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Biomedical subjects

K Wasserman

Publications and source records attributed to K Wasserman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Mechanism of the exercise hyperkalemia: an alternate hypothesis.

A progressive hyperkalemia is observed as exercise intensity increases. The current most popular hypothesis for the hyperkalemia is that the Na+-K+ pump cannot keep pace with the K+ efflux from muscle during the depolarization-repolarization process of the sarcolemmal membrane during muscle contraction. In this report, we present data that suggest an alternate hypothesis to those previously described. Because phosphocreatine (PCr) is a highly dissociated acid and creatine is neutral at cell pH, the concentration of nondiffusible anions decreases, and an alkaline reaction takes place when PCr hydrolyzes. This creates a state of cation (K+) excess and H+ depletion in the cell. To examine the balance of K+ and H+ for exercising muscle during the early period of exercise when PCr changes most rapidly, catheters were inserted into the brachial artery and femoral vein (FV) in five healthy subjects who performed two 6-min cycle ergometer exercise tests at 40 and 85% of peak oxygen uptake. FV blood was sampled every 5 s during the first 2 min, then every 30 s for the remaining 4 min of exercise and the first 3 min of recovery, and then less frequently for the next 12 min. Arterial sampling was every 30 s during exercise and simultaneous with FV sampling during recovery. Arterial K+ concentration ([K+]) increase lagged FV [K+] increase. The hyperkalemia observed during early exercise results from K+ release from skeletal muscle. FV [K+] increased by 5 s of the start of exercise and followed the rate of H+ loss from the FV blood for the first 30 s of exercise. FV lactate and Na+ kinetics differed from K+ kinetics during exercise and recovery. As predicted from the PCr hydrolysis reaction, the exercising limb took up H+ and released K+ at the start of exercise (first 30 s) at both exercise intensities, resulting in a FV metabolic alkalosis. K+ release was essentially complete by 3 min, the time at which oxygen uptake (and, presumably, PCr) reached its asymptote. These findings lead us to hypothesize that the early K+ release by the cell takes place with H+ exchange and that the major mechanism for the exercise hyperkalemia is the reduction in nondiffusible intracellular anions in the myocyte as PCr hydrolyzes.

Adult↗
PubMed1997

Effect of hypoxia and carbon monoxide on muscle oxygenation during exercise.

We used near-infrared spectroscopy (NIRS) to test the hypothesis that reducing oxygen availability during exercise would affect the rate of muscle oxyhemoglobin (O2Hb) desaturation when performing work above the lactic acidosis threshold (LAT), but not below it. Seven healthy men each performed two constant work intensities (60%LAT and the LAT plus 40% of the difference between the LAT and VO2max [40%delta]) four times under the following conditions: (1) 10 min air; (2) 5 min 15%O2 + 5 min air; (3) 5 min air + 5 min 15%O2; (4) 5 min after carbon monoxide (CO) loading to increase the carboxyhemoglobin (COHb) saturation to 15%. During each test, cardiorespiratory parameters and muscle oxygenation measured with NIRS were continuously monitored. Forearm venous blood lactate was measured every 2 to 3 min. Hypoxia and CO accelerated muscle deoxygenation only for exercise above the LAT; for exercise below the LAT, neither progressive deoxygenation nor lactate accumulation occurred after initital, rapid muscle deoxygenation. The rate of decrease in muscle oxygenation between 3 to 5 min of exercise correlated with the increase in VO2 (r = 0.61, p < 0.01) and blood lactate (r = 0.70, p < 0.01) over the same period. These results support the hypothesis that progressive muscle deoxygenation occurs above the LAT and that the rate of deoxygenation is sensitive to oxygen delivery.

Adult↗
PubMed1997

Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis.

