[Human experiments of metabolism, blood alkalization and oxygen effect on control and regulation of breathing. I: room air exercise test].

OBJECTIVE: Under the guidance of the holistic integrative physiology medicine, we reanalyzed the data during symptom-limited maximum cardiopulmonary exercise testing (CPET) in order to investigate control and regulatory mechanism of breathing. METHODS: This study investigated 5 normal volunteers who accepted artery catheter, performed CPET room air. Continuous measured pulmonary ventilation parameters and per minute arterial blood gas (ABG) analysis sample parameters during exercise. All CPET and ABG data changes were standard analyzed and calculated. RESULTS: With gradually increasing power, minute oxygen uptake(every breath oxygen uptake x respiratory rate = O2 paulse x heart rate) and minute ventilation (tidal volume x respiratory rate) showed nearly linear progressive increase during the CPET(compared with the rest stage, P < 0.05 - 0.001); Minute ventilation increased even more significant after the anaerobic threshold (AT) and respiratory compensation point. PaO2 was increased at recovery 2 minutes (P < 0.05); PaCO2 was decreased after anaerobic threshold 2 minutes (P < 0.05); [H+]a was increased from AT (P < 0.05), and rapidly raised at last 2 minutes, remained high at recovery. Lactate was increased rapidly from AT (compared with resting, P < 0.05); bicarbonate decreased rapidly from AT (compared with resting, P < 0.05) and it's changed direction was contrary to lactic acid. CONCLUSION: In order to overcome the resistance of the power during exercise, metabolic rate othe body increased, respiratory change depend upon the change metabolism, and the accumulation of acidic products exacerbated respiratory reactions at high intensity exercise.

[Human experiments of metabolism, blood alkalization and oxygen effect on control and regulation of breathing. II: room air exercise test after blood alkalization].

OBJECTIVE: Basis on the dynamic changes of the ventilation and arterial blood gas parameters to symptom-limited maximum cardiopulmonary exercise testing (CPET), we further investigate the effect of alkalized blood by drinking 5% NaHCO3 on ventilation during exercise. METHODS: After drinking 5% NaHCO3 75 ml (3.75 g) every 5 min, total dosage of 0.3 g/Kg, 5 volunteers repeated CPET. All CPET and ABG data changes were analyzed and calculated. At the same time, CPET and ABG parameters after alkalized blood were compared with those before alkalized blood (control) used paired t test. RESULTS: After alkalized blood, CPET response patterns of parameters of ventilation, gas exchange and arterial blood gas were very similar (P > 0.05). All minute ventilation, tidal volume, respiratory rate, oxygen uptake and carbon dioxide elimination were gradually increased from resting stage (P < 0.05-0.001), according to the increase of power loading. During CPET after alkalized blood, ABG parameters were compared with those of control: hemoglobin concentrations were lower, CaCO2 and pHa were increased at all stages (P < 0.05). The PaCO2 increased trend was clear, however only significantly at warm-up from 42 to 45 mmHg (P < 0.05). Compared with those of control, only the minute ventilation was decreased from 13 to 11 L/min at resting (P < 0.05). CONCLUSION: Even with higher mean CaCO2, PaCO2 and pHa, lower Hba and [H+]a, the CPET response patterns of ventilatory parameters after alkalized blood were similar.

[Human experiments of metabolism, blood alkalization and oxygen effect on control and regulation of breathing. III: pure oxygen exercise test after blood alkalization].

