Casey, Darren P.

We examined the effects of acute β‐adrenergic blockade on central artery hemodynamics and wave reflection characteristics in young healthy humans. High‐fidelity radial artery waveforms were recorded non‐invasively by applanation tonometry before and after intravenous propranolol (0.25 mg/kg bolus for 5 min followed by a maintenance infusion of 0.004/mg/kg/min for 20–30 min) in fourteen subjects (9 F/5M; 27 ± 2 years). Radial blood pressure (BP) was calibrated from the brachial BP (arterial catheter). Aortic augmentation index (AI a ; a measure of amplitude and timing of arterial pressure wave reflection) and roundtrip travel time of the reflected wave to and from the periphery (Δt p ; inverse of pulse wave velocity) were calculated from the generated aortic pressure waveform and are indices of central arterial stiffness. Systemic β‐blockade reduced heart rate (HR; 60 ± 2 vs. 53 ± 2 bpm, P < 0.001) and increased AI a (9.9 ± 4.3% vs. 4.3 ± 4.4%, P < 0.05), but did not alter Δt p (156 ± 4 msec vs. 152 ± 2 msec, P = 0.34). The AI a normalized to a HR of 75bpm (AI a @75) was not increased following β‐blockade (P = 0.67). Taken together, our data indicate that the increase in AI a following systemic β‐blockade is a result of a slower HR and not due to changes in β‐ mediated vascular tone. Supported by NIH K23 DK‐082424 (TBC), AHA 2170087(ECH) and CTSA RR‐024150

We examined the relationship between flow restoration and vascular resistance in the exercising forearm during hypoperfusion caused by balloon inflation in the brachial artery. 75 trials (with and without nitric oxide synthase (NOS) inhibition) were analyzed. Each included forearm exercise (10% or 20% of max), exercise with inflation, and exercise after deflation (3 min each). FBF (ultrasound), local (brachial artery; BAP), and systemic arterial pressure (SAP) were measured. FBF restoration during balloon inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir] and expressed as % recovery of FBF. Balloon resistance [(SAP‐BAP)/flow] and vascular resistance (BAP/flow) were expressed as the % change from onset of inflation to end inflation. The % recovery of FBF was strongly related to the drop in vascular resistance for all trials (r = 0.664, P <0.001). This relationship was unaffected by NOS inhibition (n= 27; r = 0.623, P < 0.001 vs. control n = 48; r = 0.685, P < 0.001). The relationship was also stronger with increasing exercise intensity (r = 0.57 vs. 0.704). The % recovery of FBF was unrelated to changes in balloon resistance under any condition. Thus, flow restoration is determined primarily by the fall in local vascular resistance during forearm exercise with hypoperfusion. Supported by NIH HL‐46493 (MJJ), AR‐55819 (DPC) and RR‐024150.

While rapid-onset vasodilation (ROV) has been shown to decrease in older individuals, it is unclear if sex contributes to the decline with aging. We sought to identify if sex-related differences exist in the ROV response to single forearm contractions in young and older adults. Our data suggest sex-related differences are present among older but not young individuals, with women having an attenuated response. These data indicate sex plays a role in decreased vasodilation with aging.

