Cutaneous Vasodilation Research Articles

Quantification and Interpretation of Nitric Oxide-Dependent Cutaneous Vasodilation During Local Heating.

Human cutaneous microdialysis approaches for assessing nitric oxide (NO)-dependent blood flow include local heating (LH) of the skin until a plateau is reached, followed by infusion of a NO synthase inhibitor such as L-NAME; however, varied methods of quantifying and expressing NO-dependent vasodilation can obfuscate data interpretation and reproducibility. We retrospectively assessed NO-dependent vasodilation during LH to 39°C or 42°C, calculated as the: (1) absolute contribution of the NO-dependent component (along with baseline and the non-NO-dependent component) to the total cutaneous vascular conductance (CVC) response to LH, normalized to maximal CVC (%CVCmax); (2) difference in %CVCmax (∆%CVCmax) between the LH plateau and post-NO inhibition (L-NAME plateau; ∆%CVCmax=LH plateau-L-NAME plateau); (3) percentage of the LH plateau attributable to ∆%CVCmax (%Plateau = ∆%CVCmax/LH plateau*100); and (4) %Plateau when correcting for baseline. The LH plateaus during 39°C and 42°C were 48±17 %CVCmax (9±5% baseline; 2±4% non-NO-dependent; 36±15% NO-dependent) and 88±10 %CVCmax (15±8% baseline; 9±10% non-NO-dependent; 64±13% NO-dependent), respectively. The absolute contributions of the non-NO-dependent and NO-dependent components of the response (p<0.0001) and the ∆%CVCmax (66±14% vs. 38±15%) were greater during 42°C compared with 39°C (all p≤0.02); however, there were no differences between the two protocols in %Plateau (75±13% vs. 80±10%; p=0.57) or %PlateauBL (88±14% vs. 95±8%; p=0.31). For both protocols, the values were greater for %PlateauBL versus ∆%CVCmax and %Plateau (p≤0.0001), and for %Plateau versus ∆%CVCmax (p≤0.05). Quantification of NO-dependent skin vasodilation responses to LH is dependent upon the mathematical approach and verbal description, which can meaningfully impact data interpretation and reproducibility.

Reduced Local Heating-mediated Nitric Oxide-dependent Cutaneous Vasodilation In Firefighters Following A Structural Training Burn

Reduced Local Heating-mediated Nitric Oxide-dependent Cutaneous Vasodilation In Firefighters Following A Structural Training Burn

The effect of endothelin a receptor inhibition and biological sex on cutaneous microvascular function in non-Hispanic Black and White young adults.

The purpose of this study was to investigate whether endothelin-A receptor (ETAR) inhibition in non-Hispanic Black (NHB) and White (NHW) young adults depends on biological sex. We recruited females during low hormone (n = 22) and high hormone (n = 22) phases, and males (n = 22). Participants self-identified as NHB (n = 33) or NHW (n = 33). Participants were instrumented with two microdialysis fibers: (1) lactated Ringer's (control) and (2) 500 nM BQ-123 (ETAR antagonist). Local heating was used to elicit cutaneous vasodilation, and an infusion of 20 mM L-NAME to quantify NO-dependent vasodilation. At control sites, NO-dependent vasodilation was lowest in NHB males (46 ± 13 %NO) and NHB females during low hormone phases (47 ± 12 %NO) compared to all NHW groups. Inhibition of ETAR increased NO-dependent vasodilation in NHB males (66 ± 13 %NO), in both groups of females during low hormone phases (NHW, control: 64 ± 12 %NO, BQ-123: 85 ± 11 %NO; NHB, BQ-123: 68 ± 13 %NO), and in NHB females during high hormone phases (control: 61 ± 11 %NO, BQ-123: 83 ± 9 %NO). There was no effect for ETAR inhibition in NHW males or females during high hormone phases. These data suggest the effect of ETAR inhibition on NO-dependent vasodilation is influenced by biological sex and racial identity.

