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Biomedical subjects

K Wasserman

Publications and source records attributed to K Wasserman.

At least 19 recordsLinked to original sources
PubMed1992

Nongranular proteolytic enzymes of rat IL-2-activated natural killer cells. I. Subcellular localization and functional role.

Our investigations indicate that a variety of neutral serine proteases exist in highly purified, IL-2-activated rat NK (A-NK) cells. These enzymatic activities are not restricted to only cytolysin-containing granules and are not defined by only the assay of N-alpha-benzyloxycarbonyl-L-lysine thiobenzylesterase activity. These activities, which we term A-NKP 1, A-NKP 2, A-NKP 3, and A-NKP 4, cleave, respectively, the following fluorogenic peptide substrates: Boc-Phe-Ser-Arg-7-amino-4-methylcoumarin (AMC, trypsin-like); Suc-Ala-Ala-Phe AMC (chymotrypsin-like); Suc-Gly-Pro-Leu-Gly-Pro AMC (collagenase-like), and Z-Phe-Arg AMC (another trypsin-like enzyme). The proteases A-NKP 1, A-NKP 2, and A-NKP 3 are not cell surface-associated and appear to be cytosolic as defined by isopycnic sucrose density gradient centrifugation. In contrast, A-NKP 4 appears to be located in lysosomes. Treatment of rat A-NK cells with protease inhibitors that inhibit A-NKP 2 and A-NKP 3 also substantially inhibit A-NK cell-mediated cytotoxicity against both NK-sensitive and -resistant targets (YAC-1 and P815, respectively). These results indicate that A-NKP2 and A-NKP 3 may play a role in IL-2-activated NK cell-mediated cytotoxicity. A variety of proteolytic enzymes, in addition to granzymes, therefore exist in A-NK cells. Our studies indicate that a prerequisite to a thorough understanding of the role of proteases in killer cell function is the investigation of several classes of enzymes in addition to granzymes contained in lytic granules.

Animals↗
PubMed1992

Factors affecting the components of the alveolar CO2 output-O2 uptake relationship during incremental exercise in man.

The VCO2-VO2 (alveolar CO2 output-alveolar O2 uptake) relationship (V-slope) during increasing work rate (ramp) cycle ergometer exercise has two approximately linear components: a lower component slope (S1) with a value of about 0.95 and a steeper, upper component (S2). We examined the effect of muscle glycogen depletion (protocol 1) and the rate of increase in work rate (ramp rate) without muscle glycogen depletion (protocol 2) on S1 and S2. In protocol 1, ten healthy men with a mean age of 31.4 years (S.D. 6.2) were studied on each of 3 days (days 1 and 3 were control days). They performed a ramp exercise test to maximum tolerance and steady-state tests at rest, during unloaded pedalling and at two constant work rates below their anaerobic threshold (AT). To deplete muscle glycogen before the test on day 2, the subjects performed 2 h of very heavy cycle exercise on the preceding day and fasted overnight. S1 was reduced on day 2 (0.79 compared with 0.95, P less than 0.001), as was the VCO2-VO2 slope derived from steady-state measurements (0.81 compared with 0.99, P less than 0.001), but AT and the slope difference (S2 - S1) were unchanged. In protocol 2, seven healthy men with a mean age of 20.6 years (S.D. 2.4) performed ramp tests at three different rates of increasing work rate (15, 30 and 60 W min-1), each ramp rate being performed twice in random sequence. The ramp rate did not affect S1 but S2 was steeper with the faster rates of work rate increase (1.27, 1.43 and 1.63, respectively, P less than 0.01). Our findings support the concept that the lower component of the V-slope plot (below AT) represents muscle substrate respiratory quotient (RQ) while the difference between S1 and S2 reflects 'excess CO2' derived from bicarbonate buffering of lactic acid.

Adolescent↗
PubMed1992

Acid-base regulation during exercise and recovery in humans.

