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Biomedical subjects

Peter D Wagner

Publications and source records attributed to Peter D Wagner.

At least 19 recordsLinked to original sources
PubMed2007

Effect of acetazolamide on pulmonary and muscle gas exchange during normoxic and hypoxic exercise.

Acetazolamide (ACZ) is used to prevent acute mountain sickness at altitude. Because it could affect O2 transport in several different and potentially conflicting ways, we examined its effects on pulmonary and muscle gas exchange and acid-base status during cycle exercise at approximately 30, 50 and 90% VO2max in normoxia (F(IO2) = 0.2093) and acute hypoxia (F(IO2) = 0.125). In a double-blind, order-balanced, crossover design, six healthy, trained men (normoxic VO2max= 59 ml kg(-1) min(-1)) exercised at both F(IO2) values after ACZ (3 doses of 250 mg, 8 h apart) and placebo. One week later this protocol was repeated using the other drug (placebo or ACZ). We measured cardiac output (QT), leg blood flow (LBF), and muscle and pulmonary gas exchange, the latter using the multiple inert gas elimination technique. ACZ did not significantly affect VO2, QT, LBF or muscle gas exchange. As expected, ACZ led to lower arterial and venous blood [HCO3-], pH and lactate levels (P < 0.05), and increased ventilation (P < 0.05). In both normoxia and hypoxia, ACZ resulted in higher arterial P(O2) and saturation and a lower alveolar-arterial P(O2) difference (AaD(O2)) due to both less VA/Q mismatch and less diffusion limitation (P < 0.05). In summary, ACZ improved arterial oxygenation during exercise, due to both greater ventilation and more efficient pulmonary gas exchange. However, muscle gas exchange was unaffected.

Acetazolamide↗
PubMed2007

Residence at 3,800-m altitude for 5 mo in growing dogs enhances lung diffusing capacity for oxygen that persists at least 2.5 years.

Mammals native to high altitude (HA) exhibit larger lung volumes than their lowland counterparts. To test the hypothesis that adaptation induced by HA residence during somatic maturation improves pulmonary gas exchange in adulthood, male foxhounds born at sea level (SL) were raised at HA (3,800 m) from 2.5 to 7.5 mo of age and then returned to SL prior to somatic maturity while their littermates were simultaneously raised at SL. Following return to SL, all animals were trained to run on a treadmill; gas exchange and hemodynamics were measured 2.5 years later at rest and during exercise while breathing 21% and 13% O(2). The multiple inert gas elimination technique was employed to estimate ventilation-perfusion (Va/Q) distributions and lung diffusing capacity for O(2) (Dl(O(2))). There were no significant intergroup differences during exercise breathing 21% O(2). During exercise breathing 13% O(2), peak O(2) uptake and Va/Q distributions were similar between groups but arterial pH, base excess, and O(2) saturation were higher while peak lactate concentration was lower in animals raised at HA than at SL. At a given exercise intensity, alveolar-arterial O(2) tension gradient (A-aDo(2)) attributable to diffusion limitation was lower while Dlo(2) was 12-25% higher in HA-raised animals. Mean systemic arterial blood pressure was also lower in HA-raised animals; mean pulmonary arterial pressures were similar. We conclude that 5 mo of HA residence during maturation enhances long-term gas exchange efficiency and Dl(O(2)) without impacting Va/Q inequality during hypoxic exercise at SL.

Acclimatization↗
PubMed2006

Measurement of cardiac output by open-circuit acetylene uptake: a computer model to quantify error caused by ventilation-perfusion inequality.

