Maximal Cutaneous Vascular Conductance Research Articles

Post-occlusive reactive hyperemia variables can be used to diagnose vascular dysfunction in hemorrhagic shock

IntroductionLaser doppler flowmetry (LDF) allows non-invasive assessment of microvascular functions. The combination of LDF with an occlusion functional test enables study of post-occlusive reactive hyperemia (PORH), providing additional information about vasomotor function, capillary blood flow reserve, and the overall reactivity of the microvascular system. AimTo identify early alterations of PORH variables in the skin of a rat in hemorrhagic shock (HS). Material and methodsMale Wistar rats (n = 14) weighing 400–450 g were anesthetized with a combination of tiletamine/zolazepam (20 mg/kg) and xylazine (5 mg/kg). The animals breathed on their own, and were placed on a heated platform in the supine position. A PE-50 catheter was inserted into the carotid artery to measure the mean arterial pressure (MAP). The optical probe of the Laser Doppler device was installed on the plantar surface of the hind limb of a rat; a pneumatic cuff was applied proximal to the same limb. The occlusion time was 3 min. The following physiological variables were measured at baseline and 30 min after blood loss: MAP, mmHg; mean cutaneous blood flow (M, PU); cutaneous vascular conductance (CVC = M/MAP); peak hyperemia (Mmax, PU) and maximum cutaneous vascular conductance (CVCmax) during PORH. In the HS group (n = 7), 30 % of the estimated blood volume was taken within 5 min. There was no blood loss in the group of sham-operated animals (Sham, n = 7). The results are presented as Me [25 %;75 %]. The U-Mann-Whitney criterion was used to evaluate intergroup differences. Differences were considered statistically significant at p < 0.05. ResultsThe groups did not differ at baseline. Blood loss led to a significant decrease in MAP (43 [31;46] vs. 94 [84;104] mmHg), M (11.5 [16.9;7.8] vs 16.7 [20.2;13.9]) and Mmax (18.1 [16.4;21.8] vs. 25.0 [23.0;26.2]) in the HS group compared to the Sham group, respectively. At the same time, both CVC (0.25 [0.23;0.30] vs. 0.16 [0.14;0.21]) and CVCmax (0.55 [0.38;0.49] vs 0.24 [0.23; 0.29]) increased after blood loss in the HS group compared to the Sham group. Arterial blood gas analysis revealed metabolic lactic acidosis in the HS group. ConclusionIn this rat model of HS, alterations in cutaneous blood flow are manifested by a decrease in perfusion (M) and the intensity of PORH (Mmax) with a simultaneous increase in vascular conductance (CVC and CVCmax).

Contribution of sensory nerves to cutaneous reactive hyperaemia in non-Hispanic Black and White young adults.

What is the central question of this study? Does cutaneous sensory nerve-mediated vasodilatation differ between non-Hispanic Black and White young adults? What is the main finding and its importance? The magnitude of cutaneous reactive hyperaemia is lower in non-Hispanic Black relative to non-Hispanic White young adults, but the overall sensory nerve contribution is the same, suggesting that sensory nerve function is similar in both non-Hispanic Black and White young adults. The aim of this study was to assess cutaneous sensory nerve function, independent of nitric oxide, in non-Hispanic Black and White young adults. We tested the hypothesis that cutaneous reactive hyperaemia and sensory nerve-mediated vasodilatation would be lower in non-Hispanic Black young adults relative to non-Hispanic White young adults. Twenty-four participants who self-identified as non-Hispanic Black (n=12) or non-Hispanic White (n=12) were recruited. All participants underwent three bouts of reactive hyperaemia. An index of skin blood flow was measured continuously using laser-Doppler flowmetry at a control site and at a site treated with topical 4% lignocaine to inhibit sensory nerve function. Peak reactive hyperaemia was lower in non-Hispanic Black relative to non-Hispanic White participants (P<0.001). Total reactive hyperaemiawas lower in non-Hispanic Black [mean (SD); control, 4085(955)%CVCmax s; lignocaine, 2127 (639) percent maximal cutaneous vascular conductance * seconds, %CVCmax s] relative to non-Hispanic White [control: 6820 (1179)%CVCmax s; lignocaine, 3573 (712)%CVCmax s] participants (P<0.001 for both sites). There was no difference between groups for the calculated contribution of sensory nerves to either the peak [non-Hispanic Black, 25 (14)%; non-Hispanic White, 19 (13)%] or total reactive hyperaemic response [non-Hispanic Black, 48 (10)%; non-Hispanic White, 47 (10)%]. These data suggest that cutaneous reactive hyperaemia is lower in non-Hispanic Black young adults, but the sensory nerve contribution is similar in non-Hispanic Black and White young adults.

Cutaneous Microvascular Function Following Ischemia-reperfusion Injury During Passive Heat Stress

Increased kidney injury risk during heat stress is mediated, in part, by renal ischemia-reperfusion (IR) injury. However, in vivo studies are not possible in humans. Eccrine sweat glands and the cutaneous circulation have been proposed as a model of the nephron given the physiological similarities (e.g., sodium reabsorption). We previously reported impairments in sweat gland sodium reabsorption following IR injury during passive heat stress, which could be contributed to by alterations in cutaneous microvascular function (i.e., oxygen supply). PURPOSE: Test the hypothesis that forearm cutaneous microvascular function is impaired following IR injury during passive heat stress. METHODS: Fifteen healthy subjects (10 women; age: 25 ± 3 y; body mass index: 23.7 ± 3.5 kg·m2) completed a cross-body design experiment consisting of ~160 min of passive heat stress (core body temperature: +1.5 ± 0.2 °C) utilizing a suit perfused with 50 °C water. At 60 min of whole-body heating, one forearm arm (randomized) was occluded (220 mmHg) for 20 min followed by reperfusion. Local thermal hyperemia tests were performed 20 min following reperfusion using a standard local heating protocol (39 °C for 40 min + 44 °C for 20 min). Forearm skin blood flow was measured continuously at two sites (one heated, one control) on each forearm using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure (PU/mmHg) and normalized to maximal CVC during local heating to 44 °C. Data are presented as mean ± SD. RESULTS: Maximal CVC was not different between IR and control arms (3.2 ± 0.7 vs. 3.4 ± 0.8 PU/mmHg, respectively; p = 0.48). Approximately 60 min after reperfusion, CVC at the control sites were not different between IR and control arms (78 ± 11 vs. 76 ± 11%, respectively; p = 0.65). Following 40 min of local heating (39 °C), CVC was not different between IR and control arms (80 ± 10 vs. 78 ± 10%, respectively; p = 0.59). CONCLUSION: Cutaneous microvascular function was maintained following IR during passive heat stress indicating that impaired sodium reabsorption is not mediated by reductions in oxygen supply necessary for active transport of sodium. Rather, a disruption in sodium transporter activity may mediate increased sodium excretion, but this remains unknown.

