The link between angiotensin-converting enzyme genotype and pulmonary artery pressure in patients with COPD

OBJECTIVE: The insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of cardiovascular diseases. In patients with primary pulmonary hypertension, the homozygous ACE DD genotype is more prevalent than the non-DD genotype. However, the relationship of ACE gene polymorphism to secondary pulmonary hypertension remains unclear, and ethnicity may be one of the factors that can modulate the effects of ACE genotypes reported in different studies. We hypothesized that in patients with chronic obstructive pulmonary disease (COPD) the presence of the D allele in the ACE gene polymorphism is associated with increased pulmonary artery pressure (Ppa). PATIENTS AND METHODS: Bodyplethysmography was used to assess lung function in 66 consecutive patients with COPD; pulmonary artery pressures were determined using echocardiography. ACE gene I/D polymorphism was identified with the polymerase chain reaction. 118 healthy persons served as the control group. All patients and controls were Caucasian. Genotype II was identified in 15 patients with COPD, genotype ID in 31 and genotype DD in 20. In the control group, genotype II was identified in 19 persons, genotype ID in 68 and genotype DD in 31. The distribution of ACE gene polymorphism did not differ between patients and the control group. RESULTS: In patients with COPD, no differences were seen between the three genotype groups in mean age, smoking history, hemoglobin concentrations or ventilometric or blood gas variables. Both systolic and mean Ppa differed significantly between the II, ID and DD groups (Systolic Ppa: 24.4 +/- 2.2 versus 31.3 +/- 2.5 and 36.7 +/- 3.9 mm Hg, respectively, ANOVA, p < 0.05; Mean Ppa: 13.0 +/- 1.5 versus 17.5 +/- 1.4 and 21.2 +/- 2.8 mm Hg, respectively, ANOVA, p < 0.05). In multiple linear regression analysis, the I/D ACE gene polymorphism (p < 0.05), SaO2 (p < 0.05) and the duration of COPD (p < 0.02) were independent predictors of systolic and mean Ppa. CONCLUSION: The results of the study suggest that I/D ACE gene polymorphism is linked to pulmonary artery pressure in Caucasian patients with COPD.     

The degree of exercise hypoxemia reflects pulmonary artery pressure during early exercise in chronic obstructive pulmonary disease patients

The causes of both exertional pulmonary hypertension and pulmonary hypertension in general in chronic obstructive pulmonary disease (COPD) remain to be elucidated. To further understand the pathophysiology in COPD patients, it may be important to recognize the existence of exertional pulmonary hypertension and to determine the severity of exertional hypoxemia. However, little is known about their relationship. To investigate whether the severity of exertional hypoxemia, as evaluated by the Deltaartery oxygen tension/Deltaoxygen consumption (PaO(2)-slope) correlates with the mean pulmonary artery pressure (Ppa), cardiopulmonary exercise testing with haemodynamics was done in 10 patients with moderate to very severe COPD. The PaO(2)-slope was significantly correlated with the mean Ppa from 25% to 40% of the maximum Watts (Wmax), and was most significant at 30% Wmax (r = -0.904, P<0.0001). In this phase, all parameters, except for the mean Ppa and the mixed venous oxygen tension, were not markedly changed from resting levels. At 30% Wmax, the mean Ppa (mean, 27 mmHg) with no or mild hypoxemia was also significantly correlated with the Deltaartery oxygen saturation/Deltaoxygen consumption (SpO(2)-slope) (r = -0.789, P = 0.004). On stepwise multiple regression analysis, the PaO(2)-slope was the most significant predictor of mean Ppa at 30% Wmax. In conclusion, the PaO(2)-slope and the SpO(2)-slope reflect Ppa during the early exercise phase. Thus, assessment of these parameters could be useful to evaluate the cardiopulmonary haemodynamic pathophysiology of COPD patients.     

