Curry, Timothy B.

Background Hypoglycemia results in a reduction in spontaneous cardiac baroreflex sensitivity (scBRS) and a shift in the baroreflex working range to higher heart rates; this effect may be mediated by the carotid chemoreceptors. We hypothesized changes in baroreflex control of heart rate with hypoglycemia would be blunted in carotid body resected patients when compared with healthy controls. Methods Five patients (3M/2F) with bilateral carotid body resection for glomus tumors and ten healthy controls (7M/3F) completed a 180‐min hyperinsulinemic, hypoglycemic (~3.3 µmol/mL) clamp. Changes in heart rate, blood pressure, and scBRS were assessed. Results scBRS was reduced from baseline during hypoglycemia (p<0.01) and was lower in carotid body resected patients when compared with controls (p=0.01). Hypoglycemia‐mediated reductions in systolic and mean blood pressure were significantly greater in patients when compared with controls (p<0.05). Despite lower blood pressures, increases in heart rate with hypoglycemia were blunted in patients (p<0.01). Conclusion Reductions in scBRS with hypoglycemia cannot be exclusively attributed to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range to higher heart rates during hypoglycemia such that a rise in heart rate is not observed in carotid body resected patients. These data support a contribution of the carotid chemoreceptors to baroreflex control of blood pressure during hypoglycemia and highlight potential widespread effects of carotid body resection in humans. Funding DK090541, HL120570

There are known interactions between the chemoreflex and baroreflex. The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of blood pressure with exposure to hypoxia. Low‐dose dopamine blunts carotid body afferent activity and can thus be used to examine the contribution of the carotid chemoreceptors to reflex responses during hypoxia. Hypothesis Spontaneous cardiac baroreflex sensitivity (scBRS) will be reduced with hypoxia and this effect will be blunted when the carotid chemoreceptors are desensitized with low‐dose dopamine. Methods Seven subjects (4M/3F) completed 2 visits randomized to IV dopamine (individualized dose shown to result in a nadir hypoxic ventilatory response, 1‐4 μg/kg/min) or placebo (saline). Subjects were exposed to 5‐min normoxia (99±0% SpO2), followed by 5‐min hypoxia (83±2%SpO2). Blood pressure (intra‐arterial catheter) and heart rate (ECG) were measured continuously and sCBRS was assessed by spectrum analysis. The relative (%) change in sCBRS with hypoxia [(Hypoxia‐Normoxia)/Normoxia x 100)] was compared between dopamine and placebo. Results scBRS was reduced with hypoxia (saline p<0.01; dopamine p<0.01). The fall in scBRS with hypoxia was blunted with dopamine (saline: ‐58±7 %, dopamine: ‐42±9 %, p=0.02). Conclusion These data are consistent with a reduction in scBRS with chemoreceptor activation. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when the chemoreceptors are desensitized with low‐dose dopamine. Funding NIH DK090541 (Joyner)

BACKGROUND Increased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF). PURPOSE The purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF. METHODS 8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO 2 ). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured. RESULTS HF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO 2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO 2 (p>0.05). CONCLUSION Inhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.

Women with uterine fibroids (UF), benign tumors of the myometrium, have a greater prevalence of hypertension than women without UF. The mechanism of this predisposition is unclear. Individuals with borderline hypertension have endothelial dysfunction in the form of decreased endothelium‐dependent vasodilation in response to intra‐arterial acetylcholine infusion. It is possible that women with UF also demonstrate impaired endothelium‐dependent vasodilation prior to overt clinical hypertension. We measured forearm blood flow (FBF) using venous occlusion plethysmography at baseline and during intra‐arterial acetylcholine (ACH; 1.0‐4.0 μg/100 ml tissue/min) and sodium nitroprusside (SNP; 0.25‐2.00 μg/100 ml tissue/min) infusions in 4 normotensive women with UF (41±3 y) and 4 age‐matched normotensive women without UF. These women did not differ in body mass index or mean arterial pressure (97±4 vs. 103±6 mmHg, Control vs. UF; p>0.05). Baseline FBF was not different between the two groups (1.6±0.4 vs. 3.0±1.3 ml/100 ml tissue/min; Control vs. UF; p>0.05). FBF increased significantly from baseline in both groups at the highest doses of ACH and SNP; however, the change in FBF was not significantly different between groups (ACH: Δ8.6±1.6 vs. 9.5±4.1 ml/100 ml tissue/min; SNP: Δ9.8±3.0 vs. 13.1±4.6 ml/100 ml tissue/min; Control vs. UF; p>0.05). Our preliminary results suggest that FBF responses to ACH and SNP do not differ between women with and without UF; thus, impairments in endothelium‐dependent and ‐independent vasodilation do not appear to contribute to hypertension risk in normotensive women with UF. Funded by AHA and NIH.

