Glucose metabolism and autonomic function in healthy individuals and patients with type 2 diabetes mellitus at rest and during exercise.

Autonomic dysfunction is a common complication of type 2 diabetes mellitus (T2DM). However, the character of dysfunction varies in different reports. Differences in measurement methodology and complications might have influenced the inconsistent results. We sought to evaluate comprehensively the relationship between abnormal glucose metabolism and autonomic function at rest and the response to exercise in healthy individuals and T2DM patients. We hypothesized that both sympathetic and parasympathetic indices would decrease with the progression of abnormal glucose metabolism in individuals with few complications related to high sympathetic tone. Twenty healthy individuals and 11 T2DM patients without clinically evident cardiovascular disease other than controlled hypertension were examined. Resting muscle sympathetic nerve activity (MSNA), heart rate variability, spontaneous cardiovagal baroreflex sensitivity (CBRS), sympathetic baroreflex sensitivity and the MSNA response to handgrip exercise were measured. Resting MSNA was lower in patients with T2DM than in healthy control subjects (P = 0.011). Resting MSNA was negatively correlated with haemoglobin A1c in all subjects (R = -0.45, P = 0.024). The parasympathetic components of heart rate variability and CBRS were negatively correlated with glycaemic/insulin indices in all subjects and even in the control group only (all, P < 0.05). In all subjects, the MSNA response to exercise was positively correlated with fasting blood glucose (R = 0.69, P < 0.001). Resting sympathetic activity and parasympathetic modulation of heart rate were decreased in relationship to abnormal glucose metabolism. Meanwhile, the sympathetic responses to handgrip were preserved in diabetics. The responses were correlated with glucose/insulin parameters throughout diabetic and control subjects. These results suggest the importance of a comprehensive assessment of autonomic function in T2DM.

Renal blood flow during exercise: understanding its measurement with Doppler ultrasound.

The sympathetic nervous system (SNS) has a critical role in continuously coordinating responses to stimuli internal and external to the human body by appropriately modulating the activity of the organs it innervates. The SNS is activated in response to various physiological stressors, including exercise, which can involve a significant increase in SNS activity. An increase in SNS activity directed toward the kidneys causes vasoconstriction of afferent arterioles within the kidneys. This sympathetically mediated renal vasoconstriction decreases renal blood flow (RBF), causing significant blood flow redistribution toward active skeletal muscles during exercise. In research studies, different modes, intensities, and durations of exercise have been used to investigate the sympathetically mediated RBF response to exercise, and several methodological approaches have been used to quantify RBF. Doppler ultrasound provides noninvasive, continuous, real-time measurements of RBF and has emerged as a valid and reliable technique to quantify RBF during exercise. This innovative methodology has been applied in studies in which the RBF response to exercise has been examined in healthy young and older adults and patient populations such as those with heart failure and peripheral arterial disease. This valuable tool has enabled researchers to produce clinically relevant findings that have furthered our understanding of the effect of SNS activation on RBF in populations of health and disease. Therefore, the focus of this narrative review is to highlight the use of Doppler ultrasound in research studies that have provided important findings furthering our knowledge of the impact of SNS activation on RBF regulation in humans.

Rapid adjustments to autonomic control of cardiac rhythm at the onset of isometric exercise in healthy young adults.

Sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) influences on cardiac rhythm at the onset of exercise, a time of rapid autonomic adjustments, are clinically important areas of investigation. Continuous wavelet transform (CWT) involves time-frequency-based heart rate variability (HRV) analysis allowing investigation of autonomic influences on cardiac rhythm during short durations of exercise. Therefore, the purpose of this study was to characterize SNS and PNS influences on cardiac rhythm at the onset of isometric exercise in healthy young adults. CWT analysis was retrospectively applied to R-R interval data (electrocardiogram) previously collected from 14 healthy young adults (26 ± 2 years) who performed 30-s, one-legged, isometric, calf exercise at 70% maximal voluntary contraction (MVC; 70% MVC trial) or rested (0% MVC trial). Absolute and normalized low-frequency (aLF, nLF; 0.04-0.15 Hz) and high-frequency (aHF, nHF; 0.15-0.4 Hz) bands and LF/HF were used to analyze one 30-s baseline period and six 5-s time windows during the 30-s exercise (70% MVC) or rest (0% MVC). Statistical analysis involved two-way analysis of variance with post-hoc analysis. aHF, aLF, LF/HF, nHF, and nLF displayed a trial-time interaction (all p ≤ 0.027). In the 70% compared to the 0% MVC trial, aHF and nHF were lower after 5-30 s (all p ≤ 0.040), aLF was lower after 20-30 s (all p ≤ 0.011) and LF/HF and nLF were higher after 5-20 s (all p ≤ 0.045). These results indicate the reduction of the PNS influence on cardiac rhythm begins sooner than the augmentation of the SNS influence at the onset of isometric exercise in healthy young adults.

