Michael D. Herr

Aging and the Exercise Pressor Reflex in Humans

Background—Blood flow limitation to exercising muscles engages the muscle reflex during exercise, evoking an increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Methods and Results—In the current study, we examined forearm flow and autonomic responses to ischemic handgrip in young and older subjects. We studied 6 younger subjects (mean age 23.5±2.2 years) and 7 older subjects (mean age 65.0±2.4 years). Subjects performed rhythmic handgrip (thirty 1-sec contractions/min) at 30% maximal voluntary contraction during six 1-minute stages: freely perfused exercise (E1) and exercise with forearm pressure of +10, +20, +30, +40, and +50 mm Hg (E2 through E6). We measured HR, BP, MSNA, forearm flow velocity, forearm venous oxygen saturation, H+, and lactate. Compared with E1, ischemic exercise (E2 through E6) increased HR, BP, and MSNA, reduced forearm velocity, lowered venous oxygen saturation, and raised venous lactate and H+. Compared with the younger subjects, the older subjects had attenuated BP at E6, attenuated MSNA indices (%&Dgr;bursts, bursts/100 heart beats and signal averaged MSNA), attenuated H+ at E6, a trend toward higher levels of oxygen saturation, and similar forearm velocity and HR responses. Conclusions—Aging attenuates the muscle reflex.

A real-time device for converting Doppler ultrasound audio signals into fluid flow velocity

A Doppler signal converter has been developed to facilitate cardiovascular and exercise physiology research. This device directly converts audio signals from a clinical Doppler ultrasound imaging system into a real-time analog signal that accurately represents blood flow velocity and is easily recorded by any standard data acquisition system. This real-time flow velocity signal, when simultaneously recorded with other physiological signals of interest, permits the observation of transient flow response to experimental interventions in a manner not possible when using standard Doppler imaging devices. This converted flow velocity signal also permits a more robust and less subjective analysis of data in a fraction of the time required by previous analytic methods. This signal converter provides this capability inexpensively and requires no modification of either the imaging or data acquisition system.

Changes of central haemodynamic parameters during mental stress and acute bouts of static and dynamic exercise

Chronic dynamic (aerobic) exercise decreases central arterial stiffness, whereas chronic resistance exercise evokes the opposite effect. Nevertheless, there is little information available on the effects of acute bouts of exercise. Also, there is limited data showing an increase of central arterial stiffness during acute mental stress. This study aimed to determine the effect of acute mental and physical (static and dynamic exercise) stress on indices of central arterial stiffness. Fifteen young healthy volunteers were studied. The following paradigms were performed: (1) 2 min of mental arithmetic, (2) short bouts (20 s) of static handgrip at 20 and 70% of maximal voluntary contraction (MVC), (3) fatiguing handgrip at 40% MVC and (4) incremental dynamic knee extensor exercise. Central aortic waveforms were assessed using SphygmoCor software. As compared to baseline, pulse wave transit time decreased significantly for all four interventions indicating that central arterial stiffness increased. During fatiguing handgrip there was a fall in the ratio of peripheral to central pulse pressure from 1.69±0.02 at baseline to 1.56±0.05 (P<0.05). In the knee extensor protocol a non-significant trend for the opposite effect was noted. The augmentation index increased significantly during the arithmetic, short static and fatiguing handgrip protocols, whereas there was no change in the knee extensor protocol. We conclude that (1) during all types of acute stress tested in this study (including dynamic exercise) estimated central stiffness increased, (2) during static exercise the workload posed on the left ventricle (expressed as change in central pulse pressure) is relatively higher than that posed during dynamic exercise (given the same pulse pressure change in the periphery).

Effect of cold air inhalation and isometric exercise on coronary blood flow and myocardial function in humans

The effects of cold air inhalation and isometric exercise on coronary blood flow are currently unknown, despite the fact that both cold air and acute exertion trigger angina in clinical populations. In this study, we used transthoracic Doppler echocardiography to measure coronary blood flow velocity (CBV; left anterior descending coronary artery) and myocardial function during cold air inhalation and handgrip exercise. Ten young healthy subjects underwent the following protocols: 5 min of inhaling cold air (cold air protocol), 5 min of inhaling thermoneutral air (sham protocol), 2 min of isometric handgrip at 30% of maximal voluntary contraction (grip protocol), and 5 min of isometric handgrip at 30% maximal voluntary contraction while breathing cold air (cold + grip protocol). Heart rate, blood pressure, inspired air temperature, CBV, myocardial function (tissue Doppler imaging), O(2) saturation, and pulmonary function were measured. The rate-pressure product (RPP) was used as an index of myocardial O(2) demand, whereas CBV was used as an index of myocardial O(2) supply. Compared with the sham protocol, the cold air protocol caused a significantly higher RPP, but there was a significant reduction in CBV. The cold + grip protocol caused a significantly greater increase in RPP compared with the grip protocol (P = 0.045), but the increase in CBV was significantly less (P = 0.039). However, myocardial function was not impaired during the cold + grip protocol relative to the grip protocol alone. Collectively, these data indicate that there is a supply-demand mismatch in the coronary vascular bed when cold ambient air is breathed during acute exertion but myocardial function is preserved, suggesting an adequate redistribution of blood flow.

