Passive smoking in asthmatic children: effect of a "smoke-free house" measured by urinary cotinine levels.

Environmental tobacco smoke (ETS) decreases pulmonary function and increases both airway reactivity and frequency of child asthma exacerbations. True exposure is related not only to parents smoking and to the number of cigarettes that they smoke, but also to involuntary smoking in public places. The aim of this study was to evaluate, by measuring urinary cotinine levels, the exposure to ETS in asthmatic children and the contribution of unapparent smoke exposure. Twenty asthmatic children (aged 7-12 years) were evaluated on the 1st day (TO) and after a week (T1) in a "smoke-free house." The mean level of urinary cotinine in children was 15.8 +/- 2.7 ng/mg of creatinine at TO and 4.2 +/- 0.6 ng/mg of creatinine at T1 (p < 0.0001). The urinary cotinine concentrations were higher in children living with smoking parents (21.8 +/- 3.4 ng/mg creatinine) compared with children not exposed to parental smoke (6.8 +/- 3.0 ng/mg creatinine; p = 0.017). The number of cigarettes smoked by parents correlates with the urinary cotinine levels (p = 0.005; r = 0.64). Urinary cotinine levels significantly decreased after the avoidance of ETS in children exposed to parental smoke (21.8 +/- 3.4 ng/mg at TO; 5.0 +/- 0.8 ng/mg at T1; p < 0.001) and also in children whose parents declared to be nonsmokers (6.8 +/- 1.2 ng/mg at TO; 3.0 +/- 0.8 ng/mg at T1; p = 0.006). Our data confirm the widespread indirect and undetected tobacco smoke exposure in children with chronic asthma and the relevance of an evaluation with an objective method of the exposure to second-hand smoke.     

支气管哮喘大鼠气道重塑中肺泡巨噬细胞的作用

目的研究支气管哮喘(简称哮喘)大鼠气道重塑过程中肺泡巨噬细胞(AM)的变化及其作用。方法48只清洁级雄性幼年SD大鼠按随机数字表法分为正常对照组(A组)、哮喘3d组(B组)、哮喘14d组(C组)和哮喘30d组(D组),每组12只。应用鸡卵白蛋白(OVA)建立哮喘大鼠模型,纯化支气管肺泡灌洗液(BALF)中的AM,测定AM中肿瘤坏死因子α(TNF-α)、前列腺素E2(PGE2)的含量和基质金属蛋白酶9基因(MMP-9mRNA)及其组织抑制物1基因(TIMP-1mRNA)的表达,并测量大鼠支气管壁总面积和平滑肌面积,计算单位基底膜周径(Pbm)的支气管壁厚度(WAt)和平滑肌厚度(WAm)。结果D组WAt和WAm[(85±9)μm2/μm、(28.6±4.9)μm2/μm]与A组[(67±10)μm2/μm、(16.8±2.4)μm2/μm]比较差异有统计学意义(t值分别为2.938、3.227,P均<0.01);D组AM中TNF-α和PGE2含量[(0.68±0.25)μg/L、(0.122±0.030)μg/L]与A组[(0.37±0.09)μg/L、(0.079±0.018)μg/L]比较差异有统计学意义(t值分别为2.683、3.016,P均<0.01),与B组[(0.74±0.29)μg/L、(0.120±0.028)μg/L]、C组[(0.71±0.23)μg/L、(0.117±0.028)μg/L]比较差异无统计学意义(t值分别为1.624、0.472、0.935、0.533,P均>0.05);D组AM中MMP-9mRNA及TIMP-1mRNA含量吸光度(A)值分别为0.346±0.033、0.361±0.040,与C组(0.279±0.015、0.259±0.015)比较差异有统计学意义(t值分别为2.574、2.716,P均<0.01),D组(0.183±0.025)与B组(0.136±0.014)比较差异有统计学意义(t值分别为2.913、3.017,P均<0.01),D组(0.104±0.007)与A组(0.109±0.008)比较差异有统计学意义(t值分别为3.632、3.487,P均<0.01);各组AM中MMP-9mRNA含量与WAt、WAm呈正相关(r值分别为0.693、0.738,P均<0.01),AM中TIMP-1mRNA含量与WAt、WAm呈正相关(r值分别为0.823、0.876,P均<0.01)。结论哮喘大鼠AM及其分泌的一些细胞因子与气道重塑关系密切。     

Respiratory effects of environmental tobacco exposure are enhanced by bronchial hyperreactivity

