Nitroglycerin and isosorbide dinitrate in pulmonary hypertension of chronic obstructive pulmonary disease

The effects of sublingual isosorbide dinitrate (ISDN; 10 mg) or nitroglycerin (NTG; 1 mg) on pulmonary hemodynamics, gas exchange and pulmonary function were studied during right heart catheterization in two series of 27 patients with COPD. An immediate significant decrease of pulmonary arterial pressure, cardiac output and work of the right ventricle was obtained with both drugs, but NTG only was able to reduce the pulmonary vascular resistance. Arterial oxygen tension did not decrease, but venous O2 tension did, with no change in blood lactate. NTG had also a slight bronchodilating effect. After chronic use, no improvement of pulmonary function or gas exchange was observed but NTG lowered pulmonary vascular resistances significantly. The effects observed during the acute study were reproduced after six weeks with the same doses of both drugs. NTG appears effective in reducing pulmonary arterial hypertension mainly by vasodilation while the ISDN effect seems due only to the decreased cardiac output.     

Pyrrolidine dithiocarbamate attenuates the development of monocrotaline-induced pulmonary arterial hypertension

We aimed to demonstrate the potential protective effects of pyrrolidine dithiocarbamate (PDTC) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Adult male rats were randomly assigned to 4 groups: control group, MCT-treated rats only, MCT-injected rats treated with PDTC, and PDTC-treated rats only. Blood and tissue samples were collected after the sacrifice. Levels of malondialdehyde (MDA) were measured by using the thiobarbituric acid method. Total antioxidant status (TAS) was determined using a commercially available ImAnOx kit. A histopathological evaluation was accomplished by scoring the degree of severity. Endothelial damage of the main pulmonary artery was evaluated by immunohistochemical labeling of endothelial cells using anti-rat endothelial cell antigen 1 (RECA-1) antibody. MCT-induced right ventricular hypertrophy (RVH) was reduced significantly in the MCT + PDTC-treated group. MDA levels were significantly lowered in the MCT + PDTC-treated group. TAS was significantly higher in the MCT + PDTC-treated group when compared with the rats with PAH. Histopathological examination demonstrated that PDTC treatment reduced the development of inflammation, hemorrhage and congestion, and collagen deposition. In conclusion, PDTC attenuated PAH and protected pulmonary endothelium in rats administered MCT. These findings suggest that PDTC treatment may provide a new effective therapeutic approach in the treatment of PAH.     

Management of hypertension emergencies in elderly patients with isosorbide dinitrate aerosol

In this clinical trial, we assessed the effectiveness and safety of isosorbide dinitrate spray administered through the oral mucosa in 20 elderly patients (> 60 years old) with a hypertensive emergency (mean arterial pressure > 140 mmHg and target-organ damage). The patents were given a first dose of 1.25 mg of spray when they were admitted; a second dose was administered 15 min. later if the mean arterial pressure had not decreased by > 15%. An electrocardiogram (ECG) was done on every patient immediately prior and 30 min. after administering the medication. Three patients (15%) had a good response with one dose while 17 patients (85%) required a second dose. Thirty patients had a significant reduction in arterial blood pressure (193 +/- 91,123 +/- 5.4 to 154 + 7.1/92.5 + 6.2 mmHg p < 0.005) as well as of the mean arterial pressure (146.8 +/- B to 113 +/- 5 mmHg 23%, p < 0.005 > in a period of 30 min. No adverse effects, rebound hypertension nor severe hypotension were observed. These figures remained under control for 3 h. Both ECG, were normal. A reduction of 13.5% heart rate was obtained (p < 0.005). Our observations suggest that isosorbide dinitrate aerosol is an effective and safe alternative for the treatment of elderly patients with hypertensive emergencies.     

Effect of intervals between doses on the development of tolerance to isosorbide dinitrate

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.     