Objective Blood pressure (BP) reactivity to stress is predictive of the development of cardiovascular disease. Cardiovascular reactivity is attenuated in individuals after bariatric surgery; however, the underlying mechanisms are not completely understood. We hypothesized the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery when compared to obese adults and the reliance on total peripheral resistance (TPR) would be attenuated. Methods Twenty‐six individuals [7 non‐obese (28±3 yrs, 23±1 kg/m 2 ), 11 obese (33±2 yrs, 39±1 kg/m 2 ), 8 post‐bariatric surgery (35±2 yrs, 29±1 kg/m 2 )] completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30‐s of exercise. Results Compared to non‐obese controls, obese adults exhibited a slower initial rise in BP (9.3± 3.9 vs 21.7±2.5 s) and higher peak BP change (Δ6.7±2.1 vs Δ11.9±2.1 mmHg) at the onset of isometric handgrip exercise (p<0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery (14.0±4.1 s, Δ5.6±1.3 mmHg) and non‐obese controls (p>0.05). Non‐obese controls exhibited an exercise‐mediated increase in CO whereas obese adults increased TPR (p<0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery (p>0.05). Low cardiac baroreflex sensitivity (BRS) and heart rate variability (HRV: SDNN, standard deviation of normal to normal R‐R intervals) at rest were related to smaller increases in CO (BRS: R=0.47, p<0.01; SDNN: R=0.57, p<0.01) and greater increases in TPR (BRS: R=−0.49, p=0.01; SDNN: R=−0.60, p<0.01) during exercise. Conclusions In contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at the onset of isometric handgrip exercise. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest bariatric surgery attenuates BP reactivity to physical stress via improvements in the time‐course of hemodynamic responses and reflex autonomic adjustments. Support or Funding Information NIH HL130339, NIH HL083947, NIH DK82424, NIH UL1 RR024150, Mayo Clinic Department of Anesthesiology, Mayo Foundation for Medical Education and Research This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Action potentials (APs) of varying sizes and firing probabilities, that are synchronized into bursts of efferent traffic, characterize recordings of muscle sympathetic nerve activity (MSNA). Recent evidence points to ordered recruitment of these APs but the sites of this control remain unknown. This study investigated the role of the paravertebral ganglia in sympathetic AP emission patterns using pharmacological blockade of ganglionic N N ‐nicotinic receptors via trimethaphan camsylate (TM; n = 7 females, 37 ±5 years, 112 ±2/70 ±3 mmHg, 22 ±1 kg/m 2 ). Heart rate (HR; ECG), blood pressure (BP; arterial catheter) and MSNA (microneurography) were recorded during baseline, TM infusion (1–7 mg/min) and Valsalva's manoeuvre. MSNA APs were detected from the filtered raw signal using a wavelet deconstruction approach and were binned in clusters (Scott's rule) based on peak‐to‐peak amplitude (K‐means). In the final minute of MSNA burst detection during TM, HR increased (57 ±11 to 66 ±12 bpm) and mean BP decreased (97 ±7 to 90 ±7 mmHg) (both P < 0.01 compared to baseline). Relative to baseline, TM elicited a progressive reduction in total sympathetic outflow (833 ±458 to 157 ±120 AU/min), characterized by fewer integrated bursts (30 ±14 to 9 ±8 bursts/100 beats) with decaying amplitude (49 ±3 to 31 ±3 AU) (all P < 0.01). Underlying TM‐mediated attenuations in integrated MSNA were reductions in AP incidence (186 ±101 to 29 ±31 AP/100beats) and AP content per integrated burst (7 ±2 to 3 ±1 APs/burst) (all P < 0.01). Compared to baseline, the total number of active AP clusters was reduced with TM (14 ±3 to 9 ±3 AP clusters), resulting in fewer unique clusters per burst (4 ±1 to 3 ±1 AP clusters/burst) (both P < 0.01). Relative to baseline, most participants demonstrated a reduction in the within‐burst firing probability of all AP clusters, with the largest two to six AP clusters ceasing to fire in the last minute before integrated bursting activity was abolished. Following cessation of integrated MSNA bursts, the smallest 6 ±2 sympathetic AP clusters (range: 4 – 8 AP clusters) persisted to fire in an asynchronous pattern (49 ±41 AP/100beats) in all participants. Valsalva's Maneuver did not increase the incidence of these persistent small APs (60 ±42 AP/100beats, P = 0.52), or instigate any larger APs (previously active at baseline) in six of seven participants (6 ±1 total AP clusters, P = 0.30). These data suggest: 1) the paravertebral ganglia may contribute to the heterogeneity in the firing probabilities of varying sized postganglionic sympathetic APs active under baseline conditions, and 2) the presence of non‐synchronized sympathetic APs that express resistance to blockade with trimethaphan. Support or Funding Information Supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, Discovery Grant #217916‐2013. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Hypoxia during exercise augments vasodilation and blood flow to ensure adequate delivery of O 2 to active muscles. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is poorly understood. Therefore, we tested the hypothesis that the hyperemic response to exercise with hyperbaric hyperoxia would be blunted compared to exercise during normoxia. Seven subjects (6M/1F; 26 ± 2 years) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from FBF and blood pressure (mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 ATA (sea level) and 2.8 ATA while breathing normoxic (21% O 2 , 1 ATA; F I O 2 ≈ 150 mmHg), hyperbaric normoxic (7% O 2 , 2.8 ATA, F I O 2 ≈ 150 mmHg) and hyperoxic (7% O 2 , 2.8 ATA, F I O 2 ≈ 2100 mmHg) gas. The change in FBF and FVC (Δ from rest) during exercise under normoxia and hyperbaric normoxia did not differ (P > 0.05). However, the ΔFBF and ΔFVC during exercise under hyperoxia were attenuated by ~18–29% compared to both normoxic conditions (P ≤ 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia as well as hypoxia. NIH HL46493 (MJJ), AR55819 (DPC) and RR‐024150.