Rapid‐onset vasodilation (ROV) in response to a single muscle contraction is attenuated with aging. Moreover, sex‐related differences in muscle blood flow and vasodilation during dynamic exercise have been observed in young and older adults. The purpose of the present study was to explore if sex‐related differences in ROV exist in young (n=36; 21 male/15 female; 25 ± 1 yr) and older (n=32; 19 male/13 female; 66 ± 1 yr) adults. Subjects performed single forearm contractions at relative intensities of 10%, 20%, and 40% maximal voluntary contraction (MVC). Brachial artery blood velocity and diameter were measured with Doppler ultrasound, and forearm vascular conductance (FVC; ml·min −1 ·100 mmHg −1 ) was calculated from blood flow (ml·min −1 ) and blood pressure (mmHg) and used as a measure of peak ROV (peak change in FVC from baseline). Due to significant differences in MVC and consequent differences in weight used for each relative intensity between males and females, the data were analyzed two additional ways. First, responses were normalized for workload (i.e. peak FVC per kg of weight lifted). Second, the peak ROV responses in a subset of subjects (n=44; 12 young male, 10 young female, 11 older male, 11 older female) with similar absolute workloads (10–12kg) were compared. Lastly, the magnitude of change in peak ROV with increasing intensity (calculated as the slope of a linear regression line between 10, 20, and 40% MVC) was calculated and compared between groups. Peak ROV was attenuated in females across all relative intensities in the young and older groups (P < 0.05). When normalized for workload, peak ROV was attenuated with age in both males and females at all intensities (P<0.05) except at 10% for females (P=0.47). However, sex‐related differences were not observed within age when normalized by workload at any intensity (P>0.05). In the subset of subjects with a similar absolute workload (~11kg), age‐related differences in ROV remained in both the female and male groups (P<0.05). Older females demonstrated an attenuated peak ROV compared to their older male counterparts (91 ± 6 vs. 121 ± 11 ml·min −1 ·100 mmHg −1 , P<0.03), whereas no sex differences in peak ROV were observed between young females and males (134 ± 8 vs. 154 ± 11 ml·min −1 ·100 mmHg −1 , P=0.15). Examining the slope of the peak ROV response across contraction intensities revealed a main effect of age (P<0.05), with the slope being blunted in older compared to young subjects. When separated by sex, the slope was smaller in older compared to young females (5.5 ± 0.7 vs. 8.9 ± 0.9 FVC units/intensity, P<0.05) but not between older and young males (7.0 ± 0.50 vs. 8.2 ± 1.0 FVC units/intensity, P=0.38). Our data suggest that sex‐related differences in the rapid vasodilatory response to single muscle contractions exist in older but not young adults, such that older females have a blunted response compared to older males.

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-doppler-ultrasound-and-resistance-vessel-function/ .

New Findings What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high‐dose intra‐arterial infusion of either adenosine or ATP, on the rapid‐onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism. AbstractThe hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid‐onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high‐dose intra‐arterial infusion of either adenosine (ADO) or ATP. Twenty‐four healthy young participants (28 ± 1 years) performed a single forearm contraction (20% maximal voluntary contraction) 75 min after commencement of a continuous infusion of ADO (n = 6), ATP (n = 8) or saline (control; n = 10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100 mmHg per decilitre of forearm volume) was significantly higher during ADO (33 ± 17) and ATP infusion (33 ± 17) compared with the control infusion (8 ± 3; P < 0.05). The peak FVCs post‐contraction during ADO and ATP infusions were significantly greater than during the control infusion (P < 0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14 ± 1; ADO, 24 ± 2; and ATP, 23 ± 6; P = 0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333 ± 69 and 440 ± 125); however, total FVC during ATP infusion was significantly greater compared with the control value (150 ± 19; P < 0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism.

Aging is associated with increased peripheral chemoreceptor activity, reduced nitric oxide (NO) bioavailability, and attenuation of cardiovagal baroreflex sensitivity (BRS), collectively increasing the risk of cardiovascular disease. Evidence suggests that NO may attenuate peripheral chemoreflex sensitivity and increase BRS. Exogenous inorganic nitrate ([Formula: see text]) increases NO bioavailability via the [Formula: see text]-[Formula: see text]-NO pathway. Our hypothesis was that inorganic [Formula: see text] supplementation would attenuate peripheral chemoreflex sensitivity and enhance spontaneous cardiovagal BRS in older adults. We used a randomized, placebo-controlled crossover design in which 13 older (67 ± 3 yr old) adults ingested beetroot powder containing (BRA) or devoid of (BRP) [Formula: see text] and [Formula: see text] daily over 4 wk. Spontaneous cardiovagal BRS was assessed over 15 min of rest and was quantified using the sequence method. Chemoreflex sensitivity was assessed via ~5 min of hypoxia (10% fraction of inspired O2) and reported as the slope of the relationship between O2 saturation (%[Formula: see text]) and minute ventilation (in l/min) or heart rate (in beats/min). Ventilatory responsiveness to hypoxia was reduced after BRA (from −0.14 ± 0.04 to −0.05 ± 0.02 l·min−1·%[Formula: see text]−1, P = 0.01) versus BRP (from −0.10 ± 0.05 to −0.11 ± 0.05 l·min−1·%[Formula: see text]−1, P = 0.80), with no differences in heart rate responsiveness (BRA: from −0.47 ± 0.06 to −0.33 ± 0.04 beats·min−1·%[Formula: see text]−1, BRP: from −0.48 ± 0.07 to −0.42 ± 0.06 beats·min−1·%[Formula: see text]−1) between conditions (interaction effect, P = 0.41). Spontaneous cardiovagal BRS was unchanged after BRA and BRP (interaction effects, P = 0.69, 0.94, and 0.39 for all, up, and down sequences, respectively), despite a reduction in resting systolic and mean arterial blood pressure in the experimental (BRA) group ( P < 0.01 for both). These findings illustrate that inorganic [Formula: see text] supplementation attenuates peripheral chemoreflex sensitivity without concomitant change in spontaneous cardiovagal BRS in older adults. NEW & NOTEWORTHY Exogenous inorganic nitrate supplementation attenuates ventilatory, but not heart rate, responsiveness to abbreviated hypoxic exposure in older adults. Additionally, inorganic nitrate reduces systolic and mean arterial blood pressure without affecting spontaneous cardiovagal baroreflex sensitivity. These findings suggest that inorganic nitrate may attenuate sympathetically oriented pathologies associated with aging.