STUDY OBJECTIVES: Nitric oxide (NO), a potent vasodilator, is present in the exhaled air of humans. We wished to quantify NO production in patients with abnormalities of the pulmonary circulation. PARTICIPANTS: Nine patients with primary pulmonary hypertension (PPH), six with pulmonary fibrosis (PF), and 20 normal volunteers were studied. INTERVENTIONS: All subjects were studied at rest and during continuous incremental (ramp) cycle ergometry exercise. All patients with PPH and nine matched normal volunteers also performed constant exercise at equal absolute work rates. MEASUREMENTS AND RESULTS: The concentration of NO was measured continuously in mixed expired air, and the rate of NO production (VNO) calculated. Peak exercise capacity was markedly impaired in both patient groups. VNO was similar at rest in the PPH patients (142 +/- 84 nL/min) and the normal subjects (117 +/- 45 nL/min), but lower in the PF patients (66 +/- 13 nL/min; p < 0.05; analysis of variance with Bonferonni correction). While VNO in normal subjects more than doubled by peak exercise to 268 +/- 85 nL/min, there was no significant rise with exercise in either patient group (PPH, 155 +/- 81 nL/min; PF, 91 +/- 67 nL/min). Constant work rate exercise induced a significant rise in VNO in the normal subjects (rest, 101 +/- 68 nL/min; exercise, 147 +/- 87 nL/min; p < 0.001) but no significant change in the PPH patients (rest, 127 +/- 111 nL/min; exercise, 68 +/- 65 nL/min). CONCLUSIONS: We conclude that the low resting VNO in PF may be due to loss of normal functional pulmonary capillary bed. The increase in VNO seen in normal subjects may be associated with dilatation and recruitment of the pulmonary capillary bed during exercise, and failure to increase VNO during exercise in disease states may reflect an inability to recruit the capillary bed.

Adult↗
PubMed1996

Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity.

Although alterations in CD3-associated signal-transducing molecules in tumor-infiltrating T cells of patients with advanced cancer have been previously described, the mechanism behind these changes is not known. We demonstrate that macrophages isolated from metastatic lymph nodes of patients with malignant melanoma down-regulate levels of CD3 zeta in autologous peripheral blood T cells. Lipopolysaccharide (LPS)- or phorbol 12-myristate 13-acetate (PMA)-stimulated monocytes derived from peripheral blood of healthy donors also induced decreased expression of CD3 and CD16-associated zeta chains similar to that observed in T cells and natural killer (NK) cells of patients with advanced cancer. Co-culture with activated monocytes impaired Ca2+ mobilization in peripheral blood derived-T cells when stimulated with monoclonal antibodies to CD3 and also strongly inhibited melanoma-specific cytotoxic T lymphocyte (CTL) activity and NK activity. The presence of catalase, a scavenger of H2O2, during co-culture almost totally abrogated the inhibitory effect of activated monocytes on melanoma-specific CTL lines and on NK cells. Pre-treatment of CTL or NK cells with nontoxic concentrations (1 x 10(-5) M) of H2O2 also severely reduced their cytotoxic activity which could be prevented by catalase. The decrease in CD3 zeta and in CD16 zeta expression, induced by macrophages isolated from metastatic lymph nodes or by LPS-stimulated monocytes, was also prevented by catalase when maintained throughout the co-culture period. The possibility that monocyte/macrophage-derived reactive oxygen metabolites contribute directly to alterations in signal transducing molecules of T cells and NK cells and to the mechanism of immunosuppression in individuals with cancer should be considered.

CD3 Complex↗
PubMed1996

Muscle substrate utilization from alveolar gas exchange in trained cyclists.

The respiratory exchange ratio (R) during steady-state exercise is equivalent to whole-body respiratory quotient (RQ), but does not represent muscle metabolism alone. If steady-state values of carbon dioxide production (VCO2) and oxygen uptake (VO2) are plotted for different work rates, the slope of the line fitting these points should estimate muscle RQ. Twelve cyclists randomly performed five 8-min, constant work rate tests of 40, 80, 120, 160 and 200 W. Whole-body R, averaged over the final 2 min of each exercise bout, increased with increasing work rate. When VCO2 was plotted as a function of VO2, the regression lines through the five points displayed excellent linearity, had negative y-intercepts, and a slope of 0.915 (0.043) [mean (SD)], which was greater than the whole-body R at any individual work rate [range 0.793 (0.027) at 40 W to 0.875 (0.037) at 200 W]. This slope was comparable to the lower slope of the VCO2 versus VO2 plot of an increasing work rate (ramp) protocol [0.908 (0.054)]. We conclude that, during mild and moderate exercise of relatively short duration, contracting muscle has a high and constant RQ, indicating that carbohydrate is the predominant metabolic substrate. Whole-body R does not accurately reflect muscle substrate utilization and probably underestimates muscle RQ at a given work rate.

Adult↗
PubMed1996

Ventilation during exercise in chronic heart failure.

