Atrial natriuretic factor during hypoxia and mild exercise

The effect of hypoxia on plasma atrial natriuretic factor (ANF), plasma renin activity (PRA), and plasma aldosterone concentration (PAC) was evaluated during 2 h of treadmill exercise at 2 km/h, 0 grade at sea level. Six male subjects exercised on 2 separate days during normoxia (21% O2) and hypoxia (13.3 +/- 0.3% O2). No significant changes in ANF or PRA occurred during either normoxic or hypoxic exercise. However, PAC fell significantly during normoxic exercise (17.5 +/- 3.6 vs. 12.7 +/- 2.6 ng/dl, p less than 0.05) but not during hypoxic exercise. Serum potassium concentration fell during hypoxic exercise (5.0 +/- 0.1 vs. 4.4 +/- 0.1 mmol/l, p less than 0.05) along with bicarbonate (27.8 +/- 0.7 vs. 25.8 +/- 0.6 mmol/l, p less than 0.01). Between normoxic and hypoxic studies there was a significantly higher heart rate during hypoxic exercise (78 +/- 5 vs. 90 +/- 6 b/min, p less than 0.01). The major conclusion of this study is that hypoxia resulting in arterial oxygen saturations of 81 +/- 0.7% does not affect plasma atrial natriuretic factor levels during mild exercise in normal male subjects.     

Atrial natriuretic factor responses to submaximal and maximal exercise.

The aim of this study was to evaluate and compare the plasma concentration of atrial natriuretic factor (ANF), K+, Na+, blood lactate, heart rate, and blood pressure in moderately trained women. Ten healthy women were studied on a cycle ergometer during 20 min of constant submaximal and maximal exercise, as well as during recovery. The ANF concentration was determined by radioimmunoassay. The results show that, except for Na+, all the other variables increased significantly with an increase in the duration and intensity of the exercise (P < 0.05, P < 0.001). In recovery, the values fell (P < 0.01, P < 0.001). Submaximal and maximal exercise both cause increases in ANF and this increase is due to the duration and intensity of exercise. However, maximal exercise, rather than submaximal exercise, is the major stimulus for the concentration of plasma ANF. ANF concentration may be a useful test for evaluating the releasing function of ANF in the heart.     

Fluid restriction during running increases GI permeability

The purpose of this study was to determine gastrointestinal (GI) permeability during prolonged treadmill running (60 min at 70 % V.O2max) with and without fluid intake (3 ml/kg body mass/10 min). Twenty runners (11 males, 9 females; age = 22 +/- 3 (SD) yrs; mean V.O2max = 55.7 +/- 5.0 ml/kg/min) completed four experiments: 1) rest, 2) running with no fluid (NF), 3) running with ingestion of a 4 % glucose solution (GLU), and 4) running with ingestion of a water placebo (PLA). To determine GI permeability, subjects also drank a solution containing 5 g sucrose (S), 5 g lactulose (L), and 2 g rhamnose (R) immediately prior to each trial. Gastroduodenal permeability was determined by urinary S excretion, while small intestinal permeability was determined by the L/R excretion ratio. Percent body mass loss (i.e., dehydration) was negligible during rest, GLU and PLA, while NF resulted in a 1.5 % loss of body mass (p < 0.05). Gastroduodenal and intestinal permeability were significantly (p < 0.008) increased in NF compared to rest. There were no other differences in GI permeability. These results indicate that fluid restriction during 1 h of steady-state running increases GI permeability above resting levels.     

