Citations

Objective Insulin has known sympathoexcitatory effects that have been historically attributed to primarily central mechanisms. Although controversy exists, recent evidence from rodents suggests the carotid chemoreceptors may play a role in the sympathoexcitatory response to hyperinsulinemia. Therefore, we sought to examine the contribution of the carotid chemoreceptors to insulin‐mediated increases in sympathetic nervous system activity in humans. We hypothesized reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia in humans – thus supporting a role for the carotid chemoreceptors in insulin‐mediated sympathoexcitation. Methods Young, healthy adults (n=15, 8M/7F, 27±1 yrs, 24±1 kg/m 2 ) completed a 30‐min euglycemic baseline followed by a 90‐min hyperinsulinemic (1 mU/kg FFM/min), euglycemic (90–100 mg/dL) clamp. Heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA, microneurography of the peroneal nerve) were continuously measured. The role of the carotid chemoreceptors was assessed using the following protocols: 1) acute (1‐min) hyperoxia (n=13), 2) low‐dose dopamine (1–4 μg/kg/min; n=7), 3) acute hyperoxia + low‐dose dopamine (n=8). The nadir 15‐s value for MSNA within each hyperoxic condition was determined and the nadir at baseline was compared to the nadir during hyperinsulinemia. Results MSNA increased from baseline during the hyperinsulinemic, euglycemic clamp [12±2 to 18±2 bursts/min (p<0.01)]. In protocol 1, MSNA was reduced during acute hyperoxia at baseline (12±1 to 6±1 bursts/min, p<0.01) and during the hyperinsulinemic clamp (17±2 to 12±2 bursts/min, p=0.02); however, the fall in MSNA during hyperoxia did not differ between baseline and hyperinsulinemia (p=0.82). In protocol 2, when low‐dose dopamine was given prior to the hyperinsulinemic clamp, MSNA did not increase from baseline (19±2 to 22±5 bursts/min, p=0.51); this is in contrast to increases observed under saline conditions (14±3 to 22±4 bursts/min, p=0.03). In protocol 3, in the presence of low‐dose dopamine, MSNA was reduced during acute hyperoxia at baseline (16±3 to 9±2 bursts/min, p=0.048) and during the hyperinsulinemic clamp (16±4 to 9±3 bursts/min, p=0.02); however, the fall in MSNA with hyperoxia did not differ between baseline and hyperinsulinemia (p=0.97). Conclusions Low‐dose dopamine given prior to the onset of a hyperinsulinemic, euglycemic clamp attenuates the sympathoexcitatory response to hyperinsulinemia. In contrast, acute carotid chemoreceptor desensitization (1‐min hyperoxia) during steady‐state hyperinsulinemia does not augment the fall in MSNA observed at baseline. Our data suggest the carotid chemoreceptors do not contribute acutely to insulin‐mediated increases in sympathetic nervous system activity in healthy humans; however, they may play a role during longer‐term exposure. Support or Funding Information Support: DK090541 (MJJ); HL83947 (MJJ); HL130339 (JKL); AHA15SDG25080095 (JKL)