RATIONALE: Exposure to environmental tobacco smoke (ETS) is associated with increased reports of respiratory symptoms and reduced lung function, but the long-term effects of ETS are unclear, notably in healthy individuals with bronchial hyperresponsiveness (BHR). OBJECTIVE: To assess the longitudinal effects of ETS exposure on the development of respiratory symptoms and spirometry in subjects with BHR. METHODS: The study population included 1,661 never-smokers from the SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) cohort, assessed in 1991 (baseline) and 11 yr later, who were symptom-free at baseline. Incident reports of respiratory symptoms and results of spirometry were assessed at the follow-up survey. MAIN RESULTS: Exposure to ETS reported in the two surveys was strongly associated with the development of cough (odds ratio, 2.1; 95% confidence interval, 1.2-3.7; p = 0.01). In subjects with BHR exposed to ETS at both surveys, a trend for strong associations were observed for wheeze, cough, dyspnea, and chronic bronchitis; however, the association reached statistical significance only for the symptom of dyspnea (p < 0.01). Lower FEV1/FVC (mean +/- SD, 72.9 +/- 7.7 vs. 76.8 +/- 6.1%; p < 0.01) and FEF(25-75) (forced expiratory flow, midexpiratory phase)/FVC (mean +/- SD, 56.1 +/- 22.5 vs. 68.1 +/- 21.6%; p < 0.01) were observed in subjects with BHR exposed to ETS compared with nonexposed subjects without BHR. Lower values were found in subjects continuing exposure by the follow-up survey. CONCLUSION: Exposure to ETS was strongly associated with the development of respiratory symptoms in previously asymptomatic subjects with BHR within 11 yr. Furthermore, subjects with underlying BHR had reduced lung function at follow-up, thus suggesting a higher risk for the development of chronic respiratory disease in this subset of the population.     

Reverse ventricular remodelling after cardiac resynchronization therapy is associated with a reduction in serum tenascin-C and plasma matrix metalloproteinase-9 levels

BACKGROUND: In heart failure patients, cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. AIM: The aim of this study was to evaluate whether changes in levels of circulating biomarkers of extracellular matrix metabolism correlate with the response to CRT. METHODS AND RESULTS: Clinical parameters, left ventricular (LV) volumes, and circulating levels of tenascin-C (TNC), matrix metalloproteinase-2 (MMP-2), MMP-9, and amino-terminal propeptide of brain natriuretic peptide (NT-proBNP) were assessed in 64 patients at baseline and 6 months follow-up. The majority of patients (72%) showed a >10% reduction in LV end-systolic volume at follow-up, and were classified as responders to CRT. The remaining patients were classified as non-responders. In responders, a significant decrease in circulating levels of TNC (from 60+/-40 ng/mL to 47+/-30 ng/mL, p<0.01), MMP-9 (from 55+/-30 AU to 44+/-27 AU, p<0.01), and NT-proBNP (from 2106+/-1805 pg/mL to 1132+/-1289 pg/mL, p<0.001) were observed at follow-up; MMP-2 levels were unchanged. In non-responders TNC, NT-proBNP, MMP-9 and MMP-2 levels remained unchanged. CONCLUSION: At 6 months follow-up, CRT was associated with reverse LV remodelling, and a significant decrease in TNC, MMP-9, and NT-proBNP levels. This suggests an important role of ECM modulation in the process of reverse ventricular remodelling in patients responding to CRT.     

Matrix metalloproteinase-3 and coronary remodelling: implications for unstable coronary disease

OBJECTIVES: Matrix metalloproteinases (MMPs) are plausible candidates for prediction of unstable coronary syndromes. We hypothesised that the MMP-3 polymorphism (- 1171, 5A/6A) would relate to coronary plaque characteristics and unstable clinical presentation. METHODS AND RESULTS: Forty patients with de novo presentation of coronary artery disease (CAD) were classified into unstable coronary syndrome (n=19) or stable angina pectoris (n=21). On coronary intravascular ultrasound, patients with unstable disease had a greater plaque burden, more positive (outward) coronary remodelling, and all but one were MMP-3 6A allele carriers (p=0.027 compared with stable). The relationship between the 6A allele and unstable presentation was substantiated in a validation cohort of 161 CAD patients (58 stable and 103 unstable) and in the total population of 201 CAD patients (79 stable and 122 unstable, p=0.007), and was independent of conventional risk factors. Furthermore, 6A allele carriers had a higher plasma MMP-3 concentration (15.8+/-12.5 versus 11.7+/-7.2 ng/mL, p=0.01), maximum coronary stenosis on angiography (89+/-15% versus 80+/-23%, p=0.02), plaque area (12.0+/-5.2 versus 7.5+/-3.6 mm(2), p=0.03), percentage plaque burden (82+/-7 versus 71+/-13%, p=0.003), and remodelling ratio (1.03+/-0.23 versus 0.83+/-0.12, p=0.003). CONCLUSIONS: The MMP-3 6A allele promotes positive coronary remodelling, greater plaque burden, and increased susceptibility to unstable coronary syndromes in humans.     