OBJECTIVE: After performed symptom-limited maximum cardiopulmonary exercise testing (CPET) before and after acute alkalized blood, we repeated CPET with pure oxygen. METHODS: Five volunteers, 3hr after alkalizing blood room air CPET, re-performed CPET inhaling from Douglas bag connected with pure oxygen tank. We compared with those of room air CPETs before and after alkalized blood. RESULTS: After alkalized blood oxygen CPET had a similar response pattern as those of CPETs before and after blood alkalization. During the CPET, all breath frequency, minute ventilation and tidal volume at each stage were similar to those of CPETs before and after alkalized blood (P > 0.05),except there was a lower peak tidal volume than those of both CPETs and a slightly higher resting minute ventilation only than CPET after alkalized blood (P > 0.05). After alkalized blood, oxygen CPET, all PaO2 and SaO2 and most Hb were lower than those of both CPETs (P < 0.05). The pHa and [HCO3-]a were higher than those of CPET before alkalized blood (P < 0.05); but were not CPET after alkalized blood (P > 0.05). PaCO2 was similar to that of CPET before alkalized blood (P > 0.05), but was lower than that of CPET after alkalized blood at resting and warm-up (P < 0.05); then was similar to both CPETs at anaerobic threshold (P > 0.05); but was higher at peak exercise higher than those of both CPETs (P < 0.01). Oxygen increased 2,3 volunteers' workload and time at AT and peak exercises. CONCLUSION: Respiratory response pattern to oxygen CPET after alkalized blood is similar to those of both CPETs before and after alkalized blood. The CPET response is dominantly depended upon metabolic rate, but not levels of pHa, PaCO2 and PaO2.

Calculating gambling odds and lung ages for smokers.

Interpreting spirometry as normal or abnormal using 95% confidence limits can obscure milder airflow decreases. Other analyses might better persuade cigarette smokers to quit. High-quality spirometric data of ambulatory never- and current-smokers of African-, European- and Latin-American ethnicity from the Third National Health and Nutrition Evaluation Survey (n>9000) were analysed. We desired to calculate, for each decade of life, the odds that specific ratios of forced expiratory volume in 1 s to 6 s (%FEV(1)/FEV(6)) and to forced vital capacity (%FEV(1)/FVC) values came from a current- or never-smoker. We also desired to develop new, simpler and better formulas to estimate changes in physiological lung age (Deltalung age) for males and females. For each decade of life, odds increase strikingly that smoking decreases %FEV(1)/FEV(6) and %FEV(1)/FVC. At least for these three ethnicities, Deltalung age can be easily calculated as the product of (predicted - actual) %FEV(1)/FEV(6) x 4 or (predicted - actual) %FEV(1)/FVC x 3. Through the sixth decade of life, smokers' Deltalung age increase rapidly but little thereafter, presumably due to the inabilities of older smokers to participate in the survey or their deaths. Using odds and Deltalung ages rather than traditional 95% confidence limits might better persuade smokers to quit.

Should forced expiratory volume in six seconds replace forced vital capacity to detect airway obstruction?

It has been suggested that forced expiratory volume in six seconds (FEV(6)) should be substituted for forced vital capacity (FVC) to measure fractions of timed expired volume for airflow obstruction detection. The present authors hypothesised that this recommendation might be questionable because flow after 6 s of forced expiration from more diseased lung units with the longest time constants was most meaningful and should not be ignored. Furthermore, previous studies comparing FEV(6) and FVC included few subjects with mild or no disease. The present study used spirometric data from the USA Third National Health and Nutrition Evaluation Survey with prior published ethnicity- and sex-specific equations for FEV(1)/FEV(6), FEV(1)/FVC and FEV(3)/FVC, and new equations for FEV(3)/FEV(6), all derived from approximately 4,000 adult never-smokers aged 20-80 yrs. At 95% confidence intervals, 21.3% of 3,515 smokers and 41.3% of smokers aged >51 yrs had airway obstruction; when comparing FEV(1)/FEV(6) with FEV(1)/FVC, 13.5% were concurrently abnormal, 1.5% were false positives and 4.1% were false negatives; and when comparing FEV(3)/FEV(6) with FEV(3)/FVC, 11.6% were concurrently abnormal, 3.3% were false positives and 5.7% were false negatives. Substituting forced expiratory volume in six seconds for forced vital capacity to determine the fractional rates of exhaled volumes reduces the sensitivity of spirometry to detect airflow obstruction, especially in older individuals and those with lesser obstruction.

Anaerobic threshold and cardiovascular function.