Background The ability to maintain adequate cerebral blood flow and oxygenation determines tolerance to central hypovolemia. It is unclear whether exposure to acute hypoxia changes cerebral blood flow during central hypovolemia. We hypothesized that cerebral blood velocity during lower body negative pressure would be lower during hypoxic versus normoxic conditions. Methods Ten healthy subjects (35 ± 3 y, BMI 25 ± 1 kg/m 2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 minutes at 0, −15, −30, and −45 mmHg) during both normoxia and hypoxia (F i O 2 = 0.12–0.15 O 2 ). Normoxia and hypoxia protocols were randomized and blinded. Mean arterial blood pressure (MAP, brachial arterial catheter), middle cerebral artery blood velocity (MCAv, transcranial doppler) and end tidal CO 2 (ET CO2 , mass spectrometer) were continuously recorded. We calculated cardiac output (CO) and total peripheral resistance (TPR) from the arterial pressure waveform. Cerebral vascular conductance (CVC) was calculated as MCAv/MAP. The cumulative stress index (CSI) was calculated as the cumulative product of LBNP pressure and time at each LBNP stage. Results During the hypoxia protocol, 7 participants developed presyncopal symptoms and the protocol was terminated early. Three of these 7 did not complete the normoxia protocol due to presyncopal symptoms as well. Subsequently, CSI was lower during hypoxia (278 ± 63 vs. 513 ± 47 mmHg·min −1 , p < 0.01). MAP (p < 0.01), TPR (p < 0.01), MCAv (p = 0.06) and ET CO2 (p = 0.01) were lower during hypoxia than normoxia – . CO was higher (p = 0.03) during hypoxia than normoxia, while CVC (p = 0.35) was similar. Conclusion The attenuated rise in TPR during the hypoxia protocol was associated with a reduced MAP observed during hypoxia. These findings indicate that lower MCAv and LBNP tolerance during hypoxia are due to reductions in cerebral perfusion pressure (MAP). The similar CVC during both conditions renders it unlikely that significant changes in cerebrovascular resistance contribute to the differences between normoxia and hypoxia in LBNP tolerance and MCAv. Support or Funding Information Funding: W81XWH‐13‐2‐0038 Physiological responses to LBNP with hypoxia and normoxia Baseline LBNP−15mmHg LBNP−30mmHg LBNP−45mmHg MAP, mmHg Normoxia 103 ± 3 104 ± 3 101 ± 3 98 ± 41 Hypoxia 100 ± 3 94 ± 4 93 ± 4 83 ± 4 CO, 1/min Normoxia 4.6 ± 0.3 4.5 ± 0.3 4.1 ± 0.3 3.7 ± 0.31 Hypoxia 5.4 ± 0.3 4.8 ± 0.3 4.1 ± 0.3 3.6 ± 0.3 TPR, mmHg·min·mL −1 Normoxia 22.6 ± 1.3 23.7 ± 1.3 25.0 ± 1.3 26.6 ± 1.41 Hypoxia 18.5 ± 1.3 19.8 ± 1.3 22.7 ± 1.4 23.7 ± 1.6 MCAv, cm·s −1 Normoxia 65 ± 4 64 ± 4 61 ± 4 55 ± 5 Hypoxia 58 ± 4 59 ± 4 57 ± 5 54 ± 6 CVC, cm·s −1 ·mmHg −1 Normoxia 0.67 ± 0.05 0.65 ± 0.05 0.63 ± 0.05 0.58 ± 0.05 Hypoxia 0.61 ± 0.05 0.64 ± 0.05 0.63 ± 0.05 0.64 ± 0.06 ET CO2 , mmHg Normoxia 38 ± 1 38 ± 1 38 ± 1 36 ± 1 Hypoxia 37 ± 1 36 ± 1 35 ± 1 34 ± 2 Different vs. normoxia p<0.06, } indicates a main effect.