Arterial pH, PCO2, standard bicarbonate, lactate, and ventilation were measured with a high sampling density during rest, exercise, and recovery in normal subjects performing upright cycle ergometer exercise. Three 6-min constant-work exercise tests (moderate, heavy, and very heavy) were performed by each subject. We found a small respiratory acidosis during the moderate-intensity exercise and an early respiratory acidosis followed by a metabolic acidosis for the heavy- and very-heavy-intensity exercise. During recovery, arterial pH rapidly returned to the preexercise value for the moderate-intensity work. However, arterial pH decreased further during the first 2 min of recovery for the heavy- and very-heavy-intensity work, before a slower return toward the resting values. We conclude that arterial acidosis is the consistent arterial pH reaction for moderate-, heavy-, and very-heavy-intensity cycle ergometer exercise in humans and that this acidosis is blunted but not eliminated by the ventilatory response. During recovery, the return to resting arterial pH and PCO2 and standard bicarbonate appears to be determined by the rate of lactate decline.

Acid-Base Equilibrium↗
PubMed1992

Evidence that circulatory oscillations accompany ventilatory oscillations during exercise in patients with heart failure.

Periodic breathing (PB) during exercise in patients with congestive heart failure (CHF) is associated with prominent oscillations (OSC) of O2 uptake (VO2). We hypothesized that the VO2 OSC represent OSC in true O2 exchange, resulting from concomitant cardiac output fluctuations and are not merely due to OSC of lung O2 stores. We compared the amplitude of the OSC of VO2, ventilation (VE), and end-expiratory lung volume (EELV) in 17 patients with CHF and PB and in seven healthy control subjects who volitionally simulated PB. Subjects underwent an incremental and/or a constant work-rate exercise test. VE and VO2 were measured breath by breath. EELV change was estimated by summing the difference between inspiratory and expiratory tidal volumes for each breath. The amplitude of the OSC, delta, is expressed as the ratio of the difference between the peak and nadir of the oscillating variable divided by its mean [delta = (peak - nadir)/mean]. In CHF, during incremental testing, the amplitude of the VE OSC was smaller than that of the VO2 OSC (delta VE = 49 +/- 15% [SD], delta VO2 = 63 +/- 25%, p less than 0.01). In contrast, during volitional PB in the control subjects, VE OSC were larger than VO2 OSC (delta VE = 48 +/- 12%, delta VO2 = 25 +/- 11%, p less than 0.01). This suggests that changing VE itself cannot account for the marked VO2 OSC seen in CHF. In the patients, EELV showed no systematic OSC, did not correlate with delta VO2, and was not significantly different from zero.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Is the anaerobic threshold truly anaerobic?

This study was done to address the question as to whether there was an exercise metabolic rate below which the O2 supply to the muscles was adequate to meet the O2 requirement and above which the O2 supply was inadequate, ie, an anaerobic threshold (AT). The question was addressed using 2 approaches: (1) The arterial lactate/pyruvate ratio was measured to see if it increased at an O2 uptake (VO2) threshold or continuously as a log function over the entire range of exercise work rates. (2) Anticipating that the VO2 would be affected by reducing O2 supply only for work rates above the AT, the effect of reducing O2 delivery on VO2 for work rates over the entire range of the subject's work capacity was determined. Lactate (L) and pyruvate (P) were measured in arterial blood in 10 normal subjects. The L/P ratio was found not to increase until a threshold work rate was reached, the VO2 being that identified as the AT. Above that VO2, the L/P ratio climbed steeply. Arterial L/P ratio measurements fit a threshold model considerably better than a continuous model, supporting the concept that exercise done at low and moderate work rates can be performed without a change in cell redox state; but redox state does change rapidly in relation to the work rate increase above the AT. In the second study, the cardiorespiratory responses to various levels of exercise were studied in 10 normal subjects before and after carboxyhemoglobin (COHb) was increased to 10% and 20%. The lactic acidosis threshold and VO2 kinetics were examined. Blood lactate concentration increased only above the AT. The AT was systematically decreased by the percent of COHb increase. Importantly, VO2 was reduced and VO2 kinetics were slowed in response to exercise only for the metabolic rates above the AT. These studies demonstrate that lactate increase in response to exercise is O2 flow sensitive, and there is a threshold work rate above which this sensitivity becomes manifest.

