We have demonstrated that 50-mum-diameter arteriovenous pathways exist in isolated, healthy human and baboon lungs, ventilated and perfused under physiological pressures. These findings have been confirmed and extended by demonstrating the passage of 25-microm microspheres through the lungs of exercising dogs, but not at rest. Determination of blood flow through these large-diameter intrapulmonary arteriovenous pathways would be an important first step to establish a physiological role for these vessels. Currently, we sought to estimate blood flow through these arteriovenous pathways using technetium-99m ((99m)Tc)-labeled macroaggregated albumin (MAA) in healthy humans at rest and during maximal treadmill exercise. We hypothesized that the percentage of (99m)Tc MAA able to traverse the pulmonary circulation (%transpulmonary passage) would increase during exercise. Seven male subjects without patent foramen ovale were injected with (99m)Tc MAA at rest on 1 day and during maximal treadmill exercise on a separate day (>6 days). Within 5 min after injection, subjects began whole body imaging in the supine position. Six of the seven subjects showed an increase in transpulmonary passage of MAA with maximal exercise. Using two separate analysis methods, percent transpulmonary passage significantly increased with exercise from baseline to absolute values of 1.2 +/- 0.8%(P = 0.008) and 1.3 +/- 1.0%(P = 0.016), respectively (means +/- SD; paired t-test). We conclude that MAA may be traversing the pulmonary circulation via large-diameter intrapulmonary arteriovenous conduits in healthy humans during exercise. Recruitment of these pathways may divert blood flow away from pulmonary capillaries during exercise and compromise the lung's function as a biological filter.

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We investigated whether somatosensory feedback from contracting limb muscles exerts an inhibitory influence on the determination of central command during closed-loop cycling exercise in which the subject voluntarily determines his second-by-second central motor drive. Eight trained cyclists performed two 5 km time trials either without (5KCtrl) or with lumbar epidural anesthesia (5KEpi; 24 ml of 0.5% lidocaine, vertebral interspace L3-L4). Percent voluntary quadriceps muscle activation was determined at rest using a superimposed twitch technique. Epidural lidocaine reduced pre-time trial maximal voluntary quadriceps strength (553 +/- 45 N; MVC) by 22 +/- 3%. Percent voluntary quadriceps activation was also reduced from 97 +/- 1% to 81 +/- 3% via epidural lidocaine and this was unchanged following the 5KEpi indicating a sustained level of neural impairment throughout the trial. Power output was reduced by 9 +/- 2% throughout the race (P < 0.05). We found three types of significant effects of epidural lidocaine which supported a substantial role for somatosensory feedback from the exercising limbs as a determinant of central command throughout high intensity closed-loop cycling exercise: a) relative integrated electromyogram of the vastus lateralis was significantly increased; b) pedal forces were similar despite reduced number of fast-twitch muscle fibers available for activation; c) ventilation was increased out of proportion to a reduced VCO2 and heart rate and blood pressure were increased out of proportion to power output and VO2. These findings demonstrate the inhibitory influence of somatosensory feedback from contracting locomotor muscles on the conscious and/or subconscious determination of the magnitude of central motor drive during high intensity closed-loop endurance exercise. Key words: nociception, exercise hyperpnea, muscle metaboreflex, ascending sensory pathway.

This review addresses three types of causes of respiratory system limitations to O(2) transport and exercise performance that are experienced by significant numbers of active, highly fit younger and older adults. First, flow limitation in intrathoracic airways may occur during exercise because of narrowed, hyperactive airways or secondary to excessive ventilatory demands superimposed on a normal maximum flow-volume envelope. Narrowing of the extrathoracic, upper airway also occurs in some athletes at very high flow rates during heavy exercise. Examination of the breath-by-breath tidal flow-volume loop during exercise is key to a noninvasive diagnosis of flow limitation and to differentiation between intrathoracic and extrathoracic airway narrowing. Second exercise-induced arterial hypoxemia occurs secondary to an excessively widened alveolar-arterial oxygen pressure difference. This inefficient gas exchange may be attributable in part to small intracardiac or intrapulmonary shunts of deoxygenated mixed venous blood during exercise. The existence of these shunts at rest and during exercise may be determined by using saline solution contrast echocardiography. Finally, fatigue of the respiratory muscles resulting from sustained, high-intensity exercise and the resultant vasoconstrictor effects on limb muscle vasculature will also compromise O(2) transport and performance. Exercise in the hypoxic environments of even moderately high alitudes will greatly exacerbate the negative influences of these respiratory system limitations to exercise performance, especially in highly fit individuals.

The 100% Oxygen (O2) technique has been used to detect and quantify right-to-left shunt for more than 50 years. The goal of this study was to determine if breathing 100% O2 affected intrapulmonary arteriovenous pathways during exercise. Seven healthy subjects (3 females) performed two exercise protocols. In Protocol I subjects performed an incremental cycle ergometer test (60W + 30W/2 min; breathing room air, FIO2 = 0.209) and arteriovenous shunting was evaluated using saline contrast echocardiography at each stage. Once significant arteriovenous shunting was documented (bubble score >/=2), workload was held constant for the remainder of the protocol and FIO2 was alternated between 1.0 (Hyperoxia) and 0.209 (Normoxia) as follows: Hyperoxia for 180 seconds, Normoxia for 120 seconds, Hyperoxia for 120 seconds, Normoxia for 120 seconds, Hyperoxia for 60 seconds and Normoxia for 120 seconds. For protocol II, subjects performed an incremental cycle ergometer test until volitional exhaustion while continuously breathing 100% O2. In protocol 1, shunting was seen in all subjects at 120-300W. Breathing oxygen for 1 minute reduced shunting, and breathing oxygen for 2 minutes eliminated shunting in all subjects. Shunting promptly resumed upon breathing room air. Similarly, in Protocol II, breathing 100% O2 substantially decreased or eliminated exercise-induced arteriovenous shunting in all subjects at submaximal and in 4/7 subjects at maximal exercise intensities. Our results suggest that alveolar hyperoxia prevents or reduces blood flow through arteriovenous shunt pathways.