Cutaneous Microvascular Responses to Local Heating on Ventral and Dorsal Aspects of the Forearm

The cutaneous microvasculature is considered a representative vascular bed and is regularly used to interrogate the mechanisms of microvascular function in healthy and diseased humans. For instance, cutaneous dilation in response to local heating can provide an index of nitric oxide (NO) bioavailability. While the skin of the forearm is typically used for local heating studies, some studies have used the ventral forearm while others have used the dorsal forearm skin for this assessment. Since the dorsal aspect of the forearm typically has more hair and receives greater sun exposure than the ventral side, there is speculation that cutaneous dilation may differ from one side of the forearm to the other, in magnitude and/or mechanism. As such, studies utilizing different sides of the forearm may not be comparable. Therefore, we aimed to test the hypothesis that cutaneous local heating responses differ between the ventral and dorsal aspects of the forearm in response to the two most common temperature stimuli, 39°C and 42°C.MethodsTen young, normotensive individuals (6 men/4 women, age: 26 ± 2 years) were studied on two separate occasions separated by 2‐7 days. At each visit, 4 intradermal microdialysis fibers were placed in either the ventral or dorsal forearm, in a random order. Two fibers were perfused with Ringer’s solution to serve as control sites and the other 2 fibers were perfused with 10 mM N(G)‐Nitro‐L‐arginine methyl ester (L‐NAME) to inhibit NO synthase. Red blood cell flux (RBCF) was assessed at all sites via laser Doppler flowmetry. Each pair of sites (control and L‐NAME) was heated to either 39°C or 42°C for ~40‐45 min until RBCF plateaued. All sites were then infused with 28 mM sodium nitroprusside and heated to 43°C to establish maximal RBCF. Cutaneous vascular conductance (CVC) was calculated as RBCF / mean arterial pressure measured during the plateau and maximal phases. Plateau results are reported as a percentage of maximal CVC at each respective site. The relative NO contribution is reported as: [(control plateau – L‐NAME plateau)/control plateau] x 100.ResultsNo differences were observed at the control site between ventral and dorsal aspects of the forearm when heated to 39°C (62 ± 13 vs. 62 ± 16 % CVCmax, P=0.99). Likewise, the heating response to 42°C was similar across the forearm (ventral: 90 ± 9 vs. dorsal: 86 ± 12% CVCmax, P=0.21). The relative contribution of NO to the plateau was comparable across the forearm at 39°C (ventral: 70 ± 20 vs. dorsal: 66 ± 21%, P=0.71) and 42°C (ventral: 63 ± 16 vs. dorsal: 69 ± 11%, P=0.11).DiscussionThese preliminary findings suggest that cutaneous vasodilation elicited by local heating is similar on both sides of the forearm at both 39°C and 42 °C. Additionally, it appears that the relative contribution of NO to local heating‐induced microvascular vasodilation is not different across the forearm.

ACUTE DIETARY NITRATE MAY IMPAIR CUTANEOUS VASCULAR CONDUCTANCE DURING LOCAL SKIN HEATING IN POSTMENOPAUSAL WOMEN

Declining estradiol production during menopause is linked to increased oxidative stress and reduced endothelial-dependent vasodilation. It is unknown whether supplementation with dietary nitrate may improve nitric oxide (NO) bioactivity and microvascular function in postmenopausal women. PURPOSE: To determine the effects of acute dietary nitrate ingestion on NO-mediated cutaneous vascular conductance (CVC) in a cohort of postmenopausal women. METHODS: In eight women (mean ± SD: age = 62 ± 4 y, BMI = 31 ± 2 kg/m2), two laser-Doppler flowmetry probes were affixed to the dorsal aspect of the forearm for measurement of red blood cell (RBC) flux during local skin heating to 39 °C and 44 °C. Assessments were made before and 3 h after ingesting 140 mL of beetroot juice containing 12.9 mmoL of inorganic nitrate. Fractional exhaled nitric oxide (FeNO) concentrations were measured at the same time points. Cutaneous vascular conductance (CVC) at 39 °C was calculated as RBC flux/ mean arterial pressure then normalized as a proportion of maximal CVC at 44°C. During the plateau phase at 39 °C, median spectral power of the endothelial NO-dependent frequency interval was analyzed using a Morlet wavelet transform. Pre-post comparisons were performed using within-sample t-tests. RESULTS: Following beetroot juice ingestion, FeNO concentrations (mean ± SD: 18 ± 8 ppb vs. 35 ± 16 ppb; p = 0.006, dz = 1.4) and spectral power of the NO-dependent frequency interval (0.01 - 0.02 Hz; p = 0.018, dz = 1.1) increased. Despite evidence for greater NO bioavailability, CVC at 39 °C was reduced (76 ± 12% vs. 50 ± 18%; p < 0.001, dz = 2.3). There was no change in maximal CVC at 44 °C (p = 0.287). CONCLUSION: A functional consequence of increased NO-bioavailability with acute dietary nitrate ingestion appears to be a diminished NO-mediated CVC response to local skin heating in our cohort of postmenopausal women with overweight and obesity. Future research should consider the effects of dietary nitrate coupled with an antioxidant supplement as means to further support NO-mediated endothelial function in such populations.