The ability to assess cardiac output (Q(T)) noninvasively has been the focus of interest for many researchers. While the open-circuit acetylene (C2H2) method seems promising, it is prone to error due to ventilation-perfusion (V/Q) inequality. Measurements during exercise, at high altitude or in patients with chronic obstructive pulmonary disease (COPD) could be unreliable and further validation studies under these circumstances may be needed. We used a computer model based on formulae derived from the multiple inert gas elimination technique to quantify error in Q(T) measurements resulting from V/Q inequality at rest, during exercise or at high altitude. Moreover, potential errors encountered in patients with COPD were quantified. In healthy subjects, V/Q inequality related measurement error seems negligible, under both normoxic and hypoxic conditions and especially during exercise. In COPD, errors up to 20% at rest and up to 15% during exercise are expected. It is therefore concluded from our model that the open-circuit C2H2 uptake method is expected to be accurate in normal subjects. Its validity in COPD needs further study.

Acetylene↗
PubMed2006

Continued divergence in VO2max of rats artificially selected for running endurance is mediated by greater convective blood O2 delivery.

We previously showed that after seven generations of artificial selection of rats for running capacity, maximal O2 uptake (VO2max) was 12% greater in high-capacity (HCR) than in low-capacity runners (LCR). This difference was due exclusively to a greater O2 uptake and utilization by skeletal muscle of HCR, without differences between lines in convective O2 delivery to muscle by the cardiopulmonary system (QO2max). The present study in generation 15 (G15) female rats tested the hypothesis that continuing improvement in skeletal muscle O2 transfer must be accompanied by augmentation in QO2max to support VO2max of HCR. Systemic O2 transport was studied during maximal normoxic and hypoxic exercise (inspired PO2 approximately 70 Torr). VO2max divergence between lines increased because of both improvement in HCR and deterioration in LCR: normoxic VO2max was 50% higher in HCR than LCR. The greater VO2max in HCR was accompanied by a 41% increase in QO2max: 96.1 +/- 4.0 in HCR vs. 68.1 +/- 2.5 ml stpd O2 x min(-1) x kg(-1) in LCR (P < 0.01) during normoxia. The greater G15 QO2max of HCR was due to a 48% greater stroke volume than LCR. Although tissue O2 diffusive conductance continued to increase in HCR, tissue O2 extraction was not significantly different from LCR at G15, because of the offsetting effect of greater HCR blood flow on tissue O2 extraction. These results indicate that continuing divergence in VO2max between lines occurs largely as a consequence of changes in the capacity to deliver O2 to the exercising muscle.

Animals↗
PubMed2006

The effect of incomplete acetylene washout on cardiac output measurement using open circuit acetylene uptake.

The open circuit acetylene uptake method is a useful non-invasive means of measuring cardiac output. However, because of accumulation of inhaled acetylene in tissues, the cardiac output uptake is underestimated, if residual acetylene is not allowed to wash out completely in between measurements. We determined the effect of applying a correction factor that estimates mixed venous acetylene concentration from endtidal values to the calculation of cardiac output. This accounts for mixed venous acetylene present during measurements made before complete washout. Six healthy subjects performed steady-state exercise at approximately 30% and 60% of V(O2 max). Cardiac output measurements were made at each exercise intensity using the open circuit acetylene uptake method (inspired [acetylene] approximately 1%), with the first and last measurements having no detectible levels of acetylene in expired gas (reference measurement). Data were also obtained with immediate pre-measurement endtidal concentrations ranging from 3% to 15% of the inspired [acetylene], in random order in between. Oxygen consumption, carbon dioxide production and heart rate did not change significantly during testing at each exercise intensity. Reference cardiac output also did not change significantly and averaged 11.1+/-0.8 L/min at 30% of V(O2 max) and 16.5+/-2.0 L/min at 60% of V(O2 max). Uncorrected cardiac output measurements progressively underestimated cardiac output by 15% at the 3% of inspired endtidal [acetylene] and by over 50% at 15% [acetylene] (p<0.0001). However, when corrected for residual endtidal [acetylene], cardiac outputs were not significantly different from the reference measurements. The results of this study suggest that by accounting for residual endtidal acetylene in mixed venous blood, cardiac output can be accurately measured even when washout of acetylene is incomplete, allowing measurements as often as every 10-15 s.

Acetylene↗
PubMed2006

Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.