Lipid peroxidation and antioxidant system in the blood of patients with Hodgkin's disease

OBJECTIVES: The purpose of this study was to measure the extent of lipid peroxidation and the status of antioxidants in patients with Hodgkin's disease.DESIGN AND METHODS: Glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities, and malondialdehyde (MDA), selenium, zinc and copper content have been measured in 20 patients with Hodgkin's disease and 30 age-matched controls.RESULTS: Significantly higher concentrations of MDA in plasma as well as in erythrocytes were found compared to the control group. In both plasma and erythrocytes, GPX activity, selenium and zinc levels were significantly lower in patients than in controls. However, SOD activity in erythrocytes and copper levels in both plasma and erythrocytes were significantly higher in patients.CONCLUSION: We conclude that the antioxidant system is impaired in Hodgkin's disease due to the abnormal metabolism of trace elements and antioxidant enzymes.     

Efficacy of a cardioselective beta1-adrenoblocker bisoprolol in patients with chronic obstructive pulmonary disease in combination with ischemic heart disease

AIM: To study effects of a selective beta1-adrenoblocker (B1AB) bisoprolol fumarate (conkor, Nikomed, Germany) on severity of pulmonary hypertension (PH), bronchial obstruction and bioelectric activity of the myocardium in patients with chronic obstructive pulmonary disease (COPD) associated with ischemic heart disease (IHD). MATERIAL AND METHODS: Effects of an 8-week course of bisoprolol therapy on pulmonary hypertension, its efficacy and safety were studied in 30 IHD patients with COPD of stage III-IV on broncholytic therapy. The comparison group consisted of 45 IHD patients with COPD untreated with basic bisoprolol therapy. The following parameters were assessed: chest x-ray data, mean pulmonary artery pressure (MPAP) by echocardiography findings, frequency of anginal attacks by ECG monitoring, bronchial permeability by investigation of external respiration function, partial pressure and carbonic gas in blood, oxygen blood saturation (pO2, pCO2 and SaO2). RESULTS: Bisoprolol has decreased MPAP from 23.8 +/- 0.8 mmHg to 21.9 +/- 1.0 mmHg, by 8%, p < 0.05; frequency of anginal attacks, heart rate from 82.2 +/- 1.4 to 73.2 +/- 1.5 b/min; number of episodes of ST segment depression from 2.35 +/- 0.43 to 0.95 +/- 0.22, p < 0.01; total duration of ST segment depression from 10.1 +/- 2.54 to 2.89 +/- 0.76 min, p < 0.01; number of supraventricular and ventricular extrasystoles for 24 hours from 194.5 +/- 74.4 to 96.2 +/- 27.4 and from 239.1 +/- 124.9 to 111.3 +/- 44.1, respectively. Parameters of a 6 min walk test improved from 326.7 to 442 m, p < 0.01. Bisoprolol had no negative effect on bronchial obstruction. CONCLUSION: Bisoprolol is well tolerated, effective and safe in COPD patients with IHD.     

慢性阻塞性肺疾病患者氧自由基代谢对肺血流动力学的影响

目的 探讨氧自由基代谢在慢性阻塞性肺疾病（COPD）发病机制中的作用.方法 采用生化、放射免疫方法,测定 39例 COPD患者血液 MDA, SOD,ET-1, ACE,并进行血气和血流动力学参数测定.结果COPD患者 MDA水平均较正常对照组（C组）增高,而肺动脉高压组（B组）患者 MDA又较非肺动脉高压组（A组）明显增高 (F=25.30, P< 0.01)； B组患者 SOD活性较 A组和 C组明显降低 (F=4.56,P< 0.05),所有 COPD患者肺动脉血 SOD均较桡动脉血和周围静脉血明显降低 (F=6.33, P< 0.01 ). B组患者 ET-1和 ACE均较 A组和 C组明显增高（F=9.251～ 13.96, P < 0.01 ）；所有 COPD患者肺动脉血 ACE均较桡动脉血和周围静脉血明显增高（ F=10.95,P< 0.01）.肺动脉血中 MDA与 mPAP, PVRI呈正相关,与 PaO2呈负相关； ET-1与 mPAP , PVRI, TPRI呈正相关；多元回归分析显示 MDA和 ET-1分别作为独立因素影响 mPAP,其中 MDA对 mPAP的影响力大于 ET-1. 结论 COPD患者体内常处在氧化反应增强,抗氧化能力降低的氧化胁迫状态.氧自由基通过直接损伤血管内皮细胞,导致内皮功能失调,参与肺动脉高压的形成和发展.     

