Roberts, Shelly K.

This study investigated the first multiomics data for association with tolerance to central hypovolemia in humans. Analyzing gene expression, proteins, and genetic variants in individuals with high and low tolerance to simulated hemorrhage, the findings show that severe blood loss causes widespread transcriptional changes, including the activation of innate immune system pathways and inhibition of gas transport processes. This research can help identify molecular factors that influence individuals’ tolerance levels for progressive blood loss.

Local warming in human skin elicits a biphasic vasodilation with a local sensory nerve component (initial peak) and nitric oxide mediated plateau. Though microvascular dysfunction in type 2 diabetes mellitus (T2DM) is well known, effects at the neural level of control in individuals with well managed T2DM are less understood. We tested the hypothesis that local sensory nerve contributions to vasodilation are less in T2DM compared to healthy controls (C). We measured skin blood flow using laser‐Doppler flowmetry (LDF) and arterial pressure using Finometer in T2DM and C subjects at baseline and during 35 minutes of local warming (LW) of the skin to 42 °C. Two LDF sites received Ringers via microdialysis throughout LW; one site was pretreated with local lidocaine (LIDO) to block local sensory innervation. Maximum cutaneous vascular conductance (CVC) was evaluated using microdialysis of nitroprusside. In preliminary studies (N = 4 T2DM, 6 C), CVC during the initial peak at the untreated site was decreased in T2DM (73 ± 4 vs. C: 85 ± 5 % max; P = 0.05), but was not different at the LIDO site (T2DM: 54 ± 9 vs. C: 66 ± 6 % max; P > 0.05). The difference between sites (sensory nerve contribution) was similar between groups (T2DM: 19 ± 7 vs. C: 18 ± 7 % max; P > 0.05), and was lower with LIDO than was previously shown with local EMLA. Our results suggest a non‐neural component which is decreased in T2DM. Supported by NIH HL73884 and CTSA UL1 RR024150.

Thermoregulatory increases in skin blood flow in humans are brought about by a combination of cutaneous vasodilation and increased cardiac output. As such, whole body heating (WBH) in humans is associated with increased heart rate and decreased blood pressure compared to normothermic baseline conditions. We hypothesized that the tachycardia and hypotension associated with WBH in resting humans would be diminished in individuals with type 2 diabetes mellitus (T2DM) compared to controls (C) of similar age due to altered autonomic control of cardiac function in T2DM. We measured heart rate (HR; ECG) and beat‐to‐beat blood pressure (Finometer) in 6 individuals with T2DM and 6 control subjects at baseline and during WBH with a water‐perfused suit. Resting HR and blood pressure were similar in C vs. T2DM (HR: C: 59 ± 2; T2DM: 62 ± 4, P > 0.05; MAP: C: 93 ± 7; T2DM: 95 ± 7, P > 0.05). During body heating, heart rate increased significantly in both groups; at peak of WBH, HR was 91 ± 4 in C and 92 ± 1 in T2DM. This represented a change of 32 ± 3 in C and 27 ± 3 in T2DM (P > 0.05). Our preliminary data suggest a similar increase in HR and decrease in BP during body heating in T2DM when compared with C. This may have implications for clinical applications in the treatment and management of T2DM, particularly with regard to heat exposure and/or exercise.

Physical activity (PA) is inversely related with body fat, insulin resistance (IR), and leptin. However, these associations are not clear in patients after gastric bypass surgery (GBS). We hypothesized an inverse relation between PA, BMI, IR, and leptin; and a positive relation between leptin, BMI, and IR in a group of 9 patients after GBS, 8 obese (Ob), and 7 non‐obese (N‐Ob) controls (age=39.0±5.7, 27.7±6.9, 28.0±10.2 yr, respectively). Subjects wore an accelerometer from 6‐7 days, and underwent measurements of height, weight, DEXA, blood glucose, insulin and leptin. IR was estimated using HOMA. Between group differences in PA, BMI, IR, and leptin were determined with ANOVA; and the relation between these variables was determined with simple linear regressions. Between group differences were observed for BMI (Ob=38.7±1.6, GBS=30.4±1.5, N‐Ob=23.8±1.7 kg/m2), IR (Ob=3.0±0.5, GBS=1.1±0.5, N‐Ob=0.7±0.5), and leptin (Ob=55.9, GBS=28.7±4.5, N‐Ob=5.1±5.6 ng/ml). PA was not different between groups. Inverse associations were observed between PA and BMI (r= ‐ 0.55), and leptin (r= ‐ 0.56); and positive associations were observed between leptin and BMI (r= 0.92), and IR (r= 0.63). PA appears to be associated with the control of obesity and IR possibly via reductions in leptin, a mechanism that requires further study. Funded by NIH CTSA UL1‐RR24150, NIH CTSA KL2‐ RR024151