Renal medullary oxygenation decreases with lower body negative pressure in healthy young adults.

One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negative pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; -10, -20, and -30 mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; n = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured (n = 13) as LBNP was instituted. LBNP significantly reduced RBV (P = 0.041) at -30 mmHg of LBNP (Δ-8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP P = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla.NEW & NOTEWORTHY In healthy young adults, increased sympathetic activation induced by lower body negative pressure, led to a decrease in renal cortical and medullary oxygenation measured by T2*, a noninvasive magnetic resonance derived index of deoxyhemoglobin levels. In this study, we observed a significant decrease in renal cortical and medullary oxygenation with LBNP as well as an increase in renal vasoconstriction. We speculate that sympathetic renal vasoconstriction led to a significant reduction in tissue oxygenation by limiting oxygen delivery to the renal medulla.

Neural control of cardiovascular function in black adults: implications for racial differences in autonomic regulation.

Black adults are at increased risk for developing hypertension and cardiovascular and chronic kidney disease and have greater associated morbidity/mortality than white adults who are otherwise demographically similar. Despite the key role of the autonomic nervous system in the regulation of cardiovascular function, the mechanistic contributions of sympathetic nerves to racial differences in cardiovascular dysfunction and disease remain poorly understood. In this review, we present an update and synthesis of current understanding regarding the roles of autonomic neural mechanisms in normal and pathophysiological cardiovascular control in black and white adults. At rest, many hemodynamic and autonomic variables, including blood pressure, cardiac output, and sympathetic nerve activity, are similar in healthy black and white adults. However, resting sympathetic vascular transduction and carotid baroreflex responses are altered in ways that tend to promote increased vasoconstriction and higher blood pressure, even in healthy, normotensive black adults. Acute sympathoexcitatory maneuvers, including exercise and cold pressor test, often result in augmented sympathetic and hemodynamic responses in healthy black adults. Clinically, although mechanistic evidence is scarce in this area, existing data support the idea that excessive sympathetic activation and/or transduction into peripheral vasoconstriction contribute importantly to the pathophysiology of hypertension and chronic kidney disease in black compared with white adults. Important areas for future work include more detailed study of sympathetic and hemodynamic reactivity to exercise and other stressors in male and female black adults and, particularly, sympathetic control of renal function, an important area of clinical concern in black patients.

Habitual cigarette smoking raises pressor responses to spontaneous bursts of muscle sympathetic nerve activity.

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers.

Omega-3 polyunsaturated fatty acid supplementation reduces blood pressure but not renal vasoconstrictor response to orthostatic stress in healthy older adults.

Older adults exhibit augmented renal vasoconstriction during orthostatic stress compared to young adults. Consumption of omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil (FO), modulates autonomic nerve activity. However, the effect of omega-3 polyunsaturated fatty acid consumption on the renal vasoconstrictor response to orthostatic stress in young and older adults is unknown. Therefore, 10 young (25 ± 1 years; mean ± SEM) and 10 older (66 ± 2 years) healthy adults ingested 4 g FO daily for 12 weeks, and underwent graded lower body negative pressure (LBNP; -15 and -30 mmHg) pre- and post-FO supplementation. Renal blood flow velocity (RBFV; Doppler ultrasound), arterial blood pressure (BP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular values were similar between groups and visits, except diastolic BP was higher in the older group (P < 0.05). FO supplementation increased erythrocyte EPA and DHA content in both groups (P < 0.05). FO did not affect RVR or RBFV responses to LBNP in either group, but attenuated the mean BP response to LBNP in the older group (older -30 mmHg: pre-FO -4 ± 1 vs. post-FO 0 ± 1 mmHg, P < 0.05; young -30 mmHg: pre-FO -5 ± 1 vs. post-FO -5 ± 2 mmHg). In conclusion, FO supplementation attenuates the mean BP response but does not affect the renal vasoconstrictor response to orthostatic stress in older adults.