The ventilatory response to exercise in patients with chronic heart failure (CHF) is greater than normal for a given work or metabolic rate (VO2). The factors that determine the ventilatory response to exercise are: 1) the CO2 production (VCO2), 2) the arterial CO2 set-point (arterial PCO2 (PaCO2) at rest), 3) the physiological dead space/tidal volume ratio (VD/VT), and 4) the change in PaCO2 during exercise. This report illustrates how each of these factors might influence the ventilatory response to exercise in CHF patients. Thirty-one CHF patients (New York Heart Association, Classes 2 and 3) were studied, 18 from Harbor-UCLA Medical Center (cycle-ergometer exercise) and 13 from Queen's University at Belfast (treadmill exercise). A group of healthy subjects matched for size, age and gender served as control subjects. Minute ventilation (VE) was 48, 88 and 43% greater in the CHF groups compared to the control population at 6 min of the 25w and 60w cycle and low level (2.5 km h-1 and 5% grade) treadmill exercise, respectively. VO2 kinetics were slower in CHF patients than the control group, the slowing being proportional to the lactate increase. However, the increase in VO2 above rest at 6 min of exercise was approximately the same for CHF and control subjects. VCO2 at 6 min increased in the CHF patients by 7% and 34% for 25 and 60 watts cycle and 19% for treadmill exercise, respectively, compared to the control group. Because PaCO2 was not measured in this study, neither CO2 set-point nor the VD/VT could be individually calculated. Because end-tidal PCO2 will decrease when PaCO2 decreases or VD/VT increases, the combined effect of PaCO2 change and increase in VD/VT could be assessed from the difference between the patient and the control group. Since PETCO2 was significantly reduced in the patient population at the end of 60w cycle exercise (32 versus 41 mm Hg), either the VD/VT was increased and/or the PaCO2 was reduced. Because the resting PaCO2 is generally normal in CHF patients, the increase in the ventilatory response to exercise in patients with CHF can best be accounted for by three physiological mechanisms: 1) an increase in VCO2 secondary to CO2 release from bicarbonate as it buffers lactic acid, 2) the reduction in PaCO2 secondary to the lactic acidosis-induced hyperventilation, and 3) an increase in the fraction of breath that is wasted (dead space). Mathematically, these factors interact so that relatively small changes in each cause large changes in VE.

Adult↗
PubMed1996

Improving the process of care: the cost-quality value of interdisciplinary collaboration.

A multidisciplinary group of clinicians and administrators were convened to find innovative ways to contain costs and improve the quality of care on an inpatient orthopedic unit. This group was charged with examining all phases of care and recommending changes. The team proved to be a model of effective, successful collaboration and has enabled ambitious goals to be realized on this unit. The article outlines changes related to preoperative, intraoperative, and postoperative care and discusses the dynamics of effective interdisciplinary professional collaboration.

Boston↗
PubMed1996

Effects of hypoxic hypoxia on O2 uptake and heart rate kinetics during heavy exercise.

It is unclear whether hypoxia alters the kinetics of O2 uptake (VO2) during heavy exercise [above the lactic acidosis threshold (LAT)] and how these alterations might be linked to the rise in blood lactate. Eight healthy volunteers performed transitions from unloaded cycling to the same absolute heavy work rate for 8 min while breathing one of three inspired O2 concentrations: 21% (room air), 15% (mild hypoxia), and 12% (moderate hypoxia). Breathing 12% O2 slowed the time constant but did not affect the amplitude of the primary rise in VO2 (period of first 2-3 min of exercise) and had no significant effect on either the time constant or the amplitude of the slow VO2 component (beginning 2-3 min into exercise). Baseline heart rate was elevated in proportion to the severity of the hypoxia, but the amplitude and kinetics of increase during exercise and in recovery were unaffected by level of inspired O2. We conclude that the predominant effect of hypoxia during heavy exercise is on the early energetics as a slowed time constant for VO2 and an additional anaerobic contribution. However, the sum total of the processes representing the slow component of VO2 is unaffected.

Adult↗
PubMed1996

Pathophysiology of activity limitation in patients with interstitial lung disease.

OBJECTIVE: To analyze the relative importance of gas exchange, ventilatory, and circulatory abnormalities in limiting exercise in patients with interstitial lung disease. DESIGN AND SETTING: Retrospective study at a referral cardiopulmonary exercise laboratory in a university/county medical center. PATIENTS AND METHODS: A database with more than 1,300 patients with incremental cycle exercise studies was screened to find 42 patients with interstitial lung disease, but without accompanying airflow limitation, chest wall, primary heart, or systemic vascular disease, or poor motivation. All had spirometry, lung volume, and gas transfer index measures at rest and repeated gas exchange, ventilatory, and circulatory measures during exercise; 37 of the 42 patients had multiple blood gas measures during exercise. We graded the gas exchange, ventilatory and circulatory dysfunction during maximally tolerated cycle ergometry and correlated the grades of dysfunction of these three components of respiration with percent predicted peak O2 uptake (peak Vo2). RESULTS: Peak Vo2 values were not well correlated with the grades of ventilatory impairment but were well correlated with the grades of gas exchange and circulatory dysfunction. Patients who had reduced peak Vo2 values often had a normal breathing reserve with physiologic evidence of pulmonary vascular disease. CONCLUSIONS: The pathophysiology of the pulmonary circulation is usually more important than ventilatory mechanics in limiting exercise in patients with interstitial lung disease.