Left ventricular assist device in end-stage heart failure: persistence of structural myocyte damage after unloading. An immunohistochemical analysis of the contractile myofilaments

OBJECTIVES: We sought to evaluate the contractile proteins in cardiomyocytes of patients with end-stage heart failure (HF) before and after mechanical support with a left ventricular assist device (LVAD). BACKGROUND: Improvement of myocyte dysfunction has been suggested after LVAD support. METHODS: Fourteen patients' myocardial biopsies taken at the time of LVAD implantation and after explantation, at the time of heart transplantation, were processed for routine hematoxylin-eosin staining and immunohistochemistry using monoclonal antibodies against actin, myosin, tropomyosin, troponin C and T and titin. A grading scale from 1 (abnormal staining of all myocytes, no cross-striation) to 5 (normal fiber anatomy and striation) was used. The cross-sectional area of cardiomyocytes was also measured. RESULTS: The cardiomyocytes' cross-sectional area decreased after support, from 519 +/- 94 microm(2) to 319 +/- 53 microm(2) (p < 0.001). Actin, tropomyosin, troponin C, troponin T and titin at the time of LVAD implantation showed widespread distortion of architecture; their grades were 1.4 +/- 0.6, 2.3 +/- 1.0, 2.1 +/- 0.9, 2.1 +/- 1.2 and 2.0 +/- 0.6, respectively. In contrast, myosin morphology was preserved (4.6 +/- 0.7). After LVAD support, actin, tropomyosin, troponin C, troponin T and titin showed improvement (grades 2.7 +/- 1.3 [p = 0.004], 3.2 +/- 1.2 [p = 0.021], 3.3 +/- 0.9 [p = 0.004], 3.0 +/- 1.1 [p = 0.048] and 3.1 +/- 0.9 [p = 0.001], respectively), but no normalization. The myosin pattern deteriorated slightly (3.6 +/- 1.6 [p = 0.058]). CONCLUSIONS: After LVAD support, during a period of 213 +/- 135 days in patients with end-stage HF, despite a decrease in the size of the cardiomyocytes, severe structural myocyte damage persisted. This does not support complete recovery of myocyte histologic features.     

Role of matrix metalloproteinases in early hypertensive vascular remodeling

Hypertension is associated with vascular remodeling characterized by rearrangement of extracellular matrix proteins. To evaluate how matrix metalloproteinase (MMP)-9 contributes to the progression of hypertensive vascular disease in vivo, wild-type (wt) or MMP-9(-/-) mice were treated with angiotensin II (Ang II; 1 microg/kg per minute, by minipump) plus a 5% NaCl diet during 10 days. Baseline blood pressure was equivalent in wt and knockout mice, but Ang II treatment increased systolic blood pressure to a greater extent (P<0.05) in MMP-9(-/-) mice (94+/-6 to 134+/-6 mm Hg; P<0.001) than in wt animals (93+/-4 to 114+/-6 mm Hg; P<0.01). In wt mice, Ang II treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981+/-19 microm (P<0.01 versus sham; 891+/-10 microm). In contrast, in MMP-9(-/-) mice, carotid artery compliance was actually reduced after Ang II (P<0.05), and maximal diameter only reached 878+/-13 microm. Ang II treatment induced MMP-2 and increased carotid media thickness equally in both phenotypes. However, MMP-9 induction and in situ gelatinase activity were only enhanced in Ang II-treated wt mice, and vessels from these mice also produced more collagen I breakdown products than their MMP-9(-/-) counterparts (P<0.05). Inversely, staining for collagen IV was particularly enhanced in vessels from MMP-9(-/-) mice treated with Ang II. These results demonstrate the following: (1) the onset of Ang II-induced hypertension is accompanied by increased MMP-9 activity in conductance vessels; (2) absence of MMP-9 activity results in vessel stiffness and increased pulse pressure; and (3) MMP-9 activation is associated with a beneficial role early on in hypertension by preserving vessel compliance and alleviating blood pressure increase.     