Acidosis, Lactic↗
PubMed1992

Dynamic and steady-state ventilatory and gas exchange responses to arm exercise.

Previous studies have suggested that, for the same power output, arm exercise requires higher oxygen uptake (VO2), carbon dioxide output (VCO2), and ventilation (VE) than leg exercise and that response kinetics are slower. To evaluate these differences, four healthy subjects performed a total of 95 arm cranking tests. Each subject performed several tests at each of three or four power outputs spaced evenly below the maximum the subject could sustain (average = 53 W). Breath-by-breath responses to identical stimuli were averaged. End-exercise blood lactate was determined at each power output. Responses were compared to leg exercise responses in these subjects (J. Appl. Physiol. 67:547-555, 1989). For power outputs unassociated with lactic acidosis, differences between steady-state VO2, VCO2, and VE responses for arm and leg exercise were not significant. At higher power outputs, the higher VO2, VCO2, and VE during arm exercise were well correlated with higher lactate. For power outputs not engendering lactic acidosis, the time constants (tau) for VO2, VCO2 and VE were not greatly different for arm than for leg exercise. For each variable, at higher power outputs tau became longer by an amount correlated with higher lactate level. Like leg exercise, the slower kinetics of VO2 and VE (but not VCO2) at higher power outputs were well described as a superimposed slower component. We conclude that both dynamic and steady-state responses of VE and gas exchange to arm exercise do not differ substantially from those to leg exercise so long as the power output does not elevate blood lactate.

Adult↗
PubMed1992

Effect of acute reduction in oxygen transport on parameters of aerobic function during exercise.

The binding of haemoglobin by carbon monoxide reversibly decreases the blood O2 carrying capacity, providing a useful model of impaired circulatory O2 transport. We evaluated noninvasive parameters of aerobic function during exercise to detect small changes in O2 transport, using carbon monoxide. Ten normal subjects performed both symptom-limited incremental and two levels of constant work rate on a cycle ergometer while breathing air and air with added carbon monoxide to cause carboxyhaemoglobin (COHb) to be approximately 11% (level of heavy cigarette smoker) and 20%. Maximal O2 uptake (VO2 max), the anaerobic threshold (AT) determined from the plot of CO2 output as a function VO2 (V-slope, the ratio of increase in VO2 to work rate increment (delta VO2/delta WR) and the upper slope of the V-slope analysis were measured while progressively increasing work rate. These changed in approximately the same percent as the increase in COHb. For the constant work rate tests, the time constant of VO2 and the difference in VO2 at six minutes as compared to three minutes of exercise (delta VO2 (6-3)) were significantly increased when COHb was increased. These noninvasive parameters of aerobic function, determined from the cardiopulmonary response to incremental and constant work rate exercise, particularly when used in combination, proved to be sufficiently sensitive to objectively detect small changes in O2 transport to the working muscles during exercise.

Adolescent↗
PubMed1991

Accumulation of adoptively transferred adherent, lymphokine-activated killer cells in murine metastases.

While close contact between lymphokine-activated killer (LAK)/adherent, lymphokine-activated killer (A-LAK) cells and tumor cells is believed to be a prerequisite for initiating the events leading to tumor cell lysis, clear evidence for the ability of these effector cells to infiltrate tumors or tumor metastases in vivo still has to be obtained. In the present study, we report that a significant fraction of adoptively transferred A-LAK cells, labeled with fluorochromes for identification, accumulates in lung and liver metastases of the B16 melanoma, the MCA 102 sarcoma and the Lewis lung carcinoma lines. Thus, 5- to 10-fold higher numbers of A-LAK cells were found in the malignant lesions compared to the surrounding normal tissue. The infiltration seemed very heterogeneous after intravenous injection of moderate numbers of A-LAK cells (15 x 10(6)). However, after adoptive transfer of 45 million A-LAK cells, an A-LAK cell/tumor cell ratio higher than 1:1 in most metastases was observed. Surprisingly, approximately 5% of the lung metastases seemed totally resistant to infiltration even though neighboring metastases were highly infiltrated. While substantial infiltration of lung metastases was seen after i.v. injection, significant infiltration of liver metastases was seen only after intraportal injection of the A-LAK cells indicating impaired traffic of intravenous injected A-LAK cells through the lung capillaries. These results present direct evidence that A-LAK cells, upon a proper route of administration, have the potential to migrate to and heavily infiltrate metastases from murine tumors of different origin.

