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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↗
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↗
PubMed1979

Ventilation and gas exchange during phasic hindlimb exercise in the dog.

To investigate the importance of the major neural afferent component from the exercising extremities in exercise hyperpnea, rhythmic contraction of hindlimb muscles was produced in the dog, by electrically stimulating the peripheral cut ends of the sciatic and femoral nerves, bilaterally, for 4- to 5-min periods. VE, VCO2, and VO2 were computed breath-by-breath and PaCO2 was monitored continuously with an indwelling arterial electrode. During exercise, VO2 and VCO2 were approximately doubled in the steady state, rising with t1/2 of 25 +/- 2 and 35 +/- 4 s, respectively. VE increased within five breaths after exercise onset, and thereafter rose to a steady state with a t1/2 of 37 +/- 5 s. Mean PaCO2 increased transiently within the 1st min of stimulation but was not significantly different from control in the steady state. We conclude that the major neural afferent component from the contracting muscles is not an obligatory requirement for normal ventilatory response in the steady state of phasic exercise.

Afferent Pathways↗
PubMed1979

Anaerobic threshold alterations caused by endurance training in middle-aged men.

Nine previously sedentary middle-aged males underwent cycle endurance training 45 min/day for 9 wk with an average attendance of 4.1 days/wk. Seven males served as controls. Before and after the training period, the subjects performed three cycle ergometer tests. Work rate was incremented by 15 W/min, to the limit of the subjects' tolerance, in the first two tests; the third test consisted of contant-load cycling at an O2 uptake (VO2) just below the pretraining anaerobic threshold (AT). After training, the AT increased significantly by 44%, expressed as absolute VO2, and by 15%, expressed relative to VO2 max. Significant increases were also noted in VO2max (25%), maximal minute ventilation (19%), and maximal work rate (28%). The test-retest correlation coefficients for the AT (%VO2max) were 0.91, pre- and posttraining. Training did not alter steady-state VO2 during the submaximal exercise test whereas significant decreases occurred in CO2 output, VE, respiratory quotient, and VE/VO2. No changes occurred in the control subjects during this period. These results demonstrate that the AT is profoundly influenced by endurance training in previously sedentary middle-aged males.

Adult↗
PubMed1979

Determinants of gas exchange kinetics during exercise in the dog.

Following exercise onset, CO2 output (VCO2) and O2 uptake (VO2) increase exponentially, but with appreciably different time constants. To determine the sensitivity of the time courses of these variables to altered ventilatory kinetics, rhythmic exercise was induced abruptly in anesthetized dogs by bilateral stimulation of the peripheral ends of the cut sciatic and femoral nerves. This increased the metabolic rate by 83 +/- 25 (SD) %. The dogs were ventilated with a constant-volume pump, the frequency of which was changed exponentially from the start of the exercise up to the ventilation that returned arterial CO2 and O2 pressure (PCO2 and PO2) in the steady state to resting levels. The time constant (tau) of the increase in ventilation (VE) was varied among trials. VCO2, VO2, end-tidal PCO2 and PO2, and arterial PCO2 were measured breath by breath. tauVO2 was constant at approximately 18 s regardless of alterations in tauVE. In contrast, tauVCO2 was strongly dependent on tauVE, apparently due to the larger body stores for CO2; the transitions were isocapnic when tau VE was approximately 40 s. We conclude that ventilatory dynamics can markedly influence the dynamics of CO2 exchange during exercise, but has no appreciable effect on O2 uptake dynamics.

Animals↗
PubMed1979

Hypopnea consequent to reduced pulmonary blood flow in the dog.

The ventilatory responses to diminished pulmonary blood flow (Qc), as a result of partial cardiopulmonary bypass (PCB), were studied in chloralose-urethan-anesthetized dogs. Qc was reduced by diverting vena caval blood through a membrane gas exchanger and returning it to the ascending aorta. PCB flows of 400--1,600 ml/min were utilized for durations of 2--3 min. Decreasing Qc, while maintaining systemic arterial blood gases and perfusion, results in a significant (P less than 0.05) decrease in expiratory ventilation (VE) (15.9%) and alveolar ventilation (VA) (31.0%). The ventilatory decreases demonstrated for this intact group persist after bilateral cervical vagotomy (Vx), carotid body and carotid sinus denervation (Cx), and combined Vx and Cx. The changes in VE and VA were significantly (P less than 0.001) correlated with VCO2 changes, r = 0.80 and r = 0.93, respectively. These ventilatory changes were associated with an overall average decrease in left ventricular PCO2 of 2.1 Torr; this decrease was significant (P less than 0.05) only in the intact and Cx groups. Decreasing pulmonary blood flow results in a decrease in ventilation that may be CO2 related; however, the exact mechanism remains obscure but must have a component that is independent of vagally mediated cardiac and pulmonary afferents and peripheral baroreceptor and chemoreceptor afferents.