Quercetin attenuates the progression of monocrotaline-induced pulmonary hypertension in rats

Pulmonary arterial hypertension (PAH) is a progressive disease associated with increased constriction and remodeling of the pulmonary vasculature.Quercetin is a natural flavonoid and has a variety of pharmacological effects including improvement of endothelial cell function.However,its pharmacological effects on pulmonary hypertension have been rarely reported.We sought to observe the protective effect of quercetin in rats with monocrotaline induced PAH.We divided 30 male Sprague-Dawley rats randomly into three groups with ten rats in each group:the monocrotaline group,the quercetin group and the control group.We found that,compared with the controls,the mean pulmonary artery pressure (mPAP) and the right ventricular hypertrophy index in the monocrotaline group were significantly higher (P < 0.01).Quercetin caused a significant reduction both in the mPAP and right ventricular hypertrophy index compared with the monocrotaline group (P < 0.01) while no difference was found between the quercetin group and the control group (P > 0.05).Monocrotaline induced a marked increase in the wall thickness (WT) in small and mid-sized pulmonary arteries compared with the controls (P < 0.01).Monocrotaline also induced a marked increase in the wall area (WA) in small [(56.38±6.65)% in monocrotaline vs.(19.80±4.63)% in control] and mid-sized [(43.71±5.38)% in monocrotaline vs.(14.24±3.66)% in control] pulmonary arteries (P < 0.01).Quercetin treatment markedly reduced monocrotaline induced increase in both WT and WA (P < 0.01),which,however,still remained significantly elevated compared with those of the controls (P < 0.01).Furthermore,compared with controls,proliferating cell nuclear antigen (PCNA) expression in the pulmonary artery tissues was markedly increased by monocrotaline [(45.59±1.27) in monocrotaline vs.(9.64±0.69) in controls],which was significantly attenuated by quercetin.Our animal experiment indicated that quercetin could have protective effects on monocrotaline-induced PAH.     

Changes in main pulmonary artery of rats with monocrotaline-induced pulmonary hypertension

Hypertension is one of the most important risk factors for atherosclerosis, yet no morphologic evidence exists to explain it. This study is an attempt to identify lesions in the main pulmonary artery of rats in which pulmonary hypertension was induced by a single dose of monocrotaline. Pulmonary artery pressure was measured directly by catheterization or indirectly by measuring right ventricular thickness. Lesions were studied by both light and electron microscopy. As in previous studies in which monocrotaline was given chronically, we found thickening of the main pulmonary artery. We also found widening of subendothelial space, change in smooth-muscle cell polarity, shape, and organelle content (indicating change from contractile to secretory), focal areas of muscle necrosis and elastolysis. Interestingly, cardiac muscle was observed in adventitia of both controls and treated animals.     

5-羟色胺在野百合碱引起大鼠肺动脉高压发病中的作用

目的：探讨５－ＨＴ在ＭＣＴ性肺动脉高压中的作用。方法：用免疫组化方法和图象分析技术,测定肺组织中５－ＨＴ及其受体的变化;采用ＭＴＴ法和测微网及钙荧光指示剂Ｆｕｒａ２／Ａｍ测定培养的肺动脉平滑肌细胞生长情况和收缩功能以及细胞内游离Ｃａ２＋浓度。结果：发现ＭＣＴ引起大鼠肺动脉高压时肺组织中５－ＨＴ（１２７４９４±２０７３６／ｍｍ２）及其受体（１４６２４±３０１０／ｍｍ２）阳性细胞数目比对照组（３７２０±１０１８,３４３０±８２１／ｍｍ２）的均显著增加（Ｐ＜００１）。５－ＨＴ能使培养的肺动脉平滑肌细胞增生和收缩这种作用与其引起的Ｃａ２＋内流有关。结论：５－ＨＴ的收缩血管作用和促血管平滑肌细胞增殖作用在ＭＣＴ性肺动脉高压的发病机制中可能具有重要的意义     