高原地区肺心病患者血清碱性成纤维细胞生长因子水平与肺动脉压的关系

目的探讨血清碱性成纤维细胞生长因子(bFGF)在低氧性肺动脉高压发病中的作用。方法采用双抗体夹心酶联免疫吸附法(ELISA)检测高原地区(海拔2260~3300m)38例慢性肺源性心脏病(肺心病)急性加重期患者、30例慢性阻塞性肺疾病(COPD)缓解期患者和30例当地健康人血清bFGF含量,并使用彩色多普勒超声心动仪测定肺动脉血流频谱,计算平均肺动脉压(MPAP),使用血气分析仪测定动脉血氧分压(PaO2)。结果肺心病组血清bFGF(87.54±12.15)ng/L、MPAP(45.86±5.63)mmHg(1mmHg=0.133kPa)显著高于COPD组分别为(55.72±9.08)ng/L和(22.95±2.56)mmHg,P均<0.01,COPD组显著高于健康对照组分别为(49.83±8.78)ng/L和(20.34±2.23)mmHg,P均<0.05;肺心病组PaO2(38.79±4.56)mmHg显著低于COPD组(58.22±6.18)mmHg,P<0.01,COPD组则显著低于健康对照组(66.57±5.48)mmHg,P<0.01。肺心病组和COPD组血清bFGF水平与MPAP均呈显著正相关(r肺心病=0.788,rCOPD=0.674,P均<0.01),与PaO2均呈显著负相关(r肺心病=-0.735,rCOPD=-0.587,P均<0.01)。结论慢性肺心病患者血清bFGF水平明显升高,可能与其慢性低氧性肺动脉高压形成有一定关系。     

Oxidative stress and antioxidant status in non-metastatic prostate cancer and benign prostatic hyperplasia

OBJECTIVES: We undertook the present study to investigate the possible alteration of oxidant/antioxidant status in the circulation of patients with prostate cancer and benign prostatic hyperplasia. DESIGN AND METHODS: Thiobarbituric acid reactive substances (TBARS), the enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT) and copper (Cu) and zinc (Zn) levels were estimated in the erythrocytes of 25 non-metastatic prostate cancer patients, 36 benign prostatic hyperplasia (BPH) patients and 24 age- and sex-matched healthy subjects (controls). RESULTS: TBARS concentrations were significantly increased, while erythrocyte GPX and SOD activities were significantly decreased in the prostate cancer group versus controls (P < 0.001) and BPH group (P < 0.05). Zn levels were lowered in prostate cancer patients versus controls (P < 0.01) with no significant changes between BPH and cancer groups. Similarly, lipid peroxidation was increased (P < 0.05) with decreased SOD activity and Zn level (P < 0.05) in BPH versus controls. CONCLUSION: These results reveal an alteration in the lipid peroxidation index, with concomitant changes in the antioxidant defense system in prostate cancer patients compared to BPH patients. We hypothesize that an altered prooxidant-antioxidant balance may lead to an increase in oxidative damage and consequently may play an important role in prostate carcinogenesis.     

Influence of cardiac output level on oxygen exchange in chronic obstructive pulmonary disease patients