The cardiopulmonary exercise test is a valuable method for quantifying global cardiovascular function. It is quantitative, cheap, safe and highly reproducible. Unfortunately, it is highly under-utilized in favor of less quantitative, more expensive and perhaps less safe and reproducible methods. But even if performed, the peak Vo2 is often the only measurement made, and the data for determining the patient's anaerobic threshold (AT) and other parameters are discarded by the examiner. The discarding of such valuable physiological data is likely due to the lack of recognition by the physician that these measurements, and the physiological parameters that could be calculated from them, reflect cardiovascular function. Furthermore, the information can be extracted without additional expense. The AT, as a marker of the severity of cardiovascular function, is particularly, under-utilized relative to its clinical usefulness. With the development of the V-slope method, the AT is easily measured in all patients whose exercise is limited by cardiovascular factors. While the AT is a very valuable measurement in all patients, it is especially valuable in patients who should not be maximally stressed, e.g., the elderly or post-myocardial infarction patients.

Effects of dobutamine on critical capillary PO(2) and lactic acidosis threshold in patients with cardiovascular disease.

BACKGROUND: Muscle capillary PO(2) has been found to reach a minimal value, ie, a critical capillary PO(2), in the midrange of work capacity in patients with cardiovascular disease. However, it is not known if the critical capillary PO(2) can be influenced by a change in blood flow response to exercise. This study was carried out to determine the effect of changing the blood flow response to exercise, using low-dose infusion of dobutamine, on muscle end-capillary PO(2) (as approximated by femoral vein PO(2)), lactate concentration, oxygen uptake (O(2)), and the relation among these variables. METHODS: Eleven male patients with coronary artery disease performed an incremental exercise test on a cycle ergometer with and without continuous infusion of dobutamine, 6 microg/kg/min. Respiratory gas analysis was performed on a breath-by-breath basis; femoral vein blood was sampled every minute through a percutaneous catheter. RESULTS: Dobutamine increased resting O(2) and O(2) at the lactic acidosis threshold (LAT) but not peak O(2). The femoral vein PO(2) rapidly decreased toward a minimal value with increasing work rate (O(2)) irrespective of the infusion of dobutamine. After reaching its nadir (critical PO(2)), femoral vein lactate began to increase without further decrease in PO(2). Infusion of dobutamine significantly increased femoral vein resting PO(2) (27.4 +/- 4.9 mm Hg vs 32.5 +/- 3.8 mm Hg) and critical PO(2) (20.5 +/- 1.5 mm Hg vs 21.9 +/- 1.7 mm Hg), but not the PO(2) at peak O(2) (22.1 +/- 3.3 mm Hg vs 22.0 +/- 2.9 mm Hg). CONCLUSIONS: Infusion of dobutamine was found to raise the critical PO(2) and LAT but not peak O(2). These findings suggest that some of the acute increase in blood flow induced by dobutamine infusion benefits exercising muscle by increasing capillary PO(2), thereby delaying the onset of lactic acidosis.

The body weight-walking distance product as related to lung function, anaerobic threshold and peak VO2 in COPD patients.

The product of walking distance and body weight (D x W) mimics the work of walking. We hypothesized the superiority of D x W to walking distance (D) alone in any correlation with lung function, anaerobic threshold (AT) and maximal oxygen uptake (VO2max). We further hypothesized that the D x W product for a 6-min walk test (6 MWT) would correlate with the AT and VO2max because all three are markers of exercise ability. Thirty-three male chronic obstructive pulmonary disease (COPD) patients with mean forced expiratory volume in 1 sec (FEV1) of 1.2+/-0.4 l (range 0.58-1.86 l) were enrolled. Six patients were excluded due to inability to achieve a maximal test. Lung function and self-assessed every-day activities using a oxygen-cost diagram were evaluated before entry of the study. A maximal effort ramp-pattern cardiopulmonary exercise test (CPET) and a 6 MWT were conducted in random order. Borg score, heart rate, and O2 saturation with pulse oximetry (SpO2) were measured during both exercise tests. VO2 AT and minute ventilation were also measured during the CPET. Correlations were sought between the distance covered in the 6 MWT, and the D x W product with AT, VO2max and other variables. The average D and D x W were 456 m and 27.5 kg km(-1), respectively. D x W was superior to D alone when correlated with the VO2max and AT determined from the CPET, while modestly correlated with the change (delta) in Borg score and delta SpO2 in the 6 MWT and self-assessed every-day activities. Distance x weight product was correlated with the AT and VO2max. In addition, D x W was better correlated with diffusing capacity for carbon monoxide and vital capacity than D alone. We conclude that D x W mimics the work of walking better than D and is suggested as a parameter for evaluation of patients' fitness if gas exchange measurements are not available.