Acute Consumption of a Caffeinated Soft Drink Sweetened with High Fructose Corn Syrup Does Not Modify the Cutaneous Microvascular Response to Ischemia‐Reperfusion Injury

Background Copious intake of soft drinks sweetened with high fructose corn syrup (HFCS) is associated with a heightened risk of cardiovascular disease, which is likely contributed to by chronic HFCS mediated endothelial dysfunction occurring secondary to decreased nitric oxide (NO) bioactivity. Acute consumption of a soft drink sweetened with HFCS does not affect cutaneous vasodilation during local heating, a functional test of NO bioactivity in the cutaneous microvasculature. However, this study was undertaken in the absence of a basal reduction in NO bioactivity, such as is speculated to occur with chronic intake of HFCS. Therefore, the present study tested the hypothesis that the cutaneous vasodilatory response to local skin heating following ischemia-reperfusion injury, which acutely reduces NO bioactivity, is attenuated following acute consumption of a caffeinated soft drink sweetened with HFCS compared to water. Methods In a randomized, counter-balanced crossover design, fourteen healthy young adults (six women) consumed 500 mL of either tap water (H2O) or a caffeinated soft drink sweetened with HFCS (Mtn. Dew®, DEW). 30 min following consumption, participants underwent 20 min of forearm ischemia and 20 min of reperfusion. Local skin heating at the forearm to 39⁰C was performed for 40 min and increased to 44⁰C for 20 min. Skin blood flow (SkBF) was measured on the dorsal forearm using laser Doppler flowmetry, blood pressure was measured using the Penaz method, and heart rate was measured via 3-lead electrocardiogram. Cutaneous vascular conductance (CVC) was calculated as the quotient of SkBF and mean arterial pressure (MAP). SkBF and CVC data during local heating to 39⁰C, which is mostly a NO mediated response, were normalized as a percentage of maximal values obtained during local skin heating to 44⁰C. Data are presented as mean ± SD. Results During local skin heating at 44⁰C, there were no differences observed between H20 and DEW trials for SkBF (H2O: 252 ± 37 PU; DEW: 240 ± 35 PU, p = 0.317), CVC (H2O: 2.6 ± 0.4 PU/mmHg; DEW: 2.4 ± 0.5 PU/mmHg, p =0.215), MAP (H2O: 96 ± 6 mmHg; DEW: 101 ± 10 mmHg, p = 0 .162), and heart rate (H2O: 59 ± 7 bpm; DEW 60 ± 10 bpm, p = 0.654). During local skin heating to 39°C, no differences were observed in absolute SkBF (H2O: 154 ± 44 PU; DEW: 152 ± 44 PU, p = 0.879), percent of maximal SkBF (H20: 60.6 ± 12.2%; DEW 62.4 ± 12.7% p = 0.272), absolute CVC (H2O: 2 ± 0.5 PU/mmHg; DEW: 1.5 ± 0.5 PU/mmHg, p = 0.368), or percent of maximal CVC (H2O): 63.8 ± 13.9%; DEW 62.6 ± 13.7% p = 0.787) in the DEW and H2O trials. However, during local heating at 39°C DEW did result in a higher MAP (H2O: 92 ± 7 mmHg; DEW: 100 ± 12 mmHg, p = 0.022) and heart rate (H2O: 56 ± 7 bpm; DEW 59 ± 8 bpm, p = 0.032) compared to H2O. Conclusion Under conditions of ischemia-reperfusion injury, these data indicate that, compared to an equivalent volume of water, consumption of 500 mL of a caffeinated soft drink sweetened with HFCS does not affect the cutaneous vasodilatory response to local heating, a mostly nitric oxide mediated response.

Skin Viability and Microvascular Function Under Localised Applications of Heat and Pressure

Soft tissue pressure injuries are localised injuries to surface and deep tissue, caused by sustained compression of skin and muscle between a bony area of the body, and for example, a hospital mattress or medical device. Prolonged cell deformation is known to reduce the structural integrity of the cell cytoskeleton, leading to cascade of cell death, inflammation, oedema and oxidative stress, factors that are likely exacerbated by inadequate blood flow and oxygen delivery. Numerous secondary factors are thought to accelerate this cascade, including systemic hypoxia and changes in tissue temperature. By examining the responses of various skin viability markers, both during and after the application of temperature and pressure stimuli, the present study aims to expand understanding of the secondary factors affecting pressure ulcer onset and progression. In the present study, a custom skin deformation device, with an area of 33cm2, was used to apply a combination of pressures (6, 20 and 40mmHg) and temperatures (23, 33, 38°C) at the sacrum of four healthy volunteers (data collection ongoing). A laser doppler flowmetry probe, embedded into the skin deformation device, was used to measure baseline skin blood flow, skin blood flow under pressure, and reactive hyperaemia (RH) on pressure release. All measurements were calculated as a percentage of heat-induced maximal cutaneous vascular conductance (%CVCmax). Changes in stratum corneum and epidermal hydration were calculated using the difference in tissue electrical capacitance (corneometry) measurements before and after skin deformation. The results indicated a significant difference in loaded skin blood flow between the pressures of 6-20mmHg (p=0.045), and 6-40mmHg (p=0.018), decreasing from 30.5 ± 9.1 %CVCmax to 21.8 ± 9.0 %CVCmax and 17.5 ± 6.7 %CVCmax respectively. Furthermore, there was a significant increase (p=0.030) from 16.9 ± 8.2 %CVCmax to 29.8 ± 5.4 %CVCmax in loaded skin blood flow, between the temperatures of 28-38°C. Finally, blood flow saw a significant (p=0.005) increase on pressure release, from a loaded average of 19.7 ± 8.2 %CVCmax to an unloaded average of 29.0 ± 12.0 %CVCmax, however there was no significant effect of pressure level or temperature on reactive hyperemia. Changes in stratum corneum hydration between 28-33°C (p=0.044), and 28-38°C (p=0.019), increased from 20.8 ± 11.3% to 38.8 ± 12.7% and 48.5 ± 15.5% respectively. Differing pressures and temperatures had no significant effect on epidermal hydration. Initial indications from the present study suggest low local tissue temperature reduces tissue blood flow under pressure, thereby potentially reducing oxygen transport to, and metabolites away from, areas of loaded tissue. However, increased local temperature results in greater moisture accumulation on the surface layer of the cutaneous tissues, potentially resulting in a lower structural integrity. On balance, a neutral skin temperature may be best to balance the harmful effects pressure on tissue viability, but further investigation is required to fully understand the influence of temperature on each aspect of the pressure injury cascade, including cell cytoskeleton integrity, inflammation, and oedema, as well as blood flow dynamics, oxygen delivery, cell metabolism and oxidative stress.