Baroreflex and neurovascular responses to skeletal muscle mechanoreflex activation in humans: an exercise in integrative physiology.

Cardiovascular adjustments to exercise resulting in increased blood pressure (BP) and heart rate (HR) occur in response to activation of several neural mechanisms: the exercise pressor reflex, central command, and the arterial baroreflex. Neural inputs from these feedback and feedforward mechanisms integrate in the cardiovascular control centers in the brain stem and modulate sympathetic and parasympathetic neural outflow, resulting in the increased BP and HR observed during exercise. Another specific consequence of the central neural integration of these inputs during exercise is increased sympathetic neural outflow directed to the kidneys, causing renal vasoconstriction, a key reflex mechanism involved in blood flow redistribution during increased skeletal muscle work. Studies in humans have shown that muscle mechanoreflex activation inhibits cardiac vagal outflow, decreasing the sensitivity of baroreflex control of HR. Metabolite sensitization of muscle mechanoreceptors can lead to reduced sensitivity of baroreflex control of HR, with thromboxane being one of the metabolites involved, via greater inhibition of cardiac vagal outflow without affecting baroreflex control of BP or baroreflex resetting. Muscle mechanoreflex activation appears to play a predominant role in causing renal vasoconstriction, both in isolation and in the presence of local metabolites. Limited investigations in older adults and patients with cardiovascular-related disease have provided some insight into how the influence of muscle mechanoreflex activation on baroreflex function and renal vasoconstriction is altered in these populations. However, future research is warranted to better elucidate the specific effect of muscle mechanoreflex activation on baroreflex and neurovascular responses with aging and cardiovascular-related disease.

Muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction in healthy humans.

Reflex renal vasoconstriction occurs during exercise, and renal vasoconstriction in response to upper-limb muscle mechanoreflex activation has been documented. However, the renal vasoconstrictor response to muscle mechanoreflex activation originating from lower limbs, with and without local metabolite accumulation, has not been assessed. Eleven healthy young subjects (26 ± 1 yr; 5 men) underwent two trials involving 3-min passive calf muscle stretch (mechanoreflex) during 7.5-min lower-limb circulatory occlusion (CO). In one trial, 1.5-min 70% maximal voluntary contraction isometric calf exercise preceded CO to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex; 70% trial). A control trial involved no exercise before CO (mechanoreflex alone; 0% trial). Beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; photoplethysmographic finger cuff), and heart rate (electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. All baseline cardiovascular variables were similar between trials. Stretch increased RVR and decreased RBFV in both trials (change from CO with stretch: RVR - 0% trial = Δ 10 ± 2%, 70% trial = Δ 7 ± 3%; RBFV - 0% trial = Δ -3.8 ± 1.1 cm/s, 70% trial = Δ -2.7 ± 1.5 cm/s; P < 0.05 for RVR and RBFV). These stretch-induced changes were of similar magnitudes in both trials, e.g., with and without local metabolite accumulation, as well as when thromboxane production was inhibited. These findings suggest that muscle mechanoreflex activation via passive calf stretch causes renal vasoconstriction, with and without muscle metaboreflex activation, in healthy humans.

Omega-3 polyunsaturated fatty acid supplementation attenuates blood pressure increase at onset of isometric handgrip exercise in healthy young and older humans.