Atrial natriuretic peptide and the renin-aldosterone axis during exercise in man

Under non-exercise conditions, atrial natriuretic peptide (ANP) elevation suppresses plasma renin activity (PRA) and aldosterone (PA). A similar effect of ANP on PRA-PA during exercise has been suggested but not demonstrated. We measured ANP, PRA, PA, plasma potassium (K+), and changes in plasma volume (PV) and blood volume (BV) at rest and during incremental cycle ergometer exercise to exhaustion in ten healthy males. Plasma concentrations (mean +/- SE) of hormones and electrolytes increased (P less than 0.05) during exercise: ANP (68 +/- 14 to 207 +/- 48 pg.ml-1), PA (11.2 +/- 2.2 to 18.8 +/- 3.4 ng.dl-1), PRA (5.1 +/- 1.1 to 8.2 +/- 1.6 ng.ml-1.90 min-1), and K+ (4.2 +/- 0.1 to 5.5 +/- 0.1 mEq). PV and BV declined, reaching maximal deflections from baseline during the 100% stage (12.9 +/- 1.5 and 8.4 +/- 0.8% decreases, respectively). There were positive correlations between ANP and PRA (r = 0.58; P less than 0.01), ANP and PA (r = 0.56; P less than 0.01), and PRA and PA (r = 0.80; P less than 0.001). Increases in K+ did not correlate with increases in PA. The fall in PV correlated with elevations in PRA (r = -0.67; P less than 0.01) and PA (r = -0.58; P less than 0.01), and the fall in BV correlated with elevations in PRA (r = -0.62; P less than 0.01) and PA (r = -0.44; P less than 0.02). ANP production was related to exercise intensity (gauged by heart rate response; r = 0.58; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

A noninvasive technique for monitoring lung vascular permeability in man

Increased microvascular permeability resulting in increased plasma protein extravasation is the hallmark of acute inflammatory oedema and hence radiolabelled proteins can be used to monitor this process. The adult respiratory distress syndrome (ARDS) is characterized by acute inflammatory oedema and thus provides an ideal model for studying this type of oedema in the human lung. A noninvasive technique applicable to the intensive care unit has been developed for monitoring the pulmonary accumulation of the plasma protein transferrin. Transferrin was radiolabelled in vivo with indium-113m and its accumulation was monitored using a portable probe radiation detector. After correcting for changes in intrathoracic blood distribution, by simultaneously monitoring the accumulation of technetium-99m-labelled red blood cells, an index of plasma protein accumulation was calculated. In all patients with established ARDS (n = 10) the index values were greater than 1.0 X 10(-3) min-1 and these were clearly separate from the values of less than 0.5 X 10(-3) min-1 in all healthy volunteers (n = 5; P less than 0.001). The technique can clearly detect raised plasma protein accumulation indices in the lungs of patients with established inflammatory oedema of ARDS and hence may provide a pharmacological tool for the rapid evaluation in these conditions of the effects of drugs (like corticosteroids) which are known to modulate inflammatory oedema.     

Nitric oxide protects against contrast media-increased pulmonary vascular permeability in rats

RATIONALE AND OBJECTIVES: Nitric oxide (NO) regulation of endothelial function is involved in the development of acute lung injury. The role of NO in contrast media-induced increases in pulmonary vascular permeability was investigated in a rat model. METHODS: Nonionic (iohexol) and ionic (ioxaglate) contrast media were intravenously injected at 1.5 mL/min in rats. Pulmonary vascular permeability was evaluated by measuring the amount of Evans blue dye uptake as a quantitative marker of albumin extravasation in lung tissue. RESULTS: Intravenous injections of contrast media at doses of 4 and 6 g I/kg induced a dose-dependent increase in pulmonary vascular permeability. L-Arginine (an NO synthase substrate) and N(G)-nitro-L-arginine (L-NNA) (an NO synthase inhibitor) prevented and aggravated, respectively, the increase in pulmonary vascular permeability induced by the contrast medium. An aggravating action of L-NNA was confirmed by morphological and histological observations, this action being blocked by L-arginine (300 mg/kg) but not by D-arginine. Isosorbide dinitrate (1-20 mg/kg), an NO donor, had a dose-dependent protective effect on ioxaglate-increased vascular permeability. CONCLUSIONS: Our experimental findings suggest that contrast media at high doses produce pulmonary edema by inhibiting endothelial NO production, and nitrovasodilators protect against this adverse effect in rats.     

Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin

We quantified pulmonary vascular permeability with positron emission tomography (PET) and gallium-68-(68Ga) labeled transferrin. Six dogs with oleic acid-induced lung injury confined to the left lower lobe, two normal human volunteers, and two patients with the adult respiratory distress syndrome (ARDS) were evaluated. Lung tissue-activity measurements were obtained from sequential 1-5 min PET scans collected over 60 min, after in vivo labeling of transferrin through intravenous administration of [68Ga]citrate. Blood-activity measurements were measured from simultaneously obtained peripheral blood samples. A forward rate constant describing the movement of transferrin from pulmonary vascular to extravascular compartments, the pulmonary transcapillary escape rate (PTCER), was then calculated from these data using a two-compartment model. In dogs, PTCER was 49 +/- 18 in normal lung tissue and 485 +/- 114 10(-4) min-1 in injured lung. A repeat study in these dogs 4 hr later showed no significant change. Values in the human subjects showed similarly marked differences between normal and abnormal lung tissue. We conclude that PET will be a useful method of evaluating vascular permeability changes after acute lung injury.     

