Maximal O2 delivery and O2 uptake (VO2) per 100 g of active muscle mass are far greater during knee extensor (KE) than during cycle exercise: 73 and 60 ml. min-1. 100 g-1 (2.4 kg of muscle) (R. S. Richardson, D. R. Knight, D. C. Poole, S. S. Kurdak, M. C. Hogan, B. Grassi, and P. D. Wagner. Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H1453-H1461, 1995) and 28 and 25 ml. min-1. 100 g-1 (7.5 kg of muscle) (D. R. Knight, W. Schaffartzik, H. J. Guy, R. Predilleto, M. C. Hogan, and P. D. Wagner. J. Appl. Physiol. 75: 2586-2593, 1993), respectively. Although this is evidence of muscle O2 supply dependence in itself, it raises the following question: With such high O2 delivery in KE, are the quadriceps still O2 supply dependent at maximal exercise? To answer this question, seven trained subjects performed maximum KE exercise in hypoxia [0.12 inspired O2 fraction (FIO2)], normoxia (0.21 FIO2), and hyperoxia (1.0 FIO2) in a balanced order. The protocol (after warm-up) was a square wave to a previously determined maximum work rate followed by incremental stages to ensure that a true maximum was achieved under each condition. Direct measures of arterial and venous blood O2 concentration in combination with a thermodilution blood flow technique allowed the determination of O2 delivery and muscle VO2. Maximal O2 delivery increased with inspired O2: 1.3 +/- 0.1, 1.6 +/- 0.2, and 1.9 +/- 0.2 l/min at 0.12, 0.21, and 1.0 FIO2, respectively (P < 0.05). Maximal work rate was affected by variations in inspired O2 (-25 and +14% at 0.12 and 1.0 FIO2, respectively, compared with normoxia, P < 0.05) as was maximal VO2 (VO2 max): 1.04 +/- 0.13, 1. 24 +/- 0.16, and 1.45 +/- 0.19 l/min at 0.12, 0.21, and 1.0 FIO2, respectively (P < 0.05). Calculated mean capillary PO2 also varied with FIO2 (28.3 +/- 1.0, 34.8 +/- 2.0, and 40.7 +/- 1.9 Torr at 0.12, 0.21, and 1.0 FIO2, respectively, P < 0.05) and was proportionally related to changes in VO2 max, supporting our previous finding that a decrease in O2 supply will proportionately decrease muscle VO2 max. As even in the isolated quadriceps (where normoxic O2 delivery is the highest recorded in humans) an increase in O2 supply by hyperoxia allows the achievement of a greater VO2 max, we conclude that, in normoxic conditions of isolated KE exercise, KE VO2 max in trained subjects is not limited by mitochondrial metabolic rate but, rather, by O2 supply.

Aging appears to attenuate leg blood flow during exercise; in contrast, such data are scant and do not support this contention in the arm. Therefore, to determine whether aging has differing effects on blood flow in the arm and leg, eight young (22 Ϯ 6 yr) and six old (71 Ϯ 15 yr) subjects separately performed dynamic knee extensor [0, 3, 6, 9 W; 20, 40, 60% maximal work rate (WR max)] and handgrip exercise (3, 6, 9 kg at 0.5 Hz; 20, 40, 60% WR max). Arterial diameter, blood velocity (Doppler ultrasound), and arterial blood pressure (radial tonometry) were measured simultaneously at each of the submaximal workloads. Quadriceps muscle mass was smaller in the old (1.6 Ϯ 0.1 kg) than the young (2.1 Ϯ 0.2 kg). When normalized for this difference in muscle mass, resting seated blood flow was similar in young and old subjects (young, 115 Ϯ 28; old, 114 Ϯ 39 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 ). During exercise, blood flow and vascular conductance were attenuated in the old whether expressed in absolute terms for a given absolute workload or more appropriately expressed as blood flow per unit muscle mass at a given relative exercise intensity (young, 1,523 Ϯ 329; old, 1,340 Ϯ 157 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 at 40% WRmax). In contrast, aging did not affect forearm muscle mass or attenuate rest or exercise blood flow or vascular conductance in the arm. In conclusion, aging induces limbspecific alterations in exercise blood flow regulation. These alterations result in reductions in leg blood flow during exercise but do not impact forearm blood flow. exercise; vascular conductance; Doppler AGED HUMANS have consistently displayed a 20 -30% attenuation in supine resting leg blood flow that has been attributed to ϳ50% greater leg vascular resistance (6,7,23,24). However, this age-related reduction in resting blood flow has not been documented in the human forearm (5, 15, 35). There are currently no leg blood flow data that allow a comparison of nonsupine resting young and old people before an exercise assessment.In addition to supine rest, aging appears to attenuate skeletal muscle blood flow in the leg at submaximal and maximal workloads (2,14,21,27,29,36). Again, this reduction may be a consequence of increased vascular resistance in older individuals at a given exercise intensity. Surprisingly, only a single study has examined blood flow as a consequence of exercise in the forearm of young and old individuals. This seminal study by Jasperse et al. (15) was limited to postcontraction hyperemia measurements, but it demonstrated that there was no significant difference between young and old subjects. However, there are currently no data directly comparing arm blood flow in young and old subjects during dynamic forearm exercise.Despite our growing understanding of vascular changes with age, several gaps in the literature and newly emerging concepts have clouded this area. Specifically, there appear to be significant positional-, limb-, and site-specific differences in terms of vascular responsiveness that may blur the assimilation of some age-relate...