Dehydration in humans decreases orthostatic tolerance and alters sympathetic neural control of the circulation, but the mechanisms involved are unclear. Our goal was to evaluate the role of angiotensin II (AngII) in altering the sympathetic control mechanisms in dehydration. We hypothesized that dehydration would increase resting muscle sympathetic nerve activity (MSNA) and increase sensitivity of baroreflex control of MSNA and that these changes are mediated in part by AngII via AT1 receptors. We measured resting MSNA and baroreflex control of MSNA in healthy young adults under two conditions: euhydration and dehydration after 24 hr fluid restriction. We continuously measured heart rate (ECG), beat‐to‐beat blood pressure (Finometer), central venous pressure (peripherally inserted central catheter) and MSNA (peroneal microneurography) in both conditions. In each condition, measurements were taken before and after 50 mg losartan (AT1 antagonist). Dehydration was associated with a ~52 % increase in resting MSNA, but losartan did not consistently influence resting MSNA. Contrary to our hypothesis, baroreflex sensitivity increased ~39 % following losartan administration during dehydration. Our results confirm the sympathoexcitatory influence of dehydration, but the role of AngII in this process requires further evaluation. Supported by AHA 0750036Z and NIH CTSA UL1‐RR24150.

In humans, sympathetic nerves in the skin provide tonic vasoconstrictor innervation. Although neural changes in type 2 diabetes mellitus (T2DM) are well recognized, it is unclear to what extent the activity of these vasoconstrictor nerves is altered in individuals with relatively uncomplicated T2DM. We tested the hypothesis that skin sympathetic nerve activity (SSNA) is decreased at rest in individuals with T2DM compared to healthy controls (C), and that the increase in SSNA with whole body cooling is smaller in T2DM than in C. We measured SSNA using microneurography, skin blood flow using laser‐Doppler flowmetry (LDF), and arterial pressure using Finometer in T2DM and C subjects at baseline and during 3–5 minutes of whole body cooling. LDF was measured on the foot at the site of innervation of the measured SSNA signal. Whole body cooling was followed by 35 min of local warming of the skin to 42°C to determine maximum cutaneous vascular conductance. In preliminary studies (N=3 per group), SSNA at baseline (T2DM: 22 ± 8 vs. C: 30 ± 1 bursts/min) and during whole body cooling (T2DM: 28 ± 11 vs. C: 43 ± 2 bursts/min; deltas: T2DM: + 6 ± 3 vs. C: +13 ± 1 bursts/min) tended to be lower in T2DM compared to C. Our data suggest that changes in control of SSNA in T2DM contribute to altered thermoregulatory responses in these individuals. Supported by NIH R01 HL73884 and CTSA UL1‐RR24150.

The physiological changes that occur after gastric bypass surgery (GBS) are not well understood but changes in activation of the sympathetic nervous system may be involved. We hypothesized that GBS would be associated with greater sympathetically mediated resting energy expenditure as measured by a greater decrease in REE after beta‐blockade (beta‐REE). Subjects who had undergone GBS (average reduction in BMI of 31.6% from peak, N=7) along with lean (BMI<25 kg/m 2 , N=5) and obese (BMI=35–45 kg/m 2 , N=4) subjects underwent measurements of REE before and after IV propranolol (0.25 mg/kg bolus followed by an infusion of 0.004 mg/kg/min). The decrease in REE (mean±SD) after beta‐blockade tended to be greater in lean (102±58 kcal) compared with obese (−22±100 kcal) and GBS (26±55 kcal) subjects (P=0.06). The decrease in REE after beta‐blockade negatively correlated with the % body fat (r=0.54, P<0.05) and VO 2max (r=0.67, P=0.01) of the subjects, but not with resting catecholamine or leptin levels. We did not find that subjects who had undergone GBS had a significant difference in the amount of their REE that is dependent on sympathetic stimulation. Beta‐REE appears to be related to fitness and also to fatness and the fact that GBS subjects had high body fat even after significant weight loss may explain our results. Support: NIH HL46493, NIH CTSA UL1‐RR24150, Department of Anesthesiology.