Contrast media increase vascular endothelial permeability by inhibiting nitric-oxide production.

RATIONALE AND OBJECTIVES: Contrast media induce adverse effects including edema of the face, glottis, or lung. The endothelial function is maintained by nitric oxide (NO). The present study was designed to elucidate the role of NO in mediating endothelium-related adverse effects of contrast media. METHODS: Human microvascular endothelial cells grown on a Transwell membrane were incubated with iohexol or ioxaglate in the absence or presence of N(G)-monomethyl-L-arginine or sodium nitroprusside. After washing cells, the permeability of sodium fluorescein or Evans blue albumin and the accumulation of NO(2)(-) was examined. RESULTS: Contrast media (50-150 mgI/mL) dose-dependently increased the permeability coefficient by 30% to 230% and inhibited the formation of NO(2)(-) by 40% to 80%. Sodium nitroprusside and N(G)-monomethyl-L-arginine produced protective and aggravating effects on contrast media-increased permeability, respectively. CONCLUSIONS: The present study suggested that contrast media increase vascular endothelial permeability by inhibiting NO production, leading to vascular endothelium-related adverse effects of contrast media.     

Identifying tumor vascular permeability heterogeneity with magnetic resonance imaging contrast agents

RATIONALE AND OBJECTIVES: Dynamic contrast enhanced (DCE) MR mammography (MRM) uses tumor capillary density differences for prognosis. The heterogeneous response of permeability-surface area products (PS = Kp<-->t) was examined in mammary tumors, as a function of contrast agent size, to determine what effect ROI size might have on PS and prognosis. METHODS: DCE FLASH signal intensities were converted to gadolinium concentrations by a standard curve, which was fitted by a two-compartment model for the tumor's extravascular extracellular space (EES) volume fraction (ve), and the tumor volume normalized transfer rate between plasma and EES (Kp<-->t/VT). RESULTS: For Gd-DTPA ve = 9% to 13% Kp<-->t/VT = 0.01 to 0.06 minutes-1, and the macromolecular agent, PAMAM-TU-DTPA G = 4 ve = 0.8% to 1% Kp<-->t/VT = 0.008 to 0.04 minutes(-1). Significant differences in Kp<-->t/VT for local regions were found for both agents relative to the whole tumor and the macromolecular agent had greater dynamic range. CONCLUSIONS: Smaller ROI values or pixels should yield more accurate assessment of neovascularization.     

Combination of vascular endothelial growth factor antisense oligonucleotide therapy and radiotherapy increases the curative effects against maxillofacial VX2 tumors in rabbits

Purpose

The purpose of this study was to investigate correlations between the aorto-popliteal bolus transit speed and aortic and popliteal bolus transit time in order to evaluate the possibility for prediction of bolus transit speed by single test injection technique.

Materials and methods

Approval was obtained from our institutional review board for this study, which included 42 patients, from all of whom written informed consent was obtained. Low-dose serial CT scanning after injection of 12 ml contrast material (300 mg/ml) at a rate of 3 ml/s followed by saline flush was performed twice, first at the level of the upper abdomen and second at the level of the knee joint. The times needed to reach peak enhancement of the upper abdominal aorta (T-aorta) and bilateral popliteal arteries (T-popliteal) were obtained, and aorto-popliteal bolus transit speeds between the abdominal aorta and popliteal arteries were calculated. ABI was recorded for the bilateral feet. The Pearson's product-moment correlation coefficient was used to investigate the correlation between the bolus transit speed and T-aorta, T-popliteal, ABI, and patient age.

Result

The respective correlation coefficients for bolus transit speed on the one hand and T-aorta, T-popliteal, ABI, patient age on the other were −0.50, −0.84, 0.36, and −0.52.

Conclusion

The time to peak enhancement for popliteal arteries showed the strongest correlation with aorto-popliteal bolus transit speeds, and was considered to be the most accurate predictor for aorto-popliteal bolus transit speeds.     