Endothelium‐Independent, but Not Endothelium‐Dependent, Human Microvascular Vasodilation Differs Between Young, Healthy Females and Males

Estrogen increases nitric oxide production, but a direct comparison of endothelium-dependent and endothelium-independent mechanisms of human microvascular vasodilation between females and males has not been completed. The purpose of this study was to examine endothelium-dependent and endothelium-independent mechanisms of human cutaneous microvascular vasodilation between young, healthy females and males. Females were grouped by menstrual cycle phase to assess the influence of female sex hormones. We hypothesized that females in menstrual cycle phases of elevated estrogen would have an increased endothelium-dependent vasodilation response compared to females in phases of decreased estrogen or males. Eighteen participants (7 males; 6 females in early follicular phase, F-EF; 5 females in luteal phase, F-L) were instrumented with two microdialysis fibers in the skin of the forearm. A dose-response was completed at each site: 1) acetylcholine (ACh; 10-10 – 10-1 M) to assess endothelium-dependent vasodilation, and 2) sodium nitroprusside (SNP; 10-10 – 10-1 M) to assess endothelium-independent vasodilation. Doses were perfused for 5 minutes. Maximal vasodilation was elicited by heating the skin to 43°C and infusing 54 mM SNP. Laser-Doppler flowmetry (LDF) provided an index of skin blood flow. Cutaneous vascular conductance (CVC) was calculated (LDF/mean arterial pressure) and normalized to maximal blood flow (%CVCmax). Data are presented as mean ± SD. There was no interaction between main effects of group and dose in %CVCmax response to ACh, but there was a main effect of dose (p < 0.0001). The ACh logEC50 was similar between all groups (males: -3.8 ± 0.76M; F-EF: -2.7 ± 1.00M; F-L: -4.0 ± 0.61M). There was a significant interaction between group and dose in %CVCmax response to SNP (p = 0.04). At 10-4 M SNP, F-L (20 ± 9%CVCmax) displayed a lower response compared to males (46 ± 19%CVCmax, p = 0.004). At 10-3 M SNP, F-EF (46 ± 25%CVCmax, p = 0.038) and F-L (36 ± 15%CVCmax, p = 0.002) displayed lower responses compared to males (64 ± 16%CVCmax). The response to 10-2 M and 10-1 M SNP were not statistically different between groups. The SNP logEC50 was not different between F-EF and F-L; however, the SNP logEC50 was lower in males (-4.6 ± 0.47M) compared to F-EF (-3.3 ± 0.64M, p = 0.02) and F-L (-2.8 ± 0.36M, p < 0.0001). There was no difference between groups or phase for maximal CVC responses (p > 0.05). Endothelium-dependent mechanisms of microvascular vasodilation were similar between males and females, regardless of menstrual cycle phase. Males displayed heightened endothelium-independent vasodilation in response to lower doses of SNP, but also appeared to exhibit tachyphylaxis at the higher concentrations, compared to females.

Thermoregulatory reflex control of cutaneous vasodilation in healthy aging

ABSTRACT Reflex cutaneous vasodilation during heating is attenuated in healthy human aging secondary to blunted increases in efferent skin sympathetic nervous system activity (SSNA) and reductions in end-organ sensitivity. Whether age-related alterations in the mean body temperature ( b) threshold for increasing SSNA and/or the sensitivity of responses are evident with aging have not been examined. We tested the hypotheses that the Tb threshold for SSNA and cutaneous vascular conductance (CVC) would be increased, but the sensitivity would be reduced, with aging. Reflex vasodilation was induced in 13 young (23 ± 3 y) and 13 older (67 ± 7 y) adults using a water-perfused suit to systematically increase mean skin and esophageal temperatures. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome were continuously measured. SSNA was normalized to baseline; CVC was normalized as a percentage of maximal CVC. Baseline b was lower in older adults (36.0 ± 0.4°C vs 36.4 ± 0.3°C; p = 0.005). During passive heating, the ∆ b thresholds for increasing SSNA and CVC were greater (1.3 ± 0.4°C vs 0.9 ± 0.3°C; p = 0.007 and 1.3 ± 0.4°C vs 0.8 ± 0.3°C; p = 0.002, respectively) in older adults. The slope of the relation between both SSNA (0.31 ± 0.23 vs 0.13 ± 0.10 V⋅s⋅°C −1; p = 0.01) and CVC (87.5 ± 50.1 vs 32.4 ± 18.1%max⋅°C−1; p = 0.002) vs b was lower in older adults. The relative b threshold for activation of SSNA and the initiation of reflex cutaneous vasodilation is higher in older adults, and once activated, the sensitivity of both responses is diminished, supporting the concept that the efferent component of the thermoregulatory reflex arc is impaired in healthy aging. Abbreviations: CI: confidence interval; CVC: cutaneous vascular conductance; SSNA: skin sympathetic nervous system activity; b: mean body temperature; Tes: esophageal temperature; sk: mean skin temperature.

Impact of tetraplegia vs. paraplegia on venoarteriolar, myogenic and maximal cutaneous vasodilation responses of the microvasculature: Implications for cardiovascular disease

Objective: Cardiovascular disease (CVD) is a leading cause of mortality in persons with SCI. While macrovascular remodeling and function after SCI is well documented, changes in the microvascular structure and function are comparably understudied, but importantly predict CVD risk. Specifically, the integrity of venoarteriolar (VAR), myogenic (MYO) and maximal vasodilation responses are largely unknown after SCI, especially in persons with tetraplegia (TP) at highest risk of CVD. This is the first to examine the differences in VAR (cuff inflation), MYO (limb dependency) and maximal vasodilation responses of the microvasculature between able bodied (AB) versus those with TP and paraplegia (PP). Design: Observational. Setting: Laboratory. Participants: Eight AB, 6 TP, and 8 PP persons. Interventions: One forearm and calf were treated topically with lidocaine 2.5%/prilocaine 2.5% while contralateral limb served as a control. Laser doppler flowmeters were applied over treated and control sites during limb dependency, cuff inflation and local skin heating (Tloc) up to 42°C. Outcome measures: Skin vascular resistance (SkVR) change with cuff inflation and limb dependency and maximal cutaneous vascular conductance (CVC) during local heating. Results: Change in SkVR was not significantly different between groups or extremity (upper vs. lower) during cuff inflation or limb dependency. However, CVC at Tloc 42°C was significantly different in the lower extremity (LE) of TP and PP (P = 0.007, 0.35) compared to AB. Conclusion: Increases in SkVR during cuff inflation (VAR) and limb dependency (VAR and MYO) are unaltered after SCI, however maximal vasodilation in the LE post-SCI is higher than AB persons.