川芎嗪对大鼠支气管哮喘模型气道重塑的影响及机制

目的　观察川芎嗪对支气管哮喘 (简称哮喘 )大鼠模型气道重塑的抑制作用并探讨其作用机制。方法　 32只SD大鼠按随机数字表法分成正常对照组 (A组 )、哮喘模型组 (B组 )、小剂量川芎嗪组 (C组 ,4 0mg/kg)和大剂量川芎嗪组 (D组 ,80mg/kg) ,以卵白蛋白 (OVA)致敏并长期吸入激发制备大鼠慢性哮喘模型。采用免疫组化半定量法测定气道壁胶原和转化生长因子 β1(TGF β1)含量 ,同时测定气道内、外径及平滑肌层、网状基底膜的厚度。结果　D组气道平滑肌层、网状基底膜的厚度为 (11 3± 1 3) μm、(11 3± 1 7) μm ,B组分别为 (19 7± 1 8) μm、(19 8± 1 6 ) μm ,两组比较差异有统计学意义 (P均 <0 0 1) ,但D组与A组 [(10 6± 1 2 ) μm、(9 8± 1 6 ) μm]、C组 [(11 6± 0 9) μm、(12 3± 1 8) μm]比较差异无统计学意义 (P均 >0 0 5 ) ;D组气道内外径比值为 0 77± 0 0 6 ,B组为0 6 3± 0 0 5 ,D组与B组比较差异有统计学意义 (P <0 0 1) ;D组气道壁Ⅲ型胶原及TGF β1含量吸光度 (A)值分别为 2 1± 5、2 6± 5 ,B组分别为 5 5± 7、6 9± 14 ,两组比较差异有统计学意义 (P <0 0 1) ,D组与C组 (32± 8、38± 10 )比较差异有统计学意义 (P <0 0 5 ) ,C组与B组比较差异也有统计学意义 (P <0 0     

一氧化氮对哮喘大鼠基质金属蛋白酶的表达调控

目的　观察一氧化氮 (NO)对哮喘大鼠基质金属蛋白酶 (MMP)及金属蛋白酶组织抑制物表达的影响 ,探讨其在哮喘气道结构重建中的作用。方法　 30只雄性Wistar大鼠随机分为对照组、哮喘组和左旋精氨酸组 (L Arg组 ) ,每组 1 0只。肺组织作病理切片并HE染色 ,通过病理图像分析系统测定支气管基底膜周径 (Pbm)、总管壁面积 (WAt)、内壁面积 (WAi) ,平滑肌面积 (WAm)等形态学参数。用NO与一氧化氮合酶 (NOS)试剂盒测定肺组织中亚硝酸盐 /硝酸盐 (NO- 2 /NO- 3)水平与NOS活性。半定量逆转录聚合酶链反应技术 (RT PCR)分析肺组织中MMP 2与TIMP 1mRNA的表达。结果(1 )WAt/Pbm、WAi/Pbm及WAm/Pbm哮喘组 [分别为 (2 5 3± 2 1 ) μm2 / μm、(2 0 4± 2 3) μm2 / μm、(4 2±2 0 ) μm2 / μm]和L Arg组 [分别为 (35 1± 2 6) μm2 / μm、(2 5 3± 2 0 ) μm2 / μm、(8 7± 1 5) μm2 / μm]与对照组 [分别为 (2 0 8± 1 3) μm2 / μm、(1 5 3± 2 1 ) μm2 / μm、(3 1± 1 1 ) μm2 / μm]比较 ,差异有显著性(P <0 0 1 ) ;L Arg组与哮喘组比较差异亦有显著性 (P <0 0 5)。 (2 )肺组织中NO- 2 /NO- 3水平哮喘组[(7 2± 2 1 )nmol/mg]和L Arg组 [(1 1 8± 1 7)nmol/mg]与对照组 [(3 1± 1 2 )n     

基质金属蛋白酶在大鼠慢性阻塞性肺疾病模型气道细胞外基质重塑中的作用

目的 研究基质金属蛋白酶（MMPs)及其组织抑制剂（TIMP－1）在大鼠慢性阻塞性肺疾病（COPD）模型气道和肺组织中的表达及其在细胞外基质重塑中的作用。方法 采用熏香烟加气管注内毒素法,建立大鼠COPD模型,观察其气道重塑的病理改变、肺功能及血气变化;用生化法测定支气管肺组织羟脯氨酸含量;用免疫组化法观察MMP－9、MMP－2及TIMP－1的蛋白定位及表达;用逆转录－聚合酶链反应法测定MMP－9、MMP－2及TIMP－1mRNA表达;用SDS－PAGE明胶酶谱学测定支气管肺组织MMPs酶活性。结果 用熏香烟加气管注内毒素法建立的大鼠COPD模型,其病理形态学改变、肺功能及血气变化均与人类COPD的改变相似。COPD模型组支气管肺组织羟脯胺酸含理、支气管黏膜下成纤维细胞、淋巴细胞数和肺泡巨噬细胞数及以I型胶原为主的细胞外基质含量显著高于健康对照组（P值均＜0.001)。COPD模型组MMP－9、MMP－2及TIMP－1在气道上皮、成纤维细胞、肺泡巨噬细胞、血管内皮细胞及部分肺泡壁细胞表达均明显增强,支气管肺组织MMP－9、MMP－2及TIMP－1 mRNA表达亦显著增强,72000MMP－2及92000 MMP-9酶活性亦显著增高。结论 MMPs表达增强提示细胞外基质降解增加,支气管肺结构破坏增加。TIMP－1在抑制MMPs活性的同时,促进成纤维细胞增生及胶原等合成增多,是导致细胞外基质修复和重塑的重要机制之一。     

Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: impact on plaque stabilization?

