Jennifer L. Taylor

Cerebrovascular reactivity is associated with maximal aerobic capacity in healthy older 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 (Vo2max) 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 Vo2max in 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 Vo2max (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.

Contribution of nitric oxide in the contraction-induced rapid vasodilation in young and older adults

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 N(G)-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.

Acute effects of a mixed meal on arterial stiffness and central hemodynamics in healthy adults.

BACKGROUND Elevated central pressures 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 after a meal. METHODS We examined these effects using high-fidelity radial arterial pressure waveforms and carotid-femoral pulse wave velocity measured noninvasively by applanation tonometry before and 60 and 180 minutes after ingestion of a liquid mixed meal (Ensure; 40% of daily energy expenditure) in 17 healthy adults (9 men/8 women; aged 29 ± 2 years). Additionally, we measured sympathetic activity by microneurography at baseline and up to 60 minutes after the meal. RESULTS Although sympathetic activity increased after the meal, both peripheral and central pressures were reduced at 180 minutes from baseline (all P < 0.05). Contrary to our hypothesis, augmentation index (14% ± 3% vs. 2% ± 3% vs. 8% ± 3%), augmentation index normalized for heart rate (8% ± 3% vs. -3% ± 3% vs. 3% ± 3%), augmented pressure (5 ± 1 mm Hg vs. 1 ± 1 mm Hg vs. 3 ± 1 mm Hg), and pulse wave velocity (7.1 ± 0.2 m/s vs. 6.7 ± 0.2 m/s vs. 6.7 ± 0.1 m/s) were substantially reduced at 60 and 180 minutes after the meal (all P < 0.05). CONCLUSIONS Taken together, our results suggest that a liquid mixed meal acutely decreases central hemodynamics and arterial stiffness in healthy adults, which may be a result of meal-related increases in insulin and/or visceral vasodilation.

Effect of Bilateral Carotid Body Resection on Cardiac Baroreflex Control of Blood Pressure During Hypoglycemia

Hypoglycemia results in a reduction in cardiac baroreflex sensitivity and a shift in the baroreflex working range to higher heart rates. This effect is mediated, in part, by the carotid chemoreceptors. Therefore, we hypothesized hypoglycemia-mediated changes in baroreflex control of heart rate would be blunted in carotid body–resected patients when compared with healthy controls. Five patients with bilateral carotid body resection for glomus tumors and 10 healthy controls completed a 180-minute hyperinsulinemic, hypoglycemic (≈3.3 mmol/L) clamp. Changes in heart rate, blood pressure, and spontaneous cardiac baroreflex sensitivity were assessed. Baseline baroreflex sensitivity was not different between groups (P>0.05). Hypoglycemia resulted in a reduction in baroreflex sensitivity in both the groups (main effect of time, P<0.01) and responses were lower in resected patients when compared with controls (main effect of group, P<0.05). Hypoglycemia resulted in large reductions in systolic (−17±7 mm Hg) and mean (−14±5 mm Hg) blood pressure in resected patients that were not observed in controls (interaction of group and time, P<0.05). Despite lower blood pressures, increases in heart rate with hypoglycemia were blunted in resected patients (interaction of group and time, P<0.01). Major novel findings from this study demonstrate that intact carotid chemoreceptors are essential for increasing heart rate and maintaining arterial blood pressure during hypoglycemia in humans. These data support a contribution of the carotid chemoreceptors to blood pressure control and highlight the potential widespread effects of carotid body resection in humans.

Role of the carotid body chemoreceptors in baroreflex control of blood pressure during hypoglycaemia in humans.

What is the central question of this study? Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor‐mediated responses in humans. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia). What is the main finding and its importance? We show that hypoglycaemia‐mediated changes in heart rate variability and baroreflex sensitivity cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range during hypoglycaemia. These results provide a potential mechanism for impaired glycaemic control and increased risk of cardiac arrhythmias in patients with carotid chemoreceptor overactivity (i.e. sleep apnoea).

Effect of bilateral carotid body resection on the counterregulatory response to hypoglycaemia in humans

What is the central question of this study? Hyperoxia blunts hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in carotid body‐resected patients; and (ii) carotid body‐resected patients would exhibit an impaired counterregulatory response to hypoglycaemia. What is the main finding and its importance? Our data indicate that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, a relatively normal counterregulatory response to hypoglycaemia in carotid body‐resected patients highlights: (i) the potential for long‐term adaptations after carotid body resection; and (ii) the importance of redundant mechanisms in mediating hypoglycaemia counterregulation.

Effect of vitamin C on hyperoxia-induced vasoconstriction in exercising skeletal muscle

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.

The effect of ageing and indomethacin on forearm reactive hyperaemia in healthy adults

What is the central question of this study? We aimed to investigate the effects of the cyclo‐oxygenase (COX) inhibitor indomethacin on resistance vessel function in young and older adults and to test the hypothesis that indomethacin will attenuate forearm vascular conductance during reactive hyperaemia. What is the main finding and its importance? Older adults demonstrated an attenuated vasodilator response to ischaemia after COX inhibition compared with their younger counterparts. This suggests that older adults do not compensate for the vascular changes induced by an acute dose of indomethacin. Long‐term use of indomethacin may increase vascular resistance and reduce the response to acute haemodynamic stress in older adults. The risk for potential adverse cardiovascular consequences of COX inhibition should be considered.

Reply to Pancheva, Panchev, and Pancheva

to the editor: We thank Pancheva and colleagues (4) for their interest in our study investigating the association between maximal aerobic capacity and cerebrovascular reactivity. In this study, we measured cerebral blood flow velocity during resting conditions through the middle cerebral artery (MCA), where little dilation is expected with a hypercapnic stimulus. In our group of older healthy adults, we found that greater maximal aerobic capacity was positively associated with the ability of the MCA to increase blood flow velocity in response to hypercapnia. Although we believe this finding has relevance to cognition, we are not able to confirm that aerobic exercise necessarily improves cognitive function (all subjects were screened for potential cognitive dysfunction using a standard battery of tests). We presume that the microvasculature is responding to CO2 and is responsible for increasing blood flow. Regular exercise may help protect the microvasculature so that it can respond to CO2 and increased neural activity. Pancheva and colleagues bring up an excellent point regarding the potential for capillary pumps in controlling blood flow to the brain, particularly in relation to exercise and exercise training. Our interpretation follows the conventional physiological data demonstrating the contribution of prostaglandins to blood flow regulation in both animals and humans, but we believe there are distinct mechanisms of CO2-mediated vasodilation and prostaglandin-mediated vasodilation. However, our study is unable to distinguish the exact mechanism underlying the association between aerobic capacity and cerebrovascular reactivity. The interaction between the capillaries and red blood cells (RBCs) is of great importance in the regulation of blood flow in any vascular bed. As Pancheva and colleagues have described, RBC rigidity and the functioning of capillary pumps may contribute to blood flow regulation (3). Aging likely increases RBC rigidity, yet it is unclear if RBC rigidity is affected by regular exercise, at least in middle-aged adults (2). RBC quality may be under-recognized in many human physiology studies. Additionally, it is unknown if regular exercise or endurance training in aging humans modifies capillary pump function. It is well accepted that exercise training induces angiogenesis and increases capillary density within the cortex (1). Such structural changes to the framework (capillary size or number), especially in aged animals with reduced capillarity, will certainly affect the regulation of cerebral blood flow. In our human physiology studies, investigating capillary pumps is not possible. Therefore, the role of capillary pumps in vivo, and how they fit into the currently accepted explanation for exercise-induced changes in the brain, needs to be elucidated.