Exercise pathophysiology in patients with primary pulmonary hypertension.

BACKGROUND: Patients with primary pulmonary hypertension (PPH) have a pulmonary vasculopathy that leads to exercise intolerance due to dyspnea and fatigue. To better understand the basis of the exercise limitation in patients with PPH, cardiopulmonary exercise testing (CPET) with gas exchange measurements, New York Heart Association (NYHA) symptom class, and resting pulmonary hemodynamics were studied. METHODS AND RESULTS: We retrospectively evaluated 53 PPH patients who had right heart catheterization and cycle ergometer CPET studies to maximum tolerance as part of their clinical workups. No adverse events occurred during CPET. Reductions in peak O(2) uptake (VO(2)), anaerobic threshold, peak O(2) pulse, rate of increase in VO(2), and ventilatory efficiency were consistently found. NYHA class correlated well with the above parameters of aerobic function and ventilatory efficiency but less well with resting pulmonary hemodynamics. CONCLUSIONS: Patients with PPH can safely undergo noninvasive cycle ergometer CPET to their maximal tolerance. The CPET abnormalities were consistent and characteristic and correlated well with NYHA class.

Carbon dioxide pressure-concentration relationship in arterial and mixed venous blood during exercise.

To calculate cardiac output by the indirect Fick principle, CO(2) concentrations (CCO(2)) of mixed venous (Cv(CO(2))) and arterial blood are commonly estimated from PCO(2), based on the assumption that the CO(2) pressure-concentration relationship (PCO(2)-CCO(2)) is influenced more by changes in Hb concentration and blood oxyhemoglobin saturation than by changes in pH. The purpose of the study was to measure and assess the relative importance of these variables, both in arterial and mixed venous blood, during rest and increasing levels of exercise to maximum (Max) in five healthy men. Although the mean mixed venous PCO(2) rose from 47 Torr at rest to 59 Torr at the lactic acidosis threshold (LAT) and further to 78 Torr at Max, the Cv(CO(2)) rose from 22.8 mM at rest to 25.5 mM at LAT but then fell to 23.9 mM at Max. Meanwhile, the mixed venous pH fell from 7.36 at rest to 7.30 at LAT and to 7.13 at Max. Thus, as work rate increases above the LAT, changes in pH, reflecting changes in buffer base, account for the major changes in the PCO(2)-CCO(2) relationship, causing Cv(CO(2)) to decrease, despite increasing mixed venous PCO(2). Furthermore, whereas the increase in the arteriovenous CCO(2) difference of 2.2 mM below LAT is mainly due to the increase in Cv(CO(2)), the further increase in the arteriovenous CCO(2) difference of 4.6 mM above LAT is due to a striking fall in arterial CCO(2) from 21.4 to 15.2 mM. We conclude that changes in buffer base and pH dominate the PCO(2)-CCO(2) relationship during exercise, with changes in Hb and blood oxyhemoglobin saturation exerting much less influence.

A noninvasive assessment of pulmonary perfusion abnormality in patients with primary pulmonary hypertension.