Inflammatory pathways are involved in destabilization of atherosclerotic plaques. We assessed the hypothesis that endurance training decreases circulating concentrations of inflammatory markers in persons with coronary artery disease (CAD) and cardiovascular risk factors (CVRFs). Thirty-two subjects with CAD and/or CVRFs joined a 12-week supervised endurance training. We found a significant decrease of the chemokines interleukin (IL)-8 (pre: 3.9+/-0.6, change: -1.2+/-0.4 pg/ml, -21%, p=0.002) and monocyte chemoattractant protein-1 (pre: 213+/-9, change: -20.4+/-8.2 pg/ml, -5%, p=0.03). Diabetes mellitus (DM) significantly influenced changes of IL-8 (p=0.002). IL-8 substantially dropped by 39% in diabetics. Moreover, matrix metalloproteinase-9 (MMP-9) highly significantly decreased in response to training (pre: 750+/-98, change: -278+/-77 ng/ml, -18%, p=0.005). Exercise-induced changes of MMP-9 were influenced by concomitant use of statins (p=0.038). We observed a particularly strong MMP-9 reduction of 44% in patients treated with statins. Acute phase reactants IL-6 (pre: 1.7+/-0.3, change: +0.25+/-0.7 pg/ml, +4%, p=0.58) and high sensitivity C-reactive protein (pre: 2.1+/-0.5, change: -0.25+/-0.4 mg/l, -9%, p=0.54) did not change in response to training. In conclusion, endurance training decreased circulating chemokines and MMP-9, which may in part explain its beneficial effect on coronary risk. Patients with DM or treated with statins because of hypercholesterolemia may particularly take advantage.     

Autonomic nervous system tone measured by baroreflex sensitivity is depressed in patients with end-stage liver disease

OBJECTIVES: Chronic liver disease is often associated with impairment of autonomic nervous system (ANS) reflexes. Baroreflex sensitivity (BRS) testing is an inexpensive, relatively noninvasive test that can be used to assess ANS tone. The aims of the present study were to determine the prevalence of ANS dysfunction in cirrhotics who are being considered for liver transplantation and to explore the potential use of BRS as a prognostic tool in identifying patients awaiting transplantation who are at increased risk for death. METHODS: We studied nine cirrhotics who were awaiting liver transplantation and seven controls without liver disease. BRS (ms/mm Hg) was measured using the phenylephrine method. RESULTS: BRS (mean +/- SEM) (ms/mm Hg) was significantly lower in cirrhotics compared with controls (4.2 +/- 0.9 vs 21.1 +/- 3.8 ms/mm Hg; p < 0.05). Furthermore, BRS was lower in cirrhotics with hepatic encephalopathy compared with those without (2.6 +/- 0.9 vs 6.1 +/- 1.0 ms/mm Hg; p < 0.05) and there was a trend toward lower BRS values in Child-Pugh class C patients as compared with class B (3.8 +/- 1.3 vs 5.3 +/- 1.2 ms/mm Hg; p = 0.3). At follow-up (9 months), one patient had died and one underwent liver transplantation. These two patients also had the most severely impaired vagal tone (BRS = 0 and 1.2 ms/mm Hg, respectively). CONCLUSIONS: Vagal tone, as assessed by BRS, is markedly depressed in cirrhotic patients awaiting liver transplantation.     