STUDY OBJECTIVES: In the course of chronic obstructive pulmonary disease (COPD), pulmonary gas exchange deteriorates as a result of ventilation/perfusion inequalities and hypoxaemia. The aim of the present study was to evaluate the influence of cardiac output (CO) level observed at rest in COPD patients on interaction between central and peripheral O(2) exchange. METHODS: One hundred and nine patients with advanced but stable COPD were analysed in a retrospective study by the multiple inert gas elimination technique. As a function of CO, simulations were conducted to evaluate the respective part of PvO(2) and VA/Q inequalities on the degree of hypoxaemia. MEASUREMENTS AND RESULTS: PaO(2) was linked (i) to cardiac index (CI), (ii) to mean VA/Q ratio of blood flow distribution and (iii) to PvO(2), but PvO(2) was not correlated with CO. By comparing two groups with CI above and below the mean value of the series respectively, a significant difference was identified in PaO(2) (57 +/- 9 mmHg in the high CI group versus 63 +/- 10 mmHg in the low CI group, P<0.05) because of higher VA/Q inequalities in the high CI group. Comparing two other groups with values of PvO(2) above and below the mean value of the series respectively, a significant difference was identified in PaO(2): (mean +/- SD was 65 +/- 8 in high PvO(2) group versus 56 +/- 9 mmHg, P<0.001) but with no difference in either CI or perfusion distribution. Analysis of the cumulated effects of PvO(2) and CI values, indicated that high CI and low PvO(2) gave rise to the lowest PaO(2) (53 +/- 8 mmHg), with the highest PaO(2) (68 +/- 8 mmHg) being found in the low CI and normal PvO(2) group. CONCLUSIONS: We concluded that in COPD patients, PaO(2) appeared to be maintained better when peripheral gas exchange coped with tissue demand without an increase in CO. Conversely, when the physiological increase in CO could not maintain adequate tissue gas exchange, PaO(2) continued to fall due to the cumulative effects of increasing CO on VA/Q inequalities and low PvO(2).     

Effects of irbesartan on intracellular antioxidant enzyme expression and activity in adolescents and young adults with early diabetic angiopathy

OBJECTIVE: Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. The objective of this study was to evaluate the effects of irbesartan, an angiotensin II receptor antagonist, on IAP in adolescents and young adults with type 1 diabetes and early signs of retinopathy and nephropathy. RESEARCH DESIGN AND METHODS: This prospective, matched case-control study was conducted between November 2001 and December 2002 among 14 type 1 diabetic patients with early signs of angiopathy (ages 14-21 years), 11 type 1 diabetic patients without angiopathy (ages 12-22 years), and 10 healthy volunteers (ages 16-22 years). Skin fibroblasts were obtained by skin biopsies from the anterior part of the forearm and cultured in Dulbecco's modified Eagle's medium. The activity and mRNA expression of CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) were measured before and after 6 months of treatment with irbesartan (150 mg/day); on both occasions, antioxidant enzyme activity was evaluated at different glucose concentrations (5 and 22 mmol/l). RESULTS: At a normal glucose concentration (5 mmol/l), the activity and mRNA expression of CuZnSOD (0.50 +/- 0.21 units/mg protein, 4.4 +/- 1.5 mRNA/glyceraldehyde-3-phosphate dehydrogenase), MnSOD (0.26 +/- 0.04 units/mg protein, 0.08 +/- 0.07 mRNA), CAT (0.32 +/- 0.08 units/mg protein, 4.8 +/- 1.3 mRNA), and GPX (0.53 +/- 0.09 units/mg protein, 2.2 +/- 0.9 mRNA) were not different among the three groups (only values of diabetic subjects with angiopathy are shown). At high glucose concentrations, the activity and mRNA expression of CuZnSOD increased similarly in all groups (diabetic subjects with angiopathy: 0.93 +/- 0.26 units/mg protein, 9.4 +/- 2.1 mRNA); that of CAT and GPX increased in only control subjects and diabetic subjects without angiopathy (diabetic subjects with angiopathy: 0.33 +/- 0.09 units/mg protein and 5.0 +/- 1.4 mRNA; 0.54 +/- 0.10 units/mg protein and 2.3 +/- 1.0 mRNA, respectively). MnSOD did not change in any group. Treatment with irbesartan in adolescents with diabetic angiopathy was able to restore CAT and GPX activity and mRNA expression after exposure to high glucose concentrations. Markers of oxidative stress (serum malondialdehyde, fluorescent products of lipid peroxidation, monocyte chemoattractant protein-1, and 8-isoprostanes prostaglandin F(2alpha)) were significantly reduced after treatment with irbesartan. CONCLUSIONS: Adolescents and young adults with early signs of diabetic angiopathy have defective intracellular antioxidant enzyme production and activity. Treatment with irbesartan can substantially improve the activity and production of these enzymes in skin fibroblasts.     