STUDY OBJECTIVES: The ventilatory equivalent for CO(2) (ie, the ratio of minute ventilation [VE] to carbon dioxide output [VCO(2)]) is increased in patients with primary pulmonary hypertension (PPH) consequent to an increase in physiologic dead space and alveolar ventilation. We wished to see whether the VE/V(2) ratio correlated with the abnormality in pulmonary hemodynamics in PPH patients and whether it changed in response to prostacyclin infusion. METHODS: Following right-sided heart catheterization, 10 patients with severe PPH were studied in the coronary-care unit while hemodynamic and gas exchange measurements were measured simultaneously before and after infusion with epoprostenol (Epo), a prostacyclin analog. Studies were performed at baseline and during IV infusion of two to three increasing dosages of Epo in 10 PPH patients (NYHA class III-IV). Four patients had radial artery catheters for simultaneous blood gas measurements. Nine healthy subjects who were matched by sex, height, and weight underwent gas exchange analyses only. RESULTS: The mean (+/- SD) VE/VCO(2) ratio was higher in PPH patients than in control subjects (50.7 +/- 9.7 vs 30.6 +/- 3.8; p < 0.001). Thirteen measurements made in four patients showed that the VE/VCO(2) ratio correlated with the physiologic dead space/tidal volume ratio (r = 0.78; p = 0.002). The VE/VCO(2) ratio measurement at baseline correlated significantly with total pulmonary vascular resistance (TPVR) (r = 0.70; p = 0.02) but not with mean pulmonary artery pressure (mPAP) or cardiac index. During Epo infusion, the VE/VCO(2) ratio decreased with increasing dosage in 6 of 10 patients, with no change or slight increases in the 4 remaining patients. Considering all doses, the VE/VCO(2) ratio decreased significantly in response to the short-term administration of Epo. The decrease tended to parallel the pattern of decrease in TPVR, but the changes in both variables were too small to provide a statistically significant correlation. The mPAP did not change significantly in response to Epo infusion, although TPVR did change at the highest dosage. CONCLUSIONS: In patients with severe PPH, the VE/VCO(2) ratio correlated significantly with TPVR but not with mPAP or cardiac index. The VE/VCO(2) ratio decreased systematically from baseline with the dose of Epo in some but not all patients. The VE/VCO(2) ratio and TPVR decreased significantly in response to Epo when all doses were considered. Further studies are needed to elucidate whether noninvasive gas exchange measurements may be clinically useful in the evaluation of the severity of pulmonary vascular disease and the effectiveness of pulmonary vasodilator therapy.

Frustrations in polymer conformation in gels and their minimization through molecular imprinting.

We report an experimental realization of a gel system in which frustrations exist and can be minimized, thus meeting two crucial criteria predicted to enable memory of conformations in polymers. The gels consist of a thermosensitive major monomer component and two minor components. One minor component is positively charged and will form complexes around negatively charged target molecules placed in solution. The complexes can be imprinted into the gel by then cross-linking the second minor component, which will form cross-links additional to those in the major polymer matrix. The complexes are destroyed and reformed upon swelling and reshrinking of the gels, showing that memorization has been achieved.

Gas exchange responses to continuous incremental cycle ergometry exercise in primary pulmonary hypertension in humans.