The effect of acute estrogen suppression on cutaneous endothelium-dependent vasodilation in women with endometriosis

Cardiovascular disease risk is elevated in women with endometriosis and may be exacerbated by treatments that suppress estrogen. The purpose of this study was to determine the effects of acute estrogen suppression on endothelial function in women with endometriosis. We hypothesized that estrogen suppression would attenuate cutaneous endothelium-dependent vasodilation in endometriosis patients (ENDO; n = 2, 30 (1) y, 21.4 (0.2) kg·m2) but not in healthy controls (CON; n = 6, 28 (5) y, 24.9 (5.2) kg·m2). Trials were conducted with (POST) and without (PRE) 4 days of estrogen suppression (400 mg/day gonadotropin-releasing hormone antagonist, Elagolix®) during the first week of separate menstrual cycles. The cutaneous circulation was utilized as a model of microvascular vasodilatory function. Laser Doppler flowmetry was continuously measured during graded perfusions of acetylcholine through intradermal microdialysis (ACh, 1x10−10 – 1x10−1 M). Maximal vasodilation was elicited via 28 mM sodium nitroprusside perfusion and local heating (42°C). Cutaneous vascular conductance was calculated as LDF/mean arterial pressure (MAP). Dose response curves were generated with nonlinear modeling of normalized data with constraints and compared via median effective ACh dose (ED50) and HillSlope. Data are presented as mean (SD) and significance was set at α = 0.05. Baseline MAP was similar between trials for CON (PRE, 80.70 (6.32) mmHg; POST, 82.30 (5.37) mmHg; t[5] = -0.74, P = 0.49) and ENDO (PRE, 72.22 (0.31) mmHg; POST, 79.17 (7.31) mmHg; t[1] = -1.29, P = 0.42). ED50 was not impacted by estrogen suppression in CON (PRE, -3.61 (2.19) logM; POST, -2.80 (1.13) logM; t[5] = -1.04, P = 0.35) or ENDO (PRE, -3.08 (1.74); POST, -2.85 (0.68); t[1] = -0.13, P = 0.91). Similarly, HillSlope was not altered in CON (PRE, 1.00 (0.96); POST, 0.99 (1.14); t[5] = 0.01, P = 0.99) or ENDO (PRE, 0.81 (0.72); POST, 1.16 (1.15); t[1] = -0.26, P = 0.84). Acute estrogen suppression did not impact cutaneous endothelium-dependent vasodilation in healthy controls or women with endometriosis. A greater sample size will further evaluate this relationship. National Institutes of Health Grant 1R01HL161000. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of home-based heat therapy on 24-h blood pressure and cutaneous microvascular function in post-menopausal women with hypertension

Hypertension is a leading risk factor for cardiovascular morbidity and mortality and is often accompanied by microvascular dysfunction. Despite a clear effcacy in men, standard antihypertensive medications are less effective in post-menopausal women. Consequently, adjuvant therapies are needed to improve blood pressure control and microvascular function in post-menopausal women. Heat therapy may fill this therapeutic gap as it has been shown to reduce blood pressure and improve microvascular function in healthy and certain clinical populations. Therefore, the purpose of this study was to test the hypothesis that 8 weeks of home-based heat therapy would improve 24-h blood pressure and cutaneous nitric oxide-dependent vasodilation in post-menopausal women with hypertension. Post-menopausal women (69 ± 5 y) with hypertension were randomized to 8 weeks of sham ( N = 15) or heat therapy ( N = 13). Participants immersed their lower legs ~33 cm into a circulated and temperature-controlled (sham: 35 °C; heat therapy: 42 °C) water bath 4 days per week, and 45 min per session. Blood pressure and cutaneous microvascular function and were assessed before (pre) and after (post) the 8-week intervention. Mean arterial blood pressure was measured across 24-h using an ambulatory monitor. To assess microvascular function, an intradermal microdialysis probe was inserted in the anterior aspect of the lower leg at a site directly exposed to water (immersed) and at another site not directly exposed (non-immersed). Red blood cell flux was measured (laser doppler flowmetry) during cutaneous hyperemia induced by 39 °C local heating. N(G)-nitro-L-arginine methyl ester (L-NAME; 20mM) was then infused in each probe until a nadir in red blood cell flux was achieved. Cutaneous vascular conductance was calculated as red blood cell flux divided by mean arterial pressure and normalized to maximal vasodilation (42 °C heating + 56 mM sodium nitroprusside; CVC%max). Nitric oxide-dependent dilation was calculated as the difference between CVC%max measured during the 39 °C plateau and the L-NAME nadir. Mean arterial blood pressure did not differ across time or between groups (sham: pre, 96 ± 5 mmHg vs. post, 96 ± 6 mmHg; heat therapy: pre, 97 ± 4 mmHg vs. 99 ± 7 mmHg; P = 0.5 for interaction). Cutaneous vasodilation induced by local heating did not differ across time for either group (sham: pre, 60 ± 19 CVC%max vs. post, 64 ± 12 CVC%max; heat therapy: pre, 68 ± 15 CVC%max vs. post, 63 ± 13 CVC%max) or between immersed and non-immersed sites ( P = 0.9 for interaction). Similarly, nitric oxide-dependent vasodilation did not differ across time or between sites for either group ( P = 1.0 for interaction). Taken together, 8 weeks of home-based heat therapy does not improve blood pressure or cutaneous microvascular function in post-menopausal women with hypertension. This work was supported by grants from the National Institutes of Health (T32 AG020494; R01AG059314; F32HL167556) and the American Heart Association (TPA958179). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Divergent Vasodilator Mechanisms to Endothelial-Dependent Agonists with Advancing Age

