Casey, Darren P.

Aortic wave reflection increases with age, and is influenced by numerous factors, including sympathetic nerve activity. The purpose of this study was to examine the effect of autonomic blockade using trimethaphan camsylate on indices of aortic wave reflection in young (23±4 yr) and older postmenopausal (57±3 yr) women and determine if aging alters these interactions. Arterial tonometry was used to non‐invasively measure arterial waveforms from the radial artery before and during trimethaphan infusion. Aortic augmentation index (AI x ), augmented pressure, and left ventricular wasted energy (E w ) were higher in older women compared to young women at baseline (p<0.05). Mean arterial pressure was similar between young (93±5 mmHg) and older women (91±2 mmHg) at baseline. AI x (Δ −12±5%), augmented pressure (Δ −11±4 mmHg), and E w (Δ −2364±1020 dyne·cm 2 ·sec) decreased after autonomic blockade in older women (p<0.05 for all). In addition, the age‐related differences in AI x and aortic wave reflection persisted during autonomic blockade (p<0.05). In conclusion, autonomic blockade reduces augmentation index and aortic wave reflection in older women. Our results suggest that sympathetic activity contributes to the higher aortic wave reflection observed in older women.

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.

β‐adrenergic receptor activation causes a substantial portion of hypoxic vasodilation at rest and during forearm exercise. Recent evidence suggests that β‐receptors are either more sensitive or upregulated in young women vs. men. Therefore, we examined whether sex influences hypoxic vasodilation in 31 subjects (15F/16M; 26± 1 yr). We also examined whether potential sex related differences existed in a group of older adults (6F/5M; 61± 2 yr). All subjects performed forearm exercise at 10% and 20% of maximum under normoxic and hypoxic (80% arterial O2 saturation) conditions. Forearm vascular conductance (FVC; ml/min/100 mmHg) was calculated from blood flow (ml/min) and blood pressure (mmHg). At rest young females demonstrated a greater vasodilator response to hypoxia compared to men (39 ± 12% vs. 13 ± 6%, P < 0.05). The compensatory vasodilator response to hypoxia exercise (% change in ΔFVC compared to respective normoxic exercise trial) was also greater in young womenat 10% (46 ± 8% vs. 29 ± 5%, P < 0.05) and 20% exercise (38 ± 6% vs. 23 ± 4%, P < 0.05). Interestingly the compensatory vasodilator responses between older women and men were similar at 10% (28 ± 6% vs. 28 ± 10%, P = 0.99) and 20% exercise (13 ± 6% vs. 15 ± 7%, P = 0.84), respectively. Our data suggest that the compensatory vasodilator response to hypoxic exercise is greater in young women compared to 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=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.

Elevated central hemodynamics and arterial stiffness are associated with increased peripheral resistance and higher sympathetic nervous system activity. Additionally, consumption of a meal is known to be sympathoexcitatory. However, the acute effects of a meal on aortic wave reflection and stiffness are unknown. Therefore, we tested the hypothesis that aortic wave reflection and stiffness would increase following a meal. We examined these effects using high‐fidelity radial arterial pressure waveforms and carotid‐femoral pulse wave velocity (PWV), measured non‐invasively via applanation tonometry, before and 60 and 180 min after ingestion of a liquid mixed meal (Ensure, 40% of daily energy expenditure) in 15 healthy adults (25 ± 2 y; 8M/7F). Both peripheral and central pressures were reduced 180 min from baseline. Yet contrary to our hypothesis, augmentation index (15 ± 4 vs. 2 ± 3 vs. 8 ± 3%), augmentation index normalized for heart rate (9 ± 4 vs. −2 ± 3 vs. 3 ± 3%), augmented pressure (6 ± 2 vs. 1 ± 1 vs. 3 ± 1 mmHg) as well as carotid‐femoral PWV (7.3 ± 0.2 vs. 6.7 ± 0.2 vs. 6.7 ± 0.1 m/s) were substantially reduced at 60 and 180 min following the meal (P < 0.05 for all). Taken together, our results suggest that a liquid mixed meal acutely decreases central hemodynamics and arterial stiffness in healthy adults. NIH K23 DK82424 (TC) P30 DK50456 (MNOC) UL1 RR024150 (MCCTSA) HL105467 (DPC)