Repeated studies using human dynamic knee-extensor exercise have reported high mass specific blood flows. These studies suggest that the high perfusion-to-muscle mass ratio can approach 400 ml(-1) x min x 100 g(-1) in the human quadriceps. However, in these studies mass specific blood flows were calculated based on the assumption that the quadriceps are the only muscles involved in the knee-extensor exercise, which is difficult to verify in an in vivo human model. Previous validations of this assumption have been performed using electromyography (EMG) and assessments of strain gauge tracings, but neither has been able to completely assess the involvement of all thigh muscles in this exercise. To address this issue four subjects exercised at 90% of their work rate maximum for 2.0-2.5 minutes (45-100 watts) and then a transverse section of the thigh (20 cm proximal to the knee) was studied using proton (1H) transverse relaxation time (T2) weighted magnetic resonance (MR) imaging to distinguish active from non-active muscles by the increased signal intensity (SI). On a separate occasion, measurements following 2.0-2.5 minutes of conventional two legged cycle ergometry at 90% of maximum work rate (150-400 watts) were made in the same subjects to contrast this traditional "whole leg" exercise with the unique muscle recruitment in dynamic knee-extension. Following knee-extensor exercise there was a clearly visible change in SI and a significant increase in T2 only in the four muscles of the quadriceps (P<0.05). After bicycle exercise SI changes and T2 revealed a varied muscle use across all muscles. From these MR data it can be concluded that unlike cycle exercise, in which all muscles are recruited to varying extents, single leg knee-extensor exercise is limited to the four muscles of the quadriceps. Thus, the common practice of normalizing blood flow and metabolic data to the quadriceps muscle mass in human knee-extensor exercise studies appears appropriate.

Angiogenesis is a component of the multifactoral adaptation to exercise training, and vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation. However, there is limited evidence supporting the role of VEGF in the exercise training response. Thus we studied mRNA levels of VEGF, using quantitative Northern analysis, in untrained and trained human skeletal muscle at rest and after a single bout of exercise. Single leg knee-extension provided the acute exercise stimulus and the training modality. Four biopsies were collected from the vastus lateralis muscle at rest in the untrained and trained conditions before and after exercise. Training resulted in a 35% increase in muscle oxygen consumption and an 18% increase in number of capillaries per muscle fiber. At rest, VEGF/18S mRNA levels were similar before (0.38 +/- 0.04) and after (1.2 +/- 0.4) training. When muscle was untrained, acute exercise greatly elevated VEGF/18S mRNA levels (16.9 +/- 6.7). The VEGF/18S mRNA response to acute exercise in the trained state was markedly attenuated (5.4 +/- 1.3). These data support the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis and appears to be subject to a negative feedback mechanism as exercise adaptations occur.

Originally thought of as simply damaging or toxic "accidents" of in vivo chemistry, free radicals are becoming increasingly recognized as redox signaling molecules implicit in cellular homeostasis. Indeed, at the vascular level, it is plausible that oxidative stress plays a regulatory role in normal vascular function. Using electron paramagnetic resonance (EPR) spectroscopy, we sought to document the ability of an oral antioxidant cocktail (vitamins C, E, and alpha-lipoic acid) to reduce circulating free radicals, and we employed Doppler ultrasound to examine the consequence of an antioxidant-mediated reduction in oxidative stress on exercise-induced vasodilation. A total of 25 young (18-31 yr) healthy male subjects partook in these studies. EPR spectroscopy revealed a reduction in circulating free radicals following antioxidant administration at rest ( approximately 98%) and as a consequence of exercise ( approximately 85%). Plasma total antioxidant capacity and vitamin C both increased following the ingestion of the antioxidant cocktail, whereas vitamin E levels were not influenced by the ingestion of the antioxidants. Brachial artery vasodilation during submaximal forearm handgrip exercise was greater with the placebo (7.4 +/- 1.8%) than with the antioxidant cocktail (2.3 +/- 0.7%). These data document the efficacy of an oral antioxidant cocktail in reducing free radicals and suggest that, in a healthy state, the aggressive disruption of the delicate balance between pro- and antioxidant forces can negatively impact vascular function. These findings implicate an exercise-induced reliance upon pro-oxidant-stimulated vasodilation, thereby revealing an important and positive vascular role for free radicals.