Exercise-induced intrapulmonary arteriovenous shunting, as detected by saline contrast echocardiography, has been demonstrated in healthy humans. We have previously suggested that increases in both pulmonary pressures and blood flow associated with exercise are responsible for opening these intrapulmonary arteriovenous pathways. In the present study, we hypothesized that, although cardiac output and pulmonary pressures would be higher in hypoxia, the potent pulmonary vasoconstrictor effect of hypoxia would actually attenuate exercise-induced intrapulmonary shunting. Using saline contrast echocardiography, we examined nine healthy men during incremental (65W + 30W/2min) cycle exercise to exhaustion in normoxia and hypoxia (FIO2=0.12). Contrast injections were made into a peripheral vein at rest and during exercise and recovery (3-5 min post-exercise) with pulmonary gas exchange measured simultaneously. At rest, no subject demonstrated intrapulmonary shunting in normoxia (PaO2= 98 +/- 10 Torr), whereas, in hypoxia (PaO2= 47 +/- 5 Torr) intrapulmonary shunting developed in 3/9 subjects. During exercise,~90%(8/9) of the subjects shunted during normoxia whereas all subjects shunted during hypoxia. Four of the nine subjects shunted at a lower workload in hypoxia. Furthermore, all subjects continued to shunt at 3 min and 5 subjects shunted at 5 min post exercise in hypoxia. Hypoxia has acute effects by inducing intrapulmonary arteriovenous shunt pathways at rest and during exercise and has long term effects by maintaining patency of these vessels during recovery. Whether oxygen tension specifically regulates these novel pathways or opens them indirectly via effects on the conventional pulmonary vasculature remains unclear. Key words: AaDO2, contrast echocardiography, pulmonary circulation, EIAH.

During the last two decades, various Doppler methods have been successfully used to screen patients with significant cerebral and peripheral vascular disease. In general terms, the principal advantages of Doppler ultrasound techniques in the evaluation of atherosclerotic lesions are that they: 1) are noninvasive, 2) are nontraumatic, 3) are relatively inexpensive, 4) provide anatomical and physiological data, and 5) provide direct and dynamic measurements. Nevertheless, the general limitations of the techniques are of equal importance: 1) the techniques are difficult in some subjects due to obesity and anatomical variations; 2) the technique cannot examine tissues surrounded by air or bone; 3) the techniques require operator skill and a thorough knowledge of human anatomy and cardiovascular dynamics; 4) the techniques have finite spatial resolutions which may compromise the important measurement of vessel diameter, ulceration, and percent stenosis; and 5) the techniques have finite velocity measuring capabilities which may compromise some measurements of highly disturbed blood velocities outside the range of 2-200 cm/sec. As clinical demands for the early diagnosis and quantification of vascular lesions increased, improvements in Doppler ultrasonics and spectra analysis significantly increased the technical and clinical capabilities of existing simple, inexpensive instruments. Presently, both anatomical and physiological images along with quantitative Doppler spectra from superficial and deep-lying vessels can be obtained. Consequently, the ability of new expensive imaging equipment to quantitate atherosclerotic lesions using spectral analysis techniques compares favorably with the interpretational precision of standard invasive or intravenous digital angiography.

RATIONALE: Previously we have shown, using contrast echocardiography, that intra-pulmonary arteriovenous pathways are inducible in healthy humans during exercise, however this technique does not allow for determination of arteriovenous vessel size or shunt magnitude. OBJECTIVES: The purpose of this study was to determine if large diameter (>25 microm) intra-pulmonary arteriovenous pathways are present in the dog, and whether exercise recruits these conduits. METHODS: Through the right fore-limb, 10.8 million 25 microm stable isotope-labeled microspheres (BioPAL, Inc.(TM)) were injected either at rest (n=8) or during high-intensity exercise (6-8mph, 10-15% grade, n=6). Systemic arterial blood was continuously sampled during, and for three minutes after injection. Following euthanasia, tissue samples were obtained from the heart, liver, kidney and skeletal muscle. In addition, 25 and 50 microm microspheres were infused into four isolated dog lungs that were ventilated and perfused at constant perfusion pressures similar to exercise. MEASUREMENTS AND MAIN RESULTS: Blood and tissue samples were commercially analyzed for the presence of microspheres (BioPAL, Inc.(TM)). No microspheres were detected in the arterial blood or tissue samples from resting dogs. In contrast, five of six exercising dogs showed evidence of exercise-induced intra-pulmonary arteriovenous shunting, as microspheres were detected in arterial blood and/or tissue. Furthermore, shunt magnitude was calculated to be 1.4+/-0.8% of cardiac output (n=3). Evidence of intra-pulmonary arteriovenous anastomoses >/= 50microm was also found in three of four isolated lungs. CONCLUSIONS: Consistent with previous human findings, these data demonstrate that intra-pulmonary arteriovenous pathways are functional in the dog and are recruited with exercise.