Central (aortic) blood pressure, arterial stiffness, and sympathetic nerve activity increase with age in women. However, it is unknown if the age-related increase in sympathetic activity influences aortic hemodynamics and carotid-femoral pulse wave velocity (cfPWV), an index of central aortic stiffness. The goal of this study was to determine if aortic hemodynamics and cfPWV are directly influenced by sympathetic nerve activity by measuring aortic hemodynamics, cfPWV, and muscle sympathetic nerve activity (MSNA) in women before and during autonomic ganglionic blockade with trimethaphan camsylate. We studied 12 young premenopausal (23 ± 4 yr) and 12 older postmenopausal (57 ± 3 yr) women. These women did not differ in body mass index or mean arterial pressure ( P > 0.05 for both). At baseline, postmenopausal women had higher aortic pulse pressure, augmented pressure, augmentation index adjusted for a heart rate of 75 beats/min, wasted left ventricular pressure energy, and cfPWV than young women ( P < 0.05). During ganglionic blockade, postmenopausal women had a greater decrease in these variables in comparison to young women ( P < 0.05). Additionally, baseline MSNA was negatively correlated with the reductions in aortic pulse pressure, augmented pressure, and wasted left ventricular pressure energy during ganglionic blockade in postmenopausal women ( P < 0.05) but not young women. Baseline MSNA was not correlated with the changes in augmentation index adjusted for a heart rate of 75 beats/min or cfPWV in either group ( P > 0.05 for all). Our results suggest that some aortic hemodynamic parameters are influenced by sympathetic activity to a greater extent in older postmenopausal women than in young premenopausal women.NEW & NOTEWORTHY Autonomic ganglionic blockade results in significant decreases in multiple aortic pulse wave characteristics (e.g., augmented pressure) and central pulse wave velocity in older postmenopausal women but not in young premenopausal women. Certain aortic pulse wave parameters are negatively influenced by sympathetic activity to a greater extent in older postmenopausal women.

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 (1 s contraction/2 s relaxation) from forearm blood flow (FBF; ml/min) and blood pressure (mmHg) and fit with a monoexponential model. The main parameters derived from the model were the amplitude of the FBF and FVC response and the number of duty cycles for FBF and FVC to change 63% of the steady-state amplitude (τFBF and τFVC). Under control conditions 1) the amplitude of the FVC response at 30% maximal voluntary contraction (MVC) was lower in older compared with young adults (319 ± 33 vs. 462 ± 52 ml·min−1·100 mmHg−1; P < 0.05) and 2) τFVC was slower in older (10 ± 1, 13 ± 1, and 15 ± 1 duty cycles) compared with young (6 ± 1, 9 ± 1, and 11 ± 1 duty cycles) adults at all intensities ( P < 0.05). In young adults, NOS inhibition blunted the amplitude of the FVC response at 30% MVC and prolonged the τFVC 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 blood flow and vasodilator kinetics in exercising muscle are altered with aging possibly due to blunted NO signaling.

This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans.