Joyner, Michael J.

This study was performed to examine the role of the carotid bodies (CB) in glucoregulation during prolonged exercise in humans. Six healthy males (35 ± 5 yrs) completed two 120 minute bouts of cycling exercise (65% VO 2 max), during a dopamine infusion (D; 2 μg/kg/min) to acutely inactivate the CB, or a placebo, saline infusion (P). Arterial blood was drawn for glucose and counter‐regulatory hormones at baseline and during exercise (60–80: 60–80 minute mean; EE: end exercise). All variables at baseline were similar between conditions. Glucose concentration decreased throughout exercise and was similar between trials (60–80: 90 ± 7 vs. 98 ± 14; EE: 75 ± 12 vs. 80 ± 10 mg/dl; D vs. P respectively). However, when compared to baseline values, EE glucose had a greater decrease in 4 subjects during D, whereas 2 subjects had a greater attenuation during P. Glucagon was similar at 60–80 (108 ± 42 vs. 84 ± 40 pg/ml; D vs. P respectively), but was greater at EE in D than P (204 ± 104 vs. 136 ± 70 pg/ml). Cortisol (60–80: 13 ± 5 vs. 16 ± 4; EE: 22 ± 3 vs. 20 ± 7 μg/dl; D vs. P respectively) and growth hormone (60–80: 13 ± 3 vs. 12 ± 3; EE: 12 ± 4 vs. 10 ± 4 ng/ml; D vs. P respectively) concentrations were not different between conditions. Our preliminary results indicate that blood glucose during exercise with CB desensitization varies between subjects, and that the CB might contribute to blood glucose regulation during exercise. Funding: NIH R01DK090541

Cerebral vasodilator responses to hypercapnia decrease with aging, and recent data suggests sex differences in cerebrovascular regulation exist. Yet, it is unknown how sex and age interact in response to the stress of cyclooxygenase inhibition. We examined cerebral vasodilator responses to hypercapnia in 7 young men (YM), 8 young women (YW), 7 older men (OM), and 6 older women (OW) before (CON) and during cyclooxygenase (COX) inhibition via indomethacin (INDO). There was no age by sex interaction in middle cerebral artery velocity responses to hypercapnia (MCAv Slope). However, when accounting for mean arterial pressure during hypercapnia, there was an age by sex interaction in cerebrovascular conductance index (CVCi Slope). YM demonstrated higher CVCi Slope (1.27 ± 0.21 AU) compared with YW (0.65 ± 0.10 AU) and older adults (0.58 ± 0.10 AU in OM; 0.66 ± 0.06 AU in OW; p<0.05 for all). There was no difference in CVCi Slope between YW and OW, indicating that the age‐associated reduction in CVCi Slope only pertains to men. During INDO, there was an age by sex interaction for the ΔCVCi Slope (from CON to INDO) with YM having a greater slope compared with both YW (0.72 ± 0.15 vs. 0.27 ± 0.13 AU; p<0.01) and OM (0.26 ± 0.18 AU; p<0.01). Taken together, our results suggest that sex differences exist in the cerebrovascular response to hypercapnia with and without COX inhibition and that the effect of age is different in women compared to men.

Elevated central hemodynamics 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 following a meal. We examined these effects using high‐fidelity radial arterial pressure waveforms and carotid‐femoral pulse wave velocity (PWV), measured non‐invasively via applanation tonometry, before and 60 and 180 min after ingestion of a liquid mixed meal (Ensure, 40% of daily energy expenditure) in 15 healthy adults (25 ± 2 y; 8M/7F). Both peripheral and central pressures were reduced 180 min from baseline. Yet contrary to our hypothesis, augmentation index (15 ± 4 vs. 2 ± 3 vs. 8 ± 3%), augmentation index normalized for heart rate (9 ± 4 vs. −2 ± 3 vs. 3 ± 3%), augmented pressure (6 ± 2 vs. 1 ± 1 vs. 3 ± 1 mmHg) as well as carotid‐femoral PWV (7.3 ± 0.2 vs. 6.7 ± 0.2 vs. 6.7 ± 0.1 m/s) were substantially reduced at 60 and 180 min following the meal (P < 0.05 for all). Taken together, our results suggest that a liquid mixed meal acutely decreases central hemodynamics and arterial stiffness in healthy adults. NIH K23 DK82424 (TC) P30 DK50456 (MNOC) UL1 RR024150 (MCCTSA) HL105467 (DPC)

Vascular function in older women versus young women may differ based on the β‐adrenergic receptor‐mediated contribution to basal vascular tone. Thus, we tested the hypothesis that forearm blood flow (FBF) responses to the β‐receptor agonist isoproterenol (ISO) are blunted in older, postmenopausal women compared to young, premenopausal women. We used venous occlusion plethysmography to measure FBF in young (26 ± 3 yr; n = 13) and older (61 ± 6 yr; n = 12) women. FBF and mean arterial pressure (MAP) were measured at baseline and during ISO infusion at 1.0, 3.0, 6.0, and 12.0 ng/100 ml tissue/min. The two groups did not differ in body mass index or MAP. Baseline FBF (3.7 ± 1.7 vs. 2.9 ± 1.3 ml/100 ml/min, respectively) and forearm vascular conductance (FVC) (0.04 ± 0.02 vs. 0.03 ± 0.01 AU, respectively) were similar between young and older women. FBF and FVC remained similar between the groups for all ISO doses, including the 12.0 ng/100 ml tissue/min dose of ISO, for which the greatest difference between the groups would be expected; FBF was 10.7 ± 2.3 vs. 9.4 ± 2.1 ml/100 ml/min (young vs. older, respectively) and FVC was 0.11 ± 0.02 vs. 0.10 ± 0.02 AU (young vs. older, respectively). In conclusion, β‐adrenergic receptor‐mediated forearm responses to stimulation are similar between young and older women, suggesting that β‐adrenergic receptor response and contribution to vascular tone are preserved with aging in women. Funded by NIH

Feedback from active locomotor muscles contributes to the pressor response and may be more prominent in heart failure (HF) due to muscle myopathy, greater metabolite production and/or heightened sensitivity of receptors. We sought to examine the influence of metaboreflex stimulation on mean arterial pressure (MAP) in HF. Eleven HF patients (51±15yrs, NYHA Class I/II, LVEF 32±9%) and 11 controls (CTL) (42±9yrs) were recruited. Participants completed 3 study visits; 1) maximal cycle ergometry, 2) and 3) constant‐work cycling (60% peak power) for 4 min with 2 min recovery. Recovery was randomized to normal or regional circulatory occlusion (metaboreflex stimulation). Oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), blood pressure and heart rate (HR) were measured at rest, end‐exercise and recovery. With metaboreflex stimulation, MAP and systolic blood pressure (SBP) increased in HF compared to CTL (6.8±5.8% vs −3.0±7.8%, p <0.01 and 3.4±6.4% vs −12.7±10.4%, p <0.01, respectively), with no difference in diastolic pressure ( p =0.61). HR and O 2 pulse demonstrated an attenuated return to baseline in HF (6.7±5.9% vs 1.0±6.6%, p <0.01 and −50.4±15.6 vs −72.4±6.9%, p <0.01, respectively). Metaboreflex stimulation resulted in a marked pressor response in HF relative to CTL due primarily to an influence of SBP and attenuated cardiac recovery as suggested by the persistent elevation in HR and O 2 pulse.