In patients suffering from primary pulmonary hypertension (PPH), a raised pulmonary vascular resistance may limit the ability to increase pulmonary blood flow as work rate increases. We hypothesised that oxygen uptake (VO2) may not rise appropriately with increasing work rate during incremental cardiopulmonary exercise tests. Nine PPH patients and nine normal subjects performed symptom-limited maximal continuous incremental cycle ergometry exercise. Mean peak VO2 [1.00 (SD 0.22) compared to 2.58 (SD 0.64) l x min(-1)] and mean VO2 at lactic acidosis threshold [LAT, 0.73 (SD 0.17) compared to 1.46 (SD 0.21 x 1) ml x min(-1)] were much lower in patients than in normal subjects (both P<0.01, two-way ANOVA with Tukey test). The mean rate of change of VO2 with increasing work rate above the LAT [5.9 (SD 2.1) compared to 9.4 (SD 1.3) ml x min(-1) x W(-1), p<0.01)] was also much lower in patients than in normal subjects [apparent delta efficiency 60.3 (SD 38.8)% in patients compared to 31.0 (SD 4.9)% in normal subjects]. The patients displayed lower mean values of end-tidal partial pressure of carbon dioxide than the normal subjects at peak exercise [29.7 (SD 6.8) compared to 42.4 (SD 5.8) mm Hg, P<0.01] and mean oxyhaemoglobin saturation [89.1 (SD 4.1) compared to 93.6 (SD 1.8)%, P<0.05]. Mean ventilatory equivalents for CO2 [49.3 (SD 11.4) compared to 35.0 (SD 7.3), P<0.05] and O2 [44.2 (SD 10.7) compared to 29.9 (SD 5.1), P<0.05] were greater in patients than normal subjects. The sub-normal slopes for the VO2-work-rate relationship above the LAT indicated severe impairment of the circulatory response to exercise in patients with PPH. The ventilatory abnormalities in PPH suggested that the lung had become an inefficient gas exchange organ because of impaired perfusion of the ventilated lung.

Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells.

The basis for the angiogenic effects of CXC chemokines such as interleukin 8 (IL-8) and for angiostatic chemokines such as interferon-inducible protein 10 (IP-10) has been difficult to assess. We recently reported, based on an RNase protection assay, that human umbilical vein endothelial cells (HUVECs) did not express detectable mRNA for the IL-8 receptors CXCR1 and CXCR2. This raised the possibility of heterogeneity of receptor expression by different endothelial cell (ECs) types. Since systemic angiogenesis induced by IL-8 would more likely involve microvessel ECs, we investigated CXC receptor expression on human microvascular dermal endothelial cells (HMECs). By confocal microscopy and immunofluorescence we observed that HMECs consistently expressed high levels of CXCR1 and CXCR4 (mean fluorescence intensity of 261+/-22.1 and 306.2+/-19, respectively) and intermediate levels of CXCR3 and CXCR2 (173.9+/-30. 2 and 156+/-30.9, respectively). In contrast, only a small proportion of HUVEC preparations expressed low levels of CXCR1, -2, and -3 (66+/-19.9; 49+/-15, and 81.4+/-17.9, respectively). However, both HMECs and HUVECs expressed equal levels of CXCR4. As expected, HMECs had more potent chemotactic responses to IL-8 than HUVECs, and this was correlated with the levels of IL-8 receptors on the ECs. Antibodies to CXCR1 and CXCR2 each had inhibitory effects on chemotaxis of HMECs to IL-8, indicating that both IL-8 receptors contributed to the migratory response of these cells toward IL-8. Assessment of the functional capacity of CXCR3 unexpectedly revealed that HMECs migrated in response to relatively higher concentrations (100-500 ng/ml) of each of the 'angiostatic' chemokines IP-10, ITAC, and MIG. Despite this, the 'angiostatic' chemokines inhibited the chemotactic response of HMECs to IL-8. IL-8 and SDF-1alpha but not IP-10 induced calcium mobilization in adherent ECs, suggesting that signaling events associated with calcium mobilization are separable from those required for chemotaxis. Taken together, our data indicated that functional differences among EC types is dependent on the level of the expression of CXC chemokine receptors. Whether this heterogeneity in receptor expression by ECs reflects distinct differentiation pathways remains to be established.

Comparison of exercise cardiac output by the Fick principle using oxygen and carbon dioxide.