Animals↗
PubMed1991

The role of fitness on VO2 and VCO2 kinetics in response to proportional step increases in work rate.

The purpose of this study was to determine the effect of fitness and work level on the O2 uptake and CO2 output kinetics when the increase in work rate step is adjusted to the subject's maximum work capacity. Nine normal male subjects performed progressive incremental cycle ergometer exercise tests in 3-min steps to their maximum tolerance. The work rate step size was selected so that the symptom-limited maximum work rate would be reached in four steps at 12 min in all subjects. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were calculated breath by breath. For the group, the time (mean, SEM) to reach 75% of the 3-min response (T0.75) for VO2 increased significantly (P less than 0.01) at progressively higher work rate steps, being 53.3 (5.5) s, 63.5 (4.6) s, 79.5 (5.0) s, and 94.5 (5.8) s, respectively. In contrast, T0.75 for VCO2 did not change significantly [74.9 (7.4) s, 75.6 (5.0) s, 85.1 (5.3) s, and 89.4 (6.3) s, respectively]. VCO2 kinetics were slower than VO2 kinetics at the low fractions of the subjects' work capacities but were the same or faster at the high fractions because of the slowing of VO2 kinetics. The first step showed the fastest rise in VO2. While VO2 kinetics slowed at each step, they were faster at each fraction of the work capacity in the fitter subjects. The step pattern in VO2 disappeared at high work rates for the less fit subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

O2 uptake in hyperthyroidism during constant work rate and incremental exercise.

To investigate the effect of hyperthyroidism on the pattern and time course of O2 uptake (VO2) following the transition from rest to exercise, six patients and six healthy subjects performed cycle exercise at an average work rate (WR) of 18 and 20 W respectively. Cardiorespiratory variables were measured breath-by-breath. The patients also performed a progressively increasing WR test (1-min increments) to the limit of tolerance. Two patients repeated the studies when euthyroid. Resting and exercise steady-state (SS) VO2 (ml.kg-1.min-1) were higher in the patients than control (5.8, SD 0.9 vs 4.0, SD 0.3 and 12.1, SD 1.5 vs 10.2, SD 1.0 respectively). The increase in VO2 during the first 20 s exercise (phase I) was lower in the patients (mean 89 ml.min-1, SD 30) compared to the control (265 ml.min-1, SD 90), while the difference in half time of the subsequent (phase II) increase to the SS VO2 (patient 26 s, SD 8; controls 17 s, SD 8) were not significant (P = 0.06). The O2 cost per WR increment (delta VO2/delta WR) in ml.min-1.w-1, measured during the incremental period (mean 10.9; range 8.3-12.2), was always within two standard deviations of the normal value (10.3, SD 1). In the two patients who repeated the tests, both the increment of VO2 from rest to SS during constant WR exercise and the delta VO2/delta WRs during the progressive exercise were higher in the hyperthyroid state than during the euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The work-rate-dependent effect of carbon monoxide on ventilatory control during exercise.

The effect of low levels of carbon monoxide (CO) was studied during exercise in order to determine the work-rate dependent effect of CO breathing on exercise ventilation (VE). Ten normal subjects (aged 32.8 +/- 7.1 years) were studied during air breathing and air with added CO to bring carboxyhemoglobin (COHb) to approximately 11% and 20%. During the incremental exercise test, VE was not affected by CO breathing at work rates below the lactic acidosis threshold (LAT), defined as the O2 uptake above which CO2 is excreted by the lungs consequent to buffering of metabolic acid (not hyperventilation) (Beaver et al. (1986) J. Appl. Physiol. 60: 2020-2027). However, VE was increased above the LAT as work rate and COHb saturation were increased. At the end of constant work rate exercise, the increase in VE caused by increased COHb was positively correlated (r = 0.83, P less than 0.0001) with the increase in venous lactate sampled 2 min into recovery. This was complemented by a decrease in end-tidal PCO2 versus lactate (r = 0.76, P less than 0.0001). We conclude that the increase in exercise VE resulting from COHb levels up to 20%, is restricted to work rates above the LAT, and is proportionately higher, the greater the lactic acidosis.

