Casey, Darren P.

Hyperoxia can cause substantial reductions in peripheral and coronary blood flow at rest and during exercise, which may be caused by reactive oxygen species (ROS) generated during hyperoxia. The aim of this study was to investigate the role of ROS in hyperoxia-induced reductions in skeletal muscle blood flow during forearm exercise. We hypothesized that infusion of vitamin C would abolish the effects of hyperoxia on the forearm blood flow (FBF) responses to exercise. Twelve young healthy adults performed rhythmic forearm handgrip exercise (10% of maximum voluntary contraction for 5 min) during normoxia and hyperoxia. For each condition, two trials were conducted with intra-arterial administration of saline or vitamin C. FBF was measured using Doppler ultrasound. During hyperoxia with saline, FBF and forearm vascular conductance (FVC) were 86.3 ± 5.1 and 86.8 ± 5.2%, respectively, of the normoxic values (100%) ( P < 0.05). During vitamin C, hyperoxic FBF and FVC responses were 90.9 ± 4.2 and 90.9 ± 4.1%, respectively, of the normoxic values ( P = 0.57 and 0.59). Subjects were then divided into three subgroups based on their percent decrease in FBF (>20, 10–20, and <10%) during hyperoxia. In the subgroup that demonstrated the greatest hyperoxia-induced changes (>20%), FBF and FVC during hyperoxia were 67.1 ± 4.0 and 66.8 ± 3.6%, respectively, of the normoxic values. Vitamin C abolished these effects on FBF and FVC with values that were 102.0 ± 5.2 and 100.8 ± 6.1%, respectively. However, vitamin C had no effect in the other two subgroups. This analysis is consistent with the idea that ROS generation blunts the FBF responses to exercise in the subjects most affected by hyperoxia.

Blood flow increases to exercising skeletal muscle, and this increase is driven primarily by vasodilation in the contracting muscles. When oxygen delivery to the contracting muscles is altered by changes in arterial oxygen content, the magnitude of the vasodilator response to exercise changes. It is augmented during hypoxia and blunted during hyperoxia. Because the magnitude of the increased vasodilation during hypoxic exercise tends to keep oxygen delivery to the contracting muscles constant, we have termed this phenomenon “compensatory vasodilation.” In a series of studies, we have explored metabolic, endothelial, and neural mechanisms that might contribute to compensatory vasodilation. These include the contribution of vasodilating substances like nitric oxide (NO) and adenosine, along with altered interactions between sympathetic vasoconstriction and metabolic vasodilation. We have also compared the compensatory vasodilator responses to hypoxic exercise with those seen when oxygen delivery to contracting muscles is altered by acute reductions in perfusion pressure. A synthesis of our findings indicate that NO contributes to the compensatory dilator responses during both hypoxia and hypoperfusion, while adenosine appears to contribute only during hypoperfusion. During hypoxia, the NO-mediated component is linked to a β-adrenergic receptor mechanism during lower intensity exercise, while another source of NO is engaged at higher exercise intensities. There are also subtle interactions between α-adrenergic vasoconstriction and metabolic vasodilation that influence the responses to hypoxia, hyperoxia, and hypoperfusion. Together our findings emphasize both the tight linkage of oxygen demand and supply during exercise and the redundant nature of the vasomotor responses to contraction.

In humans, β-adrenergic receptor activation causes a substantial portion of hypoxic vasodilation in skeletal muscle at rest and during forearm exercise. Recent evidence suggests that β-adrenergic receptors are either more sensitive or upregulated in young women vs. men. Therefore, we examined whether sex influences hypoxic vasodilation in 31 young subjects (15 women/16 men; 26 ± 1 yr). We also examined whether potential sex-related differences existed in a group of older adults (6 women/5 men; 61 ± 2 yr). All subjects performed forearm exercise at 10 and 20% of maximum under normoxic and hypoxic [80% arterial O2 saturation (So2)] conditions. Forearm vascular conductance (FVC; ml·min−1·100 mmHg−1) was calculated from blood flow (ml/min) and blood pressure (mmHg). At rest, young women demonstrated a greater vasodilator response to hypoxia compared with men (39 ± 12 vs. 13 ± 6%, P < 0.05). The absolute compensatory vasodilator response (hypoxic FVC-normoxic FVC) during exercise was similar between sexes, but the relative change was greater in young women at 10% (28 ± 5 vs. 17 ± 3%, P < 0.05) and 20% exercise (29 ± 4% vs. 15 ± 3%, P < 0.01). Additionally, the absolute changes in vasodilation after normalizing the response to forearm volume or workload were greater in young women during exercise ( P < 0.05). Interestingly, the compensatory vasodilator responses between older women and men were similar at 10 and 20% exercise, regardless of whether the response is expressed as absolute, relative, or absolute change normalized for forearm volume or workload ( P = 0.054–0.97). Our data suggest that the compensatory vasodilator response to hypoxic exercise is greater in young women compared with men. However, sex-specific differences appear to be lost with aging.