Blood pressure and microvascular complications in type 1 (insulin dependent) diabetic patients without hypertension

To specify the influence of blood pressure on diabetic microangiopathy, the factors related to retinopathy and nephropathy were studied among 56 consecutive type 1 (insulin-dependent) diabetic out-patients without hypertension. Diabetes mellitus had been diagnosed for at least one year (mean duration of diabetes +/- SEM = 11.4 +/- 0.9 years). Diabetic patients did not take any treatment liable to influence blood pressure. Clinical parameters, including blood pressure, tobacco and alcohol consumption, were recorded by the same investigator. Retinopathy was defined as more than 5 microaneurysms on a fluorescein angiogram, clinical and incipient nephropathy as an albumin excretion rate over than 300 mg/d and between 30 and 300 mg/d, respectively. On average, retinopathy (n = 25) was associated with longer duration of diabetes (16.5 +/- 1.2 vs 7.4 +/- 0.9 years; p less than 0.001) and higher systolic blood pressure (136.2 +/- 4.1 vs 126.3 +/- 2.8 mm Hg; p less than 0.05). Clinical (n = 9) and incipient (n = 23) nephropathies were associated with duration of diabetes (17.9 +/- 2.0 and 11.8 +/- 1.7 vs 8.7 +/- 1.6 years, respectively; p less than 0.01), and with systolic (145.0 +/- 7.9, 132.7 +/- 4.7 vs 123.5 +/- 4.2 mm Hg; p less than 0.01) and diastolic blood pressure (83.3 +/- 6.2, 77.3 +/- 3.2 vs 72.2 +/- 3.4 mm Hg; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Alterations in vascular matrix metalloproteinase due to ageing and chronic hypertension: effects of endothelin receptor blockade

OBJECTIVE: To determine the effects of age and dual endothelin (ET)A/ETB receptor antagonism (bosentan) on aortic matrix metalloproteinase (MMP) abundance and tissue inhibitor of metalloproteinase (TIMP) expression in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). METHODS: Male SHR and control WKY rats were randomly assigned to receive placebo or bosentan (100 mg/kg per day) for 3 months. Animals were killed under terminal anaesthesia at either 20 weeks (adult) or 17-20 months (senescent). Aortic gelatinase activity was determined by zymography, whereas MT-1 MMP and TIMP-1 expression were assessed by immunoblotting. RESULTS: In WKY rats, aortic MMP-2 but not proMMP-2 activity was 3.6-fold higher (P < 0.02) in the senescent compared with the adult group. TIMP-1 (twofold) and MT-1 MMP (3.8-fold) expression increased (P < 0.05) with age in the WKY groups. Short-term hypertension (adult SHR versus adult WKY) increased MMP-2 to 74.7 +/- 14.1 from 18.9 +/- 3.5 arbitrary units (AU) (P = 0.0012), but did not alter proMMP-2 activity. This increased further on progression to chronic hypertension (117.4 +/- 12.2 versus 74.7 +/- 14.1 AU; P < 0.02). Bosentan decreased MMP-2 (78.9 +/- 3.8 versus 117.4 +/- 12.2 AU; P = 0.014) and proMMP-2 activity (P < 0.006) in the senescent SHR group. CONCLUSION: Ageing and the development/progression of hypertension are associated with increased MMP-2 activity in the aorta, which is consistent with ongoing remodelling of the vasculature. However, the underlying mechanisms regulating MMP-2 abundance in ageing and hypertension appear to be divergent, as MT-1 MMP expression is differentially altered. Dual ETA/ETB receptor antagonism did not alter the age-dependent increase in aortic MMP activity in normotensive rats. However, bosentan decreased pro and active MMP-2 activity in senescent SHR rats, indicating that ET modulates late events in vascular remodelling in hypertension.     

Unexplained pulmonary hypertension is associated with systolic arterial hypertension in patients undergoing routine Doppler echocardiography

STUDY OBJECTIVE: To determine the validity of the association between systemic hypertension (HTN) and unexplained pulmonary hypertension (PHTN) as identified with Doppler echocardiography. METHODS: All patients with a reported systolic pulmonary artery pressure (SPAP) on routine Doppler echocardiography from our 1997 echocardiographic database were identified. Exclusions included all diseases known to be associated with PHTN. Of 1,174 patients, 503 had PHTN (defined as a SPAP of >/= 40 mm Hg), of whom 42 (8.4%) had unexplained PHTN. These PHTN patients were matched for age (mean [+/- SD] age, 70 +/- 11 years) with 84 randomly selected patients from the same database who had normal SPAP values and no diseases associated with PHTN. RESULTS: The mean SPAP of those patients with unexplained PHTN was 48 +/- 9 mm Hg vs 31 +/- 5 mm Hg for those without unexplained PHTN. HTN was more prevalent in those with PHTN (98% vs 72%, respectively; p = 0.0008). Patients with unexplained PHTN had significantly higher mean systolic BP, as routinely measured at the end of the echo (154 +/- 26 vs 138 +/- 21 mm Hg, respectively; p = 0.0006), but they did not differ in diastolic BP (80 +/- 14 vs 78 +/- 11 mm Hg, respectively; p = 0.39). PHTN patients and control subjects did not differ with respect to gender (women, 74% vs 70%, respectively), race (white, 64% vs 65%, respectively), body mass index (30 +/- 8 vs 28 +/- 8 kg/m(2), respectively), or left ventricular ejection fraction (64 +/- 6% vs 63 +/- 7%, respectively). When only those with known HTN were considered, PHTN patients still had higher systolic arterial BP (155 +/- 25 vs 143 +/- 21 mm Hg, respectively; p = 0.013) and tended to be on more BP medications (1.6 +/- 1.1 vs 1.2 +/- 0.9, respectively; p = 0.09). CONCLUSIONS: Unexplained PHTN occurs mostly in the elderly, is associated with systolic HTN, and those hypertensive patients with concomitant PHTN have higher systolic arterial pressures.     

Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine

In rats with large myocardial infarctions, we compared the effects of captopril, a presumed arterial and venous vasodilator, with hydralazine, which is thought primarily to be an arterial vasodilator. To determine if the effects of captopril were dependent on the pathophysiological consequences of heart failure, we also studied a group of noninfarcted rats treated with captopril. In noninfarcted rats treated with captopril, left ventricular (LV) systolic and mean aortic pressures decreased from 132 +/- 12 to 107 +/- 15 mm Hg and 122 +/- 1 to 100 +/- 2, respectively (p less than 0.01). In noninfarcted rats, captopril decreased LV weight, LV weight/body weight, and total heart weight/body weight but produced no effects on the peripheral venous circulation. Rats subjected to coronary artery ligation were selected by ECG criteria to have large myocardial infarctions and were treated for 4 weeks with captopril (n = 8), hydralazine (n = 5), or placebo (n = 9). In infarcted rats treated with captopril, LV systolic, mean aortic pressures and LV end-diastolic pressure (LVEDP) decreased (p less than 0.01) from 115 +/- 4 to 86 +/- 3 mm Hg, 106 +/- 4 to 74 +/- 3 mm Hg, and 23 +/- 2 to 11 +/- 2 mm Hg, respectively. Mean circulatory filling pressure decreased (p less than 0.05) from 11.2 +/- 0.6 to 8.7 +/- 0.8 mm Hg and venous compliance increased (p less than 0.05) from 2.04 +/- 0.07 to 2.70 +/- 0.20 ml/mm Hg/kg. Blood volume decreased (p less than 0.05) from 67.3 +/- 0.9 to 58.2 +/- 1.8 ml/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung function of school children with low levels of alpha1-antitrypsin and tobacco smoke exposure.

Exposure to environmental tobacco smoke (ETS) and other air pollutants has been associated with small decrements in lung function. The susceptibility to pollution exposure may, however, vary substantially between individuals. Children with an impaired protease-antiprotease balance may be particularly vulnerable. Therefore this study aimed to investigate the effects of ETS exposure on children with reduced levels of alpha1-antitrypsin (alpha1-AT). Random samples of school children (aged 9-11 yrs) (n=3,526) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol, including parental questionnaires, pulmonary function and allergy testing. Blood samples were obtained to measure plasma levels of alpha1-AT and to genotype for pleomorphic protein inhibitor (Pi)Z and PiS alleles. Children with low levels of alpha1-AT (< or = 116 mg x dL(-1)) showed significant, albeit small decrements in baseline lung function. When exposed to ETS, pronounced decrements of pulmonary function, particularly in measures of mid- to end-expiratory flow rates, were seen in these children as compared to exposed children with normal levels of alpha1-AT. The mean levels of % predicted+/-SE in both groups were: maximum expiratory flow at 50% of vital capacity 79.4+/-7.2 versus 99.0+/-1.5, maximum expiratory flow at 25% of vital capacity 67.4+/-10.0 versus 100.3+/-2.1, maximal midexpiratory flow 73.7+/-8.6 versus 99.9+/-1.7. These findings suggest that school children with low levels of alpha1-antitrypsin are at risk of developing pronounced decrements in pulmonary function, particularly if they are exposed to environmental tobacco smoke. Parents of children with heterozygous alpha1-antitrypsin deficiency resulting in significantly reduced blood concentrations should be advised to prevent their children from being exposed to environmental tobacco smoke and dissuade them from taking up smoking.     