Hemodynamic effects of vasodilators on pulmonary hypertension in decompensated chronic obstructive pulmonary disease

Vasodilators have been reported to improve the hemodynamic status of some patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD). We investigated the effects of sodium nitroprusside (50 micrograms/min) and hydralazine (25 mg) on pulmonary hemodynamics in 12 patients during acute exacerbation of COPD. Apart from its known systemic effects, nitroprusside decreased significantly mean pulmonary artery pressure (MPAP) from 36 +/- 10 to 31 +/- 12 mm Hg (p less than .04), decreased slightly pulmonary vascular resistance, and did not change cardiac index. Except for a slight but significant increase in MPAP from 35 +/- 5 to 38 +/- 5 mm Hg (p less than .002), hydralazine produced no significant hemodynamic changes. These results suggest that vasodilator therapy with sodium nitroprusside and hydralazine for pulmonary hypertension secondary to acute COPD is probably not helpful.     

Glutathione S-transferase M1 gene polymorphism is related to COPD in patients with non-small-cell lung cancer

OBJECTIVE: Oxidative stress contributes to the development of both lung cancer and chronic obstructive pulmonary disease (COPD). Antioxidative enzymes may protect against such damage. We hypothesized that genetic variations in glutathione S-transferase M1 and/or T1 genes (GSTM1 and GSTT1, respectively) may influence susceptibility to COPD in patients with non-small-cell lung cancer. PATIENTS AND METHODS: The polymorphisms in GSTM1 and GSTT1 genes were examined in 110 patients (age: 63+/-1 years) with newly diagnosed non-small-cell lung cancer using the polymerase chain reaction. Respiratory function was assessed by bodyplethysmography. RESULTS: In the GSTM1 null (-/-) genotype, both FEV1 and FEV1/FVC were significantly lower than in the GSTM1 plus genotype (GSTM1 -/+ or +/+) (75.8+/-2.5 versus 86.6+/-3.6%, p<0.02; 69.1+/-1.6 versus 77.0+/-2.4, p<0.01, respectively). Among the patients with GSTM1 null genotype, 49% suffered from COPD as opposed to 21% of patients with GSTM1 plus genotype. In contrast, no differences were seen in FEV1 or FEV1/FVC when comparing patients with GSTT1 null genotype and GSTT1 plus genotype (81.4+/-4.9 versus 79.3+/-2.3, p=NS; 71.1+/-2.9 versus 72.2+/-1.6, p=NS). Multiple stepwise regression analysis identified the GSTM1 genotype (p<0.02) as a significant independent predictor of FEV1 in this group of patients. CONCLUSION: The present study suggests that in patients with non-small-cell lung cancer the presence of at least one active allele in GSTM1 has a protective effect against the development of COPD.     

Influence of hormone replacement therapy on blood antioxidant enzymes in menopausal women

BACKGROUND: Natural loss of estrogen occurring in menopausal process may contribute to various health problems many of them possibly related to oxidative stress. Hormone replacement therapy (HRT) is the most common treatment to attenuate menopausal disturbances. This study was aimed at evaluating the influence of HRT on the activity of antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx) and lipid peroxidation (thiobarbituric acid reactive substances, TBARS) in menopausal women. METHODS: Blood antioxidant enzyme activities were determined in premenopausal (n=18) and in postmenopausal healthy women without (n=21) or with (n=19) HRT (mean ages: 47, 59, and 57 years, respectively). RESULTS: TBARS, CAT, and GPx activity were not significantly different among the groups of study. However, SOD activity was significantly lower in postmenopausal women without HRT (0.68+/-0.04 U/mg Hb) when compared both to premenopausal women (0.91+/-0.04 U/mg Hb) and to postmenopausal women with HRT (0.89+/-0.07 U/mg Hb). SOD activity was positively correlated to the duration of HRT in the postmenopausal groups (r=0.33, p<0.05). CONCLUSIONS: HRT antagonizes the decrease of SOD activity that occurs after menopause, suggesting that HRT may play a beneficial role in the protection against oxidative stress.     