过表达miRNA-29a对野百合碱诱导的大鼠肺动脉高压的作用

目的:检测微小RNA(miRNA)-29a在野百合碱诱导的肺动脉高压大鼠肺动脉血管壁组织中的表达,研究过表达miRNA-29a对肺动脉高压大鼠的影响,并探讨其初步机制。方法:在野百合碱诱导的肺动脉高压大鼠模型上,用实时荧光定量PCR测定肺组织miRNA-29a的表达水平;尾静脉注射miRNA-29a-mimic后,记录大鼠肺动脉压和体循环动脉压,苏木素-伊红染色观察肺动脉组织的形态,Western blot检测肺动脉组织中p-Akt与peNOS的蛋白水平。结果:野百合碱诱导的肺动脉高压大鼠肺动脉血管壁组织中miRNA-29a呈低表达;过表达miRNA-29a后,大鼠肺动脉压明显下降,体循环血压无显著变化,肺动脉中膜增厚程度显著减弱,肺血管重构现象不明显,p-Akt与p-eNOS的蛋白水平上调。结论:过表达miRNA-29a对野百合碱诱导的大鼠肺动脉高压具有改善作用,可能与激活PI3k/Akt-eNOS信号通路有关。     

Long-term research of stem cells in monocrotaline-induced pulmonary arterial hypertension

Our previous studies have shown that bone marrow mesenchymal stem cells (BMSCs) can inhibit the progression of pulmonary artery hypertension (PAH) in the monocrotaline (MCT) model in the short term. The aim of this study was to further investigate the long-term effect of BMSCs on PAH and to explore the mechanism of the protective effect including the pulmonary vascular remodeling and cell differentiation. PAH model was established by subcutaneous injection of 50 mg/kg MCT as previously study. Postoperatively, the animals were randomly divided into three groups (n = 10 in each group): control, PAH group, and BMSCs implantation group. Six months after injection, immunology and immunohistochemistry analysis indicated the MCT-induced intima-media thickness in muscular arteries was reduced (P < 0.05); the area of collagen fibers in lung tissue was lower (P < 0.05), and the proliferating cell nuclear antigen level in pulmonary artery smooth muscle cells was decreased (P < 0.05). Immunofluorescence showed that the cells have the ability to differentiate between von Willebrand factor and vascular endothelial growth factor. Six months after intravenous injection, BMSCs could significantly improve pulmonary function by inhibiting the ventricular remodeling and the effect of cell differentiation.     

Comparative effects of etodolac,indomethacin, and benoxaprofen on icosanoid biosynthesis

Etodolac (Ultradol^®) is a new tetrahydropyrano-indole derivative which has shown pronounced analgesic and antiinflammatory properties. Its effects on the different pathways of metabolism of arachidonic acid have been studied and compared to the effects of indomethacin and benoxaprofen. All three drugs tested inhibited the cyclooxygenase activity of the parenchyma as assessed by inhibition of LTB₄- and LTD₄-induced contraction. However, the activity of human polymorphonuclear leukocyte 5-lipoxygenase and of human platelet 12-lipoxygenase was inhibited only by very high concentrations (1×10^–4 M and over) of these compounds, whereas nordihydroguaiaretic acid (NDGA) was active at concentrations 100 times lower. In the Schultz-Dale reaction of the guinea pig trachea, etodolac, benoxaprofen, and indomethacin produced increases of the myotropic contractile activity of the tissues sensitized to qvalbumin. Our results do not lend support to the hypothesis that the mechanism of action of these antiinflammatory drugs is linked to the inhibition of lipoxygenases.     

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate

Summary The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min,P<0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.Abbreviations AUC Area under curve - ISDN Isosorbide dinitrate - ISMN Isosorbide-5-mononitrate Supported in part by grant OC 10/6-4 from the Deutsche Forschungsgemeinschaft, and a grant from Boehringer Mannheim, Federal Republic of Germany     

Comparative effects of carprofen,benoxaprofen and indomethacin on the development and decay phases of a carrageenan pleurisy in the rat

The effects of three non-steroidal anti-inflammatory drugs (NSAID), carprofen, benoxaprofen and indomethacin, on 4-hour and 24-hour carrageenan pleurisy, has been investigated. All three compounds inhibited both the oedematous and cellular components of the 4-hour pleurisy. In the 24-hour pleurisy only indomethacin affected cell accumulation and the inhibitory effect observed was selective for mononuclear cells. The volume of exudate recovered from the pleural cavity at 24 hours, in animals which had received any of the three drugs, was greater than in animals receiving vehicle. The results of a time-course experiment with indomethacin suggest that the observed effects of the NSAID may be a consequence of their inhibition of both the development and decay phases of the pleural inflammation, particularly with regard to the exudative component of the response.     