Aging is associated with alterations of autonomic nerve activity, and dietary intake of omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil (FO), can modulate autonomic nerve activity. However, the effect of omega-3 polyunsaturated fatty acid consumption on age-related cardiovascular responses at the onset of isometric handgrip exercise, a time of rapid autonomic adjustments, is unknown. Accordingly, 14 young (25 ± 1 years; mean ± SE) and 15 older (64 ± 2 years) healthy subjects ingested 4 g FO daily for 12 weeks. On pre- and postintervention visits, participants performed 15-sec bouts of isometric handgrip at 10%, 30%, 50%, and 70% maximal voluntary contraction (MVC) while beat-to-beat systolic, diastolic, and mean arterial blood pressure (SBP, DBP, MAP; Finometer) and heart rate (HR; electrocardiogram) were recorded. All baseline cardiovascular variables were similar between groups and visits, except DBP was higher in older subjects (P < 0.05). FO increased erythrocyte EPA and DHA content in both groups (P < 0.05). FO attenuated MAP and DBP increases in response to handgrip in both age groups (change from baseline during 70% MVC handgrip pre- and post-FO: young MAPΔ 14 ± 2 mmHg versus 10 ± 2 mmHg, older MAPΔ 14 ± 3 mmHg versus 11 ± 2 mmHg; young DBPΔ 12 ± 1 mmHg versus 7 ± 2 mmHg, older DBPΔ 12 ± 1 mmHg versus 7 ± 1 mmHg; P < 0.05). FO augmented the PP (SBP-DBP) increase with 70% MVC handgrip in both groups (P < 0.05), but did not alter SBP or HR increases with handgrip. These findings suggest that FO supplementation attenuates MAP and DBP increases at the onset of isometric handgrip exercise in healthy young and older humans.

Aging augments renal vasoconstrictor response to orthostatic stress in humans.

The ability of the human body to maintain arterial blood pressure (BP) during orthostatic stress is determined by several reflex neural mechanisms. Renal vasoconstriction progressively increases during graded elevations in lower body negative pressure (LBNP). This sympathetically mediated response redistributes blood flow to the systemic circulation to maintain BP. However, how healthy aging affects the renal vasoconstrictor response to LBNP is unknown. Therefore, 10 young (25 ± 1 yr; means ± SE) and 10 older (66 ± 2 yr) subjects underwent graded LBNP (-15 and -30 mmHg) while beat-to-beat renal blood flow velocity (RBFV; Doppler ultrasound), arterial BP (Finometer), and heart rate (HR; electrocardiogram) were recorded. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as mean BP/RBFV. All baseline cardiovascular variables were similar between groups, except diastolic BP was higher in older subjects (P < 0.05). Increases in RVR during LBNP were greater in the older group compared with the young group (older: -15 mmHg Δ10 ± 3%, -30 mmHg Δ20 ± 5%; young: -15 mmHg Δ2 ± 2%, -30 mmHg Δ6 ± 2%; P < 0.05). RBFV tended to decrease more (P = 0.10) and mean BP tended to decrease less (P = 0.09) during LBNP in the older group compared with the young group. Systolic and diastolic BP, pulse pressure, and HR responses to LBNP were similar between groups. These findings suggest that aging augments the renal vasoconstrictor response to orthostatic stress in humans.

Healthy older humans exhibit augmented carotid-cardiac baroreflex sensitivity with aspirin during muscle mechanoreflex and metaboreflex activation.

Low-dose aspirin inhibits thromboxane production and augments the sensitivity of carotid baroreflex (CBR) control of heart rate (HR) during concurrent muscle mechanoreflex and metaboreflex activation in healthy young humans. However, it is unknown how aging affects this response. Therefore, the effect of low-dose aspirin on carotid-cardiac baroreflex sensitivity during muscle mechanoreflex with and without metaboreflex activation in healthy older humans was examined. Twelve older subjects (6 men and 6 women, mean age: 62 ± 1 yr) performed two trials during two visits preceded by 7 days of low-dose aspirin (81 mg) or placebo. One trial involved 3 min of passive calf stretch (mechanoreflex) during 7.5 min of limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise (mechanoreflex and metaboreflex). HR (ECG) and mean arterial blood pressure (MAP; Finometer) were recorded. CBR function was assessed using rapid neck pressure application (+40 to -80 mmHg). Aspirin significantly decreased baseline thromboxane B2 production by 83 ± 4% (P < 0.05) but did not affect 6-keto-PGF1α. After aspirin, CBR-HR maximal gain and operating point gain were significantly higher during stretch with metabolite accumulation compared with placebo (maximal gain: -0.23 ± 0.03 vs. -0.14 ± 0.02 and operating point gain: -0.11 ± 0.03 vs. -0.04 ± 0.01 beats·min(-1)·mmHg(-1) for aspirin and placebo, respectively, P < 0.05). In conclusion, these findings suggest that low-dose aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in healthy older humans. This increased sensitivity appears linked to reduced thromboxane sensitization of muscle mechanoreceptors, which consequently improves CBR-HR control.

Limb suction evoked during arterial occlusion causes systemic sympathetic activity in humans.

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP). We hypothesized that the application of suction to the human limbs would activate this venous distension reflex and raise sympathetic outflow. We placed airtight pressure tanks and applied 100 mmHg negative pressure to an arterially occluded limb (occlusion and suction, O&S) to induce tissue deformation without fluid translocation. BP, heart rate (HR), and MSNA were assessed in 19 healthy subjects during 2 min of arm or leg O&S. Occlusion without suction served as a control. During a separate visit, saline (5% forearm volume) was infused into veins of the arterially occluded arm (n = 13). The O&S increased limb circumference, MSNA burst rate (arm: Δ6.7 ± 0.7; leg: Δ6.8 ± 0.7 bursts/min), and total activity (arm: Δ199 ± 14; leg: Δ172 ± 22 units/min) and BP (arm: Δ4.3 ± 0.3; leg: Δ9.4 ± 1.4 mmHg) from the baseline. The MSNA and BP responses during arm O&S correlated with those during leg O&S. Occlusion alone had no effect on MSNA and BP. MSNA (r = 0.607) responses during arm O&S correlated with those evoked by the saline infusion into the arm. These correlations suggest that sympathetic activation during limb O&S is likely, at least partially, to be evoked via the venous distension reflex. These data suggest that suction of an occluded limb evokes sympathetic activation and that the limb venous distension reflex exists in arms and legs of normal humans.

Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease.

Prostanoids are produced during skeletal muscle contraction and subsequently stimulate muscle afferent nerves, thereby contributing to the exercise pressor reflex. Humans with peripheral arterial disease (PAD) have an augmented exercise pressor reflex, but the metabolite(s) responsible for this augmented response is not known. We tested the hypothesis that intravenous injection of ketorolac, which blocks the activity of cyclooxygenase, would attenuate the rise in mean arterial blood pressure (MAP) and heart rate (HR) evoked by plantar flexion exercise. Seven PAD patients underwent 4 min of single-leg dynamic plantar flexion (30 contractions/min) in the supine posture (workload: 0.5-2.0 kg). MAP and HR were measured on a beat-by-beat basis; changes from baseline in response to exercise were determined. Ketorolac did not affect MAP or HR at rest. During the first 20 s of exercise with the most symptomatic leg, ΔMAP was significantly attenuated by ketorolac (2 ± 2 mmHg) compared with control (8 ± 2 mmHg, P = 0.005), but ΔHR was similar (6 ± 2 vs. 5 ± 1 beats/min). Importantly, patients rated the exercise bout as "very light" to "fairly light," and average pain ratings were 1 of 10. Ketorolac had no effect on perceived exertion or pain ratings. Ketorolac also had no effect on MAP or HR in seven age- and sex-matched healthy subjects who performed a similar but longer plantar flexion protocol (workload: 0.5-7.0 kg). These data suggest that prostanoids contribute to the augmented exercise pressor reflex in patients with PAD.

Effect of oxidative stress on sympathetic and renal vascular responses to ischemic exercise.