We tested the hypothesis that reduced nitric oxide (NO) bioavailability contributes to the attenuated peak and total vasodilation following single-muscle contractions in older adults. Young ( n = 10; 24 ± 2 yr) and older ( n = 10; 67 ± 2 yr) adults performed single forearm contractions at 10, 20, and 40% of maximum during saline infusion (control) and NO synthase (NOS) inhibition via NG-monomethyl-l-arginine. Brachial artery diameters and velocities were measured using Doppler ultrasound and forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak and total vasodilator responses [change (Δ) in FVC from baseline] were attenuated in older adults at all intensities ( P < 0.05). NOS inhibition reduced the peak ΔFVC at 10% (88 ± 12 vs. 52 ± 9 ml·min−1·100 mmHg−1), 20% (125 ± 13 vs. 83 ± 13 ml·min−1·100 mmHg−1), and 40% (207 ± 26 vs. 133 ± 20 ml·min−1·100 mmHg−1) in young subjects, ( P < 0.05 for all) and in older adults at 10% (59 ± 5 vs. 47 ± 7 ml·min−1·100 mmHg−1, P < 0.05) and 20% (88 ± 9 vs. 68 ± 9 ml·min−1·100 mmHg−1, P < 0.05), but not 40% (128 ± 12 vs. 105 ± 11 ml·min−1·100 mmHg−1, P = 0.11). The relative (%) reduction in peak ΔFVC due to NOS inhibition was greater in young vs. older adults at 20% (−36 ± 5 vs. −23 ± 5%, P < 0.05) and 40% (−35 ± 6 vs. −16 ± 7%, P < 0.05). The reduction in the total vasodilator response (area under the curve) with NOS inhibition was also greater in young vs. older adults at all intensities. Our data suggest that contraction-induced rapid vasodilation is mediated in part by NO, and that the contribution of NO is greater in young adults.

Prehypertensives exhibit marked endothelial dysfunction, a risk factor for future cardiovascular morbidity and mortality. However, the ability of exercise to ameliorate endothelial dysfunction in prehypertensives is grossly underinvestigated. This prospective randomized and controlled study examined the separate effects of resistance and endurance training on conduit artery endothelial function in young prehypertensives. Forty-three unmedicated prehypertensive (systolic blood pressure [SBP]=120–139 mmHg; diastolic blood pressure [DBP]=80–89 mmHg) but otherwise healthy men and women and 15 normotensive matched time-controls (NMTC); n = 15) between 18 and 35 y of age met screening requirements and participated in the study. Prehypertensive subjects were randomly assigned to either a resistance exercise training (PHRT; n = 15), endurance exercise training (PHET; n = 13) or time-control group (PHTC; n = 15). The treatment groups performed exercise training three days per week for eight weeks. The control groups did not initiate exercise programs throughout the study. Flow mediated dilation (FMD) of the brachial artery, biomarkers of enodothelial function and peripheral blood pressure were evaluated before and after exercise intervention or time-matched control. PHRT and PHET reduced resting SBP (9.6 ± 3.6 and 11.9 ± 3.4 mmHg, respectively; P < 0.05) and DBP (8.0 ± 5.1 and 7.2 ± 3.4 mmHg, respectively; P < 0.05). Exercise training improved brachial artery FMD absolute diameter, percent dilation and normalized percent dilation by 30%, 34% and 19% for PHRT, P < 0.05; and by 54%, 63% and 75% for PHET, P < 0.05; respectively. PHRT and PHET increased plasma concentrations of 6-keto prostaglandin F1 α (19% and 22%, respectively; P < 0.05), NO x (19% and 23%, respectively; P < 0.05), and reduced endothelin-1 by (16% and 24%, respectively; P < 0.01). This study provides novel evidence that resistance and endurance exercise separately have beneficial effects on resting peripheral blood pressure, brachial artery FMD and endothelial-derived vasoactive agents in young prehypertensives.