Adolescent↗
PubMed1991

Role of the carotid bodies in the respiratory compensation for the metabolic acidosis of exercise in humans.

1. In response to an acute exercise-induced metabolic acidosis, the fall of arterial pH is constrained by the magnitude of the compensatory hyperventilation. To determine the role of the carotid bodies in this regulatory process, subjects performed prolonged (24 min) square-wave cycle ergometry from a background of unloaded cycling at inspired oxygen fractions (FI,O2) of 0.12 O2 (high carotid body gain), 0.21 O2 (normal carotid body gain) and 0.80 O2 (low carotid body gain). The work rates were selected to provide the same exercise intensity, despite the different inspirates; i.e. resulting in a constant increase in arterial blood [lactate] (delta [L-] approximately 4 mequiv l-1. 2. Ventilatory and pulmonary gas exchange variables were computed breath-by-breath and arterial blood was sampled at intervals throughout the tests and analysed subsequently for [lactate], [pyruvate], arterial partial pressures of oxygen and carbon dioxide (PO2, PCO2), pH, [bicarbonate] and [potassium]. 3. Hypoxia markedly reduced, and hyperoxia magnified, the transient decrease in arterial pH following exercise onset. However, there was a slow acid-base compensatory component, even when carotid chemosensitivity was suppressed by hyperoxia. We therefore conclude that, in humans, carotid body chemosensitivity plays a dominant role in constraining variations of arterial pH in response to the acute metabolic acidosis of heavy exercise, but that secondary-presumably central chemosensory-mechanisms subserve a slower compensatory role.

Acidosis↗
PubMed1991

Effects of chronic acid-base changes on the rebreathing hypercapnic ventilatory response in man.

The CO2 rebreathing method can be very useful to test the hypercapnic ventilatory response in patients, including those with chronic acid-base changes (e.g. chronic metabolic acidosis due to renal failure). The ventilatory response to hypercapnia (CO2-R) was measured in 4 normal men by the rebreathing method under control conditions (CaCO3: 0.1 g.kg-1.day-1) and with induced metabolic acidosis (NH4Cl: 0.3 g.kg-1.day-1) and alkalosis (NaHCO3: 0.7 g.kg-1.day-1). The slope of the CO2-R did not change as a result of the acid-base alterations, but was shifted to the left of normal by metabolic acidosis, and to the right by metabolic alkalosis. These results compare favorably with previous reports on the CO2-R as measured by the steady-state technique, and validate the rebreathing method as a reliable and useful technique for evaluating CO2-R in man with altered acid-base states.

Acid-Base Equilibrium↗
PubMed1991

Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease.

Though exercise training is part of most pulmonary rehabilitation programs, whether there is a physiologic basis for increased exercise tolerance is unclear. We sought to determine whether patients with chronic obstructive pulmonary disease (COPD) are capable of obtaining a physiologic training effect, as manifested by a reduction in blood lactate and ventilation (VE) at a given level of exercise. We also sought to determine whether training work rate determines the size of the training effect. Nineteen participants with COPD of predominantly moderate severity in an inpatient rehabilitation program performed two cycle ergometer exercise tests at a low and a high work rate for 15 min or to tolerance and also an incremental exercise test to tolerance. Arterial blood was sampled for blood gas and lactate analyses. Identical tests were performed before and after 5-day-per-week cycle ergometer training for 8 wk either for 45 min/day at a high work rate (average, 71 W) or for a proportionally longer time at a low work rate (average, 30 W). Average FEV1 was 56 +/- 12% predicted and did not change with training. Peak exercise lactate (average, 6.5 mEq/L) was not correlated with FEV1. For the high work rate training group, identical work rates engendered less lactate (4.5 versus 7.2 mEq/L) and less VE (48 versus 55 L/min) after training; the low work rate training group had significantly less lactate and VE decrease (p less than 0.01). Further, endurance time for the high constant work rate increased 73% in the high work rate training group but only 9% in the low work rate training group. At identical work rates, VE decrease average 2.5 L/min per mEq/L decrease in lactate (r = 0.75). We conclude that most COPD subjects studied increased blood lactate at low work rates. Many of these patients were able to achieve a physiologic training effect. Though total work was the same, training at a high work rate was more effective than was training at a low work rate. The lower VE requirement to perform exercise was in proportion to the lower lactate level, but the VE decrease for a given decrease in lactate was smaller than that seen in normal subjects (7.2 L/min/mEq/L), apparently because patients with COPD fall to hyperventilate in response to lactic acidosis (PaCO2 does not drop). These findings provide a physiologic rationale for exercise training of patients with COPD.