Plasminogen activator expression correlates with genetic differences in vascular remodeling

Intima-media thickening (IMT) of the carotid artery, a form of vascular remodeling, correlates well with coronary artery disease risk in humans. Vascular remodeling in response to blood flow is a complex process that critically involves altered cell matrix interactions. To gain insight into these events, we performed partial carotid ligation (left carotid (LCA) = low flow and right carotid (RCA) = high flow) in 2 inbred mouse strains: C57Bl/6J (C57) and FVB/NJ (FVB). To evaluate the role of the 2 major matrix-degrading systems, plasminogen activators (PAs) and matrix metalloproteinases (MMPs), we compared the expression of u-PA, t-PA, MMP-2 and MMP-9 in ligated carotids of C57 and FVB mice. The extent of remodeling was greater in response to low LCA than high RCA flow. Despite a similar decrease in LCA flow in both strains, maximal IMT volume was greater in FVB (82 +/- 7 x 10(-6) microm(3)) than in C57 (38 +/- 4 x 10(-6) microm(3)) after ligation. Among PAs and MMPs, increased expression of t-PA and u-PA correlated with increased IMT (p < 0.0005 and p < 0.001, respectively). MMP-2, MMP-9 and tissue inhibitors of metalloproteinase-2 expression also increased, but did not differ between strains. In summary, flow-induced IMT of the carotid is genetically determined and correlates with t-PA and u-PA expression in 2 inbred mouse strains.     

Gastric mucosal cytoprotection in the rat by scavenging oxygen-derived free radicals.

Oxygen-derived free radicals are cytotoxic and promote tissue damage. Dimethyl sulfoxide (DMSO) and allopurinol scavenge hydroxyl radicals, and the latter agent also inhibits the enzyme xanthine oxidase, which is responsible for the formation of superoxide anions. These agents were given daily by gavage (1 ml/d). After 2 days of administration as 1, 2, or 5% solutions, the H+ output of the rat with or without pyloric ligation was not significantly affected. After six hours reserpine (5 mg/kg i.p.) or serotonin (50 mg/kg i.p.) produced ischemic mucosal injury in all stomachs (39 +/- 5.2 mm2 and 25.9 +/- 2.8 mm2, mean +/- standard error of the mean [SEM], n = 10). Pretreatment for 2 days with 1 ml/d of 1% allopurinol or DMSO significantly (p less than 0.001) protected the rat against the reserpine (23 +/- 2.1 mm2 and 24 +/- 1.9 mm2, respectively, vs 39 +/- 5.2 mm2, n = 10) and serotonin injury (10 +/- 1.5 mm2 and 11 +/- 1.8 mm2, respectively, vs 25.9 +/- 2.8 mm2, n = 10). However, 2 days pretreatment with 1 ml/d of 2% allopurinol or DMSO was more effective (p less than 0.001) in this respect, and injury only developed in 40% of the rats given reserpine (8 +/- 1.2 mm2 and 9 +/- 1.6 mm2) and in 20% of those given serotonin (2.4 +/- 0.4 mm2 and 1.9 +/- 0.5 mm2). Similar pretreatment with 5% solutions completely protected the rat stomach against the reserpine and serotonin injuries without significantly influencing the H+ output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of restenosis in major vessels and side branches

OBJECTIVES: The indications for concurrent intervention for stenosis of a side branch during the treatment for stenosis of the main vessel were investigated using quantitative coronary angiography. METHODS: The retrospective study included 451 patients treated for a stenotic main vessel incorporating a side branch, who underwent follow-up angiography within 6 months. Patients were divided into Group I with the side branch treated by coronary angioplasty, and Group II with the side branch left untreated. Quantitative coronary angiography was used to measure the minimum luminal diameter (MLD) and percentage diameter stenosis (%DS) of the main vessel and the side branch. RESULTS: The MLD of the side branch after treatment was larger in Group I (1.4 +/- 0.1 mm) than in Group II (0.7 +/- 0.1 mm), and the %DS of the side branch after treatment was smaller in Group I (34 +/- 3%) than in Group II (63 +/- 2%). These differences decreased at follow-up to 1.1 +/- 0.1 mm, 48 +/- 2% in Group I; 0.9 +/- 0.04 mm, 46 +/- 2% in Group II, respectively. The MLD and %DS of the side branch at follow-up in Groups I and II were affected by the presence of main vessel restenosis[Restenosis(+): 0.9 +/- 0.1 mm, 57 +/- 4%; restenosis(-): 1.2 +/- 0.1 mm (p < 0.05), 43 +/- 3% (p < 0.05) in Group I; Restenosis(+): 0.9 +/- 0.1 mm, 51 +/- 8%; restenosis(-): 1.0 +/- 0.1 mm, 44 +/- 3% in Group II]. Multivariate analysis showed that %DS of the main vessel at follow-up was the only powerful predictor of restenosis of the side branch (p = 0.0249, odds ratio = 1.031, confidence interval = 1.004-1.059) in Groups I and II. CONCLUSIONS: Restenosis of the main vessel rather than the initial outcome of the side branch is the major influence on restenosis of the side branch.