Intradermal Administration of Atrial Natriuretic Peptide Attenuates Cutaneous Vasodilation but Not Sweating in Young Men during Exercise in the Heat

Introduction: Prolonged exercise in the heat stimulates plasma release of atrial natriuretic peptide (ANP) in association with dehydration-induced reductions in blood volume. Elevated plasma ANP levels under these conditions may indirectly attenuate cutaneous blood flow and sweating responses due to the effects of this hormone on central blood volume and plasma osmolality and the resulting stimulation of nonthermal reflexes. However, it remains unclear whether cutaneous blood flow and sweating are directly modulated by ANP at the level of the cutaneous end organs (cutaneous microvessels and eccrine sweat glands) during prolonged exercise in the heat. Objective: Therefore, we evaluated the effects of local ANP administration on forearm cutaneous vascular conductance (CVC) and local sweat rate (LSR) during rest and exercise in the heat. Methods: In 9 habitually active young men (26 ± 6 years) CVC and LSR were evaluated at 3 intradermal microdialysis sites continuously perfused with lactated Ringer solution (control) or ANP (0.1 or 1.0 μM). Participants rested in a non-heat-stress condition (25°C) for approximately 60 min followed by 70 min in the heat (35°C). They then performed 50 min of moderate-intensity cycling (approx. 55% VO_{2 peak}), with a 30-min recovery. Thereafter, 50 mM sodium nitroprusside was administered at all sites to elicit maximum CVC, which was subsequently used to normalize all values (CVC_%max). Results: No effects of ANP on CVC_%max were observed in the non-heat-stress resting condition compared to the untreated control site (both p > 0.05). Conversely during rest in the heat there was an 11% (5–17%) reduction in CVC_%max at the 1.0 μM ANP site relative to the untreated control site (p < 0.05). At the end of exercise CVC_%max was attenuated by 12% (1–23%) at the 0.1 μM ANP site and by 21% (7–35%) at the 1.0 μM ANP site relative to the untreated control site (all p < 0.05). Conversely, neither concentration of ANP influenced sweating at any time point (all p > 0.05). Conclusion: Intradermal ANP administration directly attenuated cutaneous blood flow, but not sweating, in habitually active young men during rest and exercise in the heat.

Controlled Feeding of an 8-d, High-Dairy Cheese Diet Prevents Sodium-Induced Endothelial Dysfunction in the Cutaneous Microcirculation of Healthy, Older Adults through Reductions in Superoxide

Background:While excess dietary sodium impairs vascular function by increasing oxidative stress, the dietary incorporation of dairy foods improves vascular health. We demonstrated that single-meal cheese consumption ameliorates acute, sodium-induced endothelial dysfunction. However, controlled feeding studies examining the inclusion of cheese, a dairy product that contains both bioactive constituents and sodium, are lacking. Objectives:We tested the hypothesis that microcirculatory endothelium-dependent dilation (EDD) would be impaired by a high-sodium diet, but a sodium-matched diet high in dairy cheese would preserve EDD through oxidant stress mechanisms. Methods:We gave 11 adults without salt-sensitive blood pressure (<10 mmHg Δ mean arterial pressure; 64 ± 2 y) 4 separate 8-d controlled dietary interventions in a randomized, crossover design: a low-sodium, no-dairy intervention (LNa; 1500 mg/d sodium); a low-sodium, high-cheese intervention (LNaC; 1500 mg/d sodium, 170 g/d cheese); a high-sodium, no-dairy intervention (HNa; 5500 mg/d sodium); and a high-sodium, high-cheese intervention (HNaC; 5500 mg/d sodium, 170 g/d cheese). On Day 8 of each diet, EDD was assessed through a localized infusion (intradermal microdialysis) of acetylcholine (ACh), both alone and during coinfusion of NG-nitro-L-arginine methyl ester (NO synthase inhibitor), L-ascorbate (nonspecific antioxidant), apocynin [NAD(P)H oxidase inhibitor], or tempol (superoxide scavenger). Results:Compared with LNa, microvascular responsiveness to ACh was attenuated during HNa (LNa: –4.82 ± 0.20 versus HNa: –3.21 ± 0.55 M logEC50; P = 0.03) but not LNaC (–5.44 ± 0.20 M logEC50) or HNaC (–4.46 ± 0.50 M logEC50). Further, ascorbate, apocynin, and tempol administration each increased ACh-induced vasodilation during HNa only (Ringer's: 38.9 ± 2.4; ascorbate: 48.0 ± 2.5; tempol: 45.3 ± 2.7; apocynin: 48.5 ± 2.6% maximum cutaneous vascular conductance; all Pvalues < 0.01). Conclusions:These results demonstrate that incorporating dairy cheese into a high-sodium diet preserves EDD by decreasing the concentration of superoxide radicals. Consuming sodium in cheese, rather than in nondairy sources of sodium, may be an effective strategy to reduce cardiovascular disease risk in salt-insensitive, older adults. This trial was registered at clinicaltrials.govas NCT03376555.