Activities of Daily Living↗
PubMed1995

Non-invasive prediction of blood lactate response to constant power outputs from incremental exercise tests.

We determined the ability of gas exchange analyses during incremental exercise tests (IXT) to predict blood lactate levels associated with a range of constant power output cycle ergometer tests. Twenty-seven healthy young men performed duplicate IXT and four 15-min constant power output tests at intensities ranging from moderate to very severe, before and after a training program. End-exercise blood lactate levels were approximated from superficial venous samples obtained 60 s after each constant power output test. From IXT, the power outputs corresponding to peak oxygen uptake (Wmax) and lactic acidosis threshold (WLAT), were determined. We examined the ability of four measures of exercise intensity to predict blood lactate levels for power outputs above the LAT: (1) power output (W), (2) power difference (W-WLAT), (3) power fraction (W/Wmax) and (4) power difference to delta ratio [(W-WLAT)/(Wmax-WLAT)]. Correlation coefficients were r = 0.38, 0.69, 0.75, and 0.81, respectively. The best linear regression prediction equation was: lactate (mmol.l-1) = 12.2[(W-WLAT)/(Wmax-WLAT)] + 0.7 mmol.l-1. This relationship was not significantly affected by training, despite increased values of LAT and peak oxygen uptake. Normalizing exercise intensity to the range of power outputs between WLAT and Wmax provided an estimate of blood lactate response to constant power outputs with a standard error of the estimate of 1.66 mmol.l-1.

Adult↗
PubMed1995

Changes in skeletal muscle oxygenation during incremental exercise measured with near infrared spectroscopy.

To determine the change in muscle oxygenation in response to progressively increasing work rate exercise, muscle oxyhemoglobin + oxymyoglobin saturation was measured transcutaneously with near infrared spectroscopy in the vastus lateralis muscle during cycle ergometry. Studies were done in 11 subjects while gas exchange was measured breath-by-breath. As work rate was increased, tissue oxygenation initially either remained constant near resting levels or, more usually, decreased. Near the work rate and metabolic rate where significant lactic acidosis was detected by excess CO2 production (lactic acidosis threshold, LAT), muscle oxygenation decreased more steeply. As maximum oxygen uptake (VO2max) was approached, the rate of desaturation slowed. In 8 of the 11 subjects, tissue O2 saturation reached a minimum which was sustained for 1-3 min before VO2max was reached. The LAT correlated with both the VO2 (r = 0.95, P < 0.0001) and the work rate (r = 0.94, P < 0.0001) at which the rate of tissue O2 desaturation accelerated. These results describe a consistent pattern in the rate of decrease in muscle oxygenation, slowly decreasing over the lower work rate range, decreasing more rapidly in the work rate range of the LAT and then slowing at about 80% of VO2max, approaching or reaching a minimum saturation at VO2max.

Acidosis, Lactic↗
PubMed1995

The VCO2/VO2 relationship during heavy, constant work rate exercise reflects the rate of lactic acid accumulation.

Oxygen uptake (VO2) kinetics have been reported to be modified when lactic acid accumulates; however little attention has been given to the simultaneous carbon dioxide production (VCO2) kinetics. To demonstrate how VCO2 changes as a function of VO2 when lactic acid is buffered by bicarbonate, eight healthy subjects performed 6-min constant work rate cycle ergometer exercise tests at moderate, heavy and very heavy exercise intensities. VCO2 and VO2 were measured breath-by-breath, and arterial blood samples were obtained every 7.5 s during the first 3 min of exercise, and were analyzed for pH, partial pressure of carbon dioxide, standard bicarbonate, and lactate. VCO2 abruptly increased relative to VO2 between 40 and 50 s after the start of exercise for the high exercise intensities. These gas exchange events were observed to correlate well with the time and VO2 at which lactic acid increased and plasma bicarbonate decreased (r = 0.90, r = 0.95, respectively). We conclude that bicarbonate buffering of lactic acid can be determined from the acceleration of VCO2 relative to VO2 kinetics in response to constant work rate exercise and the increase is quantitatively related to the magnitude of the lactic acid increase. This is easily visualized from a plot of VCO2 as a function of VO2.