Association between varicocele and chronic obstructive pulmonary disease

PURPOSE: To evaluate the relationship between varicocele and chronic obstructive pulmonary disease (COPD) via color duplex sonography. MATERIALS AND METHODS: Forty-four male patients with COPD (age range, 50-89 years; mean +/- SD, 66 +/- 9) and 44 male healthy controls (age range, 47-75 years; mean +/- SD, 65 +/- 6) were evaluated with color duplex sonography for unilateral or bilateral varicocele. RESULTS: The incidence of right, left, and bilateral varicocele was 47.7%, 65.9%, and 38.6% respectively, in the COPD group, versus 22.7%, 52.3%, and 13.6% in the control group. The incidence of right and bilateral varicocele in the COPD group was significantly higher than in the control group (p < 0.05). The incidence of varicocele also increased with increase in COPD severity. CONCLUSIONS: The incidence of varicocele in COPD patients is high. Varicocele might be one of the most important causes of scrotal pain and infertility in COPD patients.     

Metabolic disorders in patients with chronic obstructive pulmonary disease

AIM: To characterize cell dysregulation in chronic obstructive pulmonary disease (COPD) at local and systemic levels. MATERIAL AND METHODS: A total of 48 patients with COPD were examined (mean disease duration 11.2 +/- 7.2 years, mean age 58 +/- 4.2 years). Content of glutathione, and activity of glutathione peroxidase, glutathione reductase in whole blood (Novgorodtseva T.P., 2003), catalase in erythrocytes (Karpichenko A.I., 1999) were determined. Products of lipid peroxidation in exhaled breath condensate were defined to reveal diene conjugates of hydroperoxides, ketodienes, coupled trienes (Khyshiktuyev B.S., 1996). RESULTS: An evident oxidation stress at the local level was revealed in patients with COPD in deficiency of enzymatic antiperoxide link of anti-oxidant defense that is characterized by increased quantity of lipid peroxidation intermediants both in heptane and isopropanol phases.     

Endothelin-1 and asymmetric dimethylarginine in children with left-to-right shunt after intracardiac repair

BACKGROUND: Endothelin-1 (ET-1) is an endogenous vasoconstrictive peptide hormone and asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of nitric oxide synthase. We hypothesized that both could contribute to pulmonary hypertension in patients with left-to-right shunt after intracardiac repair. PATIENTS AND METHODS: We prospectively analyzed ET-1 and ADMA plasma levels in 31 patients (m = 16; f = 15) at an age of 0.6 [0.2-27] years (median [range]) with left-to-right shunt (ASD II: n = 12; VSD: n = 11; AVSD: n = 8) presenting with a Qp/Qs of 2.7 [1.4-6.3] and a pulmonary arterial mean pressure (PAP) of 23 [13-57] mmHg. Blood specimens were taken prior to cardiopulmonary bypass (CPB), after weaning from CPB and at 3, 6, 12 and 24 h after CPB. RESULTS: 12/31 patients were found to have pulmonary hypertension prior to intracardiac repair and 11/12 patients showed persistent pulmonary hypertension during the first 24 h after CPB. Patients with pulmonary hypertension at 12 h after CPB showed significant higher plasma ET-1 compared with patients with normal PAP (1.4 [0-7.9] versus 0.5 [0-2.5] pg/ml; P = 0.048 (Mann-Whitney)). Plasma ADMA decreased from 1.3 [0.75-2.3] micromol/l before CPB to 0.7 [0.4-2.1] micromol/l at 12 h (P < 0.05). However patients with pulmonary hypertension did not show different ADMA plasma levels. CONCLUSIONS: Increased plasma ET-1 but not inhibition of nitric oxide synthase by ADMA is associated with pulmonary hypertension after intracardiac repair.     