Acute consumption of flavanol-rich cocoa beverage improves attenuated cutaneous microvascular function in healthy young African Americans

Flavanols have beneficial effects on vascular health and we have recently demonstrated that cerebral vasodilatory capacity in healthy young African Americans (AA) is improved with acute flavanol intake relative to aged-matched Caucasian Americans (CA). However, whether the positive benefits of acute flavanol consumption would also be present in the cutaneous microvascular circulation of AA remains unknown. Thus, we hypothesized that acute consumption of flavanol-rich cocoa (FC) would improve the previously reported reduced cutaneous microvascular responses to local heating in young AA. Seven AA and seven CA participated in this double-blind crossover study. Data were collected on two different days, separated by a minimum of one week. Two intradermal microdialysis membranes were inserted in the forearm and each site was randomly assigned to receive lactated Ringer's solution or NO synthase (NOS) inhibitor. Participants were randomly assigned to consume either a non-flavanol containing (NF) beverage or FC beverage. Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flux/mean arterial pressure and normalized as % maximal CVC (%CVCmax). The difference in %CVCmax between the Ringer's site and NOS inhibited site was calculated to assess NO contribution (Δ %CVCmax). In the Ringer's site, acute consumption of FC beverage improved %CVCmax during 39 °C heating when compared to NF beverage in AA (NF: 36 ± 6 vs. FC: 47 ± 5%CVCmax; P < .01) while there was similar %CVCmax during 39 °C heating between beverages in CA (NF: 55 ± 4 vs. FC: 59 ± 5%CVCmax; P = .40). During 39 °C heating, NO contribution was significantly higher with FC beverage than NF beverage in AA (NF: 27 ± 5 vs. FC: 35 ± 4 Δ %CVCmax; P = .03) while there was similar NO contribution between beverages in CA (NF: 42 ± 4 vs. FC: 45 ± 4 Δ %CVCmax; P = .36). This data suggests that acute consumption of FC could be a therapeutic solution to improve an attenuated microvascular function in young AA.

EFFECTS OF THE CHRONIC INHIBITION OF TYPE 5 PHOSPHODIESTERASE ON PENILE MICROVASCULAR ENDOTHELIAL REACTIVITY AND BLOOD PRESSURE IN HYPERTENSIVE PATIENTS WITH ERECTILE DYSFUNCTION

Objective: The primary aim of this study was to test penile endothelial microvascular function and blood pressure in patients with treated primary arterial hypertension, before and after a chronic oral treatment with sildenafil citrate (SIL). Design and method: This was a prospective, randomized, double blinded and crossover study, controlled against placebo (PLA), with 30 day washout between treatments. Penile endothelial-dependent microvascular reactivity of hypertensive patients (aged 57.4 ± 5.6 years, n = 50) was evaluated using cutaneous laser speckle contrast imaging (LSCI) before and after chronic administration of placebo or sildenafil (50 mg twice daily during 30 days). LSCI was coupled with the cutaneous iontophoresis of acetylcholine (ACh) using increasing anodal microcurrents (30–180 μA). The measurements of skin blood flow (arbitrary perfusion units, APU) were divided by values of mean arterial pressure to give the cutaneous vascular conductance (CVC) in APU/mmHg. Erectile function was evaluated using the Simplified International Index of Erectile Function (IIEF-5) score. 24 hour ambulatory blood pressure monitoring (ABPM) was performed using oscillometric devices (Spacelabs). Results: IIEF-5 scores significantly increased after SIL [18(16–20) and 21.5(19.75–23); P < 0.0001] but not after PLA [18(14.75–19.25) and 17.84 ± 3.88; P = 0.16]. The basal values of CVC in the penis increased significantly after SIL (P = 0.004), but not after PLA (P = 0.86). Maximum CVC values after cutaneous ACh administration increased only with SIL treatment (P = 0.001); after PLA (P = 0.63). The area under the curve of penile microvascular vasodilation induced by ACh also significantly increased after SIL (P = 0.003) but not after PLA (P = 0.98). Finally, 24 hours diastolic arterial pressure significantly decreased after SIL (83.5 ± 8.9 and 79.9 ± 8.2; P = 0.0003) but not after PLA (P = 0.27). The decrease in 24-hour systolic blood pressure was not statistically significant after SIL or PLA, but it was significant in the office measurements after treatment with sildenafil [136(130–144.3) and 131.5 (119–139.3); P = 0.02] but not with placebo [136(130.8–145) and 134.7 ± 13;P = 0.23]. Conclusions: Penile endothelium-dependent microvascular reactivity and erectile function improved after chronic treatment with sildenafil. The treatment also reduced blood pressure suggesting that, in addition to the effects on erectile function, chronic treatment with sildenafil could improve blood pressure control.

Statin Therapy Enhances Reflex Cutaneous Vasodilation in Formerly Hypercholesterolemic Older Adults by Improving Neurovascular Coupling

Reflex cutaneous vasodilation is attenuated in healthy human aging and is mediated by alterations in both central (sympathetic outflow) and peripheral (microvascular endothelial) function. Hypercholesterolemia, a primary risk factor for cardiovascular disease, is associated with increased sympathetic nervous system activity and further impairments in endothelial function. Independent of their lipid‐lowering effect, HMG‐CoA reductase inhibitors (statins) – the most commonly prescribed medication in the U.S. – reduce sympathetic outflow and augment endothelium‐dependent dilation. However, whether statin therapy improves the relation between skin sympathetic nervous system activity (SSNA) and cutaneous vascular conductance (CVC) during passive heat stress is unknown. We hypothesized that (1) hypercholesterolemic older adults would demonstrate blunted increases in both SSNA and CVC during passive heating and (2) chronic statin treatment would improve the response range and sensitivity of the SSNA:CVC relation. Reflex vasodilation was induced in 13 healthy normocholesterolemic older adults [62±2 yrs; low‐density lipoprotein (LDL) 113±7 mg/dl), 10 hypercholesterolemic older adults (60±1 yrs; LDL 183±2 mg/dl), and 10 previously hypercholesterolemic older adults now treated with a lipophilic statin (10–40 mg daily) to normalize LDL (64±1 yrs; LDL 102±2 mg/dl) using a water‐perfused suit to elevate oral temperature (Tor) by 1.0°C. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome (the dorsum of foot) were continuously measured. SSNA was normalized to, and expressed as, a percentage of baseline and CVC was calculated as flux/mean arterial pressure and expressed as a percentage of maximal CVC (local heating to 43°C). Mean arterial pressure, baseline CVC, and maximal CVC were not significantly different among groups (all p&gt;0.05). During passive heating, the increase in SSNA was not different among groups (normal: Δ=393±96%, high: Δ=311±120%, and statin: Δ=256±90%; p=0.11). Reflex vasodilation was blunted in hypercholesterolemic adults, but not in statin‐treated adults, compared to normocholesterolemic adults (normal: 36±1%CVCmax, high: 32±1%CVCmax, and statin: 38±1%CVCmax respectively, at ΔTor=1.0°C; p&lt;0.01). There were no differences among groups for the slope of the ΔSSNA:ΔCVC relation (normal: 0.06±0.00, high: 0.07±0.01, and statin: 0.07±0.01, p=0.91); however, this relation was shifted upward in statin‐treated adults (y‐intercept; normal: 3.1±0.9, high: 4.0±0.9, and statin: 7.3±1.3; p=0.001). These data demonstrate that chronic statin treatment improves reflex cutaneous vasodilation in formerly hypercholesterolemic older adults, in part via increases in end‐organ responsiveness to sympathetic outflow during passive heat stress.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Postsynaptic cutaneous vasodilation and sweating: influence of adiposity and hydration status.

