Strom, Nicholas A.

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.

Sympathetic neural control has a central role in the regulation of blood pressure. In humans, muscle sympathetic nerve activity (MSNA) is strongly controlled by the arterial baroreflex. Our goal was to evaluate a calculation of blood pressure "error signal" for MSNA burst occurrence and test if there was a gender difference in the relationship between this signal and resting blood pressure. Baseline MSNA was measured in healthy young men (n=49) and women (n=23). T50 (the DBP at which there is a 50% likelihood of an MSNA burst) was calculated. Mean DBP was subtracted from the T50 as an approximate "error signal" for burst activation. We found a positive relationship between this "error signal" and MSNA (bursts/100 heartbeats; BI) in both young men (slope=0.19, r 2 =0.67, p<0.001) and women (slope=0.32, r 2 =0.78, p<0.001). Thus, if DBP was lower than T50, there was an increased likelihood of MSNA bursts and vice versa. Women had a greater average "error signal" (i.e., mean T50 ‐ DBP = ‐5 ± 1 in women and ‐2 ± 0.4 in men), a 59 % steeper slope of the error signal:MSNA relationship, and lower mean BI (31 ± 2 vs 42 ± 4, p<0.05), suggesting that mechanisms exist in women to counteract the larger "driving force" for generation of a MSNA burst. These apparent gender differences in control of MSNA may contribute to differences in prevalence of cardiovascular diseases such as hypertension. NIH HL83947, UL1‐RR24150, Swedish Research Council 12170.

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.

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 causes of reduced pulmonary function (PF) in heart failure (HF) patients remain unclear, but may be due to increased pulmonary congestion. Rapid fluid loading (RFL) in healthy adults has been used to simulate intra‐thoracic fluid overload common in HF. This study examined PF using plethysmography, and airway lumen cross sectional area (A lumen ), airway wall thickness (t aw ), and vascular volume using non‐contrast CT imaging before and after RFL in 22 healthy adults. Average infusion volume was 2190 ± 412 ml over 20 ± 3 min. Vascular volume, heart rate, and cardiac output increased (p<0.001). O 2 saturation and mean arterial pressure were unchanged. Forced vital capacity (FVC) and expiratory flow measures decreased post RFL (ΔFVC=−13±9%, ΔFEV1=−15±10%, ΔFEF25‐75=−17±19%, p<0.001). A lumen was unchanged from the trachea through airway generation 3; t aw decreased in the trachea (p<0.05) but remained unchanged in airway generations 1–3. Both measures increased at airway generation 4 (p<0.01). Changes in t aw and A lumen were unrelated and were also independent of any changes in vascular volume or PF. This data suggests that RFL in healthy adults results in decreases in PF, however these decreases are not due to changes in A lumen , t aw , or pulmonary blood volume of the larger airways and vessels that can be easily imaged without contrast. Further studies will be needed to assess bronchial changes in the mid to smaller airways.

Cutaneous sensory nerve-mediated vasodilation is an important component of normal microvascular responsiveness to thermal and nonthermal stimuli. Since both neural and microvascular function can be impaired in type 2 diabetes mellitus (T2DM), we tested the hypothesis that local sensory nerve-mediated vasodilation during nonpainful local warming of the skin is less in T2DM compared with healthy controls (C) matched for age and body size. The rapid vasodilation during the first ∼5 min of this local warming (“initial peak”) was previously shown to rely primarily on local sensory nerves. We measured skin blood flow in T2DM and C subjects ( n = 7 in each group) at baseline and during 35 min of local warming of the skin to 42°C at two sites on the ventral forearm. One site was pretreated with 4% lidocaine (LIDO) to block local sensory innervation. During local warming, cutaneous vascular conductance (CVC) during the initial peak was not different between groups, either at the untreated site [T2DM 75 ± 2 vs. C 81 ± 6% of maximum CVC (%maxCVC); P > 0.05] or at the LIDO site (T2DM 63 ± 7 vs. C 64 ± 6%maxCVC; P > 0.05). The difference between untreated and LIDO sites (sensory nerve contribution) was also similar between groups (T2DM 13 ± 5 vs. C 18 ± 5%maxCVC; P > 0.05) and was smaller with LIDO than was previously shown with other local anesthetics. Our results suggest that relatively healthy individuals with T2DM do not exhibit impairments in local sensory nerve vasodilation during thermal stimulation compared with controls of similar age and body size.