Introduction: Microvascular function is maintained by a number of vasodilating factors, with nitric oxide (NO) and endothelial hyperpolarizing factors (EDHF) predominating. Advancing age is an independent risk factor in the development of cardiovascular disease, and NO-mediated vasodilation declines, or is unchanged, depending on the vascular bed examined, number of cardiovascular risk factors, or specific endothelial-dependent agonist used. Mechanisms contributing to cutaneous microvascular dysfunction with age have been attributed largely to reductions in NO signaling, but the role of EDHF-mediated dilation, particularly to acetylcholine (ACh), remains unclear. The purpose of this study was to determine the endothelial mechanisms contributing to age-induced cutaneous microvascular function and compare cutaneous microvascular function responses to those from isolated adipose arteriole preparations. We hypothesized that cutaneous microvascular vasodilation to ACh in older adults will be mediated primarily by EDHFs relative to young adults and that isolated adipose arteriole preparations will corroborate these findings. Methods: Four intradermal microdialysis fibers were placed in the skin of the ventral forearm of 9 young (3F/6M; 29±7 yrs) and 3 older adults (3F/0M; 59±11 yrs) for infusion of Ringer’s solution; L-NAME (10 mM), an NO synthase inhibitor; tetraethylammonium chloride (TEA; 50 mM), a non-specific K+ channel inhibitor; and a combination of L-NAME and TEA. Laser Doppler flowmetry and brachial mean arterial pressure were measured during infusion of ACh (10 mM and 100 mM) and in response to local heating to 39°C. Maximal vasodilation was assessed with heating to 43°C and infusion of sodium nitroprusside (28 mM). Adipose resistance arterioles for pressure myography were obtained from a gluteal biopsy or from surgical discard tissue, which were pre-constricted (ET-1), and ACh responses (10−9–10−4 M) were assessed in the presence of the above inhibitors. Cutaneous vascular conductance (CVC) and isolated arteriole responses are presented as % maximum vasodilation. Results: In response to local heating in young adults, L-NAME reduced vasodilator magnitude (Ringers 69.0±18.1% vs. L-NAME 30.3±12.1%; p&lt; 0.05) while TEA did not have any effect (69±18% vs. 49±28%; p=0.20). Combined L-NAME and TEA reduced vasodilation (69±18% vs. 19±6%; p&lt;0.05). Conversely, vasodilator magnitude to ACh was not different across the Ringers, L-NAME, or TEA sites (p=0.93-0.94), while combined inhibition of NOS and K+ channels with L-NAME and TEA, respectively, reduced vasodilator responsiveness (p&lt;0.05). In isolated resistance arterioles, there were no differences in %max dilation to ACh across inhibitor sites (p=0.19) in young adults. In older adults, neither independent nor combined inhibition of NOS or K+ channels impacted vasodilator responses to local heating, while vasodilator magnitude to ACh was most impacted by combined inhibition with L-NAME and TEA (83±14% vs. 32±15%; p&lt;0.05). Conclusion: Our data demonstrate that vasodilator plasticity in response to local heating is divergent with advancing age, relying on non-NO or K+ mechanisms relative to young adults, while NO and K+ mechanisms are suffcient to maintain ACh-mediated vasodilation. These findings further support the concept of diversity in vasodilator mechanisms within the microvasculature. NHLBI K99-HL161491 (WEH), K08-HL150340 (JJM), R01-HL160752 (JKF), R01-HL133029 (AB), and NICHD R01-HD099340 (MJD). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High Intensity Interval Exercise Causes Acute Microvascular Dysfunction in Elderly Individuals with Low Cardiorespiratory Fitness - A Pilot Study