BACKGROUND AND STUDY OBJECTIVE: Theoretically, cardiac output (CO) calculated by the Fick principle should be the same using O(2) (CO[O2]) or CO2 (CO[CO2]) as the test gas. However, agreement depends on the accuracy of gas exchange and blood gas measurements and the validity of the equations to convert measured variables into blood gas contents. Considering the widespread use of indirect estimates of pulmonary artery blood PCO2 and CO2 content to measure Fick principle CO during exercise, we wished to determine whether CO[O2] and CO[CO2] were equal during exercise and whether CO[CO2] could be accurately and precisely determined using direct measures of pulmonary artery blood. PREPARATION AND METHODS: Five healthy young nonsmoking volunteer men performed incremental exercise from rest to peak exercise on two separate occasions with intervening rest. Catheters were placed in brachial and pulmonary arteries to allow repeated blood sampling every minute during concurrent breath-by-breath gas exchange measurements from rest to peak exercise. CO[O2] was compared with CO[CO2] at multiple levels of exercise. Using standard equations, arterial and mixed venous O2 contents were calculated from hemoglobin concentration (Hb), oxyhemoglobin saturation (SO2), and PO2, whereas CO2 contents were calculated from PCO2, pH, Hb, and SO2. Blood gas analyzers were used for measurement of pH, PCO2, and PO2, and a co-oximeter was used for measurement of Hb and SO2. Initial calculations suggested that exercise CO[CO2] was 14% higher than CO[O2] and helped disclose small systematic measurement errors in PCO(2) for values > 45 mm Hg detected by proficiency testing surveys and documented with blood tonometry in the blood gas analyzer. RESULTS: After correcting PCO2 for the small systematic measurement error found, the measures and equations used to calculate arterial and mixed venous O2 and CO2 contents were adequate to provide mean CO values that are reasonably similar. However CO[CO2] values were more than twice as variable as CO[O2]. CONCLUSIONS: The increased variability of Fick principle CO[CO2] compared with CO[O2] is attributable to the much lower extraction ratio for CO2 and the greater complexity in calculation of blood CO2 than O2 contents. These results raise concerns about the accuracy and precision of estimating CO and stroke volume using CO2 as a test gas, even with direct measurement of blood CO2 contents in normal subjects.

Responses to constant work rate bicycle ergometry exercise in primary pulmonary hypertension: the effect of inhaled nitric oxide.

OBJECTIVES: The purpose of this study was to investigate the responses of patients with primary pulmonary hypertension (PPH) to constant work rate exercise and to examine the effect of nitric oxide (NO) inhalation. BACKGROUND: Maximal exercise tolerance is reduced in PPH, but gas exchange responses to constant work rate exercise have not been defined. We hypothesized that increased pulmonary vascular resistance in PPH would reduce the rate of rise of minute oxygen consumption in response to a given work rate. Because NO may lower pulmonary vascular pressures in PPH, we also postulated that inhaled NO might ameliorate gas exchange abnormalities. METHODS: Nine PPH patients and nine matched normal subjects performed 6-min duration constant work rate cycle ergometry exercise (33.9+/-13.4 W). Patients performed two experiments: breathing air and breathing air with NO (20 ppm). Preexercise right ventricular systolic pressure was assessed by Doppler echocardiography. Normal subjects performed the air experiment only. Gas exchange and heart rate responses were characterized by fitting monoexponential curves. RESULTS: In PPH patients, resting right ventricular systolic pressure fell after NO inhalation (from 83.8+/-16.9 to 73.9+/-21.6 mm Hg, p<0.01, analysis of variance with Tukey correction), but not after breathing air alone (from 88.0+/-20.8 to 86.7+/-20.6 mm Hg, p = NS). Nitric oxide did not affect any of the gas exchange responses. Minute oxygen consumption was similar by the end of exercise in patients and normals, but increased more slowly in patients (mean response time [MRT]: air, 63.17+/-14.99 s; NO, 61.60+/-15.45 s) than normals (MRT, 32.73+/-14.79, p<0.01, analysis of variance, Tukey test). Minute oxygen consumption kinetics during recovery were slower in patients (MRT air: 82.50+/-29.94 s; NO, 73.36+/-15.87 s) than in normals (MRT, 34.59+/-7.11 s, p<0.01). Heart rate kinetics during exercise and recovery were significantly slower in patients than in normals. CONCLUSIONS: The cardiac output response is impaired in PPH. Nitric oxide lowered pulmonary artery pressure at rest, but failed to improve exercise gas exchange responses.

Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression.