Hyperoxia can cause substantial reductions in peripheral and coronary blood flow at rest and during exercise. We tested the hypothesis that hyperoxia may increase the time for forearm blood flow (FBF) to reach steady state (SS) levels during exercise. Young (n=11; 28±2yr) healthy adults performed rhythmic forearm contractions at 10% of their maximum voluntary contraction for 5 minutes. Each duty cycle consisted of 1 second contraction and 2 second relaxation. Brachial artery diameters and velocities were measured using Doppler Ultrasound and forearm blood flow (ml/min) was calculated from the mean velocity and diameter. The dynamics of FBF at the onset of exercise were assessed by calculating the slope of the FBF response for every duty cycle between baseline and steady state, and the number of duty cycles to reach steady state. The slope of the line plotted from baseline FBF to SS, had a significantly attenuated slope under hyperoxia (5.4±1.1 ml/min/cycle) as compared to normoxia (10.6±2.6 ml/min/cycle). In addition, the number of duty cycles performed under hyperoxia (33±4 cycles) was significantly higher as compared to normoxia (25±4 cycles) (P<0.02). Our data suggest that hyperoxia attenuates the contraction‐induced FBF from baseline to SS as compared to normoxia.

We tested the hypothesis that aging would be associated with slowed vasodilator kinetics in contracting muscle in part due to a reduced nitric oxide (NO) bioavailability. Young (n=10; 24 ± 2 yr) and older (n=10; 67 ± 2 yr) adults performed rhythmic forearm exercise (4 min each) at 10, 20 and 30% of max during saline infusion (control) and NO synthase (NOS) inhibition. Brachial artery diameter and velocities were measured using Doppler ultrasound. Forearm vascular conductance (FVC) was calculated for each duty cycle (1s contraction/2s relaxation) from blood flow (ml/min) and blood pressure (mmHg) and fit with a monoexponential model. The main parameters derived from the model were the amplitude (Amp) of the FVC response and the number of duty cycles for FVC to change 63% of the steady‐state amplitude (τFVC). Under control conditions 1) the Amp of the response at 20 and 30% MVC was lower in older (240 ± 24 and 319 ± 33 ml/min/100mmHg) compared to young adults (338 ± 45 and 462 ± 52 ml/min/100mmHg; P < 0.05) and 2) τFVC was slower in older (10 ± 1, 13 ± 1 and 15 ± 1 duty cycles) compared to young (6 ± 1, 9 ± 1 and 11 ± 1 duty cycles) adults at all intensities ( P < 0.05). NOS inhibition blunted the Amp and slowed the τFVC in young, at all intensities (10 ± 2, 12 ± 1 and 16 ± 2 duty cycles; P < 0.05), whereas it did not change in older adults. Our data indicate that the vasodilator kinetics in exercising muscle are altered with aging likely due to blunted NO signaling. Grant Funding Source : Supported by NIH grants HL105467 (DPC), HL46493 (MJJ) and by CTSA UL1 TR000135

We examined the relationship between total peripheral resistance (TPR) and central artery pressure and indices of wave reflection in 16 subjects (10F/6M; 26 ± 1 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms obtained from applanation tonometry of the radial artery. Radial blood pressure (BP) was calibrated from brachial artery BP (catheter). Central artery pressures, aortic augmentation index (AI a ), roundtrip travel time of the reflected wave to and from the periphery (Δt p ; inverse of pulse wave velocity), and wasted left ventricular energy (E w ) were calculated from the generated aortic pressure waveform. Cardiac output (CO) was measured using an open‐circuit acetylene uptake technique and used to calculate total peripheral resistance (mean arterial pressure/CO). TPR was positively related to aortic pulse pressure (r = 0.49), augmented pressure of the central artery wave (r = 0.60), pulse pressure amplification (r =0.54), AI a (r = 0.53), and E w (r = 0.66), (P < 0.05 for all). Additionally, TPR was inversely related to Δt p (r = − 0.51, P < 0.05). Our data suggests that increased levels of TPR are related to measures of central artery pressure, wave reflection characteristics and indices of central artery stiffness. Supported by NIH K23 DK‐082424 (TBC), AHA 2170087(ECH) and CTSA RR‐024150

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.