Control of Skin Sympathetic Nerve Activity During Intermittent Static Handgrip Exercise

Background—Exercise activates the sympathetic nervous system as a function of the type and intensity of exercise and of the target organ studied. Although central command and activity of metabolically sensitive afferents from exercising muscle are the principal determinants of sympathetic outflow directed to skeletal muscle, the mechanisms that govern sympathetic outflow directed to skin are less clear. Methods and Results—We measured skin sympathetic nerve activity (SSNA) during intermittent static handgrip (SHG; at 45% of maximal voluntary contraction; four 5-second contractions per minute for 3 minutes), during unrestricted forearm perfusion (control), during stimulation of forearm mechanoreceptors with venous congestion, and during ischemia produced by forearm circulatory arrest. Under all 3 conditions, SSNA increased within 1 to 2 seconds of the onset of handgrip. During ischemia but not during venous congestion, SSNA increased more compared with control (P <0.05) and remained elevated when forearm ischemia was maintained after handgrip exercise (posthandgrip circulatory arrest). In addition, simulated handgrip and intermittent forearm compression produced by a pneumatic cuff also evoked brief increases of SSNA. Conclusions—In addition to central neural factors, afferent input from exercising muscle plays an important role in modulating sympathetic outflow directed to skin.

Vasoconstrictor responses in the upper and lower limbs to increases in transmural pressure

The purpose of this study was to examine upper and lower limb vasoconstrictor responses to changes in transmural pressure in humans. Brachial and femoral blood mean blood velocity (MBV) and vessel diameter (Doppler ultrasound) were measured in 20 supine healthy subjects (10 men and 10 women; 27 +/- 1 yr; mean +/- SE) during four levels of limb suction at -25, -50, -75, and -100 mmHg, respectively. Limb suction led to an initial rise in MBV followed by a rapid fall in flow velocity to a level below MBV baseline, indicating a vasoconstriction effect. Femoral compared with brachial vessels exhibited a greater fall in flow velocity at all levels of suction (-89 +/- 17 vs. -10 +/- 2, -142 +/- 11 vs. -14 +/- 2, -156 +/- 22 vs. -13 +/- 2, and -162 +/- 29 vs. -12 +/- 2 ml/min for -25, -50, -75, and -100 mmHg, respectively; interaction effect, P < 0.05). Even at low tank suction levels (i.e., -10 and -20 mmHg), significant brachial flow velocity vasoconstriction from baseline values was demonstrated, reflecting downstream resistance vessel changes (n = 14). Brachial and femoral diameters did not change during changes in negative tank pressure. During suction, changes in limb volumes were significantly greater in the forearm (1.4 +/- 0.5%, 2.4 +/- 0.8%, 3.5 +/- 1.0%, and 4.3 +/- 1.1%) compared with the calf (0.9 +/- 0.5%, 1.4 +/- 0.7%, 2.0 +/- 0.8%, and 2.8 +/- 1.1%) at all levels of negative tank pressures (-25, -50, -75, and -100 mmHg, respectively). Simultaneous measurements of both upper limbs and both lower limbs suggested that the majority of the reduction in flow was due to myogenic influences except when -100 mmHg of suction was applied to the lower limb. The greater vasoconstriction responses in the leg compared with the arm with suction appear to be influenced by both myogenic and sympathetic mechanisms.

Sex differences in limb vasoconstriction responses to increases in transmural pressures

Women compared with men are more likely to have orthostatic intolerance. The purpose of this study was to examine whether sex affects limb vasoconstrictor response to increases in transmural pressure. Brachial and femoral mean blood velocity (MBV) and diameter (Doppler Ultrasound) were measured in 10 women and 10 men as transmural pressure was altered by applying local suction (-25, -50, -75, and -100 mmHg) via pressurized-limb tanks for 1 min to a single arm and leg. With the abrupt application of forearm suction (-75 and -100 mmHg), women compared with men had a greater initial rise in MBV (peak), followed by a quicker dynamic rate of velocity reduction. In the leg, women had a tendency for higher peak MBV but had similar dynamic velocity reductions compared with men. After 60 s of suction, women compared with men had attenuated reductions in brachial flow and conductance (-8.05 +/- 1.71 vs. -16.25 +/- 1.71 ml/min; -0.12 +/- 0.03 vs. -0.20 +/- 0.03 ml x min(-1) x mmHg(-1); main effect, P < 0.05), as well as attenuated femoral flow and conductance to sustained leg negative pressure at -100 mmHg (P < 0.05). When the data were expressed as percent change, women compared with men continued to have attenuated brachial flow responses (-24 +/- 2 vs. -36 +/- 2%, main effect, P < 0.05), with a trend toward attenuation at the highest leg pressure (-25 +/- 11 vs. -46 +/- 4%; P = 0.08). These sex differences remained after normalizing the flow responses by limb volume (percent change). Our findings suggest that young women compared with men have attenuated brachial and femoral vasoconstrictor responses to increases in transmural pressure, which may have implications for the greater incidence of orthostatic intolerance in women.