Background: Frailty is strongly associated with low physical and cardiorespiratory fitness, and unfortunately is observed in 20-50% of the ~50 million adults that experience surgical stress in the U.S. each year. The peripheral microvasculature may serve as a potential target to increase resilience to stress and improve postoperative outcomes. A better understanding of how the microvasculature responds to stress in elderly individuals with low fitness is thus needed. Objective: To define the relationship between cardiorespiratory fitness and microvascular resiliency to stress in elderly individuals. Hypothesis: Elderly individuals with low cardiorespiratory fitness will show acute reductions in acetylcholine (Ach)-mediated dilation of the skin microvasculature following the physiological stressful stimulus of high intensity interval exercise (HIIE). Methods: This was a prospective, observational study that enrolled elderly individuals aged 65-85 years from the community. Each participant was asked to complete two study visits. During visit 1, participants completed the Frailty Index and performed a graded cardiopulmonary exercise test (CPET) on a cycle ergometer with a metabolic cart to measure peak total body oxygen consumption (VO2 Peak). During visit 2, laser Doppler flowmetry with dermal microdialysis was performed on the ventral forearm to measure peak cutaneous microvascular vasodilation to Ach (10 mM). After baseline assessment, the participants performed a HIIE protocol where they repetitively switched between exercising at 70% of the peak workload achieved during the CPET for 60 seconds, followed by a 60 second active recovery at 10 watts. These intervals were repeated 12 times, for a total exercise duration of 24 min. Thirty minutes following exercise, Ach-mediated dilation of the cutaneous microvasculature was reassessed. Maximum dilator capacity of each site was assessed by infusing sodium nitroprusside (28 mM) and heating the skin to 43 °C. Results: Six individuals (1 male, 5 females; mean age 68 ±4 years) completed all study procedures. Based on age- and sex-predicted normative values for VO2 Max, three of the individuals had high physical fitness while three had low fitness (mean VO2 Peak = 27.5±1.1 vs. 13.6±3.4 ml/kg/min, respectively). Prior to HIIE there was no difference in peak dilation to Ach between the individuals with high vs. low fitness (% max dilation = 72±13 vs. 83±13, respectively). During HIIE, the individuals reached a Borg rating of perceived exertion of 15±4 (out of 20) and their peak heart rate was 74±15% of their age-predicted maximum. Ach-mediated dilation of the dermal microvasculature was reduced following HIIE in elderly individuals with low cardiorespiratory fitness (pre vs. post % maximum dilation = 82±13 vs. 49±27, respectively; mean change = -34±40 %) but unchanged in those with high fitness (pre vs. post % maximum dilation = 72±13 vs. 78±10, respectively; mean change = 5±3 %). Using Pearson correlation tests there was a strong correlation between the change in peak Ach-mediated dilation pre vs. post HIIE and both VO2 Peak (r=0.82, p=0.04) and Frailty Index score (r=-0.98, p&lt;0.001). Conclusion: Microvascular resilience to acute stress is decreased in elderly individuals with low cardiorespiratory fitness compared to those with high fitness. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Use of Infrared Thermography and Heart Rate Variability to Evaluate Autonomic Activity in Domestic Animals.

Most of the responses present in animals when exposed to stressors are mediated by the autonomic nervous system. The sympathetic nervous system, known as the one responsible for the "fight or flight" reaction, triggers cardiovascular changes such as tachycardia or vasomotor alterations to restore homeostasis. Increase in body temperature in stressed animals also activates peripheral compensatory mechanisms such as cutaneous vasodilation to increase heat exchange. Since changes in skin blood flow influence the amount of heat dissipation, infrared thermography is suggested as a tool that can detect said changes. The present review aims to analyze the application of infrared thermography as a method to assess stress-related autonomic activity, and their association with the cardiovascular and heart rate variability in domestic animals.

Inhibition of NF-κB Activation Improves Non-Nitric Oxide-Mediated Cutaneous Microvascular Function in Reproductive-Aged Healthy Women