Background Hypoxia increases susceptibility to syncope during orthostatic stress. Furthermore, cardiac baroreflex sensitivity (cBRS) is attenuated during lower body negative pressure (LBNP). Recent studies suggest that there is cross‐talk between baroreceptors and carotid body chemoreceptors. With this in mind, hypoxia may further blunt cardiac baroreflex sensitivity (cBRS) during central hypovolemia in individuals susceptible to hypoxic syncope. Therefore, we hypothesized that participants susceptible to hypoxic syncope (“fainters”) during progressive central hypovolemia would have lower spontaneous cBRS during LBNP when compared to “nonfainters”. Methods Ten healthy male participants (35 ± 3 yr, BMI 25 ± 1 kg/m 2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 minutes at 0, −15, −30, −45 mmHg) during both normoxia and hypoxia (FiO 2 = 0.12 – 0.15; S p O 2 ~85%). LBNP protocols were terminated early if participants developed presyncopal symptoms. Data from uncompleted stages were excluded. Heart rate (HR, 3 lead electrocardiogram) and mean arterial blood pressure (MAP, brachial arterial catheter) were continuously recorded. Spectral cBRS was calculated from the heart rate and blood pressure signals. Following experimentation, participants were stratified as fainters (developed presyncopal symptoms during hypoxic conditions, n=7) and nonfainters (n=3). Results MAP was lower in fainters than in nonfainters during hypoxia (interaction with LBNP p<0.05) while HR (p=0.38) and cBRS (p=0.43) were similar – . Hypoxia had a main effect vs normoxia on MAP, HR and cBRS in fainters (all p<0.02). In nonfainters hypoxia had a main effect vs normoxia on HR and cBRS (all p<0.03) and an interaction effect with LBNP on MAP (p<0.01). Conclusion Spontaneous cardiac baroreflex sensitivity is not attenuated in participants susceptible to hypoxic syncope during lower body negative pressure. This suggests that spontaneous cardiac baroreflex sensitivity does not contribute to orthostatic intolerance during hypoxia. Support or Funding Information Funding: W81XWH‐13‐2‐0038 Physiological response in fainters and nonfainters to LBNP during hypoxia and normoxia MAP, mmHg HR, beats·min −1 cBRS, ms·mmHg −1 Nonfainters Fainters Nonfainters Fainters Nonfainters Fainters Baseline Normoxia 104 ± 5 102 ± 3 62 ± 5 61 ± 3 13 ± 3 19 ± 2 Hypoxia 106 ± 6 97 ± 4 80 ± 6 72 ± 4 9 ± 3 11 ± 2 LBNP −15 mmHg Normoxia 109 ± 5 103 ± 3 68 ± 5 64 ± 3 11 ± 3 14 ± 2 Hypoxia 106 ± 6 90 ± 4 88 ± 6 72 ± 4 9 ± 3 14 ± 2 LBNP −30 mmHg Normoxia 107 ± 5 98 ± 3 79 ± 5 74 ± 3 8 ± 3 11 ± 2 Hypoxia 103 ± 6 82 ± 5 95 ± 6 79 ± 5 8 ± 3 9 ± 3 LBNP −45 mmHg Normoxia 101 ± 5 99 ± 3 92 ± 5 84 ± 4 6 ± 2 5 ± 2 Hypoxia 89 ± 6 N/A 113 ± 6 N/A 3 ± 3 N/A Different vs. nonfainters p<0.05 Different vs. normoxia p<0.05

Background The baroreflex maintains blood pressure homeostasis by modulating sympathetic activity in response to changes in arterial pressure. Baroreflex sensitivity (BRS) is blunted by activation of either the chemo‐or cardiopulmonary reflex; however, little is known about the interaction of these two reflexes on BRS. We hypothesized that activation of the chemoreflex during stimulation of the cardiopulmonary reflex would attenuate the reduction in BRS. Methods 10 healthy male volunteers (35±3 years, BMI: 25±1 kg/m 2 ) underwent lower body negative pressure (LBNP) at −15mmHg for 5 minutes to stimulate the cardiopulmonary reflex, with chemoreflex activation (hypoxia; arterial oxygen saturation: 85±1%) and without (normoxia; arterial oxygen saturation: 98±0%). Heart rate (HR; ECG), blood pressure (BP; brachial arterial catheter), oxygen saturation (finger pulse oximeter), and ventilation (expired gases) were recorded continuously. BRS was calculated by arterial pressure waveform analysis (spectrum; WinCPRS) during baseline (BL) and LBNP. Results Baseline HR was higher during hypoxia than normoxia (62±2 vs 77±3 bpm, p<0.001) while baseline systolic BP (SBP) was not statistically differentiated between conditions (151±3 vs 149±5 mmHg, normoxia vs hypoxia, p=0.669). During normoxic LBNP, HR increased (62±2 vs 66±3 bpm, p=0.001) and SBP was unchanged (151±3 vs 151±4 mmHg, BL vs LBNP, p=0.464). During hypoxic LBNP, HR remained unchanged (77±3 vs 76±4 bpm, BL vs LBNP, p=0.693) and SBP tended to decrease (149±5 vs 139±6, BL vs LBNP, p=0.067). Baseline BRS was lower during hypoxia than normoxia (15±2 vs 9±1 ms/mmHg, p=0.012). LBNP caused a similar % reduction in BRS during normoxia and hypoxia (−14±9% vs −10±7%, p=0.772). Conclusions Contrary to our hypothesis, chemoreflex activation during LBNP does not attenuate the reduction in BRS. This suggests that the cardiopulmonary reflex and the chemoreflex blunt BRS through independent mechanisms. Support or Funding Information Funding: W81XWH‐13‐2‐0038