Adult↗
PubMed1995

Evaluation of blood lactate elevation as an intensity criterion for exercise training.

We sought to determine whether exercise intensities not elevating blood lactate produce alterations in physiological responses to exercise associated with training. Twenty-seven sedentary young men performed five cycle ergometer training sessions.wk-1 for 5 wk. Training power outputs were randomized to power outputs corresponding to either 80% of the lactic acidosis threshold (LAT), 25% delta or 50% delta (where delta is the difference between LAT and peak VO2 power outputs estimated from incremental exercise tests). Exercise sessions were 30 min for the 50% delta group and were proportionately longer for other groups, so that total work did not vary among groups. Before and after training, subjects exercised for 15 min (or to tolerance) at pretraining 80% LAT, 25% delta, 50% delta, and 75% delta power outputs. Continuous O2 uptake, CO2 output, ventilation and heart rate, and end-exercise blood lactate, norepinephrine, and epinephrine were measured. For the 80% LAT group, posttraining end-exercise values for the 75% delta test were significantly lower for each of these variables. There were similar reductions in each variable in all three training groups; no significant differences among groups were seen. Thus, in healthy subjects exercise which does not elevate blood lactate alters constant power output responses as effectively as exercise which elevates lactate, provided that total training work is the same.

Adult↗
PubMed1995

Skeletal muscle oxygenation during constant work rate exercise.

We compared the slow rise in VO2 during heavy exercise (i.e., greater than lactic acidosis threshold (LAT)) with changes in muscle oxyhemoglobin+oxymyoglobin (O2Hb/O2Mb) saturation by reflectance near infrared spectroscopy. Ten subjects performed four 6-min cycle ergometer tests with two constant work rates less than and two greater than the LAT, equivalent to 20, 40, 65 and 75% peak VO2. During less than LAT exercise, O2Hb/O2Mb saturation decreased to a minimum by 2 min and then remained constant or rose slightly. For greater than LAT work rates, the initial fall in O2Hb/O2Mb saturation was greater the higher the work rate and continued to decrease with time after 3 min. Between minutes 3 and 6, the rate of decrease in O2Hb/O2Mb saturation correlated with the increase in VO2 (r = -0.69, P < 0.0001). These studies support the hypothesis that the slow rise in VO2 during heavy constant work rate exercise is associated with a progressive decline in O2Hb/O2Mb saturation in the contracting muscles themselves that may be facilitated by capillary oxyhemoglobin dissociation owing to tissue lactic acidosis (Bohr effect).

Adult↗
PubMed1994

Nongranular proteolytic enzymes of rat IL-2-activated natural killer cells. II. Purification and identification of rat A-NKP 1 and A-NKP 2 as constituents of the multicatalytic proteinase (proteasome) complex.

We have recently described nongranular, cytosolic, high-molecular-weight trypsin-like (A-NKP 1) and chymotrypsin-like (A-NKP 2) proteases of interleukin-2-activated rat natural killer (A-NK) cells. A functional correlation between the inactivation of A-NKP 2 and the inhibition of rat A-NK cell-mediated cytotoxicity was found. Herein we describe the 6,000-fold purification of A-NKP 2 to apparent homogeneity following: isopycnic sucrose gradient fractionation of postnuclear supernatants, molecular sieve chromatography, and heparin-Sepharose chromatography. We also report the novel finding that A-NKP 2 as well as A-NKP 1, derived from either rat A-NK cells or the rat NK leukemic cell line CRNK-16, are constituents of the multicatalytic proteinase (MCP/proteasome) complexes of these cells. Characteristic biochemical, biophysical, and electron microscopic/ultrastructural similarity to the rat liver proteasome was observed. However, Western blot analysis using polyclonal antibodies to the rat liver proteasome clearly indicated differences in the rat hepatic proteasome and the CRNK-16-derived proteasomal subunits. The identification, characterization, and purification of A-NKP 1 and A-NKP 2, described herein, now allow for further investigation of the potential role of these proteasome components in NK cell function. Moreover, the proteasome of NK and A-NK cells can now be compared and contrasted to the granzymes of lytic granules with respect to their role in cell-mediated cytotoxicity.

Animals↗