To investigate the consequences of inborn excessive erythrocytosis, we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney, or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in 5-mo-old tg6 mice. At about 7 mo, several tg6 animals developed spastic contractions of the hindlimbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition, and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions, and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness, or in subjects tempted to abuse Epo by means of gene doping.

Altitude Sickness↗
PubMed2006

Effects of exercise-induced arterial hypoxaemia and work rate on diaphragmatic fatigue in highly trained endurance athletes.

Diaphragmatic fatigue occurs in highly trained athletes during exhaustive exercise. Since approximately half of them also exhibit exercise-induced arterial hypoxaemia (EIAH) during high-intensity exercise, the present study sought to test the hypothesis that arterial hypoxaemia contributes to exercise-induced diaphragmatic fatigue in this population. Ten cyclists ( : 70.0 +/- 1.6 ml kg(-1) min(-1); mean +/-s.e.m.) completed, in a balanced ordering sequence, one normoxic (end-exercise arterial O(2) saturation (S(a,O(2))): 92 +/- 1%) and one hyperoxic (F(I,O(2)): 0.5% O(2); S(a,O(2)) : 97 +/- 1%) 5 min exercise test at intensities equal to 80 +/- 3 and 90 +/- 3% of maximal work rate (WR(max)), respectively, producing the same tidal volume (V(T)) and breathing frequency (f) throughout exercise. Cervical magnetic stimulation was used to determine reduction in twitch transdiaphragmatic pressure (P(di,tw)) during recovery. Hyperoxic exercise at 90% WR(max) induced significantly (P= 0.022) greater post-exercise reduction in P(di,tw) (15 +/- 2%) than did normoxic exercise at 80% WR(max) (9 +/- 2%), despite the similar mean ventilation (123 +/- 8 and 119 +/- 8 l min(-1), respectively), breathing pattern (V(T): 2.53 +/- 0.05 and 2.61 +/- 0.05 l, f: 49 +/- 2 and 46 +/- 2 breaths min(-1), respectively), mean changes in P(di) during exercise (37.1 +/- 2.4 and 38.2 +/- 2.8 cmH(2)O, respectively) and end-exercise arterial lactate (12.1 +/- 1.4 and 10.8 +/- 1.1 mmol l(-1), respectively). The difference found in diaphragmatic fatigue between the hyperoxic (at higher leg work rate) and the normoxic (at lower leg work rate) tests suggests that neither EIAH nor lactic acidosis per se are likely predominant causative factors in diaphragmatic fatigue in this population, at least at the level of S(a,O(2)) tested. Rather, this result leads us to hypothesize that blood flow competition with the legs is an important contributor to diaphragmatic fatigue in heavy exercise, assuming that higher leg work required greater leg blood flow.

Adult↗
PubMed2006

Effects of IMAGENT on pulmonary hemodynamics and gas exchange in dogs.

Imagent is an IV injected contrast echocardiography agent designed to image the left ventricle after traversing the pulmonary circulation. We examined the effect of Imagent on pulmonary function by injecting either Imagent (n = 8) or equivalent volume of saline (n = 7) IV in randomly ordered 1, 8 and 16 mg/kg doses in dogs with preexisting pulmonary hypertension. We found that Imagent had no effects on cardiac output, pulmonary gas exchange, lung wet:dry ratio or static compliance. However, the 16 mg/kg dose of Imagent increased both pulmonary artery pressure (PAP) transiently by an average of 5.7 mmHg (p < 0.05) 2 to 3 min after injection and pulmonary vascular resistance (PVR) by 5.9 mmHg per l/min (p < 0.05) 4 min after injection before returning to preinjection levels. The lower doses of Imagent did not affect PAP or PVR. These results imply that the approved clinical dose of Imagent (0.125 mg/kg) will not affect pulmonary hemodynamics, gas exchange or mechanical properties in dogs with preexisting pulmonary hypertension.

Animals↗
PubMed2006

Skeletal muscles in chronic obstructive pulmonary disease: deconditioning, or myopathy?