Background Evidence indicates that the carotid chemoreceptors play a minimal role in regulating cerebral blood flow under normoxic resting conditions. However, studies in heart failure suggest over‐active carotid chemoreceptors may decrease cerebral blood flow. With this information in mind, we hypothesized that individuals with the highest resting chemosensitivity will have the greatest increase in cerebral blood flow when the carotid chemoreceptors are desensitized with low‐dose IV dopamine. Methods Seven young, healthy men (33±3 y) participated in two randomized, double‐blinded study days separated by at least 4 weeks. Middle cerebral artery blood velocity (MCAv, transcranial Doppler) was measured continuously as a surrogate for cerebral blood flow. Cerebral vascular conductance index (CVCi) was calculated by normalizing MCAv for blood pressure as measured by brachial arterial catheter (MCAv/mean arterial blood pressure) and blood gasses were drawn. Subjects rested quietly in the supine position for 5‐minutes during intravenous saline infusion (saline and dopamine baseline). This was followed by a 25‐minute continuous IV infusion of either saline or dopamine. The dose of dopamine was individualized (1–2 μg/kg/min) such that it resulted in a nadir hypoxic ventilatory response. Data were analyzed from the last 5‐minutes of the infusion period (saline infusion or dopamine infusion) and compared to baseline data. Results Saline and dopamine infusion did not affect mean arterial blood pressure (% change saline vs dopamine day: 1.3±1.2 vs 0.9±1.3%; p>0.05) or arterial blood CO 2 (% change saline vs dopamine day: −2.6±1.7 vs 1.6±1.9%; p>0.05). Dopamine infusion resulted in a significant reduction in carotid body chemosensitivity as assessed by the hypoxic ventilatory response (dopamine baseline vs infusion HVR: 0.33±0.06 vs 0.17±0.03 L/min/%SpO 2 ; p=0.027). No changes in MCAv or CVCi were observed with saline infusion (saline baseline vs infusion: p>0.05). Dopamine did not alter MCAv (dopamine baseline vs infusion: 62±5 vs 64±5 cm/s; p>0.05). Similarly, no changes in CVCi were observed with dopamine infusion (dopamine baseline vs infusion: 0.68±0.07 vs 0.68±0.06 cm/s/mmHg; p>0.05). Although differences in group means for MCAv and CVCi were not observed with dopamine infusion, a significant negative relationship was found between baseline carotid chemosensitivity and the change in MCAv (r 2 =0.594, p=0.043), and CVCi (r 2 =0.741, p=0.013). With saline infusion, no significant relationship was found between baseline carotid chemosensitivity and the change in MCAv (r 2 =0.091, p>0.05), and CVCi (r 2 =0.089, p>0.05). Conclusions Blunting of the carotid chemoreceptors using IV dopamine has no group effect on MCAv or CVCi. However, contrary to our hypothesis, individuals with highest resting chemosensitivity had either a decrease or no change in cerebral blood flow after carotid body desensitization. Support or Funding Information W81XWH‐13‐2‐003

Activation or inhibition of the carotid body chemoreceptors (CBCs) may impact cardiac baroreflex sensitivity (cBRS). The purpose of this study was to test the hypothesis that inhibition of the CBCs will elicit a change in cBRS when compared to normal resting conditions. Young, healthy subjects (n=16, 31±2, 6 women) were given IV saline and a range of IV dopamine (DA) (1‐4 µg/kg/min) for 15 minutes prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects were initially infused with IV saline. After each HVR, the DA infusion rate was increased by 1 µg/kg/min. A 3‐lead EKG and beat‐by‐beat blood pressure (NexFin) were used to determine cBRS. Data were analyzed from the 5 minutes prior to the HVR associated with the DA dose that elicited the greatest attenuation of the HVR when compared to saline. Heart rate was not significantly different during saline vs. DA (62±3 vs. 65±3, p=0.25). Diastolic blood pressure (77±2 vs. 72±1 mmHg), mean arterial pressure (98±2 vs. 92±2 mmHg), and cBRS “up” sequence (38±7 vs. 21±3 ms/mmHg) were significantly lower during saline vs. DA (p<0.05 for all). cBRS values from the RRI spectrum were not statistically distinguishable between saline and DA (26±4 vs. 21.1±3, p=0.06). In summary, inhibiting the CBCs via DA infusion in young, healthy subjects results in a fall in blood pressure and a reduction in cBRS in response to a rise in blood pressure. These data suggest the CBCs contribute to cBRS and play an important role in modulating parasympathetic control of blood pressure. Funding: NIH R01DK090541