PURPOSE: The human cutaneous circulation is used as an in vivo bioassay to examine mechanisms of systemic vascular function and dysfunction in health and disease. In cohorts of patients with accelerated cardiovascular disease risk, systemic interventions to investigate inflammatory mechanisms [e.g., oral salsalate; nuclear factor kappa-B (NF-κB) inhibitor] have been used to elucidate mechanisms underlying microvascular dysfunction. In healthy control subjects, inhibition of inflammatory mechanisms modestly reduces microvascular function. We hypothesize that inhibition of NF-κB activation may impair nitric oxide (NO)-mediated cutaneous microvascular function in reproductive-aged healthy women. METHODS: In a randomized, single-blind, placebo-controlled design, oral salsalate (1500mg/b.i.d./5 days) was used to assess the impact of systemic inflammation on cutaneous microvascular function. Two intradermal microdialysis fibers were placed into the ventral forearm skin of eleven healthy women [Mean (SEM): 34 (2) yrs]. Laser-Doppler flowmetry was used to measure cutaneous blood flow while increasing concentrations of acetylcholine (10−10 to 10−1 M; endothelium-dependent vasodilator) were perfused with a control (lactated Ringer’s) or a NO synthase inhibitor (15 mM NG-nitro-L-arginine methyl ester). Following the dose-response protocol, maximal cutaneous vasodilation was induced by increasing local skin temperature to 43°C and perfusing 28 mM sodium nitroprusside. Cutaneous vascular conductance (CVC) was calculated as the quotient of red blood cell flux over mean arterial pressure and normalized as a percentage of the site-specific maximum (%CVCmax). The NO-dependent contribution was calculated as the difference between the area under the dose-response curve (AUC) of the control and the NO synthase-inhibited sites. RESULTS: There was an overall main effect of salsalate treatment ( p &lt; 0.001). Both the control and NO synthase-inhibited sites shifted upwards following salsalate treatment (Placebo - Control: 45.78 (8.81)% vs NO synthase inhibited: 33.62 (8.10)%; Salsalate - Control: 56.30 (8.48)% vs NO synthase inhibited: 41.57 (7.85)%; both p &lt; 0.05). There was no change in the NO-dependent contribution between treatments (Placebo: 164.30 (35.40) AU vs Salsalate: 180.30 (51.17) AU; p=0.7028).CONCLUSION: Inhibition of NF-κB activation improved cutaneous microvascular function in reproductive-aged healthy women. This improvement was mediated via non-nitric oxide-dependent mechanisms. Supported by NIH Grant R01 HL161000 (LMA) and Diversity Supplement R01 HL161000-02S2 (VGC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhibition of superoxide and iNOS augment cutaneous nitric oxide-dependent vasodilation in non-Hispanic black young adults.

We assessed the combined effect of superoxide and iNOS inhibition on microvascular function in non-Hispanic Black and non-Hispanic White participants (n = 15 per group). Participants were instrumented with four microdialysis fibers: (1) lactated Ringer's (control), (2) 10 μM tempol (superoxide inhibition), (3) 0.1 mM 1400 W (iNOS inhibition), (4) tempol + 1400 W. Cutaneous vasodilation was induced via local heating and NO-dependent vasodilation was quantified. At control sites, NO-dependent vasodilation was lower in non-Hispanic Black (45 ± 9% NO) relative to non-Hispanic White (79 ± 9% NO; p < 0.01; effect size, d = 3.78) participants. Tempol (62 ± 16% NO), 1400 W (78 ± 12% NO) and tempol +1400 W (80 ± 13% NO) increased NO-dependent vasodilation in non-Hispanic Black participants relative to control sites (all p < 0.01; d = 1.22, 3.05, 3.03, respectively). The effect of 1400 W (p = 0.04, d = 1.11) and tempol +1400 W (p = 0.03, d = 1.22) was greater than tempol in non-Hispanic Black participants. There was no difference between non-Hispanic Black and non-Hispanic White participants at 1400 W or tempol + 1400 W sites. These data suggest iNOS has a greater effect on NO-dependent vasodilation than superoxide in non-Hispanic Black participants.

GH and IGF-1 in skin interstitial fluid and blood are associated with heat loss responses in exercising young adults.

Sweat glands and cutaneous vessels possess growth hormone (GH) and insulin-like growth factor 1 (IGF-1) receptors. Here, we assessed if exercise increases GH and IGF-1 in skin interstitial fluid, and whether baseline and exercise-induced increases in GH and IGF-1 concentrations in skin interstitial fluid/blood are associated with heat loss responses of sweating and cutaneous vasodilation. Sixteen young adults (7 women) performed a 50-min moderate-intensity exercise bout (50% VO2peak) during which skin dialysate and blood samples were collected. In a sub-study (n = 7, 4 women), we administered varying concentrations of GH (0.025-4000ng/mL) and IGF-1 (0.000256-100µg/mL) into skin interstitial fluid via intradermal microdialysis. Sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC) were measured continuously for both studies. Exercise increased sweating and CVC (both P < 0.001), paralleled by increases of serum GH and skin dialysate GH and IGF-1 (all P ≤ 0.041) without changes in serum IGF-1. Sweating was positively correlated with baseline dialysate and serum GH levels, as well as exercise-induced increases in serum GH and IGF-1 (all P ≤ 0.044). Increases in CVC were not correlated with any GH and IGF-1 variables. Exogenous administration of GH and IGF-1 did not modulate resting sweat rate and CVC. (1) Exercise increases GH and IGF-1 levels in the skin interstitial fluid, (2) exercise-induced sweating is associated with baseline GH in skin interstitial fluid and blood, as well as exercise-induced increases in blood GH and IGF-1, and (3) cutaneous vasodilation during exercise is not associated with GH and IGF-1 in skin interstitial fluid and blood.