Previous data indicate that endothelin‐1 may have a direct excitatory effect on sympathetic nerve activity in animals and hypertensive humans. Whether this is true in normotensive humans is unclear. We investigated the relationship between endogenous endothelin‐1 and muscle sympathetic nerve activity (MSNA) in 15 normotensive young men and 15 women (age; 25 ± 1 vs. 25 ± 2 yrs, BMI; 25 ± 1 vs. 23 ± 1 kg/m2). MSNA was recorded via peroneal microneurography, arterial pressure was estimated from brachial arterial line and serum levels of endothelin‐1 (brachial artery) was measured by a quantitative two‐site chemiluminescent immunoassay. Mean arterial pressure (MAP, 90 ± 2 vs. 93 ± 2 mmHg), MSNA (37 ± 3 vs. 34 ± 4 bursts/100 heart beats) and endothelin‐1 (0.72 ± 0.03 vs. 0.63 pg/mL) were not different between men and women respectively. Interestingly, resting MSNA was positively related to arterial levels of endothelin‐1 in men (r = 0.69, P<0.05) but not in women (r = 0.03). Thus, men with high MSNA had high levels of endothelin‐1. These data suggest that endogenous endothelin‐1 is linked to tonic levels of sympathetic nerve activity in men but not in women. AHA 2170087 (ECJH); HL083947 (NC, MJJ, BGW); NIH RR024150 (CTSA).

Baroreflex sensitivity is calculated from the slope of the relationship between blood pressure and muscle sympathetic nerve activity (MSNA) or cardiac R‐R interval. The magnitude of decrease in blood pressure during a vasoactive drug bolus (i.e. modified Oxford) to test the baroreflex may be associated with the calculated baroreflex sensitivity (BRS) slope. We investigated whether the cardiac or sympathetic BRS are associated with the acute decrease in blood pressure during a modified Oxford in young healthy men and women. Forty‐five women (27 ± 1 yrs, BMI 22.9 ± 0.3 kg/m2) and 30 men (27 ± 1 yrs, 24.2 ± 0.4 kg/m2) were studied. MSNA was measured via peroneal microneurography and blood pressure was measured with a brachial intraarterial catheter. Women and men had similar mean arterial pressures (91 ± 1 vs. 90 ± 1 mmHg), cardiac BRS (19 ± 1 vs. 21 ± 2 ms/mmHg), and sympathetic BRS (−6 ± 0.4 vs. −7 ± 0.6 AU/beat/mmHg), respectively. The decrease in systolic blood pressure (SBP) and pulse pressure (PP) was positively related to cardiac BRS in men (r=.47; p<0.01; r=.49; p<0.01). However, there was no relationship between the decrease in blood pressure and sympathetic BRS in men. In addition, there was no association between any blood pressure transients with either cardiac or sympathetic BRS in women. Our results suggest the magnitude of decrease in blood pressure is associated with cardiac BRS in men, but not women. Funded by NIH

Background Heart failure (HF) causes abnormal ventilatory responses to exercise which are inked to poor prognosis. We examined the impact of blocking fine afferents from locomotor muscles on exercise ventilatory efficiency in HF. Methods 9 HF patients (60±6yrs, LVEF 27±6%) and 9 healthy controls (63±7yrs) underwent two 5 min cycling sessions at 65% peak workload with and without intrathecal fentanyl. VO 2 , VCO 2 , V E , breathing frequency (fb), tidal volume (V T ), and chemoreceptor sensitivity (CO 2 rebreathe) were measured. Results Fentanyl did not influence exercise VO 2 in either group (HF=1.5±0.3 vs 1.5±0.3 L/min, control=1.7±0.4 vs 1.7±0.5 L/min). V E was lower with fentanyl in HF but not control (−12.3±7.1 vs 0.8±6.2%, p<0.001) due to lower fb (−10.5±4.6 vs 0.5±7.1%, p<0.01) with no change in V T (−1.2±9.4 vs 0.4±5.7%, p=0.67). V E /VCO 2 improved during exercise with fentanyl in HF but not in controls (−14.8±7.1 vs ‐ 0.5±7.0, p<0.01). Fentanyl did not influence chemoreceptor sensitivity in either group. Conclusion Blocking group III and IV afferent feedback from the locomotor muscles during exercise improves ventilatory efficiency in HF. NIH/NCRR grant KL2‐RR024151.