Joyner, Michael J.

The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P <0.05). Muscle sympathetic nerve activity bursts were abolished by trimethaphan within minutes. Older women had a greater decrease in mean arterial pressure (−29±2 versus −9±2 mm Hg; P <0.01) and total peripheral resistance (−10±1 versus −5±1 mm Hg/L per minute; P <0.01) during trimethaphan. Baseline muscle sympathetic nerve activity was associated with the decrease in mean arterial pressure during trimethaphan ( r =−0.74; P <0.05). In summary, our results suggest that autonomic support of blood pressure is greater in older women compared with young women and that elevated sympathetic nerve activity in older women contributes importantly to the increased incidence of hypertension after menopause.

New FindingsWhat is the central question of this study?Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients.What is the main finding and its importance?Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients.Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo‐controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant‐work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor‐sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide () and a decrease in oxygen (;P< 0.05 for both) at rest. The control subjects demonstrated no change in,, ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6versus44 ± 3 l min−1,P< 0.05) due to a lower respiratory rate (30 ± 1versus26 ± 2 breaths min−1,P< 0.05). The reduced ventilation resulted in lower(97.6 ± 2.5versus79.5 ± 3.0 mmHg,P< 0.05) and increased(37.3 ± 0.9versus43.5 ± 1.1 mmHg,P< 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide;P< 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients.

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.

Recently, several high-impact reviews suggest that regular aerobic exercise is beneficial for maintaining cognitive function in aging adults. Higher cerebral blood flow and/or cerebrovascular reactivity may explain the favorable effect of exercise on cognition. In addition, prostaglandin-mediated vasodilator responses may be influenced by regular exercise. Therefore, our purpose was to evaluate middle cerebral artery (MCA) vasodilator responses in healthy adults before and after cyclooxygenase inhibition. A total of 16 young (26 ± 6 yr; 8 males, 8 females) and 13 older (64 ± 6 yr; 7 males, 6 females) healthy adults participated in the study. Aerobic fitness was determined by maximal aerobic capacity (V̇o2max) on a cycle ergometer. MCA velocity (MCAv) was measured at baseline and during stepped hypercapnia (2%, 4%, and 6% FiCO2) before and after cyclooxygenase inhibition using indomethacin. To account for differences in blood pressure, cerebrovascular conductance index (CVCi) was calculated as MCAv/mean arterial pressure. Cerebrovascular reactivity slopes were calculated from the correlation between either MCAv or CVCi and end-tidal CO2. Young adults demonstrated greater MCAv reactivity (1.61 ± 0.17 vs. 1.06 ± 0.15 cm·s−1·mmHg−1; P < 0.05) and CVCi reactivity (0.015 ± 0.002 vs. 0.007 ± 0.002 cm·s−1·mmHg−1; P < 0.05) compared with the older adults. There was no association between cerebrovascular reactivity and V̇o2maxin the combined group of subjects; however, in older adults MCAv reactivity was correlated with maximal aerobic fitness ( r = 0.64; P < 0.05). Furthermore, the change in MCAv reactivity (between baseline and indomethacin trials) was also associated with V̇o2max( r = 0.59; P < 0.05) in older adults. Cerebral vasodilator responses to hypercapnia were associated with maximal aerobic capacity in healthy older adults. These results may explain the physiological link between regular aerobic exercise and improved cognitive function in aging adults.

Omega-3 fatty acids found in fish oil have been suggested to protect against cardiovascular disease, yet underlying mechanisms remain unclear. Despite the well-documented link between mental stress and cardiovascular risk, no study has examined neural cardiovascular reactivity to mental stress after fish oil supplementation. We hypothesized that fish oil would blunt the blood pressure, heart rate (HR), and muscle sympathetic nerve activity (MSNA) responsiveness to mental stress and/or augment limb vasodilation associated with mental stress. Blood pressure, HR, MSNA, forearm vascular conductance (FVC), and calf vascular conductance (CVC) responses were recorded during a 5-min mental stress protocol in 67 nonhypertensive subjects before and after 8 wk of fish oil ( n = 34) or placebo supplementation ( n = 33). Fish oil blunted HR reactivity to mental stress (group × condition × time interactions, P = 0.012) but did not alter blood pressure reactivity to mental stress (interactions, P > 0.05). Fish oil blunted total MSNA reactivity to mental stress (interaction, P = 0.039) but did not alter MSNA burst frequency and burst incidence reactivity (interactions, P > 0.05). Finally, fish oil significantly blunted CVC reactivity to mental stress (interaction, P = 0.013) but did not alter FVC reactivity (interaction, P > 0.05). In conclusion, 8 wk of fish oil supplementation significantly attenuated both HR and total MSNA reactivity to mental stress and elicited a paradoxical blunting of calf vascular conductance. These findings support and extend the growing evidence that fish oil may have positive health benefits regarding neural cardiovascular control in humans.

Blood pressure (BP) is a key measure of cardiovascular function, and accurate measurement is important to ensure proper clinical evaluation, diagnosis, and treatment. We compared intra-arterial (direct) and cuff auscultation (manual) measurement techniques at rest and during 2 levels of submaximal constant-load exercise (9 min at 40% and 75% maximum watts). Sixty-four adults (aged 29.0 ± 0.7 years; 48% male; height, 173.7 ± 1.2 cm; mass, 73.0 ± 1.7 kg; body mass index, 24.1 ± 0.4 kg·m−2; body surface area, 1.87 ± 0.03 m2) participated in the study. At rest, low, and moderate intensity, direct measurement demonstrated higher systolic BP (SBP) and diastolic BP (DBP) (bias for SBP: 22, 31, and 27 mm Hg and for DBP: 5, 7, and 17 mm Hg; rest, low-, and moderate-intensity, respectively; p < 0.01). At rest, the correlation and agreement between the 2 methods was modest (SBP: r = 0.56, bias = +22.1 mm Hg; DBP: r = 0.53, bias = +4.9 mm Hg; p < 0.001). There was good correlation and agreement with SBP at low and moderate intensity; however, DBP demonstrated a weaker relationship (SBP: r = 0.74 and 0.74, bias = +30.2 and +26.8 mm Hg; DBP: r = 0.39 and 0.28, bias = +7.1 and +13.4 mm Hg; for low and moderate intensity, respectively; p < 0.001). Further, manual measurement demonstrated a greater slope from rest to moderate exercise for the relationship between pulse pressure (PP) and cardiac output (13.6 ± 0.4 vs 12.3 ± 0.4, p = 0.03). As exercise intensity increases, manual DBP tends to bias low compared with direct DBP, which, when combined with parallel increases in SBP, leads to no differences in PP between methods at moderate exercise. Because PP is used to calculate other cardiovascular parameters (mean arterial pressure, systemic vascular resistance), measurement technique and exercise intensity should be considered when using cardiovascular variables as outcome measures.