Reactive oxygen species (ROS), produced acutely during skeletal muscle contraction, are known to stimulate group IV muscle afferents and accentuate the exercise pressor reflex (EPR) in rodents. The effect of ROS on the EPR in humans is unknown. We conducted a series of studies using ischemic fatiguing rhythmic handgrip to acutely increase ROS within skeletal muscle, ascorbic acid infusion to scavenge free radicals, and hyperoxia inhalation to further increase ROS production. We hypothesized that ascorbic acid would attenuate the EPR and that hyperoxia would accentuate the EPR. Ten young healthy subjects participated in two or three experimental trials on separate days. Beat-by-beat measurements of heart rate (HR), mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and renal vascular resistance index (RVRI) were measured and compared between treatments (saline and ascorbic acid; room air and hyperoxia). At fatigue, the reflex increases in MAP (31 ± 3 versus 29 ± 2 mmHg), HR (19 ± 3 versus 20 ± 3 bpm), MSNA burst rate (21 ± 4 versus 23 ± 4 burst/min), and RVRI (39 ± 12 versus 44 ± 13%) were not different between saline and ascorbic acid. Relative to room air, hyperoxia did not augment the reflex increases in MAP, HR, MSNA, or RVRI in response to exercise. Muscle metaboreflex activation and time/volume control experiments similarly showed no treatment effects. While contrary to our initial hypotheses, these findings suggest that ROS do not play a significant role in the normal reflex adjustments to ischemic exercise in young healthy humans.

Aspirin augments carotid-cardiac baroreflex sensitivity during muscle mechanoreflex and metaboreflex activation in humans.

Muscle mechanoreflex activation decreases the sensitivity of carotid baroreflex (CBR)-heart rate (HR) control during local metabolite accumulation in humans. However, the contribution of thromboxane A2 (TXA2) toward this response is unknown. Therefore, the effect of inhibiting TXA2 production via low-dose aspirin on CBR-HR sensitivity during muscle mechanoreflex and metaboreflex activation in humans was examined. Twelve young subjects performed two trials during two visits, preceded by 7 days' low-dose aspirin (81 mg) or placebo. One trial involved 3-min passive calf stretch (mechanoreflex) during 7.5-min limb circulatory occlusion (CO). In another trial, CO was preceded by 1.5 min of 70% maximal voluntary contraction isometric calf exercise to accumulate metabolites during CO and stretch (mechanoreflex and metaboreflex). HR (ECG) and mean arterial pressure (Finometer) were recorded. CBR function was assessed using rapid neck pressures ranging from +40 to -80 mmHg. Aspirin significantly decreased baseline thromboxane B2 production by 84 ± 4% (P < 0.05) but did not affect 6-keto prostaglandin F1α. Following aspirin, stretch with metabolite accumulation significantly augmented maximal gain (GMAX) and operating point gain (GOP) of CBR-HR (GMAX; -0.71 ± 0.14 vs. -0.37 ± 0.08 and GOP; -0.69 ± 0.13 vs. -0.35 ± 0.12 beats·min(-1)·mmHg(-1) for aspirin and placebo, respectively; P < 0.05). CBR-HR function curves were reset similarly with aspirin and placebo during stretch with metabolite accumulation. In conclusion, these findings suggest that low-dose aspirin augments CBR-HR sensitivity during concurrent muscle mechanoreflex and metaboreflex activation in humans. This increased sensitivity appears linked to reduced TXA2 production, which likely plays a role in metabolite sensitization of muscle mechanoreceptors.

Renal vasoconstriction is augmented during exercise in patients with peripheral arterial disease.

Peripheral arterial disease (PAD) patients have augmented blood pressure increases during exercise, heightening their cardiovascular risk. However, it is unknown whether patients have exaggerated renal vasoconstriction during exercise and if oxidative stress contributes to this response. Eleven PAD patients and 10 controls (CON) performed 4-min mild, rhythmic, plantar flexion exercise of increasing intensity (0.5-2 kg) with each leg (most and least affected in PAD). Eight patients also exercised with their most affected leg during ascorbic acid (AA) infusion. Renal blood flow velocity (RBFV; Doppler ultrasound), mean arterial blood pressure (MAP; Finometer), and heart rate (HR; electrocardiogram [ECG]) were measured. Renal vascular resistance (RVR), an index of renal vasoconstriction, was calculated as MAP/RBFV. Baseline RVR and MAP were similar while HR was higher in PAD than CON (2.08 ± 0.23 vs. 1.87 ± 0.20 au, 94 ± 3 vs. 93 ± 3 mmHg, and 72 ± 3 vs. 59 ± 3 bpm [P < 0.05] for PAD and CON, respectively). PAD had greater RVR increases during exercise than CON, specifically during the first minute (PAD most: 26 ± 5% and PAD least: 17 ± 5% vs. CON: 3 ± 3%; P < 0.05). AA did not alter baseline RVR, MAP, or HR. AA attenuated the augmented RVR increase in PAD during the first minute of exercise (PAD most: 33 ± 4% vs. PAD most with AA: 21 ± 4%; P < 0.05). In conclusion, these findings suggest that PAD patients have augmented renal vasoconstriction during exercise, with oxidative stress contributing to this response.