We tested the hypothesis that elevated sympathetic tone is responsible for lower peak vasoldilation following single muscle contractions in older adults. Younger (n=8; 5M/3F, age 27 ± 2) and older (n=10; 5M/5F, age 69 ± 2) adults performed single forearm contractions at 10, 20 and 40% of maximum during 1) control, 2) sympathetic activation via lower body negative pressure (LBNP; ‐ 20mmHg), and 3) intra‐arterial infusion of phentolamine (α‐adrenergic antagonist). Brachial artery diameter and velocities were measured via Doppler ultrasound and forearm vascular conductance (FVC) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak vasodilator responses (ΔFVC from baseline) were attenuated in older adults for all intensities ( P < 0.05). LBNP reduced the ΔFVC at 10% (95 ± 18 vs. 60 ± 11), 20% (128 ± 9 vs. 91 ± 18) and 40% (192 ± 21 vs. 133 ± 23; P < 0.01 vs. control) in younger subjects, but not older adults (61 ± 6 vs. 58 ± 10; 99 ± 10 vs. 101 ± 17; 141 ± 17 vs. 129 ± 19, respectively; P = 0.53–0.97). With phentolamine ΔFVC was enhanced in older adults at each contraction intensity (91 ± 12, 136 ± 22, and 181 ± 22, respectively; P < 0.01 vs. control), but not younger adults (87 ± 9, 145 ± 12, and 192 ± 24, respectively; P = 0.31–1.0 vs. control). Our data indicate that overlying α‐adrenergic vasoconstriction plays a significant role in the age‐related decreases in skeletal muscle contraction‐induced rapid vasodilation.

In men, muscle sympathetic nerve activity (MSNA) is positively related to total peripheral resistance (TPR) and inversely related to cardiac output (CO). However, this relationship was not observed in young women. We aimed to investigate whether simultaneous β ‐adrenergic stimulation offsets this balance in young women. We measured MSNA (peroneal microneurography), arterial pressure (brachial line), CO (open‐circuit acetylene) and TPR before and after systemic β ‐blockade with propranolol in 6 young normotensive women (age; 24 ± 2 yrs, body mass index; 23 ± 1 kg/m 2 ). There was no difference in CO (5.7 ± 0.3 L vs. 5.3 ± 0.4 L), mean arterial pressure (MAP; 95 ± 3 mmHg vs. 95 ± 2 mmHg) before and after beta‐blockade. However, there was significant reduction in heart rate (HR; 61 ± 3 beats/min vs. 55 ± 2 beats/min, P <0.05). β ‐blockade caused an increase in TPR (17.4 ± 1.2 mmHg/ml/min vs. 18.5 ± 1.3 mmHg/ml/min; P =0.07) and MSNA (28 ± 3 bursts/100hb vs. 33 ± 3 bursts/100hb, P =0.08). Before β ‐blockade there was no relationship of MSNA to TPR, CO or MAP. Following β ‐blockade, there was a positive relationship between TPR and MSNA (r=0.60). However, there was no relationship of MSNA to cardiac output (r = −0.12). Interestingly, MAP became related to MSNA (r = 0.56). In summary, the β ‐adrenergic receptors appear to play a key role in the sympatho‐hemodynamic balance in young women. AHA 09POST2170087

Nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to hypoperfusion during exercise. We tested the potential for adenosine/NO interaction in the compensatory dilation. Eight males (25 ± 2 yrs) performed forearm exercise (20% of max) during intra‐arterial balloon inflation. Each trial included; exercise, exercise with balloon inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and brachial artery catheter pressure (BAP) were measured. Exercise was repeated during NO synthase inhibition (L‐NMMA) alone and with the combination of L‐NMMA/aminophylline (adenosine receptor blockade). Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from BF (ml/min) and BAP (mmHg). The % recovery in FVC during inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir]. FVC fell acutely with balloon inflation during all trials (P < 0.01). During the control trial, the % recovery in FVC was 111 ± 8%. The % recovery in FVC was attenuated with NOS inhibition alone (80 ± 9%; P < 0.001 vs. control) and attenuated further with combined inhibition of NO/adenosine (63 ± 9%; P < 0.05 vs. L‐NMMA). Thus, adenosine has an NO independent role in the compensatory vasodilatation during exercise with acute hypoperfusion. NIH HL46493 (MJJ), AR55819 (DPC) and RR‐024150.