Association Between Early Patient Characteristics and IgE-Mediated Allergy in the Perioperative Setting

BackgroundEarly recognition of perioperative anaphylaxis, a life-threatening, usually immunoglobulin E [IgE]-mediated, immediate hypersensitivity, is essential, but bedside diagnosis is not always straightforward as clinical presentation may vary. ObjectivesTo describe early characteristics of perioperative immediate hypersensitivity (POH), with a special attention on cutaneous phenotypes, and identify risk factors for IgE-mediated allergy. MethodsWe retrospectively analyzed data from adults with suspected POH who were investigated in two academic medical centers. Multivariable logistic regression was conducted to evaluate associations between patient, clinical, and paraclinical characteristics and IgE-mediated allergy. ResultsOut of 145 patients enrolled, 99 (68.3%) and 46 (31.7%) were respectively categorized in the IgE-mediated allergy and non-allergy groups. Cutaneous vasoconstriction phenotype (pallor, piloerection, thelerethism, sweating ± cyanosis) occurring within minutes (or even one minute) of drug-exposure, was strongly associated with IgE-mediated allergy (adjusted odds ratio [aOR]: 28.02, 95% confidence interval [CI]: 4.41-305.18). IgE-mediated allergy was always life-threatening in this setting. Other early factors associated with allergy were low end-tidal carbon dioxide (ETco2) ≤25mmHg (aOR: 5.45, 95%CI: 2.39-26.45), low mean arterial pressure (MAP) ≤60mmHg (aOR: 3.82, 95%CI: 1.28-17.31), and early cutaneous vasodilation (erythema, urticaria and/or angioedema) (aOR: 2.78, 95%CI: 0.73-20.54). Late cutaneous vasodilation following restoration of hemodynamics corroborated the diagnosis of allergy (aOR: 23.67, 95%CI: 4.94-205.09). The best-fit model including three readily available variables (cutaneous phenotype involving the three modalities [reference lack of cutaneous signs], low MAP and low ETco2) had an AUC of 0.91. ConclusionsCutaneous vasoconstriction phenotype is associated with the strongest risk of life-threatening allergy and may thus be regarded as pathognomonic of perioperative IgE-mediated anaphylaxis.

A new perspective on cardiovascular function and dysfunction during endurance exercise: identifying the primary cause of cardiovascular risk.

Exercise mechanical efficiency typically falls within the range of approximately 20 to 25%. This means that a great part of the metabolic energy converted to generate movement is released as heat. Therefore, the rise in core temperature during endurance exercise in humans is proportional to generated work. Cutaneous vasodilation occurs when the core temperature threshold is reached. The rise in heart rate in response to thermal stress is a cardiovascular response that increases cardiac output and skin blood flow. The cardiovascular response during endurance exercise is a complex phenomenon potentially influenced by the involvement of nitric oxide in active thermoregulatory vasodilation. Excessive exercise can create high oxidative stress by disrupting the balance between free radicals' production and scavenging, resulting in impaired cardiovascular function. The above considerations are related to the severity and duration of endurance exercise. The first focus of this narrative review is to provide an updated understanding of cardiovascular function during endurance exercise. We aim to explore the potential role of oxidative stress in causing cardiovascular dysfunction during endurance exercise from a fresh perspective. Additionally, we aim to identify the primary factors contributing to cardiovascular risk during strenuous prolonged exercise by highlighting recent progress in this area, which may shed light on previously unexplained physiological responses. To ascertain the effect of endurance exercise on cardiovascular function and dysfunction, a narrative review of the literature was undertaken using PubMed, ScienceDirect, Medline, Google Scholar, and Scopus. The review highlighted that high oxidative stress (due to high levels of catecholamines, shear stress, immune system activation, and renal dysfunction) leads to a rise in platelet aggregation during endurance exercise. Importantly, we clearly revealed for the first time that endothelial damage, vasoconstriction, and blood coagulation (inducing thrombosis) are potentially the primary factors of cardiovascular dysfunction and myocardial infarction during and/or following endurance exercise.

Short-term cutaneous vasodilatory and thermosensory effects of topical methyl salicylate.