Obesity and hypohydration independently affect postsynaptic endothelial function, but it is unknown if hypohydration affects lean and obese individuals differently. To examine the effect of hypohydration on postsynaptic cutaneous vasodilation and sweating in men with high and low adiposity (HI- and LO-BF, respectively). Ten males with LO-BF and ten with HI-BF were instrumented for forearm microdialysis when euhydrated and hypohydrated. Changes in cutaneous vascular conductance (CVC) with intradermal infusion of sodium nitroprusside (SNP) and methacholine chloride (MCh) were assessed. Local sweat rate (LSR) was simultaneously assessed at the MCh site. At the end of the last dose, maximal CVC was elicited by delivering a maximal dose of SNP for 30min to both sites with simultaneous local heating at the SNP site. The concentration of drug needed to elicit 50% of the maximal response (EC50) was compared between groups and hydration conditions. When euhydrated, EC50 of MCh-induced CVC was not different between LO- vs. HI-BF [- 3.04 ± 0.12 vs. - 2.98 ± 0.19 log (MCh) M, P = 0.841]. EC50 of SNP-induced CVC was higher in euhydrated HI- vs. LO-BF (- 1.74 ± 0.17 vs. - 2.13 ± 0.06 log (SNP) M, P = 0.034). Within each group, hydration status did not change MCh- or SNP-induced CVC (P > 0.05). LSR was not different between groups or hydration condition (P > 0.05). These data suggest reduced sensitivity of endothelium-independent vasodilation in individuals with high adiposity when euhydrated. However, hypohydration does not affect cutaneous vasodilation or local sweat rate differently between individuals with low or high adiposity.

Inclusion of Dairy Cheese In An 8‐day Controlled Dietary Intervention Prevents Sodium‐Induced Endothelial Dysfunction in the Cutaneous Microcirculation of Healthy Older Adults

Excess dietary sodium is associated with impaired vascular function and increased cardiovascular mortality. In controlled feeding studies, the inclusion of 3 daily servings of any dairy product improves blood pressure and measures of vascular health. Few studies have examined the inclusion of individual dairy products that contain both the beneficial bioactive dairy proteins and sodium. We recently demonstrated that single‐meal cheese consumption ameliorates acute sodium‐induced impairments in nitric oxide‐dependent vasodilation. However, controlled feeding studies examining the vasoprotective role of dairy cheese on sodium‐induced microvascular dysfunction are lacking. We hypothesized that (1) endothelium‐dependent vasodilation would be impaired by a high‐sodium diet compared to a low sodium diet, and (2) that a high‐cheese diet would preserve endothelium‐dependent vasodilation that is otherwise impaired by a high‐sodium diet. In a randomized, crossover study design, seven healthy older adults (63 ± 3 years; salt‐resistant: &lt;10 mmHg increase in mean arterial pressure, 24 hour monitoring) with normal to elevated blood pressure completed 4 separate 8‐day controlled dietary interventions: 1) low‐sodium (LNa: 1500 mg sodium) diet devoid of dairy products, 2) low‐sodium high‐cheese diet (LNaC: 1500 mg sodium, 6 oz/d cheese), 3) high‐sodium (HNa: 5500 mg sodium) diet devoid of dairy products, and 4) high‐sodium high‐cheese diet (HNaC: 5500 mg sodium, 6 oz/d cheese). At the end of each dietary intervention, subjects participated in an intradermal microdialysis protocol in which one microdialysis fiber was inserted into the forearm skin for measurement of red cell flux (laser Doppler flowmetry) during local infusion of the endothelium‐dependent agonist acetylcholine (Ach; 10−12 to 10−1 M). Data were expressed as a percentage of maximum cutaneous vascular conductance (%CVCmax; 28 mM sodium nitroprusside, 43°C). Ach‐induced vasodilation was significantly attenuated during the HNa diet compared to the LNa diet (LNa: −5.06±0.20 M vs HNa: −3.22±0.63 M logEC50: p &lt; 0.05). Conversely, Ach‐induced dilation during either the LNaC or HNaC diet was not different from the LNa diet (p &gt; 0.05). These results demonstrate that increased dietary sodium intake impairs endothelium‐dependent dilation whereas the inclusion of cheese prevents sodium‐induced endothelial dysfunction in salt‐insensitive older adults.Support or Funding InformationSupported by National Dairy CouncilThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Self‐Reported Everyday Psychosocial Stressors are Associated with Greater Impairments in Endothelial Function in Young Adults with Major Depressive Disorder

