Walker, Branton G.

We tested the hypothesis that local inhibition of NOS would 1) alter the kinetics of vasodilation during dynamic forearm (FA) exercise and 2) prolong the time to reach steady state (SS). Subjects (n=22) performed rhythmic FA exercise (20% of maximum) during saline infusion (control) and NOS inhibition (L‐NMMA). Additionally, a subset of subjects performed a third trial of FA exercise during combined inhibition of either 1) NOS and adenosine (aminophylline; n=9), or 2) NOS and prostaglandins (Ketorolac; n=8). Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from blood flow (ml/min) and blood pressure (mmHg). Vasodilator kinetics were assessed by calculating the slope of the FVC response for every duty cycle between baseline and SS exercise as well as the number of duty cycles (1s contraction/2s relaxation) to reach SS. NOS inhibition reduced the kinetics of vasodilation during dynamic FA exercise (8.5 ± 0.6 vs. 11.1 ± 0.8 FVC/duty cycle; P < 0.001 vs. control) and increased the time to reach SS (25.1 ± 1 vs. 32 ± 1 duty cycles; P < 0.001 vs. control). The kinetics of vasodilation were reduced further with combined inhibition of NOS and adenosine (6.2 ± 0.8 vs. 7.5 ± 0.6 FVC/duty cycle; P < 0.05 vs. L‐NMMA alone), but not with combined inhibition of NOS and prostaglandins. Our data indicate that NOS inhibition blunts the kinetics of vasodilation during dynamic FA exercise and prolongs the time to reach SS.

We tested the hypothesis that elevated sympathetic tone is responsible for lower peak vasoldilation following single muscle contractions in older adults. Younger (n=8; 5M/3F, age 27 ± 2) and older (n=10; 5M/5F, age 69 ± 2) adults performed single forearm contractions at 10, 20 and 40% of maximum during 1) control, 2) sympathetic activation via lower body negative pressure (LBNP; ‐ 20mmHg), 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) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak vasodilator responses (ΔFVC from baseline) were attenuated in older adults for all intensities ( P < 0.05). LBNP reduced the ΔFVC at 10% (95 ± 18 vs. 60 ± 11), 20% (128 ± 9 vs. 91 ± 18) and 40% (192 ± 21 vs. 133 ± 23; P < 0.01 vs. control) in younger subjects, but not older adults (61 ± 6 vs. 58 ± 10; 99 ± 10 vs. 101 ± 17; 141 ± 17 vs. 129 ± 19, respectively; P = 0.53–0.97). With phentolamine ΔFVC was enhanced in older adults at each contraction intensity (91 ± 12, 136 ± 22, and 181 ± 22, respectively; P < 0.01 vs. control), but not younger adults (87 ± 9, 145 ± 12, and 192 ± 24, respectively; P = 0.31–1.0 vs. control). Our data indicate that overlying α‐adrenergic vasoconstriction plays a significant role in the age‐related decreases in skeletal muscle contraction‐induced rapid vasodilation.

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=8; 25 ± 2 yr) and older (n=9; 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 L‐NMMA. Brachial artery diameter and velocities were measured using Doppler ultrasound and forearm vascular conductance (FVC) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak and total vasodilator responses (ΔFVC from baseline) were attenuated in older adults at all intensities (P < 0.05). NOS inhibition reduced the peak ΔFVC at 10% (95 ± 13 vs. 59 ± 10), 20% (134 ± 11 vs. 90 ± 12) and 40% (222 ± 30 vs. 143 ± 24) in young subjects (P < 0.05 for all) and in older adults at 10% (61 ± 5 vs. 48 ± 7, P < 0.05) and 20% (90 ± 8 vs. 70 ± 8, P < 0.05), but not 40% (129 ± 13 vs. 105 ± 11, P = 0.12). The relative (%) reduction in peak ΔFVC due to NOS inhibition was greater in young vs. older adults at 20% (−36 ± 5 vs. −22 ± 5%, P < 0.05) and 40% (−35 ± 7 vs. −17 ± 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 20 and 40%. Our data suggest that contraction‐induced rapid vasodilation is mediated in part by NO; however, it appears the NO contribution in the response is greater in young adults.

We examined the reproducibility of the hyperemic response to ischemic exercise (IE) in the forearm and compared the magnitude of this response to ischemia alone (reactive hyperemia, RH). Eight subjects (6M/2F; 26 ±1 yrs) performed 3 trials of IE and 2 of RH. IE consisted of 5 min of forearm ischemia with rhythmic forearm exercise (20% of max) during the final 2 min. RH consisted of 5 min of forearm ischemia. Peak and total (area under the curve) forearm blood flow (FBF; venous occlusion plethysmography) and blood pressure (MAP; Finometer) were measured for 3 min after each stimulus. Forearm vascular conductance (FVC; ml/100ml/min/mmHg) was calculated from FBF (ml/100ml/min) and MAP (mmHg). The mean intra‐individual coefficient of variation (CV) across the 3 IE trials was 13.0±1.4% and 16.3±1.2% for baseline‐adjusted peak FBF and FVC, respectively. The CVs for total FBF and FVC were 10.4±1.0% and 14.9±1.0%, respectively. Mean peak FBF was greater for IE compared to RH (37.3±2.7 and 30.0±1.3, P < 0.002), however mean peak FVC was not different (35.1±2.6 and 34.5±1.1, P = 0.80). Mean total FBF (67.6±3.9 and 18.0±2.5, P < 0.001) and mean total FVC (64.7±2.7 and 20.8±3.2, P < 0.001) were greater for IE compared to RH, respectively. Thus, our data suggest that the hyperemic response to IE is reproducible, and that the magnitude of this response is greater than that of ischemia alone. NIH HL‐46493 (MJJ), CTSA RR‐024150 and RR‐024152

Nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to hypoperfusion during exercise. We tested the potential for adenosine/NO interaction in the compensatory dilation. Eight males (25 ± 2 yrs) performed forearm exercise (20% of max) during intra‐arterial balloon inflation. Each trial included; exercise, exercise with balloon inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and brachial artery catheter pressure (BAP) were measured. Exercise was repeated during NO synthase inhibition (L‐NMMA) alone and with the combination of L‐NMMA/aminophylline (adenosine receptor blockade). Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from BF (ml/min) and BAP (mmHg). The % recovery in FVC during inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir]. FVC fell acutely with balloon inflation during all trials (P < 0.01). During the control trial, the % recovery in FVC was 111 ± 8%. The % recovery in FVC was attenuated with NOS inhibition alone (80 ± 9%; P < 0.001 vs. control) and attenuated further with combined inhibition of NO/adenosine (63 ± 9%; P < 0.05 vs. L‐NMMA). Thus, adenosine has an NO independent role in the compensatory vasodilatation during exercise with acute hypoperfusion. NIH HL46493 (MJJ), AR55819 (DPC) and RR‐024150.

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.

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.