Methyl salicylate, the main compound of wintergreen oil, is widely used in topical applications. However, its vascular and thermosensory effects are not fully understood. The primary aim was to investigate the effects of topical methyl salicylate on skin temperature (Tskin), skin microcirculation (MCskin) and muscle oxygen saturation (SmO2) compared to a placebo gel. The secondary aim was to assess thermosensory responses (thermal sensation, thermal comfort) and to explore to which extent these sensations correspond to the physiological responses over time. 21 healthy women (22.2 ± 2.9years) participated in this single-blind, randomized controlled trial. Custom-made natural wintergreen oil (12.9%), containing methyl salicylate (>99%) and a placebo gel, 1 g each, were applied simultaneously to two paravertebral skin areas (5cm × 10cm, Th4-Th7). Tskin (infrared thermal imaging), MCskin (laser speckle contrast imaging) and SmO2 (deep tissue oxygenation monitoring) and thermosensation (Likert scales) were assessed at baseline (BL) and at 5-min intervals during a 45min post-application period (T0-T45). Both gels caused an initial decrease in Tskin, with Tskin(min) at T5 for both methyl salicylate (BL-T5: Δ-3.36°C) and placebo (BL-T5: Δ-3.90°C), followed by a gradual increase (p < .001). Methyl salicylate gel resulted in significantly higher Tskin than placebo between T5 and T40 (p < .05). For methyl salicylate, MCskin increased, with MCskin(max) at T5 (BL-T5: Δ88.7%). For placebo, MCskin decreased (BL-T5: Δ-17.5%), with significantly lower values compared to methyl salicylate between T0 and T45 (p < .05). Both gels had minimal effects on SmO2, with no significant differences between methyl salicylate and placebo (p > .05). Thermal sensation responses to topical methyl salicylate ranged from "cool" to "hot", with more intense sensations reported at T5. The findings indicate that topical methyl salicylate induces short-term cutaneous vasodilation, but it may not enhance skeletal muscle blood flow. This study highlights the complex sensory responses to its application, which may be based on the short-term modulation of thermosensitive transient receptor potential channels.

Cooling-induced cutaneous vasodilatation is mediated by small-conductance, calcium-activated potassium channels in tail arteries from male mice.

Cooling causes cutaneous dilatation to restrain cold-induced constriction and prevent tissue injury. Cooling increases communication through myoendothelial gap junctions (MEGJs), thereby increasing endothelium-derived hyperpolarization (EDH)-type dilatation. EDH is initiated by calcium-activated potassium channels (KCa ) activated by endothelial stimuli or muscle-derived mediators traversing MEGJs (myoendothelial feedback). The goal of this study was to determine the individual roles of KCa with small (SK3) and intermediate (IK1) conductance in cooling-induced dilatation. Vasomotor responses of mice isolated cutaneous tail arteries were analyzed by pressure myography at 37°C and 28°C. Cooling increased acetylcholine-induced EDH-type dilatation during inhibition of NO and prostacyclin production. IK1 inhibition did not affect dilatations to acetylcholine, whereas SK3 inhibition inhibited dilatation at both temperatures. Cooling uncovered myoendothelial feedback to inhibit constrictions in U46619. IK1 inhibition did not affect U46619 constrictions, whereas SK3 inhibition abolished the inhibitory effect of cooling without affecting U46619 constriction at 37°C. Immunoblots confirmed SK3 expression, which was localized (immunofluorescence) to holes in the internal elastic lamina consistent with myoendothelial projections. Immunoblots and Immunofluorescence did not detect IK1. Studies in non-cutaneous arteries have highlighted the predominant role of IK1 in EDH-type dilatation. Cutaneous arteries are distinctly reliant on SK3, which may enable EDH-type dilation to be amplified by cooling.

Aging is associated with impaired triggering of TRPV3-mediated cutaneous vasodilation: a crucial process for local heat exposure.

Sensing temperature is vitally important to adapt our body to environmental changes. Local warm detection is required to initiate regulation of cutaneous blood flow, which is part of the peripheral thermoregulatory mechanisms, and thus avoid damage to surrounding tissues. The mechanisms mediating cutaneous vasodilation during local heat stress are impaired with aging. However, the impact of aging on the ability of the skin to detect subtle thermal changes is unknown. Among heat-activated cation channels, transient receptor potential vanilloid 3 (TRPV3) is a thermo-sensor predominantly expressed on keratinocytes and involved in local vascular thermoregulatory mechanisms of the skin in young mice. In the present study, using a murine in vivo model of local heat exposure of the skin, we showed that heat-induced vasodilation was reduced in old mice associated with reduced expression of TRPV3 channels. We also found a decrease in expression and activity of TRPV3 channel, as well as reduced TRPV3-dependent adenosine tri-phosphate release in human primary keratinocytes from old donors. This study shows that aging alters the epidermal TRPV3 channels, which might delay the detection of changes in skin temperature, thereby limiting the mechanisms triggered for local vascular thermoregulation in the old skin.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Abstract P217: The Role Of Angiotensin-(1-7) In Regulating Vascular Endothelial Function In Postmenopausal Women