Muscle oxygenation during dynamic plantar flexion exercise: combining BOLD MRI with traditional physiological measurements

Blood‐oxygen‐level‐dependent magnetic resonance imaging (BOLD MRI) has the potential to quantify skeletal muscle oxygenation with high temporal and high spatial resolution. The purpose of this study was to characterize skeletal muscle BOLD responses during steady‐state plantar flexion exercise (i.e., during the brief rest periods between muscle contraction). We used three different imaging modalities (ultrasound of the popliteal artery, BOLD MRI, and near‐infrared spectroscopy [NIRS]) and two different exercise intensities (2 and 6 kg). Six healthy men underwent three separate protocols of dynamic plantar flexion exercise on separate days and acute physiological responses were measured. Ultrasound studies showed the percent change in popliteal velocity from baseline to the end of exercise was 151 ± 24% during 2 kg and 589 ± 145% during 6 kg. MRI studies showed an abrupt decrease in BOLD signal intensity at the onset of 2 kg exercise, indicating deoxygenation. The BOLD signal was further reduced during 6 kg exercise (compared to 2 kg) at 1 min (−4.3 ± 0.7 vs. −1.2 ± 0.4%, P < 0.001). Similarly, the change in the NIRS muscle oxygen saturation in the medial gastrocnemius was −11 ± 4% at 2 kg and −38 ± 11% with 6 kg (P = 0.041). In conclusion, we demonstrate that BOLD signal intensity decreases during plantar flexion and this effect is augmented at higher exercise workloads.

Distension of central great vein decreases sympathetic outflow in humans

Classic canine studies suggest that central great vein distension evokes an autonomic reflex tachycardia (Bainbridge reflex). It is unclear whether central venous distension in humans is a necessary and sufficient stimulus to evoke a reflex increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Prior work from our laboratory suggests that limb venous distension evokes a reflex increase in BP and MSNA in humans. We hypothesized that in humans, compared with the limb venous distension, inferior vena cava (IVC) distension would evoke a less prominent increase in HR and MSNA. IVC distension (monitored with ultrasonography) was induced by two methods: 1) head-down tilt (HDT, N = 13); and 2) lower-body positive pressure (LBPP, N = 10). Two minutes of HDT induced IVC distension (Δ2.6 ± 0.2 mm, P < 0.001, ~27% in cross-sectional area), slightly increased mean BP (Δ2.3 ± 0.7 mmHg, P = 0.005), decreased MSNA (Δ5.2 ± 0.8 bursts/min, P < 0.001, N = 10), and did not alter HR (P = 0.37). LBPP induced similar IVC distension, increased BP (Δ2.0 ± 0.7 mmHg, P < 0.01), and did not alter HR (P = 0.34). Thus central venous distension leads to a rapid increase in BP and a subsequent fall in MSNA. Central venous distension does not evoke either bradycardia or tachycardia in humans. The absence of a baroreflex-mediated bradycardia suggests that the Bainbridge reflex is engaged. Clearly, this reflex differs from the powerful sympathoexcitation peripheral venous distension reflex described in humans.

Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans

Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole + L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial Po2 ~37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole + L-NMMA reduced (P < 0.05) forearm vascular conductance (FVC) by ~10% and ~18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 ± 0.37 and 0.95 ± 0.35 units in control and experimental forearms, respectively (P < 0.05). During hypoxia and fluconazole + L-NMMA (trial 2), FVC increased by 2.32 ± 0.51 and 0.72 ± 0.22 units in control and experimental forearms, respectively (P < 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n = 8) FVC increased by 1.51 ± 0.46 and 0.45 ± 0.32 units in control and experimental forearms, respectively (P < 0.05). These effects were not due to altered skin blood flow. We conclude that endothelium-derived hyperpolarizing factor contributes to basal vascular tone and to hypoxia-induced skeletal muscle vasodilation and could be particularly relevant when other vasodilator systems are impaired.