Oxidative stress contributes to the augmented exercise pressor reflex in peripheral arterial disease patients.

Exaggerated blood pressure (BP) responses to dynamic exercise predict cardiovascular mortality in patients with peripheral arterial disease (PAD). However, the underlying mechanisms are unclear and no attempt has been made to attenuate this response using antioxidants. Three physiological studies were conducted in patients with PAD and controls. In Protocol 1, subjects underwent 4 min of low-intensity (0.5-2.0 kg), rhythmic plantar flexion in the supine posture. In Protocol 2, patients with PAD received high-dose ascorbic acid intravenously before exercise. In Protocol 3, involuntary exercise was conducted via electrical stimulation of the tibial nerve. The primary outcome measure was Δ mean arterial pressure (MAP) during the first 20 s of exercise (i.e. the onset of sympathoexcitation by muscle afferents). Compared to controls, patients with PAD had significantly greater ΔMAP during plantar flexion, particularly at 0.5 kg with the most affected leg (11 ± 2 vs. 2 ± 1 mmHg) as well as the least affected leg (7 ± 1 vs. 1 ± 1 mmHg). This augmented response occurred before the onset of claudication pain and was attenuated by ∼50% with ascorbic acid. Electrically evoked exercise also elicited larger haemodynamic changes in patients with PAD compared to controls. Further, the ΔMAP during 0.5 kg plantar flexion inversely correlated with the ankle-brachial index, indicating that patients with more severe resting limb ischaemia have a larger BP response to exercise. The BP response to low-intensity exercise was enhanced in PAD. Chronic limb ischaemia may sensitize muscle afferents and potentiate the BP response to muscle contraction in a dose-dependent manner.

Aging attenuates the coronary blood flow response to cold air breathing and isometric handgrip in healthy humans.

The purpose of this echocardiography study was to measure peak coronary blood flow velocity (CBV(peak)) and left ventricular function (via tissue Doppler imaging) during separate and combined bouts of cold air inhalation (-14 ± 3°C) and isometric handgrip (30% maximum voluntary contraction). Thirteen young adults and thirteen older adults volunteered to participate in this study and underwent echocardiographic examination in the left lateral position. Cold air inhalation was 5 min in duration, and isometric handgrip (grip protocol) was 2 min in duration; a combined stimulus (cold + grip protocol) and a cold pressor test (hand in 1°C water) were also performed. Heart rate, blood pressure, O(2) saturation, and inspired air temperature were monitored on a beat-by-beat basis. The rate-pressure product (RPP) was used as an index of myocardial O(2) demand, and CBV(peak) was used as an index of myocardial O(2) supply. The RPP response to the grip protocol was significantly blunted in older subjects (Δ1,964 ± 396 beats·min(-1)·mmHg) compared with young subjects (Δ3,898 ± 452 beats·min(-1)·mmHg), and the change in CBV(peak) was also blunted (Δ6.3 ± 1.2 vs. 11.2 ± 2.0 cm/s). Paired t-tests showed that older subjects had a greater change in the RPP during the cold + grip protocol [Δ2,697 ± 391 beats·min(-1)·mmHg compared with the grip protocol alone (Δ2,115 ± 375 beats·min(-1)·mmHg)]. An accentuated RPP response to the cold + grip protocol (compared with the grip protocol alone) without a concomitant increase in CBV(peak) may suggest a dissociation between the O(2) supply and demand in the coronary circulation. In conclusion, older adults have blunted coronary blood flow responses to isometric exercise.