We hypothesized that demographic/anthropometric parameters can be used to estimate effective reflecting distance (EfRD), required to derive aortic pulse wave velocity (APWV), a prognostic marker of cardiovascular risk, from peripheral waveforms and that such estimates can discriminate differences in APWV and EfRD with aging and habitual endurance exercise in healthy adults. Ascending aortic pressure waveforms were derived from peripheral waveforms (brachial artery pressure, n = 25; and finger volume pulse, n = 15) via a transfer function and then used to determine the time delay between forward- and backward-traveling waves (Δ tf-b). True EfRDs were computed as directly measured carotid-femoral pulse wave velocity (CFPWV) × ½Δ tf-b and then used in regression analysis to establish an equation for EfRD based on demographic/anthropometric data (EfRD = 0.173·age + 0.661·BMI + 34.548 cm, where BMI is body mass index). We found good agreement between true and estimated APWV (Pearson's R2 = 0.43; intraclass correlation = 0.64; both P < 0.05) and EfRD ( R2 = 0.24; intraclass correlation = 0.40; both P < 0.05). In young sedentary (22 ± 2 years, n = 6), older sedentary (62 ± 1 years, n = 24), and older endurance-trained (61 ± 2 years, n = 14) subjects, EfRD (from demographic/anthropometric parameters), APWV, and ½Δ tf-b (from brachial artery pressure waveforms) were 52.0 ± 0.5, 61.8 ± 0.4, and 60.6 ± 0.5 cm; 6.4 ± 0.3, 9.6 ± 0.2, and 8.1 ± 0.2 m/s; and 82 ± 3, 65 ± 1 and 76 ± 2 ms (all P < 0.05), respectively. Our results demonstrate that APWV derived from peripheral waveforms using age and BMI to estimate EfRD correlates with CFPWV in healthy adults. This method can reliably detect the distal shift of the reflecting site with age and the increase in APWV with sedentary aging that is attenuated with habitual endurance exercise.

Large increases in systemic oxygen content cause substantial reductions in exercising forearm blood flow (FBF) due to increased vascular resistance. We hypothesized that 1) functional sympatholysis (blunting of sympathetic α-adrenergic vasoconstriction) would be attenuated during hyperoxic exercise and 2) α-adrenergic blockade would limit vasoconstriction during hyperoxia and increase FBF to levels observed under normoxic conditions. Nine male subjects (age 28 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Studies were performed in a hyperbaric chamber at 1 atmosphere absolute (ATA; sea level) while breathing 21% O2 and at 2.82 ATA while breathing 100% O2 (estimated change in arterial O2 content ∼6 ml O2/100 ml). FBF (ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC) was calculated from FBF and blood pressure (arterial catheter). Vasoconstrictor responsiveness was determined using intra-arterial tyramine. FBF and FVC were substantially lower during hyperoxic exercise than normoxic exercise (∼20–25%; P < 0.01). At rest, vasoconstriction to tyramine (% decrease from pretyramine values) did not differ between normoxia and hyperoxia ( P > 0.05). During exercise, vasoconstrictor responsiveness was slightly greater during hyperoxia than normoxia (−22 ± 3 vs. −17 ± 2%; P < 0.05). However, during α-adrenergic blockade, hyperoxic exercise FBF and FVC remained lower than during normoxia ( P < 0.01). Therefore, our data suggest that although the vasoconstrictor responsiveness during hyperoxic exercise was slightly greater, it likely does not explain the majority of the large reductions in FBF and FVC (∼20–25%) during hyperbaric hyperoxic exercise.

We tested the hypothesis that elevated sympathetic tone is responsible for lower peak vasodilation after single muscle contractions in older adults. Young ( n = 13, 7 men and 6 women, age: 27 ± 1 yr) and older ( n = 13, 7 men and 6 women, age: 69 ± 2 yr) adults performed single forearm contractions at 10%, 20%, and 40% of maximum during 1) control, 2) sympathetic activation via lower body negative pressure (LBNP; −20 mmHg), and 3) intra-arterial infusion of phentolamine (α-adrenergic antagonist). Brachial artery diameter and velocities were measured via Doppler ultrasound, and forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from blood flow (in ml/min) and blood pressure (in mmHg). Peak vasodilator responses [change in (Δ) FVC from baseline] were attenuated in older adults at 20% and 40% of maximum ( P < 0.05). LBNP reduced peak ΔFVC at 10% (98 ± 17 vs. 70 ± 12 ml·min−1·100 mmHg−1), 20% (144 ± 12 vs. 98 ± 3 ml·min−1·100 mmHg−1), and 40% (209 ± 20 vs. 161 ± 21 ml·min−1·100 mmHg−1, P < 0.01 vs. control) in younger adults but not in older adults (71 ± 11 vs. 68 ± 11, 107 ± 13 vs. 106 ± 16, and 161 ± 22 vs. 144 ± 22 ml·min−1·100 mmHg−1, respectively, P = 0.22–0.99). With phentolamine, peak ΔFVC was enhanced in older adults at each contraction intensity (100 ± 14, 147 ± 22, and 200 ± 26 ml·min−1·100 mmHg−1, respectively, P < 0.01 vs. control) but not in younger adults (94 ± 13, 153 ± 13, and 224 ± 27 ml·min−1·100 mmHg−1, respectively, P = 0.30–0.81 vs. control). Our data indicate that α-adrenergic vasoconstriction and/or blunted functional sympatholysis might contribute to the age-related decreases in skeletal muscle contraction-induced rapid vasodilation in humans.