Vascular dysfunction is evident in adults with Major Depressive Disorder (MDD) and likely contributes to increased cardiovascular disease risk. Exposure to psychological stress plays a critical role in the etiology of MDD and is itself associated with endothelial dysfunction, accelerated atherosclerosis progression, and increased cardiovascular disease morbidity and mortality. Despite this clear epidemiological association, to date, no studies have examined the relation between everyday psychosocial stressors and direct measures of vascular endothelial function in adults with MDD. We tested the hypothesis that young adults with MDD exposed to everyday psychosocial stressors would exhibit more severe impairments in microvascular endothelium‐dependent dilation (EDD). Twenty young healthy adults (HC; 22±1 yrs) and 23 otherwise healthy young adults with MDD (20±0.3 yrs), classified via the structured diagnostic Mini International Neuropsychiatric Interview, participated. Subjects completed a psychosocial experiences survey to document their exposure to any of seven stressors over the preceding week (e.g., arguments, work stressors, home stressors). Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium‐dependent agonist acetylcholine (ACh; 10−10–10−1 M). EDD was expressed as a percentage of maximum cutaneous vascular conductance (CVC=flux·mmHg−1). Stepwise multiple regression was used to determine the associations between self‐reported psychosocial stress, depression, and endothelial function. Adults with MDD reported a greater number of stressors, stressor severity, stressor‐related negative emotions, and rumination about stressors compared to HC (all p&lt;0.05), validating the established link between stress and MDD. As expected, EDD was blunted in adults with MDD (HC: 91±2 vs. MDD: 74±3%; P&lt;0.001), reflecting pronounced endothelial dysfunction. There was a significant interaction between experiencing a psychosocial stressor in the preceding week and depression status in predicting EDD (β = −17.28; p=0.049). In adults with MDD, the experience of a stressor was related to more severe impairments in EDD (no stressor: 81±3 vs. 1+ stressors: 69±5%; p=.04). In HC, experiencing a psychosocial stressor in the preceding week did not affect EDD (no stressor: 87±6 vs. 1+ stressors: 91±2%; p= 0.48). Neither the number of stressors (β = −2.85; p=0.13) nor stressor severity (β = −6.15; p=0.14) was related to endothelial function. These preliminary data provide the first evidence that exposure to everyday psychosocial stressors is associated with greater impairments in endothelial function in young otherwise healthy adults with MDD, suggesting a potential mechanistic link between daily stress and depression in increased cardiovascular disease risk.Support or Funding InformationHL133414This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Attenuated cutaneous microvascular function in healthy young African Americans: Role of intradermal l-arginine supplementation

It has been established that endothelial function in conduit vessels is reduced in young African Americans (AA) relative to Caucasian Americans (CA). However, less is known regarding endothelial function in microvasculature of young AA. We hypothesized that microvascular function in response to local heating of skin is attenuated in young AA relative to age-matched CA due largely to the lack of NO bioavailability, which is in turn improved by intradermal l-arginine supplementation and/or inhibition of arginase. Nine AA and nine CA adults participated in this study. Participants were instrumented with four microdialysis membranes in the cutaneous vasculature of one forearm and were randomly assigned to receive 1) lactated Ringer's solution as a control site; 2) 20 mM NG-nitro-l-arginine (l-NAME) to inhibit NO synthase activity; 3) 10 mM l-arginine to local supplement l-arginine; or 4) a combination of 5.0 mM (S)-(2‑boronoethyl)-l-cysteine-HCL (BEC) and 5.0 mM Nω-hydroxy-nor-l-arginine (nor-NOHA) at a rate of 2.0 μl/min to locally inhibit arginase activity. Cutaneous vascular conductance (CVC) was calculated as red blood cell flux divided by mean arterial pressure. All CVC data were presented as a percentage of maximal CVC (%CVCmax) that was determined by maximal cutaneous vasodilation induced by 44 °C heating plus sodium nitroprusside administration. The response during the 42 °C local heating plateau was blunted in the AA at the control site (CA: 84 ± 12 vs. AA: 62 ± 6 vs. %CVCmax; P < 0.001). This response was improved in AA at the l-arginine site (Control: 62 ± 6 vs. l-arginine: 70 ± 18%CVCmax; P < 0.05) but not in the arginase inhibited site (Control: 62 ± 6 vs. Arginase inhibited: 62 ± 13%CVCmax; P = 0.91). In addition, the AA group had an attenuated NO contribution to the plateau phase during 42 °C local heating relative to the CA group (CA: 56 ± 14 vs. AA: 44 ± 6 Δ %CVCmax; P < 0.001). These findings suggest that 1) cutaneous microvascular function in response to local heating is blunted in young AA when compared to age-matched young CA; 2) this attenuated response is partly related to decrease in NO bioavailability in young AA; and 3) a local infusion of l-arginine, but not arginase inhibition, improves cutaneous microvascular responses to local heating in young AA relative to CA.

Tempol augments the blunted cutaneous microvascular thermal reactivity in healthy young African Americans.

What is the central question of this study? The purpose was to determine whether there is a difference between African Americans and Caucasians in cutaneous microvascular function and whether this difference is attributable to elevated oxidative stress. What is the main finding and its importance? The main finding is that African Americans have an attenuated cutaneous vasodilatation during local heating relative to Caucasians that is restored with local infusion of the superoxide dismutase mimetic, tempol. This suggests that superoxide mediates microvascular dysfunction and might contribute to the greater prevalence of cardiovascular disease in this population. African Americans (AA) have elevated risk for cardiovascular disease relative to other populations. We hypothesized that the cutaneous hyperaemic response to local heating is reduced in young AA relative to Caucasian Americans (CA) and that this is attributable to elevated oxidative stress. As such, ascorbic acid (a global antioxidant) and tempol (a superoxide dismutase mimetic) would improve this response in AA. Microdialysis fibres received lactated Ringer solution (control), 10mm ascorbic acid or 10μm 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) at a rate of 2.0μlmin-1 . Cutaneous vascular conductance (CVC) was calculated as the red blood cell flux divided by mean arterial pressure. Data were presented as a percentage of maximal CVC (%CVCmax ) induced by 44°C heating plus sodium nitroprusside. Twenty-four (12 AA, 12 CA) young (23±4years old) subjects participated. During 39°C heating, the %CVCmax was lower in AA at the control (CA, 65±20% versus AA, 47±15%; P<0.05) and ascorbic acid sites (CA, 73±14% versus AA: 49±17%; P<0.01). At the tempol site, there were no differences between groups. This was followed by infusion of 10mm l-NAME at all sites to assess the contribution of nitric oxide to vasodilatation during local heating. The contribution of nitric oxide was lower in AA relative to CA at 39°C; however, this was restored with tempol. These data suggest that: (i)cutaneous vasodilatation in response to local heating is blunted in AA relative to CA; and (ii)elevated superoxide generation attenuates nitric oxide-mediated cutaneous vasodilatation in AA.