Animals↗
PubMed1979

Hyperoxic attenuation of exercise-induced bronchospasm in asthmatics.

To investigate the mechanism of exercise-induced bronchospasm, we measured specific airway conductance before and after exercise in 7 healthy normals, 12 asthmatics with intact carotid bodies, and 5 asthmatics who had had bilateral carotid body resection. The subjects breathed either air or oxygen (randomly assigned) during cycle ergometer exercise. Post-exercise bronchodilation was the usual pattern in normals, whereas post-exercise bronchospasm occurred in all asthmatics who breathed air during exercise. Oxygen breathing during exercise markedly attenuated the post-exercise bronchospasm in those asthmatics with intact carotid bodies, but had no significant effect in those without effect in those without carotid bodies. The attenuation of the bronchospasm with oxygen occurred with either incremental or constant load exercise of high intensity. The degree of attenuation did not correlate significantly with changes in end-tidal PCO2, maximum work rate, maximum exercise ventilation, or maximum heart rate. These studies indicate that oxygen attenuates exercise-induced bronchospasm in asthmatics through its action on the carotid bodies.

Adolescent↗
PubMed1979

Post-pneumonectomy syndrome. Surgical correction using Silastic implants.

A post-right pneumonectomy syndrome is described which manifests symptoms of exertional dyspnea and inspiratory stridor on rapid inspiration. These symptoms were associated with marked rightward and posterior deviation of the trachea, over-distention of the left lung with its herniation into the right side of the chest and kinking of the left lower lobe bronchus. At the time of surgery, the tracheal deviation, lung herniation and the kink in the left lower lobe bronchus were immediately corrected by releasing the adhesions between the malpositioned structures and the right chest wall. To maintain the corrected positions, Silastic implants totalling a volume of 990 ml were placed into the space created in the right chest. Following surgery, exertional dyspnea was present with only extraordinary activity, and inspiratory stridor was eliminated. The patient remains asymptomatic three years following surgical correction, and is able to carry on a normal and productive life. We conclude that a syndrome associated with marked exertional dyspnea and inspiratory stridor might develop in situations of marked tracheal shift and overdistention of the remaining lung following right pneumonectomy.

Adult↗
PubMed1979

Doxapram hydrochloride: a respiratory stimulant for patients with primary alveolar hypoventilation.

Four patients (ages 43 to 51) with primary alveolar hypoventilation (PAH) syndrome were studied to characterize the pharmacologic augmentation of ventilation with intravenous doxapram hydrochloride. Doxapram hydrochloride evoked a rapid ventilatory increase of 50 to 100 percent in all four subjects with a consequent decrease in arterial CO2 tension. Blood pressure and heart rate measurements showed small increases during the doxapram infusion. These responses, however, were only sustained during the infusion, decreasing to their predoxapram level when the drug was discontinued. The ventilatory response to the drug was more marked in the pressence of hypoxia than during high O2 breathing, suggesting that the carotid bodies are a site of action for this drug in man. Doxapram hydrochloride can be an effective respiratory stimulant in patients with PAH.

Doxapram↗
PubMed1978

Ventilatory and gas exchange responses to cycling with sinusoidally varying pedal rate.

To investigate factors controlling ventilation under conditions where the applied work load remains constant, but where hypothesized proprioceptive influences would be expected to vary, five subjects exercised at a constant work rate of 50 W on a cycle ergometer at pedaling rates which varied sinusoidally between 40 and 80 rpm. Each subject exercised continuously for 30 min at each of five sinusoidal periods. Minute ventilation (VE), carbon dioxide output (VCO2), oxygen uptake (VO2), and heart rate were computed breath-by-breath and amplitude and phase relations were extracted. We observed small fluctuations in VCO2 and VO2 engendered by varying metabolic requirements of moving the legs at varying rates. VE fluctuations were closely in phase with VCO2 and the amplitudes of the fluctuations were highly significantly correlated (r = 0.83, P less than 0.001); consequently end-tidal carbon dioxide tension fluctuations were small. Variation of pedaling rate, therefore, did not produce a ventilatory response independent of the effect of VCO2. The ventilatory responses to these forcings are inconsistent with an appreciable role for neurally mediated influences from the exercising limbs and provide further evidence that the exercise hyperpnea is linked to CO2 flow to the central circulation.

Adult↗