Background In models of congestive heart failure, carotid body denervation decreases ventilatory oscillations, thereby increasing ventilatory stability. Low‐dose dopamine can acutely blunt carotid body chemosensitivity assessed by a reduction of the hypoxic ventilatory response (HVR), but whether it affects ventilatory stability was previously unknown. We hypothesized ventilatory oscillations [as assessed by coefficient of variation of tidal volume (%CV V t ) and breathing frequency (%CV F b )] would be reduced when the carotid chemoreceptors were desensitized by low‐dose dopamine. Methods Healthy adults (n=20, 6F/14M, 31±2 years) rested quietly for 5‐min and breath‐by‐breath ventilation was measured during normoxia under 2 IV infusion conditions: 1) saline, 2) an individualized dose of dopamine (1‐4 ug/kg/min) shown to result in a nadir HVR. Results Dopamine infusion increased breathing frequency (13±1 to 14±1 breaths/min, p=0.03) with no change in mean tidal volume (740±65 to 700±68 mL, p=0.18). Infusion of dopamine in young healthy adults increased ventilatory oscillations (%CV V t : saline = 21±2, dopamine = 30±4, p=0.01; %CV F b : saline = 17±1, dopamine = 21±2, p=0.07). There was no relationship between the decrease in HVR and the increase in ventilatory oscillations (V t : r=0.15, p=0.54; F b : r=0.33, p=0.16). Conclusion Contrary to our hypothesis, IV dopamine (at an individualized dose that attenuates HVR) significantly increases ventilatory oscillations in healthy subjects. These data suggest the effect of low‐dose dopamine on ventilatory oscillations in healthy adults is in contrast to that seen with carotid body denervation in disease. Funding : NIH DK090541

We tested the hypothesis that hemodynamic responses would be similar during lower body negative pressure (LBNP) and hemorrhage (HEM). We measured central venous pressure (CVP), mean arterial pressure (MAP), and heart rate (HR) in 6 men during LBNP and HEM. The LBNP protocol consisted of 5‐minute stages at 0, ‐15, ‐30, and ‐45 mmHg of pressure. After a 45 minute break, the HEM protocol began and included 5 minutes at baseline and following three stages of 333 mL of HEM (1 L total). HR during LBNP increased from baseline to ‐45 mmHg (61 ± 3 vs. 86 ± 10 bpm, P < 0.01) while HR was unchanged after 1 L HEM (59 ± 4 vs. 66 ± 5 bpm, P = 0.07). HR was higher during LBNP at ‐30 mmHg vs. HEM at 667 mL (71 ± 7 vs. 63 ± 4 bpm, P = 0.03) and at the final stage (P < 0.01). From baseline, MAP tended to be reduced to a similar degree during ‐45 mmHg LBNP (90.9 ± 3.0 vs. 82.2 ± 4.0 mmHg) and 1 L HEM (89.5 ± 2.1 vs. 80.8 ± 4.0 mmHg) (P = 0.06). From baseline, CVP declined similarly during −45 mmHg LBNP (7.9 ± 1.1 vs. 0.1 ± 1.2 mmHg, P < 0.01) vs. 1 L HEM (5.8 ± 1.1 vs. 1.1 ± 1.4 mmHg, P < 0.01). Using the amalgamated r 2 across each level of LBNP and HEM, HR ( r 2 = 0.98, P < 0.01) and CVP were significantly correlated ( r 2 = 0.98, P < 0.01), but MAP was not ( r 2 = 0.53, P = 0.27). Although LBNP models the changes in MAP and CVP observed in HEM, differences in the HR response to LBNP and HEM require further exploration. Funding: US Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11–1‐0823.

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

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