In recent years, COPD has become increasingly thought of as a systemic disease affecting many tissues and organs in addition to the lungs. The skeletal muscles in particular have been the target of much research focusing on whether the universally observed exercise limitation reflects a systemic myopathic effect of COPD, or simply the consequences of extreme, long-term inactivity. In this paper, the evidence is reviewed for COPD patients without loss of muscle mass and who are not taking systemic steroids. While altered levels of antioxidant defences (lower), circulating inflammatory biomarkers (higher) and anabolic hormones (lower) have been found in COPD, cause and effect remains to be established for the link of inflammation/oxidative stress to muscle dysfunction. Other evidence used to propose a myopathic state (early lactate release, reduced power output, lower metabolic enzyme capacities, greater phosphocreatine breakdown and slower phosphocreatine restoration after exercise, and altered fibre type distribution) also occur in normal subjects who are extremely inactive. Furthermore, intense small muscle mass training can normalize small muscle function in these patients. Based on these data, it remains to be shown that the muscles in COPD patients without loss of muscle mass are myopathic. The interesting discussion about systemic effects of COPD should not get in the way of systematic muscle training, which has been shown to be an effective component of rehabilitation.

Exercise Therapy↗
PubMed2005

Muscle-targeted deletion of VEGF and exercise capacity in mice.

Methods to study exercise are evolving from classically integrative organ approaches towards the more fundamental cellular reactions. While in vitro cellular and molecular methods are well established, only recently has in vivo molecular manipulation been widely used. This review discusses two complementary methods for determining in vivo the significance of one gene thought important to exercise: vascular endothelial growth factor (VEGF). Because VEGF deletion is embryonically lethal, its study requires conditional and/or organ-targeted strategies. We inactivated the muscle VEGF gene in two ways:

Animals↗
PubMed2005

Systemic oxygen transport in rats artificially selected for running endurance.

The relative contribution of genetic and environmental influences to individual exercise capacity is difficult to determine. Accordingly, animal models in which these influences are carefully controlled are highly useful to understand the determinants of intrinsic exercise capacity. Studies of systemic O(2) transport during maximal treadmill exercise in two diverging lines of rats artificially selected for endurance capacity showed that, at generation 7, whole body maximal O(2) uptake ((.)V(O(2)(max)) was 12% higher in high capacity (HCR) than in low capacity runners (LCR) during normoxic exercise. The difference in (.)V(O(2)(max) between HCR and LCR was larger during hypoxic exercise. Analysis of the linked O(2) conductances of the O(2) transport system showed that the higher (.)V(O(2)(max) was not due to a higher ventilatory response, a more effective pulmonary gas exchange, or an increased rate of O(2) delivery to the tissue by blood. The main reason for the higher (.)V(O(2)(max) of HCR was an increased tissue O(2) extraction, due largely to a higher tissue diffusive O(2) conductance. The enhanced tissue O(2) diffusing capacity was paralleled by an increased capillary density of a representative locomotory skeletal muscle, the gastrocnemius, in HCR. Activities of skeletal muscle oxidative enzymes citrate synthase and beta-HAD were also higher in HCR than LCR. Thus, the functional characteristics observed during exercise are consistent with the structural and biochemical changes observed in skeletal muscle that imply an enhanced capacity for muscle O(2) uptake and utilization in HCR. The results indicate that the improved (.)V(O(2)(max) is solely due to enhanced muscle O(2) extraction and utilization. However, the question arises as to whether it is possible to maintain a continually expanding capacity for O(2) extraction at the tissue level with successive generations, without a parallel improvement in the capacity to deliver O(2) to the exercising muscles.

Animals↗
PubMed2005

Why doesn't exercise grow the lungs when other factors do?

Exercise training enhances every component of the O(2) transport and metabolic system--except the lungs. Consequently, the lungs can contribute to the limitation of VO(2)max. Only hypoxia early in life and substantial lung resection reproducibly stimulate growth in normal lungs across species. Possible pathways involve genes activated by hypoxia or mechanical strain, or both, including growth factors, hormones, nitric oxide, and retinoids.

Exercise↗