungs from both groups of rats, and fasudil (intravenous) reversed the increased phosphorylation in the late group. Thus, in addition to structural occlusion, Rho kinase-mediated vasoconstriction is an important component of severe PAH in SUGEN 5416/hypoxia-exposed rats, and PAH can be significantly reduced in the setting of a severely remodeled lung circulation if an unconventional vasodilator is used.     

Cilostazol therapy attenuates monocrotaline-induced pulmonary arterial hypertension in rat model.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by a proliferation of vascular endothelial and smooth muscle cells, resulting in occlusion of the lumen of small pulmonary arteries. Cilostazol, with its antiproliferative effects on vascular endothelial and smooth muscle cells, may ameliorate monocrotaline (MCT)-induced PAH in rats. METHODS AND RESULTS: Male Sprague - Dawley rats (n=10/each group) were randomized to receive MCT (75 mg/kg) only (group 1), MCT plus cilostazol (20 mg .kg(-1 ). day(-1)) (group 2) and saline injection only (group 3). Hemodynamic measurement on day 28 following MCT treatment indicated the development of significant PAH on MCT-treated groups (p<0.0001). Cilostazol was given to group 2 orally on days 28-90. By day 90 following MCT treatment, the right ventricular (RV) systolic blood pressure and RV hypertrophy were significantly higher in group 1 than in groups 2 and 3 (all values of p<0.01). Additionally, connexin43 and endothelial nitric oxide synthase gene expressions of lung and RV, and Bcl-2 protein expression of RV, were significantly lower in group 1 than in groups 2 and 3 (all values of p<0.01). Furthermore, the number of alveolar sac and small arterioles of the lung were significantly lower in group 1 than in groups 2 and 3 (all values of p<0.01). CONCLUSION: Cilostazol therapy effectively attenuates of MCT-induced PAH.     

Acute resynchronization with inhaled iloprost in a pregnant woman with idiopathic pulmonary artery hypertension.

We describe the case of a pregnant woman with idiopathic pulmonary arterial hypertension, a responder in right heart catheterization, followed since the first trimester in outpatient consultations, admitted to hospital at 23 weeks gestation. She was treated with inhaled iloprost until delivery (at 34 weeks gestation) and continuous infusion of iloprost throughout the perioperative period and following days. This line of therapy has proved efficacious in previous cases. The authors present echocardiographic images that document acute changes in ventricular synchrony during inhalation of iloprost.     

Preventive treatment with atorvastatin ameliorates endothelial dysfunction of small pulmonary arteries in monocrotaline-induced pulmonary hypertensive rats

This study examined the effects of preventive atorvastatin (Ator) treatment on vasodilatation of small pulmonary arteries (SPAs) in monocrotaline (MCT)-induced pulmonary hypertensive rats. SD rats were randomly assigned to: normal control (Ctr), pulmonary arterial hypertension (PAH), PAH treated with 5 mg/kg/d Ator (LAtor), or 10 mg/kg/d Ator (HAtor). PAH was induced by MCT injection (40 mg/kg, i.p.). Mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI%), endothelium-dependent relaxations (EDdRs), and endothelium-independent relaxations (EDiRs) were determined. Four weeks after MCT injection, mPAP was higher in PAH group compared to that in Ctr group, and this effect was suppressed by Ator treatment (PAH: 32.19 ± 0.91 mm Hg vs. LAtor: 19.13 ± 1.01 mm Hg, HAtor: 17.55 ± 0.20 mm Hg, p < 0.05). Similar trend of changes in RVHI% was found in the same way. EDdRs of SPA rings in PAH group were markedly decreased 2 and 4 weeks after MCT injection, while in Ator treated groups, the impairment can only be detected 4 weeks after MCT injection. There were no differences in EDiRs among all groups 1 week after MCT injection. However, 2 weeks and 4 weeks after MCT injection, EDiRs were significantly impaired, while in HAtor and LAtor groups, EDiR was only impaired 4 weeks but not 2 weeks after MCT injection. Preventive treatment with atorvastatin for 2 weeks ameliorated endothelium-dependent and endothelium-independent vasodilative dysfunction in small pulmonary artery rings of MCT-induced PAH rats. It suggests that MCT-induced damage of endothelial function was progressing, and Ator was only beneficial in the early stage of MCT-induced PAH.     

Chronic thromboembolic and pulmonary arterial hypertension share acute vasoreactivity properties

BACKGROUND: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the major classes of pulmonary hypertensive disorders according to the World Health Organization; both lead to right heart failure and death. A better understanding of disease mechanisms has led to the suggestion that the thromboembolic and nonthromboembolic types of pulmonary hypertension may share pathophysiologic features. We therefore compared acute vasoreactivity and proximal pulmonary artery compliance in patients with PAH and CTEPH during the initial diagnostic heart catheterization. METHODS: Right heart catheterization using a flow-directed Swan-Ganz catheter was performed in patients with CTEPH (n = 22) and PAH (n = 35). Pulmonary hemodynamics were assessed at baseline, during the inhalation of 40 ppm of nitric oxide, and 30 min after the inhalation of 10 mug of iloprost. To assess the proximal pulmonary artery compliance, the pulse pressure (PP) [systolic-diastolic pressure] and the fractional PP (PPf) [divided by the mean pressure] were calculated. RESULTS: Both vasodilators produced similar hemodynamic improvement, and the difference between CTEPH and PAH was not significant. The baseline PP and PPf did not vary between the two groups. CONCLUSION: Patients with PAH and CTEPH show similar acute vasoreactivity to inhaled nitric oxide and iloprost, and have similar pulmonary artery compliance. These findings support the presence of some shared pathophysiologic pathways in both disorders and may lead to therapeutic implications in patients with inoperable CTEPH.     

Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension

Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.