Acidosis, Lactic↗
PubMed1991

Oxygen uptake and heart rate responses during hypoxic exercise in children and adults.

Control of ventilation and heart rate during exercise appears to undergo maturation, while aerobic metabolism (VO2) may not. Since we had previously found that hypoxia during exercise produced different ventilatory responses in children (C) compared to adults (A), we hypothesized that VO2 and heart rate kinetics during exercise would show similar maturational responses to hypoxia. To test this hypothesis, we examined the responses during progressive (ramp) and constant work rate tests in children and adults breathing either room air or hypoxic gas (FiO2 = 0.15). When corrected for body weight, children and adults had similar values for lactic acidosis threshold (LAT) (C: 29.1 +/- 5.0 ml.min-1.kg-1; A: 27.9 +/- 4.3) and VO2max (C: 40.7 +/- 8.6 ml.min-1.kg-1; A: 45.2 +/- 6.7) during normoxia. Hypoxia significantly lowered LAT (C: 27.5 +/- 5.4 ml.min-1.kg-1; A: 23.2 +/- 3.8; both P less than 0.05) and VO2max (C: 37.7 +/- 8.3 ml.min-1.kg-1; A: 40.1 +/- 5.3; both P less than 0.05) in both children and adults. Metabolic efficiency (delta VO2/delta work rate) and the VO2-heart rate relationship (delta VO2/delta HR/kg) were similar in the two groups and unaffected by hypoxia. During the constant work rate exercise, VO2 kinetics (time constant during phase 2 of the response (pi 1) and the O2 deficit) were similar between children and adults and were significantly slowed by hypoxia, consistent with current understanding of the control of oxidative metabolism. Finally, heart rate was increased at rest and during exercise with hypoxia, while the time to reach 75% of the end-exercise response was delayed significantly, in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1979

Mechanism of the isoproterenol hyperpnea in the cat.

To clarify the role of peripheral chemoreceptors in the abrupt hyperpnea induced by isoproterenol injection, we measured, in anesthetized cats, the time course of VE, PETCO2, H.R. and B.P. following i.v. bolus injection of 0.5--2 microgram isoproterenol before and after bilateral section of the carotid sinus (csx), aortic (ax) and vagus (vx) nerves. We compared the hyperpneic response of isoproterenol to that of 100 microgram injections of NaCN (CN), a drug known to stimulate peripheral chemoreceptors, during air and 100% O2 breathing. The ventilatory response to isoproterenol persisted for over 90 s, whereas the CN response lasted only 30 s. Also 100% O2 markedly attenuated the CN hyperpnea but had little effect on the ventilatory response to isoproterenol. The maximum increase in ventilation in response to isoproterenol was reduced by approximately 1/3 by csx, 1/2 by combined csx and ax, and 2/3 by combined csx, ax and vx. The residual hyperpnea after csx, ax, and vs is delayed in time and lagged behind the increase in PETCO2. It is concluded that the peripheral chemoreceptors and possibly vagal afferents play a major role in the hyperpnea caused by isoproterenol, but in their absence central chemoreceptors respond to the increased PaCO2 induced by the elevated cardiac output to stimulate ventilation.

Animals↗