血管内皮生长因子在高原暴露下血脑屏障通透性改变中的作用及其与脑水肿的关系

目的:探讨血管内皮生长因子(VEGF)在高原暴露下血脑屏障(BBB)通透性改变中的作用及与脑水肿的关系。方法:将大鼠暴露于高原不同海拔下,应用RT-PCR测定脑组织内VEGFmRNA转录水平和双抗体夹心ELISA法测定脑内VEGF蛋白含量,应用比色法测定伊文思蓝(EB)的透过率以确定BBB通透性的变化,脑湿干比重法测定脑含水量百分率。结果:高原暴露下,大鼠脑内VEGF和VEGFmRNA的表达随着海拔增高而增高,随着时间延长而增高,以暴露于5 000 m的特高海拔区第9天增高最明显。与此同时,脑内EB含量和脑内含水量增高。脑内VEGF活性与脑内EB含量和脑含水量之间明显相关。结论:VEGF是高原环境下BBB通透性增高的重要因素。     

N-terminal pro brain natriuretic peptide increases after 1-h scuba dives at 10 m depth

OBJECTIVES: The N-terminal pro brain natriuretic peptide (N-BNP) is a promising cardiac natriuretic peptide used as a clinical hormonal marker in cardiac dysfunction. The main stimulus for N-BNP synthesis and secretion is cardiac wall stress, which is recognized as a common denominator of many cardiac diseases. Diving is associated with environmental factors leading to variations in thoracic blood volume and hemodynamic changes. The purpose of the present study was to examine the changes in the concentration of N-BNP in healthy men during and after scuba diving. METHOD: There were 10 healthy military divers (mean age 33 yr) who performed a dive in the sea for 1 h at 10 m depth. Venous blood samples were taken at timed intervals to allow evaluation of plasma levels of N-BNP at different steps, namely at To (before immersion), at T30 min (during the dive, after a short surfacing), at T60 min (right after surfacing), at T300 min (post-dive), and finally at T24 h. Peptide blood concentrations were determined by electrochemoluminiscence immunoassay. Data were analyzed using parametric statistics. RESULTS: When compared with To, the results show a significant increase of N-BNP levels (in % of baseline levels) at T60(128 +/- 5%, p < 0.043) and at T300 (149 +/- 8%, p < 0.001). CONCLUSION: This preliminary study reveals that N-BNP rises with scuba diving. Our findings suggest that diving involves a mechanical strain on the heart with a persistent endocrine myocardial activity post-dive.     

Enhancement of vascular permeability with low-frequency contrast-enhanced ultrasound in the chorioallantoic membrane model

PURPOSE: To characterize the effect of low-frequency contrast material-enhanced ultrasound on the vascular endothelium and to determine the parameters and techniques required to deliver a therapeutic agent by using the chorioallantoic membrane (CAM) model. MATERIALS AND METHODS: All in vivo animal procedures were conducted with institutional Animal Care and Use Committee approval. Extravasation of 8.5-nm-diameter fluorescein isothiocyanate-labeled dextran was evaluated in the vasculature of a chick CAM model. Intravital microscopy was performed during contrast-enhanced ultrasound exposure (1.00 or 2.25 MHz); results were compared with results of electron microscopy of the insonated regions. Data acquired after insonation with greater mechanical stress (n = 30 animals) (mechanical index [MI] > 1.3) and with lower mechanical stress (n = 86 animals) (MI < 1.13) were compared with measurements in control conditions (n = 46 animals). The diameter of affected vessels; number of extravasation sites; extravasation rate, area, and location; and changes in endothelial cells and basement membrane were evaluated. Differences were tested with analysis of variance or the Student t test. RESULTS: After ultrasound application, convective transport of the model drug was observed through micron-sized openings with a mean fluid velocity of 188.6 microm/sec in the low-stress class and 362.5 microm/sec in the high-stress class. Electron microscopy revealed micron-sized focal endothelial gaps and disseminated blebs, vacuoles, and filopodia extending across tens of microns. The threshold pressure for extravasation was 0.5 MPa for a transmitted center frequency of 1.00 MHz (MI = 0.5) and 1.6 MPa for a frequency of 2.25 MHz (MI = 1.06); thus, the frequency dependence of the threshold was not predicted simply by the MI. CONCLUSION: Low-frequency contrast-enhanced ultrasound can increase vascular permeability and result in convective extravasation of an 8.5-nm-diameter model drug.     