We tested the hypothesis that ventilation (VE) and the hypoxic ventilatory response (HVR) during hyperthermia would be attenuated when carotid body chemosensitivity is blunted by an IV infusion of dopamine (2 µg/kg/min) vs. IV saline. We studied 9 subjects (1 woman, 32 ± 2 years, 25.7 ± 0.7 kg/m2) over two randomized dopamine and saline study visits. We measured VE and HVR (3 minutes at: room air, 16% O2, and 10% O2) at baseline and during normothermia (NORMInf) and hyperthermia (HYPInf) (core temperature 1.2‐1.5°C above baseline) infusion conditions. VE increased during HYPInf vs. NORMInf during dopamine (8.2 ± 0.3 vs. 10.2 ± 1.1 L/min; P = 0.04) and saline (8.9 ± 0.3 vs. 9.7 ± 0.5 L/min; P = 0.04) with no difference between conditions (P = 0.95). HVR during saline increased from baseline (0.30 ± 0.1 L/min/%SaO2; P < 0.01) and NORMInf (0.42 ± 0.1 L/min/%SaO2; P = 0.02) to HYPInf (0.77 ± 0.2 L/min/%SaO2). HVR did not change throughout the dopmaine visit (baseline = 0.38 ± 0.1; NORMInf = 0.27 ± 0.1; HYPInf 0.42 ± 0.1 L/min/%SaO2; P > 0.46). Dopamine HVR was lower than saline during HYPInf (P < 0.01). These data indicate that carotid body chemosensitivity to hypoxia is augmented during hyperthermia and that low dose dopamine was unable to lower normoxic VE during hyperthermia. Grant Funding Source : Supported by NIH R01DK090541 and RO1HL61388

Carotid bodies (CB) are desensitized by hyperoxia/hyperglycemia and sensitized by hypoxia/hypoglycemia. We have reported in healthy humans that CB chemoreceptors secrete counterregulatory hormones in response to normoxia and hypoglycemia. While the role of central nervous system in glucose counterregulation is known, it is unknown whether alteration in CB response to glucose contributes to the pathogenesis of hypoglycema in T1D. We hypothesized that glucose counterregulation is impaired in T1D due to reduced sensitization of CB. 10 T1D and 12 healthy subjects (ND), matched for BMI (23 ± 3 vs 26 ± 5 kg/m 2 ) underwent a 180 min hyperinsulinemic (2 mU/kg TBW/min), hypoglycemic clamp (~3.3mM) under normoxic conditions (SpO2 98 ± 1%). T1D subjects did not report autonomic symptoms. [3‐ 3 H] glucose was infused to measure glucose turnover. Results were compared using means of last forty minutes of clamp data. Statistical analyses were done using unpaired t‐tests and p<0.05 was considered significant. In the presence of matched glucose (3.3±0.1 vs.3.3±0.1 mM) and insulin concentrations (783±106 vs. 812±185 pM;p=0.66), counterregulatory hormonal responses epinephrine (274 ± 165 vs. 742 ± 279 pg/ml) and glucagon (30 ± 11 vs 105 ± 31pg/ml) to hypoglycemia were significantly lower (p<0.001) in T1D vs. ND respectively. The glucose infusion rate required to maintain hypoglycemia was significantly higher (36 ± 1 vs.28 ± 0 µmol/kg/min, p <0.001) and endogenous glucose production was significantly lower (10 ± 3 vs.14 ± 4 µmol/kg/min, p<0.05) in T1D vs. ND with unchanged insulin stimulated glucose uptake. We conclude that in T1D the CB sensitivity to hypoglycemia is impaired and may contribute to increased risk of hypoglycemia in these individuals. Future studies are required to evaluate CB response in hypoglycemia unaware individuals with T1D. Grant Funding Source : DK90541

We tested the hypothesis that erythrocyte count (RBC), hemoglobin (Hgb), and hematocrit (Hct) would be similar during lower body negative pressure (LBNP) and graded blood loss (BL) in humans. Arterial blood pressure, central venous pressure and heart rate were measured in 12 healthy males (88 ± 3 kg) during LBNP and BL. The LBNP protocol consisted of 5 min stages at 0,‐15, ‐30, and ‐45 mmHg. The BL protocol consisted of removal of three 333 mL aliquots of blood (1 L total) which was stored for reinfusion. RBC, Hgb, and Hct were obtained via arterial catheter at baseline and at the end of the final stage for both LBNP and BL. There were no differences (P > 0.05) in baseline values between treatment groups for RBC, Hgb, or Hct. RBC (4.81 ± 0.10 to 4.97 ± 0.10 10 12 /L), Hgb (14.18 ± 0.39 to 14.68 ± 0.36 g/dL), and Hct (40.88 ± 0.82 to 42.36 ± 0.83 %) increased from baseline to final stage (p<0.001 for all) during LBNP, while all values decreased from baseline to final stage (p<0.015 for all) during BL (4.82 ± 0.11 to 4.72 ± 0.11 10 12 /L; 14.33 ± 0.37 to 13.95 ± 0.39 g/dL; 41.09 ± 0.82 to 40.25 ± 0.86 %; respectively). The final stage values were greater in LBNP than BL for RBC, Hgb, and Hct (p< 0.001 for all). LBNP results in relative hemoconcentration while BL results in relative hemodilution. The clinical significance of these findings remains to be elucidated. Grant Funding Source : Supported by U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823.