Aging is associated with increased retrograde and oscillatory shear in peripheral conduit arteries of humans. Although the mechanisms responsible for these age-related changes are not completely understood, augmented downstream α-adrenergic tone likely plays a significant role in this phenomenon. Therefore, in protocol 1, brachial artery diameter and blood velocity were measured via Doppler ultrasound during (1) rest (control), (2) endogenous norepinephrine release via intra-arterial infusions of tyramine, and (3) α-adrenergic blockade via infusions of phentolamine in young healthy humans (n=12). Tyramine increased brachial artery retrograde (−4.0±1.4 to −9.5±1.4 s –1 ) and oscillatory shear (0.05±0.02 to 0.18±0.05 arbitrary units), whereas phentolamine abolished retrograde and oscillatory shear ( P <0.05). Additionally, in protocol 2, we examined brachial artery shear patterns in young (n=12; 29±2 years) and older (n=13; 69±2 years) healthy adults during (1) rest (control), (2) sympathetic activation via lower body negative pressure, and (3) infusion of phentolamine. At rest, older adults exhibited greater brachial artery retrograde and oscillatory shear (−9.9±2.7 s –1 and 0.11±0.03 arbitrary units, respectively) compared with younger adults (−3.1±1.0 s –1 and 0.05±0.02 arbitrary units, respectively; P <0.05 for both). Lower body negative pressure increased retrograde and oscillatory shear in young ( P <0.05), but not older adults ( P =0.85–0.97), such that differences between young and older were eliminated ( P >0.05). During infusion of phentolamine, retrograde and oscillatory shear were abolished in young adults ( P <0.05) and markedly reduced, yet still persistent, in older adults ( P <0.01). Our data indicate that α-adrenergic vasoconstriction is a major contributor to age-related discrepancies in conduit artery shear-rate patterns at rest.

The augmentation index and central blood pressure increase with normal aging. Recently, cyclooxygenase (COX) inhibitors, commonly used for the treatment of pain, have been associated with transient increases in the risk of cardiovascular events. We examined the effects of the COX inhibitor indomethacin (Indo) on central arterial hemodynamics and wave reflection characteristics in young and old healthy adults. High-fidelity radial arterial pressure waveforms were measured noninvasively by applanation tonometry before (control) and after Indo treatment in young (25 ± 5 yr, 7 men and 6 women) and old (64 ± 6 yr, 5 men and 6 women) subjects. Aortic systolic (control: 115 ± 3 mmHg vs. Indo: 125 ± 5 mmHg, P < 0.05) and diastolic (control: 74 ± 2 mmHg vs. Indo: 79 ± 3 mmHg, P < 0.05) pressures were elevated after Indo treatment in older subjects, whereas only diastolic pressure was elevated in young subjects (control: 71 ± 2 mmHg vs. Indo: 76 ± 1 mmHg, P < 0.05). Mean arterial pressure increased in both young and old adults after Indo treatment ( P < 0.05). The aortic augmentation index and augmented pressure were elevated after Indo treatment in older subjects (control: 30 ± 5% vs. Indo 36 ± 6% and control 12 ± 1 mmHg vs. Indo: 18 ± 2 mmHg, respectively, P < 0.05), whereas pulse pressure amplification decreased (change: 8 ± 3%, P < 0.05). In addition, older subjects had a 61 ± 11% increase in wasted left ventricular energy after Indo treatment ( P < 0.05). In contrast, young subjects showed no significant changes in any of the variables of interest. Taken together, these results demonstrate that COX inhibition with Indo unfavorably increases central wave reflection and augments aortic pressure in old but not young subjects. Our results suggest that aging individuals have a limited ability to compensate for the acute hemodynamic changes caused by systemic COX inhibition.