氟西汀对BMPR2表达的影响以及对野百合碱诱导大鼠肺动脉高压的预防作用

目的探讨氟西汀对骨形态生成蛋白受体2(bone morphogenetic protein receptor 2,BMPR2)表达的影响以及对野百合碱(monocrotaline,MCT)诱导大鼠肺动脉高压(pulmonary arterial hypertension,PAH)的预防作用。方法将24只Wistar大鼠随机分成三组:对照组、MCT组和氟西汀处理组。采用多导生理记录仪测量血流动力学相关指标,HE染色方法观察肺动脉的形态学改变,以及利用RT-PCR方法检测肺动脉BMPR2的表达。结果与对照组相比,MCT组肺动脉压力、肺动脉中膜厚度百分比以及右心肥厚指数均明显升高,BMPR2在肺动脉上的表达明显减少(<0.01)。给予氟西汀处理后,氟西汀明显抑制了MCT诱发的肺动脉压力的升高、肺动脉重构和右心肥厚,并逆转了BMPR2的表达(<0.05)。结论肺动脉的构型重建可能与BMPR2的表达减少有关。氟西汀可能通过逆转BMPR2的表达有效地预防MCT诱导的PAH。     

端粒酶逆转录酶在野百合碱性大鼠肺动脉高压中的作用

目的:观察端粒酶逆转录酶(TERT)在野百合碱(MCT)性肺动脉高压(PH)大鼠模型中的肺组织中的表达变化。方法:用MCT复制大鼠慢性PH病理模型,用电磁血流量计观察肺血流动力学指标变化,用免疫组化法和图像分析技术测定肺组织中TERT的表达。结果:发现TERT可在大鼠肺血管平滑肌、支气管平滑肌和软骨组织中表达,并且MCT组肺组织中TERT表达较正常组呈明显阳性。结论:MCT性PH时TERT在肺血管平滑肌、支气管平滑肌的过度表达在MCT性PH的发病机制中可能具有重要意义。     

Differential effects of prednisolone and indomethacin on zymosaninduced inflammation in a modified murine tissue-chamber model

A tissue-chamber model of inflammation in mice has been modified and used to investigate the kinetics of zymosan-induced inflammatory mediators such as tumour necrosis factor (TNF), interleukin-1 (IL-1) and prostaglandin E₂ (PGE₂). In addition, the influx of polymorphonuclear leukocytes (PMN) into the chamber fluid and the granuloma surrounding the chamber was measured by myeloperoxidase (MPO) activity using a new microtitre plate assay. TNF and IL-1 reached peak concentrations at 3 and 6 h respectively after zymosan injection. Intermediate high concentrations of IL-1 were observed until the end of the experiment at 72 h, but TNF concentrations decreased from 24 h to biologically insignificant values. In contrast, exudate PGE₂ and MPO activity increased up to 24 h after zymosan injection and remained high until 72 h. At 6h after zymosan challenge, oral pre-treatment with prednisolone (3 to 30mg/kg) dose-dependently reduced TNF, IL-1 and PGE₂ concentrations while indomethacin (0.3 to 3 mg/kg) significantly attenuated PGE₂, slightly enhanced TNF and had no effect on IL-1 concentrations in the exudate. Both drugs had similar potencies against exudate and tissue MPO activities. Prednisolone inhibited IL-1 at 72 h post-zymosan. Indomethacin was more potent than prednisolone against PGE₂ (ID₅₀ of <0.3 versus 0.6mg/kg). The data obtained confirm the usefulness and reliability of this model in evaluating the effects of anti-inflammatory agents on inflammatory mediators induced by zymosan.     

Improvement of exercise capacity in monocrotaline-induced pulmonary hypertension by the phosphodiesterase-5 inhibitor Vardenafil

Vardenafil, a phosphodiesterase-5 inhibitor, is approved for the therapy of erectile dysfunction. However, in contrast to Sildenafil and Tadalafil, little is known about its effects on pulmonary hypertension.