We tested the hypothesis that the catecholamine response would be similar during lower body negative pressure (LBNP) vs. blood loss (BL). Twelve men underwent randomized LBNP and BL protocols on the same day. LBNP consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of pressure. The BL protocol included 5 minutes at baseline and then after three stages of 333 ml of whole blood draws (1000 ml total) which were stored for reinfusion. Central venous pressure (CVP) was recorded during each protocol. Blood samples were collected at baseline and at the end of the last stage of each protocol. CVP was greater in LBNP vs. BL at baseline (7.3 ± 0.6 vs. 6.1 ± 0.6 mmHg; P < 0.01) and was lower during LBNP vs. BL (‐0.2 ± 0.6 vs. 1.8 ± 0.8 mmHg; P < 0.01). The increase in epinephrine (EPI) during LBNP (53 ± 7 vs.144 ± 30 pg/ml) and BL (49 ± 7 vs. 103 ± 19 pg/ml; P < 0.01) was similar (P = 0.16). An increase in norepinephrine (NE) during LBNP (148 ± 20 vs. 354 ± 44 pg/ml; P < 0.01) was greater (P < 0.01) than the trend to increase during BL (155 ± 22 vs. 211 ± 29 pg/ml; P = 0.09). Individual slopes of catecholamines vs. CVP were calculated to determine if the responses had similar trajectories between the two protocols. The EPI vs. CVP slope was steeper in LBNP vs. BL (‐13.5 ± 4.6 vs. ‐0.6 ± 0.1 pg/ml/mmHg; P < 0.01). The NE vs. CVP slope was steeper in LBNP vs. BL (‐27.8 ± 5.6 vs. ‐8.7 ± 5.9 pg/ml/mmHg; P = 0.01). LBNP to ‐45 mmHg appears to be a greater sympathetic stressor than 1000 ml of BL. Grant Funding Source : Supported by US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

Slow‐paced breathing is a simple strategy to reduce psychological stress. We tested the hypothesis that slow paced breathing would decrease muscle sympathetic nerve activity (MSNA). Ten young, healthy males were studied. The subjects were instructed to rest supine and breathe normally (baseline) or at six breaths per minute, each for 20 minutes. MSNA was measured (peroneal microneurography) and analyzed 5 minutes into each stage for a steady state measurement. Statistical analysis was completed using one way RM ANOVA and Tukey’s posthoc analysis (reported mean±SEM). Average respiratory rate was 11.9 ± 1.1 breaths/min during baseline and 5.8 ± 0.7 breaths/min during slow‐paced breathing. There was no significant difference from baseline compared to slow paced breathing in MSNA burst frequency (18±2.0 vs 18±2.40 bursts/min), burst incidence (31.2±4.01 vs. 30.4±3.80 bursts/100 heartbeats) or burst area (12.70±2.18 vs 13.02±1.98%). However, there was a change in the pattern of burst firing with a significant increase in quiescent periods between burst clusters during slow paced breathing compared to baseline (6.50±0.61 vs. 3.59±0.41 seconds), which was accompanied by a significant decrease in the number of bursts/cluster (2.9±0.38 vs. 5.6±0.8 bursts). This has physiological relevance since there was a significant decrease in plasma norepinephrine, increase in blood flow, and a reduction in mean arterial pressure during these same periods. These findings indicate that despite no change in burst incidence, slow paced breathing alters the pattern of MSNA firing, which may contribute to favorable cardiovascular changes. Grant Funding Source : Supported by NIH HL‐083947