Although several CXC chemokines have been shown to induce angiogenesis and play roles in tumor growth, to date, no member of the CC chemokine family has been reported to play a direct role in angiogenesis. Here we report that the CC chemokine, monocyte chemotactic protein 1 (MCP-1), induced chemotaxis of human endothelial cells at nanomolar concentrations. This chemotactic response was inhibited by a monoclonal antibody to MCP-1. MCP-1 also induced the formation of blood vessels in vivo as assessed by the chick chorioallantoic membrane and the matrigel plug assays. As expected, the angiogenic response induced by MCP-1 was accompanied by an inflammatory response. With the use of a rat aortic sprouting assay in the absence of leukocytic infiltrates, we ruled out the possibility that the angiogenic effect of MCP-1 depended on leukocyte products. Moreover, the direct effect of MCP-1 on angiogenesis was consistent with the expression of CCR2, the receptor for MCP-1, on endothelial cells. Assessment of supernatant from a human breast carcinoma cell line demonstrated the production of MCP-1. Treatment of immunodeficient mice bearing human breast carcinoma cells with a neutralizing antibody to MCP-1 resulted in significant increases in survival and inhibition of the growth of lung micrometastases. Taken together, our data indicate that MCP-1 can act as a direct mediator of angiogenesis. As a chemokine that is abundantly produced by some tumors, it can also directly contribute to tumor progression. Therefore, therapy employing antagonists of MCP-1 in combination with other inhibitors of angiogenesis may achieve more comprehensive inhibition of tumor growth.

Non-invasive measurement of stroke volume during exercise in heart failure patients.

The objective of the present study was to determine the variability of the arterio-venous O(2) concentration difference [C(a-v)O(2)] at anaerobic threshold and at peak oxygen uptake (VO(2)) during a progressively increasing cycle ergometer exercise test, with the purpose of assessing the possible error in estimating stroke volume from measurements of VO(2) alone. We sampled mixed venous and systemic arterial blood every 1 min during a progressively increasing cycle ergometer exercise test and measured, in each blood sample, haemoglobin concentration and blood gas data. Ventilation, VO(2) and CO(2) uptake were also measured continuously. We studied 40 patients with normal haemoglobin concentrations and with stable heart failure due to ischaemic or idiopathic cardiomyopathy. Mean values (+/-S.D.) for C(a-v)O(2) were 7.8+/-2.6, 13.0+/-2.4 and 15. 0+/-2.7 ml/100 ml at rest, anaerobic threshold and peak VO(2) respectively. The patients with heart failure were divided into classes according to their peak VO(2). Classes A, B and C contained patients with peak VO(2) values of>20, 15-20 and 10-15 ml.min(-1). kg(-1) respectively. At anaerobic threshold, C(a-v)O(2) was 12.3+/-1. 3, 13.1+/-2.7 and 13.5+/-2.6 ml/100 ml for classes A, B and C respectively (class A significantly different from classes B and C; P<0.05). At peak exercise C(a-v)O(2) was 13.6+/-1.4, 15.6+/-2.5 and 15.4+/-3.2 ml/100 ml for classes A, B and C respectively (class A significantly different from classes B and C; P<0.05). Stroke volume was estimated for each subject using the mean values of the measured C(a-v)O(2) in each functional class and individual values of VO(2) and heart rate using the Fick formulation. The average difference between the stroke volume estimated from mean C(a-v)O(2) and that obtained using the patient's actual C(a-v)O(2) value was 9.2+/-9.7, 1.0+/-8.8 and -0.2+/-6.1 ml at anaerobic threshold, and -1.9+/-11.3, 0.9+/-10.0 and -2.3+/-8.5 ml at peak exercise, in classes A, B and C respectively. Among the various classes, the most precise estimation of stroke volume was observed for class C patients. We conclude that stroke volume during exercise can be estimated with the accuracy needed for most purposes from measurement of VO(2) at the anaerobic threshold and at peak exercise, and from population-estimated mean values for C(a-v)O(2) in heart failure patients.