大鼠烫伤后肠壁微血管通透性和肠组织含水量的变化

目的:观察大鼠烫伤后12h肠壁微血管通透性和肠组织含水量变化,探讨烫伤早期肠粘膜损伤的可能机制。方法:制作成年大鼠严重烫伤模型(Ⅲ度,30%TBSA),在未烫伤鼠及烫伤后12h应用分光光度法测量肠壁微血管通透性,测量回肠组织含水量。结果:对照组肠壁微血管对伊文思蓝有一定的通透性(12.39±5.062μg/g),烫伤后12h肠壁微血管对伊文思蓝通透性较对照组低(10.50±2.031μg/g),但无统计学意义(t=0.923,P>0.05);对照组回肠含水量为83.3±3.8%,烫伤后12h肠组织含水量比对照组稍低(82.9±1.5%),也无统计学意义(t=0.278,P>0.05)。结论:烫伤早期肠壁微血管通透性和肠组织含水量无显著变化,提示炎症介质在烫伤早期肠粘膜损伤中可能不是主要致病因子。     

Effects of androgen deprivation on prostatic morphology and vascular permeability evaluated with mr imaging

PURPOSE: To assess magnetic resonance (MR) measures of vascular permeability of prostate cancer treated with androgen deprivation and to correlate these with morphologic appearances and serum prostate-specific antigen (PSA) levels. MATERIALS AND METHODS: MR examinations in 56 consecutive patients with prostate cancer were performed before and after luteinizing hormone-releasing hormone analog treatment. T2-weighted and contrast medium-enhanced T1-weighted MR images were obtained. Pre- and posttreatment comparisons of morphologic features, glandular volume, and enhancement-related parameters (capillary permeability, leakage space, gadolinium accumulation) were made. RESULTS: Fifty-five tumors were seen before treatment; 42, after treatment. Signal intensity in the peripheral zone and seminal vesicles decreased on T2-weighted images in 42 (75%) and 25 (45%) patients, respectively. Median volume in tumor decreased by 65% (95% CI: 55%, 76%); in central gland, by 30% (95% CI: 25%, 35%). Reductions in tumor permeability (P <.001) and changes in washout patterns were observed (P <.001). Tumor permeability reductions coincided with a decrease in serum PSA levels in 91% of patients. A weak correlation between tumor permeability and volume change was seen (r = 0.55, P =.04). Reductions in peripheral zone (P <.001) and central gland (P =.009) permeability were noted. CONCLUSION: Androgen deprivation decreases tumor volume and vascular permeability and impairs detection of prostate cancers. Use of MR estimates of permeability may be an additional way of assessing prostatic tumor response to antiandrogen treatment.     

Comparative study of methods for determining vascular permeability and blood volume in human gliomas

PURPOSE: To characterize human gliomas using T1-weighted dynamic contrast-enhanced MRI (DCE-MRI), and directly compare three pharmacokinetic analysis techniques: a conventional established technique and two novel techniques that aim to reduce erroneous overestimation of the volume transfer constant between plasma and the extravascular extracellular space (EES) (Ktrans) in areas of high blood volume. MATERIALS AND METHODS: Eighteen patients with high-grade gliomas underwent DCE-MRI. Three kinetic models were applied to estimate Ktrans and fractional blood plasma volume (vp). We applied the Tofts and Kermode (TK) model without arterial input function (AIF) estimation, the TK model modified to include vp and AIF estimation (mTK), and a "first pass" variant of the TK model (FP). RESULTS: KTK values were considerably higher than KmTK and KFP values (P <0.001). KmTK and KFP were more comparable and closely correlated (rho=0.744), with KmTK generally higher than KFP (P <0.001). Estimates of vp(mTK) and vp(FP) also showed a significant difference (P <0.001); however, these values were very closely correlated (rho=0.901). KTK parameter maps showed "pseudopermeability" effects displaying numerous vessels. These were not visualized on KmTK and KFP maps but appeared on the corresponding vp maps, indicating a failure of the TK model in commonly occurring vascular regions. CONCLUSION: Both of the methods that incorporate a measured AIF and an estimate of vp provide similar pathophysiological information and avoid erroneous overestimation of Ktrans in areas of significant vessel density, and thus allow a more accurate estimation of endothelial permeability.