Charkoudian, Nisha

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.

Inter‐individual variability in hemodynamic variables appears to be important in human blood pressure regulation. It is not known whether the rat, often used for studies of cardiovascular regulation, exhibits similar inter‐individual variability. In the present study, we evaluated whether inter‐individual variability in cardiac output (CO) and total peripheral resistance (TPR) is similar in humans and in rats, and whether a balance between these variables is similar in the two species. We assessed the relationship between CO and TPR during control conditions in humans (N = 40) and in Sprague‐Dawley rats (N = 16). We further assessed whether the relationship between CO and TPR was altered during acute increases in blood pressure, which were accomplished in humans with acute systemic L‐NMMA (N = 17), and in rats with a DOCA‐salt model (N = 16). Both humans and rats showed marked inter‐individual variability in CO and TPR but low variability in blood pressure. In both species, CO and TPR showed strong inverse correlations during normotension (r 2 = 0.88 (humans) and 0.89 (rats)) and during blood pressure increases (r 2 = 0.91 (humans) and 0.58 (rats)). We conclude that inter‐individual variability CO and TPR, and the balance between these variables, are important aspects of blood pressure regulation in both humans and rats. Supported by NIH HL32352, HL83947, HL64176, UL1‐RR24150 and Swedish Research Council 12170.

Orthostatic stress such as head‐up tilt (HUT) elicits a wide range of HR and BP responses among healthy individuals. In this study, we evaluated cardiovascular dynamics of subjects with different HR responses to HUT but without autonomic dysfunction. We measured BP (brachial artery) and HR (ECG) during 5 min of 60° HUT in 76 healthy young individuals, while norepinephrine (NE) was assayed during the final 30 s. We then chose 30 individuals based on the extremes of HR responses to HUT: 15 with the highest (ΔHR≥ 20 bpm) and 15 with the lowest response (ΔHR ≤10 bpm). Age and BMI were not different between groups; however, gender distribution was different (high: 5F, 10 M; low: 10F, 5M). Peak HR during HUT was 87.2±10.4 bpm in the high and 69.1±14.1 bpm in the low group (P< 0.05). Baseline HR was not different between groups. High HR responders had lower SBP at baseline (120.9±9.4 vs. 129.4±11.0 mmHg) and during HUT (119.9±9.7 vs. 131.4±13.1 mmHg). High HR responders also had higher plasma NE response to HUT (ΔNE: 156.9±82.1 vs. 89.0±48.0 pg/ml; P< 0.05). Higher HR with lower BP during HUT is consistent with normal baroreflex mechanisms of integration. Although inter‐individual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the gender discrepancy requires further investigation. Supported by K23 RR17520, HL46493, NS32352, KL2 RR024151 ‐01.

We previously demonstrated a bimodal distribution of vasodilator responsiveness to adenosine (ADO) infusion in human subjects: one subgroup demonstrated robust vasodilator responses to ADO (ADO responders) and the other showed blunted responses (non‐responders). Furthermore, ADO receptor antagonism blunted ADO vasodilator responses only in ADO responders and blunted exercise vasodilation only at high workloads in both groups. To test the hypothesis that ADO transporter antagonism would augment vasodilator responsiveness to ADO and exercise only in ADO responders, we compared forearm vasodilation to intra‐arterial infusion of three doses of ADO to vasodilation during three workloads of forearm handgrip exercise before and after ADO transporter antagonism with dipyridamole (DYP) in 10 subjects. In ADO responders (n=5), the change in forearm vascular conductance above baseline (ml min −1 100mmHg −1 ) for the low, medium, and high doses of ADO, respectively, was 61 ± 15, 117 ± 35, 164 ± 47 before DYP and 160 ± 50, 171 ± 59, and 216 ± 87 after DYP. For non‐responders (n=5), these values were 20 ± 2, 36 ± 6, 57 ± 14 before DYP ( P < 0.05 vs. responders) and were 159 ± 40, 293 ± 53, and 377 ± 82 after DYP ( P > 0.05 vs. responders). ADO transporter blockade had no effect on exercise hyperemia in either group ( P > 0.05 for pre vs. post‐DYP). We conclude that there may be increased ADO transporter activity in non‐responders resulting in increased clearance of ADO from the interstitium and that, in both subgroups, ADO is not obligatory for exercise hyperemia.

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

Pulse wave velocity (PWV) and sympathetic nerve activity increase with age. However, it is unknown if the age‐related increase in sympathetic activity influences PWV. We determined the effect of autonomic blockade on peripheral and central arterial stiffness in young (23 ± 4 yr) and older, postmenopausal (57 ± 3 yr) women before and during administration of trimethaphan camsylate. Arterial tonometry was used to measure carotid‐radial (peripheral) and carotid‐femoral (central) PWV. The groups did not differ in height, weight, BMI, or mean arterial pressure (MAP). At baseline, peripheral PWV did not differ between the groups. However, central PWV was significantly greater in older women compared with young women (8.2 vs. 6.1 m/s, respectively; p<0.05). Trimethaphan infusion caused a substantial drop in MAP; therefore, we corrected PWV for the change in MAP. Peripheral PWV was greater in older women compared with young women (0.12 vs. 0.08 m/s·mmHg −1 ; p<0.05). In addition, central PWV remained higher in older women during trimethaphan infusion (0.11 vs. 0.08 m/s·mmHg −1 in young; p<0.05). In conclusion, central PWV was greater in older women before and during autonomic blockade, whereas peripheral PWV was only higher in the older women after autonomic blockade. This suggests that peripheral PWV is influenced by sympathetic activity to a greater extent in young vs. older women. Funded by NIH