Pulmonary vascular effects of dobutamine in experimental pulmonary hypertension

OBJECTIVE: To characterize the dose-related effects of dobutamine on pulmonary vascular tone and associated changes in right ventricular afterload in canine microembolic lung injury .DESIGN: Prospective, interventional study. SETTING: University laboratory. SUBJECTS: Ten anesthetized and ventilated dogs. INTERVENTIONS: Right heart catheterization for the measurement of pulmonary vascular resistance by multipoint mean pulmonary artery pressure (Ppa)/cardiac output (Q) plots, partitioning of pulmonary vascular resistance by the occlusion method, and determination of pulmonary arterial input impedance from spectral analysis of Ppa and Q waves, in ten anesthetized and ventilated dogs, before and after induction of acute microembolic lung injury, and without or with 5, 10, 15, and 20 microg.kg(-1).min(-1) dobutamine. MEASUREMENTS AND MAIN RESULTS: Microembolic pulmonary hypertension was associated with a shift of Ppa/Q plots to higher pressures, a slight decrease in the arterial component of pulmonary vascular resistance, a decrease in characteristic impedance, and an increase in the pulsatile component of right ventricular hydraulic load. At baseline, dobutamine had no effect on Ppa/Q plots at 5 and 10 microg.kg(-1).min(-1) but increased Ppa at 15 and 20 microg.kg(-1).min(-1). In microembolic pulmonary hypertension, the only effect of dobutamine on Ppa/Q plots was a decrease in Ppa at 20 microg.kg(-1).min(-1). Dobutamine had no effect on the partitioning of pulmonary vascular resistance or on pulmonary arterial input impedance spectrum. CONCLUSIONS: Dobutamine at doses up to 10 microg.kg(-1).min(-1) has no flow-independent effect on the normal or the acutely hypertensive pulmonary circulation. Higher doses may be constricting or dilating depending on preexisting tone.     

Lipid peroxidation during initiation of extracorporeal membrane oxygenation after hypoxia in endotoxemic rabbits

Initiation of extracorporeal membrane oxygenation (ECMO) in septic children with severe respiratory failure often improves oxygenation but not pulmonary function. The factors affecting pulmonary function following onset of ECMO are not completely understood, but are thought to involve injury mediated, in part, by reactive oxygen species. We hypothesized that induction of ECMO using 100% oxygen as the sweep gas through the oxygenator would increase lipid peroxidation in endotoxin-primed animals after severe hypoxia. We further speculated that provision of oxygenated blood to the pulmonary circulation via venovenous ECMO would promote a greater degree of oxidative damage to the lung as compared to venoarterial ECMO. Eighteen New Zealand White rabbits were assigned to a control group (control) or two intervention groups subjected to 60 min of venoarterial or venovenous ECMO. ECMO was initiated following an intravenous challenge with 0.5 mg/kg of E. coli endotoxin and a period of global hypoxia leading to an arterial pH of 6.99 +/- 0.09, PaCO2 of 103 +/- 31 mmHg and PaO2 of 27 +/- 5 mmHg. Malondialdehyde (MDA), a marker of lipid peroxidation, was measured in lung tissue homogenates and in arterial plasma. Lung tissue MDA demonstrated a strong trend towards an increase in the venoarterial group (1884 +/- 945 nmol/g protein) and in the venovenous group (1905 +/- 758 nmol/g protein) in comparison to the control group (644 +/- 71 nmol/g protein) (p = 0.1; significance at 95% in Scheffe test). Lung tissue MDA in the venovenous group had a significant correlation with mean PaO2 during ECMO by regression analysis (r2 = 0.678, p = 0.044). The change in blood MDA concentration between pre-ECMO and post-ECMO values was greater in the venovenous group (pre 1.62 +/- 0.61 versus post 5.12 +/- 0.2.07 mumol/l, p = 0.043) compared with that seen in the venoarterial group (pre 1.46 +/- 0.38 versus post 3.9 +/- 0.93 mumol/l). Our data support the hypothesis that initiation of ECMO with a circuit gas oxygen concentration of 100% after global hypoxia enhances oxidative damage to lipids in endotoxin-challenged animals. During venovenous ECMO this finding is dependent on PaO2.     

Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension

PH (pulmonary hypertension) often complicates the disease course of patients with COPD (chronic obstructive pulmonary disease) and is an indication of a worse prognosis. In the present study, we assessed whether pravastatin administration was effective in improving PH and exercise capacity in COPD patients with PH, and whether the pulmonary protection was mediated by inhibiting ET-1 (endothelin-1) production. In a double-blind parallel design, 53 COPD patients with PH were randomly assigned to receive either placebo or pravastatin (40 mg/day) over a period of 6 months at a medical centre. Baseline characteristics were similar in both groups. The exercise time remained stable throughout the study in the placebo group. After 6 months, the exercise time significantly increased 52% from 660+/-352 to 1006+/-316 s (P<0.0001) in pravastatin-treated patients. With pravastatin, echocardiographically derived systolic PAP (pulmonary artery pressure) decreased significantly from 47+/-8 to 40+/-6 mmHg. There was significant improvement in the Borg dyspnoea score after administering pravastatin. Despite unchanged plasma ET-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with an improvement in exercise time in pravastatin-treated patients (r=-0.47, P=0.01). In conclusion, pravastatin significantly improved exercise tolerance, and decreased PH and dyspnoea during exercise in COPD patients with PH, probably by inhibiting ET-1 synthesis.     

Plasma beta-endorphin concentrations are increased in chronic obstructive pulmonary disease patients

The present study is concerned with plasma beta-endorphin and glucose tolerance in patients with chronic obstructive pulmonary disease (COPD). Plasma beta-endorphin, glucagon and insulin concentrations were measured during an oral glucose tolerance test in 20 COPD patients and in 18 age-matched healthy controls (mean age 62 years). Seven patients had a moderate COPD (group I) and seven a severe COPD (group II). The remaining six severe COPD patients received long-term oxygen therapy (group III). We found that fasting levels of beta-endorphin were significantly increased in all patient groups compared to healthy controls (p < 0.01, 0.05 and 0.005, respectively). Six of the 13 severely diseased COPD patients had impaired glucose tolerance. Plasma beta-endorphin levels decreased significantly during OGTT in the COPD patients (p < 0.05). Fasting beta-endorphin levels were higher in patients with impaired glucose tolerance than in those patients with normal OGTT (42.0 pmol/L +/- 11.4 SD versus 34.8 +/- 10.2). However, this difference was not statistically significant. In conclusion, this study showed that beta-endorphin concentrations are increased in COPD patients whether or not they receive oxygen therapy.     

Oxidative and antioxidative status in pregnant women with either gestational or type 1 diabetes

OBJECTIVES: To evaluate oxidative and antioxidative status in pregnant diabetic women between 26 and 32 weeks of gestation. DESIGN AND METHODS: Free and total malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), and vitamins A and E were determined in plasma and erythrocytes of 54 pregnant women. Among these, 27 were diabetics with either gestational diabetes mellitus (GDM), sub-group I, or previous insulin-dependent diabetes mellitus (type 1 diabetes), sub-group II. The other 27 patients were controls. Fasting plasma glucose and HbA(1c) levels were determined in all women. RESULTS: HbA(1c) levels, plasma-, and erythrocyte-free MDA levels were significantly higher in all diabetic women and in both sub-groups than in controls. Plasma vitamin E and erythrocyte vitamin A levels were significantly lower in all diabetic women than in controls. Moreover, GPX and SOD activities were significantly reduced in all diabetic women, GPX in both sub-groups and SOD only in type 1 diabetes. CONCLUSIONS: The increased oxidative stress we demonstrated in pregnant women with previous type 1 diabetes or with GDM should be monitored by strictly controlling blood glucose during pregnancy with stringent recommendations and perhaps antioxidant supplementation.