Postmenopausal women (PMW) have reduced endothelial function, however, the mechanisms contributing to this decline remain unclear. Angiotensin-(1-7) [Ang-(1-7)] is a vasoactive peptide of the vasodilatory arm of the Renin-Angiotensin system and increasing bioavailable Ang-(1-7) enhances endothelial function in young women (YW) with pre-clinical cardiovascular disease. Circulating Ang-(1-7) decreases with aging and may be impacted by menopause. However, whether increasing bioavailable Ang-(1-7) improves endothelial function in PMW is unknown. The purpose of this study was to test the hypothesis that increasing bioavailable Ang-(1-7) improves endothelial function in PMW. We assessed skin blood flow responses to local heating in 8 healthy YW (27±9 yrs) and 5 healthy PMW (56±4 yrs). Cutaneous vasodilation was measured using laser-Doppler flowmetry directly over microdialysis perfusions of lactated Ringer’s (control) in YW and PMW, and in PMW only, 100 μM Ang-(1-7). Following 45 minutes of perfusion of lactated Ringer’s and Ang-(1-7), skin was heated to 42°C (0.1°C·sec -1 ) until laser-Doppler flux reached a stable plateau, indicative of endothelium-dependent dilation. Following the plateau, 28mM sodium nitroprusside was perfused while skin was heated to 43°C to achieve maximal vasodilation. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/MAP, and normalized to maximal dilation (%CVC max ). Women were normotensive (MAP: YW 86±7 mmHg; PMW 85±9 mmHg) and not obese (BMI: YW 23±3 kg/m 2 ; PMW 23±4 kg/m 2 ). YW had greater dilation during local heating (control: YW 94.54±5.4 vs. PMW 82.59±10.72 %CVC max ; P=0.021). Contrary to our hypothesis, Ang-(1-7) did not enhance heating-induced vasodilation in PMW (80.10±9.43 %CVC max ; P=0.69). These preliminary results suggest that increasing bioavailable Ang-(1-7) may not improve endothelial function in PMW. Additional studies are needed to understand if these findings are due to estrogen deficiency in PMW.

Hesperetin-7-O-glucoside/β-cyclodextrin Inclusion Complex Induces Acute Vasodilator Effect to Inhibit the Cold Sensation Response during Localized Cold-Stimulate Stress in Healthy Human Subjects: A Randomized, Double-Blind, Crossover, and Placebo-Controlled Study.

Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD; SunActive® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/βCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/βCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems.

Galanin receptors modulate cutaneous vasodilation elicited by whole-body and local heating but not thermal sweating in young adults

Galanin receptor subtypes GAL1, GAL2, and GAL3 are involved in several biological functions. We hypothesized that 1) GAL3 receptor activation contributes to sweating but limits cutaneous vasodilation induced by whole-body and local heating without a contribution of GAL2; and 2) GAL1 receptor activation attenuates both sweating and cutaneous vasodilation during whole-body heating. Young adults underwent whole-body (n = 12, 6 females) and local (n = 10, 4 females) heating. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC; ratio of laser-Doppler blood flow to mean arterial pressure) were assessed during whole-body heating (water-perfusion suit circulated with warm (35 °C) water), while CVC was also assessed by local forearm heating (from 33 °C to 39 °C and elevated to 42 °C thereafter; each level of heating maintained for ∼30 min). Sweat rate and CVC were evaluated at four intradermal microdialysis forearm sites treated with either 1) 5% dimethyl sulfoxide (control), 2) M40, a non-selective GAL1 and GAL2 receptor antagonist, 3) M871 to selectively antagonize GAL2 receptor, or 4) SNAP398299 to selectively antagonize GAL3 receptor. Sweating was not modulated by any GAL receptor antagonist (P > 0.169), whereas only M40 reduced CVC (P ≤ 0.003) relative to control during whole-body heating. Relative to control, SNAP398299 augmented the initial and sustained increase in CVC during local heating to 39 °C, and the transient increase at 42 °C (P ≤ 0.028). We confirmed that while none of the galanin receptors modulate sweating during whole-body heating, GAL1 receptors mediate cutaneous vasodilation. Further, GAL3 receptors blunt cutaneous vasodilation during local heating.